Solid Implantable Devices for Sustained Drug Delivery

Solid implantable devices for sustained drug delivery Elizabeth Magill a , Sara Demartis b , Elisabetta Gavini c , Andi Dian Permana d , Raghu Raj Singh Thakur a,e , Muhammad Faris Adrianto a,e,f , David Waite a,e , Katie Glover a , Camila J. Picco a , Anna Korelidou a , Usanee Detamornrat a , Lalitkumar K. Vora a , Linlin Li a , Qonita Kurnia Anjani a,g , Ryan F. Donnelly a , Juan Domínguez-Robles a,h, ⇑ , Eneko Larrañeta a, ⇑ a School of Pharmacy, Queen’s University Belfast, 97, Lisburn Road, Belfast BT9 7BL, UK b Department of Chemical, Physical, Mathematical and Natural Sciences, University of Sassari, Sassari, 07100, Italy c Department of Medicine, Surgery and Pharmacy, University of Sassari, Sassari, 07100, Italy d Department of Pharmaceutics, Faculty of Pharmacy, Universitas Hasanuddin, Makassar 90245, Indonesia e Re-Vana Therapeutics, McClay Research Centre, 97 Lisburn Road, Belfast BT9 7BL, UK f Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Airlangga University, Surabaya, East Java 60115, Indonesia g Fakultas Farmasi, Universitas Megarezky, Jl. Antang Raya No. 43, Makassar 90234, Indonesia h Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, Universidad de Sevilla, 41012 Seville, Spain article info Article history: Received 16 January 2023 Revised 2 June 2023 Accepted 4 June 2023 Available online 8 June 2023 Keywords: Implant Sustained drug release Local drug delivery Biodegradable polymers abstract Implantable drug delivery systems (IDDS) are an attractive alternative to conventional drug administration routes. Oral and injectable drug administration are the most common routes for drug delivery providing peaks of drug concentrations in blood after administration followed by concentration decay after a few hours. Therefore, constant drug administration is required to keep drug levels within the therapeutic window of the drug. Moreover, oral drug delivery presents alternative challenges due to drug degradation within the gastrointestinal tract or first pass metabolism. IDDS can be used to provide sustained drug delivery for prolonged periods of time. The use of this type of systems is especially interesting for the treatment of chronic conditions where patient adherence to conventional treatments can be challenging. These systems are normally used for systemic drug delivery. However, IDDS can be used for localised administration to maximise the amount of drug delivered within the active site while reducing systemic exposure. This review will cover current applications of IDDS focusing on the materials used to prepare this type of systems and the main therapeutic areas of application. Ó2023 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). Contents 1. Introduction . . . ........................................................................................................ 2 2. Classification of IDDS . . . . . . . . . . . . . . . ..................................................................................... 3 3. Materials used to prepare IDDS and manufacturing techniques .................................................................. 4 3.1. Natural polymers. . . . . . . ........................................................................................... 4 3.2. Synthetic polymers . . . . . ........................................................................................... 4 3.2.1. Biodegradable synthetic polymers. . . . . . . . . . . . . . . . ............................................................. 4 3.2.2. Non-biodegradable polymers. ................................................................................ 5 3.3. Metals . . . . . . . . . . . . . . . ........................................................................................... 5 3.4. Ceramics . . . . . . . . . . . . . ........................................................................................... 6 3.5. Manufacturing techniques . . . . . . . . . . . . . . . ........................................................................... 6 3.5.1. Hot-melt extrusion (HME) . . . ................................................................................ 6 3.5.2. Compression . . . . . . . . . . . . . . ................................................................................ 6 3.5.3. Solvent casting . . . . . . . . . . . . ................................................................................ 6 https://doi.org/10.1016/j.addr.2023.114950 0169-409X/Ó2023 The Author(s). Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). ⇑ Corresponding authors at: Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, Universidad de Sevilla, 41012 Seville, Spain (J. Domínguez- Robles); School of Pharmacy, Queen’s University Belfast, 97, Lisburn Road, Belfast BT9 7BL, UK (E. Larrañeta). E-mail addresses: [email protected] (J. Domínguez-Robles), [email protected] (E. Larrañeta). Advanced Drug Delivery Reviews 199 (2023) 114950 Contents lists available at ScienceDirect Advanced Drug Delivery Reviews journal homepage: www.elsevier.com/locate/adr 3.5.4. Injection moulding . . . . . . . . . ................................................................................ 6 3.5.5. Electrospinning . . . . . . . . . . . . ................................................................................ 7 3.5.6. 3D-printing . . . . . . . . . . . . . . . ................................................................................ 7 3.5.7. Other manufacturing techniques. . . . . . . . . . . . . . . . . ............................................................. 7 4. Applications of IDDS . . . . . . . . . . . . . . . ..................................................................................... 7 4.1. Contraception and gynaecological applications of IDDS . . . . . . . . . . . ........................................................ 7 4.1.1. Subdermal contraceptive implants . . . . . . . . . . . . . . . ............................................................. 7 4.1.2. Intrauterine devices . . . . . . . . ................................................................................ 8 4.1.3. Intravaginal rings for contraceptive and gynaecological applications. . . . . . . .......................................... 8 4.1.4. Meshes for pelvic floor reconstructive surgery. . . . . . ............................................................ 10 4.2. Cancer treatment applications of IDDS . . . . . .......................................................................... 12 4.3. IDDS for HIV treatment/prophylaxis . . . . . . . .......................................................................... 13 4.3.1. Subdermal implants for HIV treatment/prophylaxis . ............................................................ 13 4.3.2. Intravaginal rings for HIV treatment/prophylaxis. . . . ............................................................ 15 4.4. IDDS for ocular drug delivery . . . . . . . . . . . . . .......................................................................... 17 4.5. IDDS for schizophrenia treatment . . . . . . . . . .......................................................................... 19 4.6. Drug-eluting cardiovascular IDDS . . . . . . . . . .......................................................................... 20 4.6.1. Drug loaded cardiovascular stents. . . . . . . . . . . . . . . . ............................................................ 20 4.6.2. Drug loaded vascular grafts . . ............................................................................... 23 4.7. Implantable devices for cell encapsulation . . .......................................................................... 25 4.8. MNs-assisted delivery of IDDS . . . . . . . . . . . . .......................................................................... 25 4.8.1. Implantable nano/microparticles combined with MNs . . . . . . . . . . . . . . . . . . ......................................... 25 4.8.2. Implantable microtips based MNs. . . . . . . . . . . . . . . . ............................................................ 26 4.9. Implantable devices for vaccine delivery. . . . .......................................................................... 28 4.10. Other applications of IDDS . . . . . . . . . . . . . . .......................................................................... 29 5. Clinical translation of IDDS . . . . . . . . . . .................................................................................... 30 6. Conclusions. . . . ....................................................................................................... 31 Declaration of Competing Interest . . . . .................................................................................... 31 Acknowledgements . . . . . . . . . . . . . . . . .................................................................................... 31 References . . . . ....................................................................................................... 31 1. Introduction Conventional clinical therapies rely on intermittent administration of drugs using different routes. Oral and injectable drug administration are the most common routes for drug delivery providing peaks of drug concentrations in blood after administration followed by concentration decay after a few hours [1,2]. This effect is usually known as ‘‘peak and valley” effect. This can present some limitations as high drug levels can present toxicity issues while low drug levels are not effective in the patient [1,2]. Oral route is the ideal route of administration due to its convenience [3]. However, it present additional challenges. First, the drug should be stable within the gastrointestinal tract to avoid enzymatic degradation and to survive to the acidic environment. Additionally, drugs administered oral route suffer from first pass metabolism potentially reducing their bioavailability. Accordingly, oral administration requires repeated doses to keep drug levels within the therapeutic window of the drug. This is especially important for the treatment of long-term and chronic conditions [1,4]. Finally, it is important to note that most of new drugs do not show ideal properties for oral administration. Parameters such as drug solubility can limit oral administration of new drugs [5]. On the other hand, injectable formulations do not present many of these limitations. However, this method of administration is invasive and normally requires trained healthcare professionals to be administered [6]. Both injectable and oral routes provide systemic drug levels rather than localised effect. The treatment of certain conditions requires high drug levels at specific locations. To achieve this, high drug doses can be used. However, high doses can lead to toxicity issues [1]. Taking into consideration all these limitations it is obvious that new types of drug delivery systems with the ability to provide continuous drug administration for pro- Fig. 1. Number of items published per year including the key words ‘‘drug delivery” and ‘‘implant” in Scopus Ò (A). Cumulative number of FDA-approved IDDS per year (data obtained from: https://www.accessdata.fda.gov/scripts/cder/daf/) (B). E. Magill, S. Demartis, E. Gavini et al. Advanced Drug Delivery Reviews 199 (2023) 114950 2 longed periods of time. Implantable drug delivery systems (IDDS) can be used for this purpose [1,4,7]. IDDS can be used to treat a broad variety of conditions including cancer and HIV among others [8]. The use of this type of systems is especially interesting for the treatment of chronic conditions. Pharmacological treatment of chronic conditions, such as schizophrenia or HIV, requires regular drug administration. Accordingly, patient compliance is a key factor for the success of the treatment. For example, non-adherence to treatment for schizophrenic patient increase the relapse risk [9]. Moreover, relapse for this type of patient is associated with higher hospitalisation rates and higher rates of suicide [9]. All these factors have an impact not only on the health of the patient but on the cost of the treatment [10]. Therefore, IDDS can be used to address the limitations of conventional therapies for chronic conditions. IDDS have been gaining popularity over the years, however they were described for the first time during the 1930s [11]. The pioneering IDDS was a pellet loaded with a hormone. This pellet was designed to be subcutaneously implanted into livestock to improve their growth making the meat production process more efficient [11]. A few years later, in 1938, the applications of this type of devices were described for the treatment of female patients suffering from premature menopause [12]. Despite been described more than 90 years ago, there has been a growing interest in IDDS during the last 20 years (Fig. 1). This interest is not only noticeable within the academic environment. Pharma companies have shown enormous interest on the development of new drug delivery systems as can be seen in Fig. 1B. The global market for implantable drug delivery systems value in 2019 was estimated to be $10,091.9 million [13]. Moreover, it is predicted to grow at an annual growth rate of around 8% until 2027 reaching a value of $13,211.8 million [13]. There are a wide variety of long-acting drug delivery systems including self-assembled gels [14-17], micro- and nanoparticles [17-19] and solid preformed devices [1,4]. This review will be focused on solid IDDS covering the materials used to prepare this type of devices and their therapeutical applications. 2. Classification of IDDS There is not a clear classification system for IDDS due to the existence of complex implants that fall within hybrid categories. However, IDDS can be classified in two groups: active implants and passive implants [4,20]. The former type of IDDS shows active energy dependant mechanisms to generate the driving force to provide drug release. On the other hand, passive implants depend on passive diffusion to provide drug release. In addition to drug delivery mechanism implants can be classified as biodegradable or non-biodegradable depending on the type of materials used to prepare them. Passive IDDS do not contain moving parts and depends on drug diffusion to achieve sustained drug release. This type of IDDS can be prepared using biodegradable or non-biodegradable materials. These implants are normally prepared by combining drug molecules with biocompatible polymers. They do not contain any moving parts and drug release is achieved by passive drug diffusion. Depending on the drug location within the device there are two potential types of implants: reservoir type implants and monolithic implants (Fig. 2A). Monolithic-type implants contain the drug dispersed within a matrix -formed by a biocompatible compound [4,24]. In most of the cases, it is a polymeric compound. On the other hand, reservoir-type implants contain a drug loaded core surrounded by a permeable membrane that controls drug release [4,20]. Normally this type of membrane is made of nonbiodegradable materials such as silicone [25]. However, there are examples of reservoir type implants prepared using biodegradable rate-controlling membranes [26-29]. In addition to conventional polymeric membranes, advanced systems have been recently developed using silicon membranes containing micro- and Fig. 2. Schematic of reservoir-type and monolithic-type implants (A). SEM image of a rate controlling membrane made of silicon containing micro- and nano-channels (scale bar: 1 l m) (B). Diagram of a transcutaneous refillable implant (C). Diagram of ALZET Ò osmotic pump (D). Schematic of an electrostatically gated nanofluidic membrane (E). Reproduced with permission from DURECT Corporation, [21], [22] and [23]. E. Magill, S. Demartis, E. Gavini et al. Advanced Drug Delivery Reviews 199 (2023) 114950 3 nano-channels to sustain drug release (Fig. 2B) [21]. Interestingly, advanced refillable reservoir type IDDS have been described in the literature [22,30,31]. These systems can be refilled using a conventional needle as they have a port, or a catheter attached to them. Fig. 2D shows a diagram of a transcutaneous refillable implant. Active polymeric implants do not rely on passive diffusion of drugs from the implant matrix or trough membranes. This type of implants present a positive driving force to control drug release [24]. This type of devices are normally pump-type implants such as osmotic pumps [4,20]. A diagram of a osmotic pump can be seen in Fig. 2B. Osmotic pumps are composed of a drug core surrounded by a semipermeable membrane containing a hole to allow drug release [32]. Osmotic gradients contribute to the flow of fluid trough the membrane, forcing the drug to be release trough the orifice [32]. This type of design allows a steady drug release (zero order drug release kinetics) [4,20,32]. In addition to osmotic pumps during the last decade micro-electro-mechanical systems (MEMS) have been described as implantable devices for drug delivery [33-35]. These types of devices can be controlled externally or just respond to local changes in the environment due to the presence of sensors [33-35]. MEMS are reservoir type implants that rely on different mechanisms to achieve drug delivery. They can contain a single reservoir system with electro-mechanically controlled pump systems to control the release [35] or multiple smaller reservoirs [34]. Micropumps control the flux of drug formulation. In order to pump the drug formulation different mechanisms are used [35]. In some cases not even a pump is required and electric current is the driven mechanism to increase drug permeation across membranes (Fig. 2D) [23,36,37]. On the other hand, micro reservoir systems contain a capping membrane that can be activated to release the cargo [34,38,39]. This type of systems are rapidly advancing and they can be prepared containing fully biodegradable electronical mechanisms to trigger drug release [40]. 3. Materials used to prepare IDDS and manufacturing techniques 3.1. Natural polymers As these polymers are found in nature, they tend to exhibit excellent biocompatibility, non-cytotoxicity, and biodegradability [4]. Despite these advantages there are still limitations, they have unpredictable properties, and in terms of production, have low batch-to-batch consistency [4]. Cellulose, chitosan, alginate, collagen, gelatin and silk protein are the main natural polymers used to produce implantable drug delivery systems. Cellulose is a natural polysaccharide consisting of chains of b-d- glucopyranose monomers and is the most abundant organic compound on earth [41,42]. Cellulose and cellulose derivatives have been used for drug delivery applications [41]. Chitosan is obtained by the de-acetylation of chitin[4],a polysaccharide abundantly found in the cell walls of fungi. Chitosan has good biocompatibility and is easy to process, with controllable mechanics [43], suggesting a good candidate for drug delivery. Unfortunately, it is hydrophobic with low strength, so it tends to be brittle. It could, however, be mixed with other polymers to create a more ideal material [43]. Alginate is a linear polysaccharide naturally found in brown seaweed or algae. With its hydrophilicity, solubility, biocompatibility, and degradability, it makes a great polymer for drug delivery devices [43]. It has the abilities to form hydrogels and encapsulate molecules. This is one of the reasons why there is interest in alginate as a drug vehicle. It can be used to make copolymers to achieve rigidity for devices with drug carrier advantages [43-45]. Collagen is a protein molecule located in the connective tissue of animals [41]. This biomolecule presents special interest due to its biocompatibility and mechanical properties [41]. There are different types of of collagen molecules depending on their origin (skin, tendon, bone, cartilage, skin or vasculature) [46]. It is important to note that each have varying properties. Gelatin is a watersoluble protein derived from collagen, obtained by partially hydrolysing collagen [47]. Collagen and gelatin have been used extensively for tissue engineering applications [41], but also have use in implantable hydrogel drug delivery systems [48-50]. Silk protein obtained from silkworms, some arachnids and flies [51], presents high mechanical resistance due to the alignment of the protein chains parallel to its axis. It is has thus been used for the development of surgical sutures [47]. This is a highly versatile polymer used for a variety of medical applications, among these are subcutaneous implants and drug-eluting stents [52-54]. 3.2. Synthetic polymers These polymers have predictable properties and batch-to-batch consistency compared to their natural counterparts [4]. They can be either biodegradable or non-biodegradable. As mentioned earlier this review will cover solid IDDS and therefore novel materials used for long-acting injectable drug delivery systems such as depot forming formulations [55,56] or ‘‘drugamers” [57] are not described here. 3.2.1. Biodegradable synthetic polymers 3.2.1.1. Polylactic acid (PLA). PLA is a biodegradable, aliphatic polyester [4]. This polymer is hydrophilic and degradation of the ester backbone produces lactic acid, this is a natural metabolite and can therefore be removed safely by the body. It is important to note that PLA has two enantiomeric forms, an L-lactide (PLLA) and a D-lactide (PLDA). The two forms exhibit different properties, such as in strength and crystallinity [58].Itisa racemic mixture of PLA that is used in drug delivery devices as it has the advantages of PDLA with the control of PLLA [59]. A cautionary point to make is that, although the lactic acid product is well known to the body, a large accumulation can lead to inflammatory host responses [59]. In most cases however, PLA has a slow degradation time, 1–6 months approximately [4]. 3.2.1.2. Polyglycolic acid (PGA). This polymer exhibits many similar properties to PLA [4]. The main difference in PGA is its very rapid degradation by bulk erosion producing glycolic acid products [58]. This leads to inflammatory responses, a particular problem when the amount of polymer implanted is large [59,60]. Despite this polymer displaying excellent mechanical properties [4], it cannot be used alone for drug delivery devices for the reasons discussed above. It is, however, a great candidate for copolymeric materials. 3.2.1.3. Poly(lactic-co-glycolic acid) (PLGA). Another aliphatic polyester, this material is a copolymer comprised of PLA and PGA[4]. The physical properties of this polymer can be altered by adjusting the composition ratio of PLA and PGA, also adjusting degradation rate [4]. The achievable precision and modification are very attractive for drug delivery [4]. Another benefit of this material is the lack of acidic degradation products [4]. Most biomedical uses of PLGA have been in the area of tissue engineering. Many drugs, however, have varying interaction profiles with the material, so allowing for more drug-based applications [58]. An example of this is the LUPRON DEPOT Ò [58]. The same material has also been investigated for micro and nanoparticle drug delivery. Unfortunately, due to bulk degradation, it is difficult to achieve a zero-order release profile [58]. Some other current uses in drug delivery include anti-tumour, anti-infection, anti-thrombosis, angiogenesis, and wound healing E. Magill, S. Demartis, E. Gavini et al. Advanced Drug Delivery Reviews 199 (2023) 114950 4 [59]. Perhaps, also, there are opportunities for drug eluting tissue scaffolds as a new use due to excellent tissue adhesion properties. 3.2.1.4. Polycaprolactone (PCL). The last of the aliphatic polyesters, this is possibly the most investigated polymer [4]. Comparable to the previous polymers, PCL is biocompatible and mechanically strong. One of its most notable properties, however, is its long degradation time. The degradation can range anywhere from months to years, and naturally, depends on physical and environmental properties [4]. Additionally, PCL does not create an acidic degradation environment, a huge advantage for implantable devices [61]. This polymer is hydrophobic, but it is relatively easy to increase water penetration by making copolymers with hydrophilic materials. This also allows for tuning of degradation rate[4]. PCL has a high permeability and low toxicity, making it popular in drug delivery device research. Some PCL products are already on the market, such as the contraceptive implant Capronor Ò [58]. Long-term drug delivery implants have become increasingly possible thanks to this polymer [61]. An exciting development is the creation of microspheres and nanoparticles using PCL/copolymers. These particles capture the advantages of PCL while adding more surface area and porosity, leading to better drug dissolution [61]. 3.2.1.5. Polyester amides. The use of polyester amides as for drug delivery applications has been previously reported. In particular, the creation of microspheres has shown effective and efficient entrapment of ionic drugs as well as a slow and controlled release profile [62]. These polymers also have the ability to act as solubility enhancers if the drug in question is poorly water soluble [62]. This could be a great candidate for a copolymer with hydrophobic polymers such as PCL. 3.2.1.6. Polyphosphoesters (PPEs). These polymers show great biocompatibility and controlled degradation [63]. PPEs are attractive materials for drug delivery due to their likeness to nucleic acids in the body [43]. In fact, they have already been successfully developed as nanocarrier for drug and gene delivery [64]. PPEs also offer the ability of altering hydrophobicity as well as polyvalence. The latter is done through the ester group pendants and backbone variations. These modifications allow for the encapsulation of specific drugs [63]. The degradation rate of PPEs may also be adjusted through the chemical structure of the backbone [63]. Wang et al. showed that faster degradation was achievable by having amino pendant groups that hydrolyse rapidly [64]. 3.2.1.7. Polydioxanone (PDS). This polymer is a polyester prepared through the polymerisation of p-dioxanone. With a high crystallinity and hydrophobicity, it undergoes relatively slow degradation over 9–12 months [43]. The main product of PDS degradation is glycoxylate which is either excreted or converted to glycine [43]. Applications for microsphere and nanoparticle applications are already popular, mostly as a copolymer [65]. Some examples include: copolymeric microspheres of PDS/cellulose and PDS/starch [66], copolymeric nanoparticles of PDS/chitosan and copolymeric micelles [67]. Polymers such as PEG present the ability to tailor the micelles’ properties for drug release. Zhang et al. loaded these micelles with doxycycline and studied the release [68]. 3.2.2. Non-biodegradable polymers Non-biodegradable polymers have been extensively used to develop IDDS. One of the best examples of the use of this type of polymers are contraceptive implants. The advantage is that we know they are robust and strong over a prolonged period of time, and generally do not cause damage [4]. These materials are also cheaper and easier to manufacture compared to biodegradable materials [4]. The release of drugs from these materials relies on diffusion out of the matrix only, whereas biodegradables rely on degradation of the matrix itself. The main drawback is, however, that they will not degrade inside the body, thus necessitating the process of removal. This can be off-putting to patients. 3.2.2.1. Polyurethanes (PUs). Produced from isocyanates, these polymers are a very large family. There are a number of parameters that can be changed in these polymers, such as by changing the polyols or isocyanates used for polymerisation [4]. These polymers are great for long-term implants as they are biocompatible and resistant to hydrolysis [43]. Their physical properties such as rigidity [58] can be adjusted[4] preferentially, perhaps depending on the site of implant and usage. 3.2.2.2. Poly(ethylene–vinyl alcohol) (PEVA). As with most copolymers, the properties of this material can be changed with differing ratios of vinyl acetate to ethylene [4]. Naturally, modifications are areas of optimisation, an appealing advantage for use of implantable devices. Many drugs have been investigated using PEVA based implantable dosage forms: 5-fluorouricil for carcinoma [69], BCNU for brain tumours [70], and tetrodotoxin for auditory nerve blockade [71]. PEVA is a common polymer in the research of implantable drug delivery devices in the treatment of different cancers [72].It does not stop there, PEVA has been the basis of implants previously and currently available on the market. Examples include contraceptives such as Implanon Ò and Nexplanon Ò [73], ocular implants, such as Iluvien Ò [74] and subcutaneous implants like Probuphine Ò , for the treatment of opioid addiction. PEVA still possesses the disadvantage of non-biodegradability which can somewhat overshadow its assets. For example, ocular implants, while successful in delivery, add pressure to the inner eye and can cause retinal damage. These implants also need surgically removed. 3.2.2.3. Poly(ether ether ketone). Poly(ether ether ketone) (PEEK) was first used as an implantable material back in 1987 [75].Itis a non-degradable-biocompatible material. It is gaining popularity for orthopaedic applications due to its high mechanical strength, wear resistance and anticorrosive nature [76]. Moreover, it presents high chemical resistance and thermal stability. These properties make it an ideal candidate for the development of IDDS. However, due to its hydrophobic nature it limits cell adhesion and protein absorption. In order to address this issue, PEEK is combined with other compounds [76]. 3.2.2.4. Poly(siloxanes). Poly(siloxanes) are formed by a combination of silicon and oxygen atoms [77]. These types of polymer have been widely used in medical applications due to their biocompatibility, thermal stability, elastomeric characteristics and chemical inertness [77]. This polymer is hydrophobic, and therefore, it is usually loaded with hydrophobic drugs for delivery [78]. Prolonged release of drugs from PDMS is common and zero order kinetics can be achieved through the production of reservoir devices [78,79]. Silicone-based polymers are non-biodegradable materials [4], again necessitating removal. Despite this, poly(siloxanes) have been extensively used in the development of commercial implantable devices such as Norplant [80]. 3.3. Metals Most IDDS are prepared using polymeric materials. Metals, however, have been widely explored for drug delivery applications. E. Magill, S. Demartis, E. Gavini et al. Advanced Drug Delivery Reviews 199 (2023) 114950 5 The three main types of metals used for the development of implantable devices are: stainless steel, cobalt, and titanium. Titanium can be found as a pure metal or as alloys with aluminium or vanadium [81]. These types of compounds present a high resistance to corrosion, low density and high specific strength. Accordingly they are used for the development of joint replacement and other, spinal disc or dental implants among many other applications [81]. Titanium alloys have been used for the development of cardiovascular stents and the manufacturing of subcutaneous drug delivery systems [33,82]. Stainless steel is an alloy prepared with iron, nickel and/or chromium [83]. These types of metals present high mechanical strength and resistance to corrosion [81]. Normally, stainless steel is used for the manufacturing of spinal implants, cardiovascular stents, fracture fixation and hip stems [81]. Finally, cobalt and chromium allows present similar properties to the previously described metals and are used in orthodontics, joint replacements, stents and wires (such as pacemaker wires) [81]. Metal-based IDDS will be normally coated or they will act as a reservoir device [33,82]. 3.4. Ceramics Ceramics are inorganic non-metallic materials [84]. These materials are used extensively in dental and orthopaedic applications due to their biocompatibility [85]. Ceramics most used in these applications include calcium phosphates, zirconia, alumina, silica, and titania. Additional beneficial properties include their easy preparation, the ability to change their size and structure, and their surface area to volume ratios [86]. Ceramic materials typically present slow biodegradability that can be potentially beneficial for long-term IDDS, such as drug-eluting scaffolds. As such, some research is focused on the benefits of this in tissue engineering. Zirconia and alumina are known as bioinert ceramics, meaning they do not interact with biological material. Unfortunately, this can cause fibrous capsule formation around the implants [87]. These materials do, however, have advantageous antibacterial properties [88]. Bioinert ceramics are also known for their high strength and hardness [89], and therefore used mostly in loadbearing applications. Silicon is another material that has been used for IDDS. It can have various properties for various uses depending on how it is processed. Polymerised silicon has the ability to increase serum protein cell availability by binding to them. Other silicic acids can contribute to biomolecular complexes by competing with metal ions [90]. Silicon formed into bioactive glasses as silicates have excellent osteoconductive properties and so are used in orthopaedics [89]. Porous silicon, however, has been used for therapeutic applications such as drug delivery and dietary supplements [90]. There are, on the other hand, a group of ceramics that are bioactive. These ceramics can play a part in biological processes. Calcium ceramics typically make up this group, such as calcium phosphates and hydroxyapatite [89]. Bioactivity of these materials could involve supplying ions for chemical bonding or biological processes. These materials possess excellent biocompatibility and, additionally, osteoconductivity [89]. Calcium-based ceramics are less likely to be used to bear loads, but are useful in bone/tissue engineering or regeneration. Titania is quite often used in combination or as a coating with other ceramics to increase their ceramic performance and improve wettability [91]. 3.5. Manufacturing techniques The manufacturing method is an extremely important factor to consider when developing solid implants. It is based on a variety of factors including the polymeric properties of the materials used [2]. Because each technique requires very different conditions, the implant products will have differing properties depending on the method used. These properties will include mechanical characteristics, implant-body interactions, degradation rates, and drug release profiles. While these things present challenges such as API consistency and batch uniformity [92], there are also opportunities to tailor dosing regimens. This section will explore several manufacturing methods for solid-formed implantable devices including their relative advantages and disadvantages. 3.5.1. Hot-melt extrusion (HME) HME is a very common method in pharmaceutical manufacturing. By controlling melting temperature and mixing, materials are homogenously dispersed and then forced through a die [93]. Advantages to using this technique to form implants include, enhancing dissolution of poorly soluble drugs to improve bioavailability, and controlling the release of the drug [94]. Additionally, the use of solvents during production is avoided with this method, thereby improving biocompatibility of the implants [2]. HME as a process can also be easily scaled up and translated to industry without changing the product’s final properties [2,94]. Unfortunately, there are some drawbacks with this technique. Due to the use of high temperatures, thermally labile drugs cannot be used, and polymer stability has to be assessed [94]. Similarly, only certain polymers can be used due to the requirement of certain physical properties [94]. 3.5.2. Compression Rather than the use of heat and/or solvents, this method applies a force to the material until it flows and takes the shape of the die it is being forced into [2,93]. Solid implants made in this way tend to have higher densities. As stated, a main advantage to this process is the lack of solvents and heat [95], making it ideal for less stable materials and drugs [4]. The method is also basic and would be easy to scale up. However, implants made in this way tend to experience faster release rates [4]. This can be a disadvantage depending on the intended use of the implant in question. Compression has shown to cause surface irregularities with large pores and channels, contributing to the irregular release of drug [96]. To prevent this, protection would be required, such as coatings. 3.5.3. Solvent casting In this method, the polymer and/or drug are dissolved into a suitable organic solvent and the mixture is then cast into or around a mould with the desired implant shape and size [2,4]. The solvent is allowed to evaporate leaving behind the polymer mixture set in the implant shape. The ability to make implants in a variety of shapes and sizes with a homogenous drug/particle distribution is a main advantage of this method [97]. A drawback, however, comes with the fact that an organic solvent must be used as there can be toxicity issues. Some studies have shown that there are no significant cytotoxicity issues at the end of development [29,98,99]. Unfortunately, this may not be the case on an industrial scale where the volume of solvent would be much larger. Not to mention the environmental impact this would have [2,4]. 3.5.4. Injection moulding This method combines heat and pressure to inject a molten form of the drug/polymer mixture into a mould of the desired shape. It is then allowed to cool and set [2]. This technique holds a lot of versatility in terms of mould shape and another main advantage is it’s scalability through the use of larger machines [100]. Additionally, the pressure and heat used can provide au- E. Magill, S. Demartis, E. Gavini et al. Advanced Drug Delivery Reviews 199 (2023) 114950 6 tosterilisation of the product as well as improving drug-polymer interactions, advantageous for release profiles [100]. There are, however, questions of thermal degradation of drugs with the use of such high temperatures [101]. Additionally, there has to be careful selection of polymers and drugs because the physical properties of the molecules can affect the implant properties and so this may limit the extent of use of this method [4,101]. 3.5.5. Electrospinning Electrospinning creates ultrafine fibres through an electrostatic potential of high voltage and low current [102]. The method is known for its wide range of applications and robustness [2]. The polymers must be in the liquid form to move through the apparatus, and there are two ways of doing this: melting and solution. The first uses high temperatures and the latter uses organic solvents to liquefy the polymers [102]. As always, high temperatures can degrade some drugs if the polymer blend contains drugs thus limiting drug choices or requiring different API addition techniques. However, the use of organic solvents creates cytotoxicity and environmental problems. The decision of which method to employ also depends on the type of drug release profile desired, melting provides a longer, linear release with less initial burst compared to in-solution [103]. There are also a number of ways in which to add the drug to the fibres, giving different kinetic profiles and material properties. These methods are outlined well by Luraghi et al (2021). Each addition method again has its own benefits and costs. Electrospinning has been applied to antibiotics [104], anticancer therapy [105], ocular treatment [106], cardiovascular disease [107], and wound healing [108]. 3.5.6. 3D-printing 3D-printing encompasses a number of techniques capable of providing innovative drug delivery solutions [109]. Some of these techniques include, stereolithography, selective laser sintering, fused-deposition modelling (FDM), laminated object manufacturing, ink-jet based, and bioprinting [2]. Each of these provides a variety of ways to completely fine-tune drug delivery devices to have the properties required for each type of drug release. Prior to the printing process, the product is designed using computer-aided design software providing a lot of flexibility in the shape of the implant. The implant could be hollow, created to be filled with API [4] or the materials could be a homogenous drug blend that can be printed into the desired shape. Again, these aspects must be chosen carefully with the type of 3D printing depending on drug and polymer properties such as stability and crystallinity. 3D-printing is cost-effective, flexible, and adaptable, however there are some questions of scalability into industry as well as regulatory concerns. The FDA approval of a 3D printed drug product in 2015 [110] however gives a lot of promise in this area for future developments [2]. 3.5.7. Other manufacturing techniques Most of the implantable devices described in the literature are based on polymers. Therefore, the methods described previously are applicable to prepare such devices. On the other hand, other types of manufacturing methods are required when implants are made of metal or ceramics. In these cases, computer numerical control, sintering methods or are normally used [111,112].On the other hand, MEMS-based implantable devices require techniques used for the manufacturing of electronic components such as photolithography [113]. 4. Applications of IDDS IDDS have been used for different types of applications. This section will describe the main areas of applications described in the literature to date. The areas of applications are quite diverse ranging from contraception to ocular disease. 4.1. Contraception and gynaecological applications of IDDS Subdermal contraceptive implants were one of the first commercially available IDDS [114]. In addition to subdermal implants, there are a wide variety of drug eluting implantable devices for contraceptive and gynaecological applications described in the literature. These type of devices include aforementioned subcutaneous contraceptive implants [115], intrauterine devices [116], intravaginal rings [117] and meshes for female pelvic reconstructive surgery [118]. 4.1.1. Subdermal contraceptive implants Subdermal contraceptive implants have been commercially available since 1983 when the first reversible contraceptive IDDS was introduced in the market [114]. This product commercialised under the name of Norplant consisted on 6 silicone implants loaded with a synthetic progestin hormone: levonorgestrel [114,119]. The implants were applied subcutaneously in the upper arm of the patient providing contraception for up to 7 years (30–85 l g/ day) [120,121]. New systems were introduced in the market to replace and improve Norplant. Currently, levonorgestrel-based subcutaneous implants are commertialised under the brand names of Jadelle and Sino-implant [121].Fig. 3A shows a comparison of Norplant and Jadelle. On the other hand, subdermal implants containing an alternative hormone, etonogestrel, can be found in the market under the name of Nexplanon. The main difference with levonorgestrel-based implants is that these IDDS contain only a single implant improving the application procedure. These implants are reservoir type implants (40 2 mm) composed of a membrane made of etinyl-vinyl acetate and a core containing 68 mg of the hormone [121]. Some etonogestrel implants contain in its core 15 mg of barium sulphate to render them radiopaque [114]. In addition to levonorgestrel and etonogestrel, two other synthetic progestin hormones have been used: nestorone and nomegestrol. Nestorone implants are reservoir-type implants containing 60–80 mg of the hormone (3–4 mm length). On the other hand, nomegestrol-based implants are reservoir-type implants (39 2.4 mm) made of silicone containing 55 mg of the steroid. These implants provide shorter contraceptive action than levonorgestrel/etonogestrel implants. Nestorone implants can provide contraception for up to 2 years while nomegestrol provides only 1 year of contraception [121]. During the last years there has been limited developments in this area [122]. Subdermal contraceptive implants have proven to be successful, and the focus is now on developing subcutaneous injectable formulations that reduce the pain during application substantially [123]. However, a few works have been published describing new types of implantable devices for the delivery of levonorgestrel. Table 1 summarises these. The particularity of these implants is that they are prepared using biodegradable polymers. In this way they should not require extraction after depleting their drug cargo. The first type of implants were prepared using poly(glycerol sebacate) urethane, a biodegradable elastomeric poly(urethane) [124]. The resulting devices were loaded with levonorgestrel and a drug used for HIV pre-exposure prophylaxis, 4 0 - ethynyl-2-fluoro-2 0 -deoxyadenosine [124]. Interestingly this drug was hydrophilic, and the combination of both drugs allowed a faster release of the hydrophobic levonorgestrel as it acted as a poro- E. Magill, S. Demartis, E. Gavini et al. Advanced Drug Delivery Reviews 199 (2023) 114950 7 gen. This work was focused on the formulation and characterisation of the implants and did not report any in vivo data. However, the resulting implants showed in vitro linear release kinetics over 245 days [124]. On the other hand, Zhu et al. reported the use of direct compression of PLGA microparticles loaded with levonorgestrel to obtain subdermal implants [125]. Subsequently, these implants were coated with PCL to prolong the drug release [125]. The results showed that coated implants were capable of providing in vitro drug release for up to 90 days while uncoated implants providing around 60 days [125]. Moreover, the release profile for the coated implants followed a zero-order release kinetic. Additionally, the coated implants were teste in vivo using a rat animal model. The results showed that the implants were capable of providing sustained levonorgestrel for at least 58 days [125]. 4.1.2. Intrauterine devices Intrauterine devices are an alternative to subdermal contraceptive implants. This type of IDDS are placed inside the uterus of the patient offering reversible contraception (Fig. 3B) [147]. Intrauterine devices have been commercially available since 1988 [147]. There are two types of intrauterine devices: copper-based intrauterine device and levonorgestrel-loaded intrauterine devices. The copper based devices present a T-shaped polyethylene structure (32 36 mm) containing copper covering part of the implant (200–375 mm 2 )[148]. Copper ions are released from the device. However, the mechanism of action of copper ions allowing contraception is still unknown [149]. These devices are capable of providing contraception for up to 10 years [148]. Recently a few studies have reported alternative metal combinations or manufacturing techniques to improve the efficiency of these devices (Table 1). These novel devices use alternatives to copper such as zinc [128], combine copper with zinc [126,127] or use alternative alloys such as zinc-lithium/zinc-magnesium [128]. Moreover, the use of alternative materials, such as copper microparticles or copper loaded plant-based polymers can improve copper delivery and/or reduce side effects [129,130]. Alternatively, levonorgestrel intrauterine devices have been used. This type of devices contain between 13 and 52 mg of the synthetic progestin [147,148]. Like copper-based devices they present a T-shape made of polyethylene (32 32 mm) that contains a silicone capsule loaded with levonorgestrel [148]. They are capable of providing release rates of around 14 l g/day of the cargo for up to 5 years [147]. This type of implants can be used for the treatment of other conditions such as heavy menstrual bleeding, dysmenorrhea, endometrial hyperplasia or to prevent endometrial hyperplasia/cancer [148]. There are new types of intrauterine devices in development containing different hormonal compounds such as nestorone or etonogestrel among others have been described before [148]. Recently, new types of levonorgestrel loaded implants have been been reported in different studies (Table 1). These studies describe alternative materials and the effect of different parameters such as drug loading and crosslinking time [131-135]. These devices were prepared using PDMS and were capable of providing up to 4 years of levonorgestrel release [131]. It is important to note that these devices, as well as the impact of different manufacturing parameters on the performance, were tested in vitro [131-135]. However, the importance of these works is the information extracted, as it will help to optimise future PDMS- levonorgestrel systems. 4.1.3. Intravaginal rings for contraceptive and gynaecological applications In addition to subdermal and intrauterine IDDS the use of intravaginal rings has been described before [117,150].Fig. 3C shows an intravaginal ring. This type of devices are torus-shaped devices loaded with different compounds designed to be introduced inside the vaginal cavity. Thus, the device can provide prolonged local drug release [117,150]. These devices can provide sustained drug release during periods of time ranging between 1 month to 1 year Fig. 3. Diagrams showing the structure of several subdermal contraceptive implants (A), diagram showing an implanted intrauterine device (B). Image of Annovera Ò Intravaginal Ring (C). Pictures and SEM images of 3D printed meshes containing different levofloxacin loadings (D). . Reproduced with permission from: [119,141,145,146] E. Magill, S. Demartis, E. Gavini et al. Advanced Drug Delivery Reviews 199 (2023) 114950 8 [117]. This type of devices were first described in the 1970 for the delivery of medroxyprogesterone acetate, a contraceptive drug [117]. However, it was during the 1980s when the first clinical trial was conducted in the USA [151]. Intravaginal rings are used for the delivery of a wide variety of hormones for a wide variety of purposes such as contraception, the treatment of urogenital atrophy, hormone supplementation, estrogen replacement therapy and HIV prophylaxis or [146,152,153]. This type of application will be discussed in a later section. Different polymers can be used to prepare this type of devices such as EVA, PU or silicone elastomer [117]. Additionally, the drug can be dispersed within the polymeric matrix or encapsulated inside the ring forming a reservoir type implant [117]. For contraceptive applications, these IDDS are normally loaded with a different drug combinations: etonogestrel/ethinylestradiol, nesterone/ethinylextradiol or etonogestrel/etinyl estradiol [117,146]. For estrogen replacement therapy or hormone supplementation 17b-estradiol or progesterone are loaded into intravaginal rings [146]. Currently, new types of intravaginal rings are being developed (Table 1). One of the trends in this area of research is to develop devices capable of providing contraception and HIV-prophylaxis (Table 1)[136-138]. These devices are made of silicone and contain dapivirine and levonorgestrel within the polymer matrix [136-138]. In addition to silicone, EVA-based reservoir intravaginal rings have been developed for the delivery of estradiol and progestine for hormone replacement therapy and contraception (Table 1)[139]. The use of EVA presents certain advantages over silicone as it does not require curing [139]. The curing process of silicones can present issues as drugs can react with the silicone backbone [138]. Finally, the use of novel manufacturing techniques, such as 3D-printing, have been described to Table 1 Recent studies describing contraception and gynaecological applications of IDDS. Type of implant Material Target Drug Findings Ref Subdermal Implant Poly(glycerol sebacate) urethane Contraception and HIV pre-exposure prophylaxis Levonorgestrel 4 0 -ethynyl-2- fluoro-2 0 - deoxyadenosine 4 0 -ethynyl-2-fluoro-2 0 -deoxyadenosin as a porogen enhancing drug release. In vitro linear release for 245 days. [124] Subdermal Implant PLGA loaded nanoparticles compressed into an implant and coated with PCL Contraception levonorgestrel Implants were evaluated in vivo using a rat animal model. Devices provided up to 60 days of in vivo release. [125] Intrauterine Device Zinc and copper alloy Contraception Zinc and copper Zinc/copper show improved biocompatibility in vivo (rat model) than copper while maintaining contraceptive effect. Finally, showed a reduced initial copper release burst effect. [126,127] Intrauterine Device Zinc-lithium and zinc-magnesium alloys Contraception Zinc Zinc alloys displayed improved biocompatibility in vivo (rat model) than pure zinc. [128] Intrauterine Device Micro copper, loaded into devices made of low-density poly(ethylene) and methyl vinyl silicone rubber Contraception Copper Implants were tested in vivo showing satisfactory contraceptive efficacy and lower side effects than the control group with bulk copper. [129] Intrauterine Device Polymerised carvacrol Contraception Copper A novel method of depositing copper trough electrochemical oxidation reaction of carvacrol on copper was developed. Provides sustained copper release avoiding burst release. [130] Intrauterine Device PDMS Contraception Levonorgestrel PDMS-based implants were prepared using different designs, drug loadings and crosslinking ratios. These parameters have a direct influence on release kinetics. The resulting implants were tested in vitro achieving release for up to 4 years. [131- 135] Intravaginal Ring Silicone elastomer Contraception and HIV prevention Dapivirine and levonorgestrel Devices formed using a custom-made silicone formulation to prevent drug binding to the silicone. Devices showed similar mechanical properties to commercial rings while providing in vitro sustained release of clinically relevant doses of both drugs for over 30 days. [136- 138] Intravaginal Ring EVA Hormone replacement therapy and contraception Estrogen and progestine Reservoir-type intravaginal rings. The result provided in vitro release of estrogen over 28 days. The amounts released can be applied for local or systemic hormone replacement therapy or for contraception when combined with progestine. [139] Intravaginal Ring PLA, PCL, Tween 80 and PEG Hormone replacement therapy Progesterone Intravaginal rings were 3D-printed in different shapes. Formulations contained PEG and Tween 80 as excipients to enhance drug delivery. [140] Surgical Mesh Poly(urethane) Infection control Levofloxacin 3D-printed meshes containing levofloxacin to prevent post-surgical infection. Devices provided in vitro drug delivery for up to 3 days and displayed antimicrobial properties against E. Coli and S. Aureus. [141] Surgical Mesh PLA Tissue regeneration Estrogen Electrospun meshes containing estrogen sustaining drug release for up to 133 days. Ex ovo experiments displayed tissue regeneration properties. [142] Surgical Mesh Poly(urethane) Inflammation control and potential tissue regeneration Estrogen 3D-printed meshes were prepared providing up to 15 days of in vitro linear estrogen release. [143] Surgical Mesh Gelatine hydrogel Inflammation control and potential tissue regeneration Puerarin Hydrogel-based meshes containing puerarin. In vitro tests showed release of the cargo for up to 1 month. Moreover, in vivo experiment in a rabbit model confirmed the antiinflammatory and tissue regeneration properties of the hydrogel. [144] E. Magill, S. Demartis, E. Gavini et al. Advanced Drug Delivery Reviews 199 (2023) 114950 9 25 mg dapivirine and different amounts of maraviroc (50–400 mg) (Fig. 6C). Following the characterization process, IVR loaded with 25 mg of dapivirine and 100 mg of maraviroc was selected as the best IVR candidate. The formulation was able to control the release of both drugs for 28 days and possessed excellent stability performances for a one-year stability evaluation [205]. A novel IVR containing protein microbicide candidate 5P12-RANTES was developed by McBride et al. The extensive studies showed the drug release was controlled over one-month period and the formulations possessed excellent mechanical and stability properties (Fig. 6D). In vivo pharmacokinetic study in sheep revealed the sustained release behavior of 5P12-RANTES for 28-day period of study. Importantly, it was found that the concentration of 5P12- RANTES in vaginal fluid and vaginal tissue was observed be in the range of 10 and 10,000 ng/g. These concentrations were at least 50 and up to 50,000 times of IC50 values to inhibit the replication of the viruses [196]. The Bill & Melinda Gates Foundation has started making investment in the development of long-acting ARV drugs to prevent HIV in both men and women [206]. Specifically, the application of vaginal ring containing ARV drugs in clinical study has also been examined. A study performed by Baeten et al. using vaginal ring containing 25 mg of dapivirine showed that this approach could decrease the occurance of HIV-1 by 30% in comparison with placebo administration. Interestingly, 92.2% of women preferred to use the vaginal ring. Importantly, amongst 1456 women participating in this study, there were no severe adverse effects found following the administration of the vaginal ring [207]. Fig. 6. Digital photograph of IVR containing drug combinations (20 mm 4 mm) (scale: US dime = 17.91 mm) (A). Cross segments representing compartments of core and of the similar IVR formulation with a core side pore (B) and a drilled through pore (C). In vitro release behaviour of all compounds from IVR formulations (D). Reprinted with permission from [203] Digital photograph of IVR containing containing 25 mg dapivirine and 100 mg maraviroc (E). In vitro release behaviour of maraviroc (Top) and dapivirine (Bottom) from IVR formulations (D). . Reproduced with permission from [205] E. Magill, S. Demartis, E. Gavini et al. Advanced Drug Delivery Reviews 199 (2023) 114950 16 4.4. IDDS for ocular drug delivery IDDS for the eye are being investigated with greater frequency in current research due to their capacity to reduce the number of separate treatments patients require. This is particularly pertinent in chronic diseases, including glaucoma, age-related macular degeneration and diabetic retinopathy. For example, glaucoma needs eye drops to be used several times a day, making compliance difficult for patients. In contrast, AMD and DR commonly require intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents every 4–6 weeks. Whilst individual intravitreal injections pose a low risk when given repeatedly, as is the case in chronic disease treatment, the risk of significant complications, including endophthalmitis and retinal detach, increases [208]. Sustained release systems capable of providing similar efficacy to the treatments currently used for treating chronic diseases in both the anterior and posterior segments could be game-changers. Initially attempts were made to provide continuous release using periocular devices that were placed under the eyelid. This includes the Ocusert Ò ocular implant, the first FDA-approved ocular implant in 1974 to reach the market, which was designed to treat glaucoma. On the other hand, Lacrisert Ò , a hydroxypropyl cellulose rod used to treat dry eyes, is placed in the conjunctival sac in the same way. Unlike the Ocusert Ò , this device was launched in the early 1980s and is still in use today. In 47 years since the invention of Ocusert Ò implants, only eight implants for anterior and posterior segments of the eye have been successfully launched into the market. Recently, in October 2021, the FDA approved Dextenza Ò and Susvimo TM . Dextenza is an intracanalicular insert that is placed in the canaliculus after being put through the lower lacrimal punctum, which is a natural opening in the eyelid [209]. Dextenza Ò is intended to administer a gradually decreasing dosage of the steroid dexamethasone to the surface of the eye for a period of up to 30 days. After therapy, Dextenza resorbs and leaves the nasolacrimal system on its own, therefore it is not necessary to remove it [210]. Susvimo TM , a port delivery system (PDS) containing ranibizumab [211].(Fig. 7A-B). The port delivery system is a nondegradable implant designed for continuous delivery of ranibizumab into the vitreous. The innovative feature of this device is that can be refilled trough a septum when the drug cargo is depleted [31,212]. The implant contains a rate controlling metallic membrane capable of sustaining the release of the drug for up to 6 months depending on the initial drug loading [31]. It is important to note than the majority (63.5%) of the patients tested with the lower drug cargo (10 mg/mL) did not require a refill after 6 months [31]. More recently the Susvimo device had to be recalled by Roche due to a potential leakage problem. This was due to a manufacturing issue with the seal that is designed to stop the payload leaking out after it’s injected into the system, with Roche communicating that there was a concern about the possibility that the seal could fail with repeated dosing. Patients who already have the implant inserted were advised to keep getting refills, but no new patients will be able to have an implant inserted until the issues are resolved. Roche estimate this could take approximately one year [213]. Retisert Ò , Iluvien Ò , and Yutiq TM (containing fluocinolone acetonide); Vitrasert Ò (ganciclovir) are non-degradable implants with zero-order release kinetics, that are inserted or delivered in- to the vitreous humour. Once the drug has exhausted, these implants need surgical removal – making it a more invasive therapy than its biodegradable competitors. VItrasert Ò , developed by Bausch and Lomb, was approved in 1996 for the treatment of cytomegalovirus retinitis linked to AIDs. Each implant was loaded with 4.5 mg of ganciclovir with a release duration of 5–8 months [214]. Retisert Ò , developed by Bausch and Lomb, was designed to treat non-infective uveitis. It contains 0.59 mg of drug and is designed to deliver its payload for approximately 30 months. This implant, in a similar way to Vitrasert Ò , is inserted surgically and sutured to the scleral wall [215]. Illuvien Ò , developed by Alimera, contains 0.19 mg of fluocinolone acetonide and is indicated for the treatment of diabetic macular oedema. This implant, composed of PVA, is designed to sustain release over a 36 month period. One major difference to Retisert Ò is that Illuvien Ò does not require surgical insertion and is instead inserted by direct intravitreal injection using a 25 gauge needle [216]. Yutiq Ò , developed by Eyepoint, is the most recent implant to be developed for the sustained delivery of fluocinolone acetonide. This implant, which contains 0.18 mg of the steroid drug, is indicated for the treatment of non-infective uveitis. This implant, like Illuvien Ò , is delivered directly into the vitreous humour, and does not require surgical insertion. Yutiq Ò is designed to sustain release for 36 months [217]. Fig. 7. Diagram showing the main components of the Susvimo TM implant (A) and the refilling procedure (B). Image of Delpor titanium implant (C). Reproduced with permission from [31] and Delpor Inc. E. Magill, S. Demartis, E. Gavini et al. Advanced Drug Delivery Reviews 199 (2023) 114950 17 A biodegradable implant for posterior segment administration, Ozurdex Ò , launched by Allergan’s NOVADUR Ò technology is intended for the continuous delivery of dexamethasone to treat macular oedema and intraocular inflammation [218]. The NOVADUR Ò approach makes use of a PLGA polymer matrix, which gradually degrades into lactic acid and glycolic acid over time, allowing for continuous drug release for up to six months [219]. Another biodegradable ocular implant is Durysta Ò , which received FDA approval in March 2020. This is an intracameral implant designed to deliver bimatoprost to treat patients with open-angle glaucoma or ocular hypertension. Durysta Ò is composed of PLGA, making it the first approved biodegradable intracameral implant, and has a 4– 6 month release duration. This implant is delivered using an applicator with a pre-loaded 28 gauge needle [220]. IDDS described in the previous paragraphs are commercially available or in clinical trials. However, researchers are currently developing a wide variety of IDDS for ocular drug delivery. Table 4 summarises recent developments of IDDS for ocular drug delivery. Cocarta et al. developed a bilayer hydrogel-based implant, comprising of an inner pHEMA core surrounded by an outer protective barrier of hydrophobic pEOEMA for the treatment of retinoblastoma following administration to the sclera. The implant core was loaded with vincristine and topotecan, which demonstrated significant cytotoxicity towards retinoblastoma cells in vitro. Moreover, sustained release of both therapeutic agents was achieved through the hydrogel implant, with 2 and 6 days for topotecan and vincristine respectively [221]. Through later testing in an in vivo rabbit model, topotecan release was further extended (14 days) and reached therapeutic levels (10 ng/ml) in the vitreous 8 h post administration [222]. The treatment of retinal degenerative diseases has also been a major focus regarding the development of implantable drug delivery systems. Zhou et al. recently demonstrated the ability of macroporous PDMS implants loaded with 2 mg bevacizumab to lower VEGF levels at the retina in approximately 3 months, in addition to promoting corneal re-epithelialisation [223]. Furthermore, the sustained release of unoprostone to the retina through a PEGDM/TEGDM-based implant was demonstrated in vivo by Nagai et al., with rabbits showing retinal thickness preservation and a reduction in long-term retinal function decline [224]. Various implant morphologies have also been investigated, with Sato et al. creating polymer-based sheet-like implants which were capable of being compacted for administration through a needle before unfolding in the eye. The multi-layered implants were provided sustained delivery of fluorescein to the retina which was detectable four weeks post administration in an in vivo rabbit model [226]. Sheet-like implants fabricated from gelatin/chitosan and PEGDM were also developed by Nagai et al. Degradation of the gelatin/chitosan sheet implants occurred within 24 weeks in the in vivo rat model, with the detection of FITC in the retina occurring by week 6. PEGDM implants were loaded with collagen microparticles, delivering FITC to the retina by week 18, however did not degrade within the timeframe studied [227]. Innovative approaches such as 3D printed implants have also demonstrated the ability to deliver sustained release of BDNF through human retinal pigment epithelial cells in vitro for approximately two weeks [225]. There has also been research into the use of IDDS for periocular delivery. Periocular delivery refers to the area that immediately surrounds the eye, which potentially offers a good compromise between achieving therapeutic concentrations in the posterior segment without the invasiveness of a direct intravitreal injection [228]. The use of periocular routes exploit the permeability of the sclera for retinal delivery and are particularly useful for the administration of sustained release systems, including IDDS [229]. Indeed, there is an example of a bioerodible dexamethasone implant that was developed for the treatment of uveitis and postoperative cataract inflammation that could sustain release for 6 weeks with near zero-order kinetics. Histological assessments from the study Table 4 Recent studies describing IDDS for ocular drug delivery. Type of Implant Material Target Drug Findings Ref. Bilayer hydrogel implant pHEMA and pEOEMA Retinoblastoma Topotecan 14-day release of TOP in vivo using a rabbit model. TOP reaches therapeutic levels (10 ng/ml) in the vitreous 8 h post administration. Long-term biocompatibility against Rb Y79 cell line. [222] 3D printed porous capsule PEGDM and TEGDM Degenerative retinal diseases Human retinal epithelial cells 3D printed photocurable capsule loaded with ARPE-19 cells. Provided 16-day in vitro release of BDNF to the retina. Limited large molecule diffusion for cell protection, whilst enabling small molecule diffusion for cell survival. [225] Biodegradable PDMS Corneal and retinal neovascularisation Bevacizumab Administration of BEV-loaded (2 mg) macroporous implant in neovascularisation rabbit models Rapid and complete corneal re-epithelialisation (5 days) Lowered VEGF levels at the retina in approx. 3 months. [223] Sheet-shaped implant PEGDM and TEGDM Retinal diseases Fluoroscein Multi-layered sheets of photopolymerised polymers. Guard layer: unidirectional release. Morphology enabled compaction on administration and unfolding in the eye. 4-week release of fluroscein to the retina in a rabbit animal model. [226] Bilayer hydrogel implant pHEMA and pEOEMA Retinoblastoma Vincristine and topotecan Cytotoxicity towards retinoblastoma cells. 2-day release of TOP and 6-day release of VIN from HEMA reservoir in vitro. VIN was stable but topotecan stability influenced by drug concentration and temperature. [226] Sheet-shaped implants Gelatin and chitosan PEGDM Choroidal neovascularisation FITC conjugated albumin Sheets loaded with collagen microparticles. Degradation of gelatin/chitosan sheets by week 24 in rat sclera, with detection of FITC in the retina by week 6. Microparticle-loaded PEGDM did not degrade, with FITC detected in the retina by week 18. [227] Implant PEGDM and TEGDM Retinitis pigmentosa Unoprostone Initial daily release of 10.2 ± 1.0 l g following transscleral administration. Rabbits showed retinal thickness preservation by OCT at week 24. Slowed long term retinal function decline (>32 weeks). [224] E. Magill, S. Demartis, E. Gavini et al. Advanced Drug Delivery Reviews 199 (2023) 114950 18 showed no signs of inflammation after use of the implant [230]. Okabe et al were able to develop a biodegradable intrascleral implant composed of PLA that was able to deliver therapeutic levels of betamethasone phosphate for up to 8 weeks. The implant was placed in a scleral pocket that was formed surgically [231,232]. Furthermore, Kawashima et al. designed an implant to sustain protein release, for transscleral delivery. The system was fabricated with TEGDM, which is impermeable to macromolecules, and a controlled-release membrane [233]. Initially this implant was tested in rabbits and achieved zero-order release of fluorescent dyes. Work by Onami et al. utilised a sustained release vasohibin-1 device and tested in a rat model with laser-induced choroidal neovascularisation, with results showing a significant reduction in lesion size after 2 weeks, when compared to direct intravitreal injection of vasohibin-1 [234]. A modified version of the implant was tested for long-term pharmacokinetics and safety of uroprostone in monkeys, with results showing no changes in retinal function, intraocular pressure, or retinal histology after 12 months [235]. Despite the promise that this route offers there has not been any products of this type released commercially to date. This could be partially due to the use of much smaller needles for intravitreal injections (30 gauge and smaller) in more recent times, which significantly reduce the invasiveness of such procedures, in combination with the long durations of release that are now possible from delivered IDDS that will reduce injection frequency. Furthermore, whilst periocular delivery does result in high drug concentrations in the posterior segment compared to topical and systemic delivery, it cannot match direct intravitreal injections in this regard. 4.5. IDDS for schizophrenia treatment Schizophrenia is a chronic mental disorder which severely distorts perception and the way of thinking [236-238]. The most commonly used treatments consist of oral administration of tablets once daily, which often leads to pill fatigue and finally discontinuation of the medication [10,239]. Poor adherence to treatment can result in higher relapse rates, increased hospitalisation, low quality of life and increased levels of residual symptoms [240]. Moreover, non-adherence to treatments has been demonstrated to have a detrimental economic impact on hospitalisation expenses and medication costs [241-244]. Long-acting injectable formulations have been developed for this purpose including solid IDDS [245,246]. Currently, two IDDS for the treatment of schizophrenia are in development stages. DLP-160 is a 6–12 month risperidone subcutaneous implant, developed by Delpor (Delpor Inc., San Francisco, CA, USA) is in phase II trials [247]. This implant uses the Prozor TM technology [248,249] which involves a small tubular reservoir containing risperidone, through which release is controlled by membranes located at both ends of the cylinder (Fig. 7C). The drug is loaded together with excipients that alter the pH to maintain an acidic environment. The acid improves risperidone solubility, resulting in its steady diffusion out of the reservoir and potentially the maintenance of therapeutic plasma levels in the body for up to one year [33]. To date, there are no solid implants in the market that can replace oral therapy for schizophrenia. Therefore, the development of new implantable formulation for the management of schizophrenia is actively sought out. In this section, recent reports on the field are critically reviewed. Table 5 shows a summary of recently developed IDDS for schizophrenia treatment. Most of the implants described in the literature aiming to treat schizophrenia described the use of biodegradable polymers such as PLA, PCL or PLGA (Table 5)[250-252]. These implants contain mainly one of the following drugs, olanzapine, paliperidone palmitate or risperidone (Table 5). Olanzapine has been combined with PCL using hot melt extrusion and 3D printing techniques to prepare subcutaneous implantable devices. The implants included matrix type implants [99,251] and reservoir type implants using a biodegradable PCL-based rate controlling membrane [29]. The resulting devices were capable of providing in vitro sustained delivery for more than Table 5 Recent studies describing IDDS for the treatment of schizophrenia. Type of implant Material Target Drug Findings Ref Subcutaneous implant TPU Schizophrenia Risperidone Drug release for 6 months at a constant rate after implantation to human volunteers. Mean concentrations of RIS were 81.3% of the min. oral concentration and 27.5% of the max. oral concentration. Moreover, the concentration of RIS released from the implant was comparable to the min. oral concentration. [253] Subcutaneous implant PCL Schizophrenia Paliperidone palmitate Implants made by pressure-extrusion based 3D-printing. Independent of the blend, the release from the rings were higher than the disks. After 3 months, devices with PCL 5% released 63 ± 3% (disks) and 79 ± 3% w/w (rings) of drug. [256] Subcutaneous implant PLA and magnesium stearate Schizophrenia Risperidone Implant consists of microspheres of PLA combined with magnesium stearate (0.5%) directly compressed to form a 3 mm diameter implant. Implants were coated with a PLA membrane. Zero-order in vitro release kinetics and capability of providing sustained drug release in vivo for 164 days. [252] Subcutaneous implant PCL Schizophrenia Olanzapine Implants produced by hot-melt extrusion. Implants were loaded with 6.78 ± 0.56 mg of the drug each. In vitro release study was performed for 4 days and showed controlled release of OLZ that followed Higuchi’s model. [251] Subcutaneous implant PCL and PEO Schizophrenia Olanzapine Implants made by 3D-printing technology with a cylindrical shape and wrapped in a PCL film. The core consists of OLZ and PEO. The release was assessed for 190 days delivering ca. 77% and ca. 64% for implants containing 50% and 80% (w/w) of drug, respectively. [29] Subcutaneous implant PCL and PEG Schizophrenia Olanzapine Implants made by 3D-printing technology with a cylindrical shape using concentrated high concentrated polymer/drug solutions. The resulting implants contained up to 80% (w/ w) drug loading. Implants containing a combination of PCL and PEG rather than only PEG showed sustained in vitro drug release over 200 days. [99] Subcutaneous implant PLA Schizophrenia Paliperidone palmitate To create the implants two different methods were used, hot-melt extrusion and fused deposition modelling 3D-printing. The in vitro release study was developed for 3 months obtained a total of drug release of 15.0 ± 0.8 % for the implants loaded with 20% of paliperidone palmitate, and 5.6 ± 0.6 % for the implants loaded with 100% drug. [255] Intranasal implant PCL, PLGA Schizophrenia Risperidone The resulting implants were developed by a casting method with a range between 25 (PCL- based) and 50 % (PLGA-based) of drug. The devices showed a sustained drug release profile for 90 days. [97] Intranasal implant PLGA Schizophrenia Risperidone PLGA devices loaded with radiolabeled risperidone were intranasally administered to rats providing up to 4 weeks of release. [254] E. Magill, S. Demartis, E. Gavini et al. Advanced Drug Delivery Reviews 199 (2023) 114950 19 150 days [29,99,251]. However, no in vivo performance was reported for these implants. In addition to olanzapine, risperidone has been extensively used IDDS for schizophrenia treatment (Table 5). Risperidone has been used in subcutaneous formulations [252,253]. These formulations were evaluated in vivo using animal models and even in clinical trials [252,253]. Braeburn Pharmaceuticals Inc tested TPU-based subcutaneous implants containin risperidone in adult patient’s suffering from schizophrenia [253]. This study showed that patients receiving implants showed comparable risperidone levels than the control group that received oral risperidone [253]. In addition to subcutaneous implants, novel intranasal IDDS for the delivery of this drug have been reported (Table 5)[97,254]. These implants were made of biodegradable polymers (PCL and PLGA) and they showed that they were capable of providing sustained risperidone release in a rat animal model [254]. Finally, paliperidone palmitate IDDS were prepared using PCL and PLA via-3D-printing extrusion techniques [255,256]. The resulting systems could provide in vitro drug release for times ranging between 90 and 180 days. No in vivo evaluation for these implants was reported (Table 5). 4.6. Drug-eluting cardiovascular IDDS Cardiovascular disease (CVD) is a general term used for conditions affecting the heart or blood vessels, which are the leading cause of death in the world and represent a main contributor to reduced quality of life [257-259]. The purpose of drug delivery in cardiovascular IDDS can be targeted at preventing the blocking of the target blood vessels after treatment or the synthetic vascular grafts used for the restoration of blood flow in damaged vessels [150,260]. The process of this complication (restenosis) is usually due to platelet deposition and thrombus formation, and neointimal hyperplasia [261]. Several therapeutic agents, including antiproliferative drugs such as Paclitaxel (PTX), sunitinib, sirolimus and other limus-family related drugs (everolimus, biolimus A9, zotarolimus, tacrolimus, and pimecrolimus); antithrombotic agents such as heparin, cilostazol (CIL), dipyridamole (DIP), acetylsalicylic acid (ASA) or nitric oxide (NO); and antibiotics such as sisomicin, rapamycin, vancomycin or rifampicin (RIF), among other molecules, have been loaded into cardiovascular IDDS to combat either thrombus formation or neointimal hyperplasia [107,150,259,260,262-267]. The use of drug-delivery systems in cardiovascular applications drastically decreased the rate of restenosis. For instance, Scheller et al. showed that only 5% of the patients treated with a PTX-coated balloon presented restenosis in comparison with 43% of patients in the control group [268]. Moreover, the use of drug-eluting stents has significantly decreased the restenosis rate to 3–20% [269]. Therefore, these drugdelivery systems are a valuable alternative to combat these risks. IDDS for the treatment of CVD include drug-eluting small diameter vascular grafts (SDVGs) and stents [270] (Fig. 8), since drugeluting balloons are removed after providing the therapeutic benefit [271]. Thus, the latter devices will not be included in this section. These IDDS are usually made from a polymeric matrix. Such matrices not only allow to increase the upper limit of the drug amount loaded/deposited onto these devices, but also can protect drugs against enzymatic degradation or regulates the release rate, among other benefits [150,272]. Moreover, these polymeric matrices can be manufactured from non-degradable or permanent polymeric materials including ethylene vinyl acetate (EVA), poly (ethylene-co-vinyl acetate) (PEVA), poly (n-butyl methacrylate) (PBMA), poly(styrene–b-isobutylene–b-styrene) (SIBS) and thermoplastic polyurethane (TPU); or biodegradable polymeric materials such as polylactic acid (PLA), poly(lactic-co-glycolic acid) (PLGA) and polycaprolactone (PCL), among others [150,260,273]. However, it has been reported that non-degradable polymeric materials could potentially lead to side effects such as thrombosis, chronic inflammation and neointimal hyperplasia, after remaining in the body for extended periods of time [272,274]. 4.6.1. Drug loaded cardiovascular stents Cypher Ò , marketed by Cordis (a Johnson & Johnson Company) in 2003, was the first commercially available drug-eluting implant [260,278]. This device was made from a non-degradable polymer coating layer including PEVA and PBMA which were used as a platform for the release of PTX or sirolimus [150,272]. Moreover, for this device, a top coating layer made from the same polymers but containing no drug was employed to avoid any burst release. Fig. 8. PLGA-based model for the manufacture of biodegradable-based stents (A). Coaxial electrospray process used for the development of a drug-eluting coating for cardiovascular IDDS consisting of a core coating of the anti-proliferative drug docetaxel (DTX) and a shell coating of the platelet glycoprotein IIb/IIIa receptor monoclonal antibody SZ-21 (B). Scheme showing the strategy of SNAP impregnated polyurethane-based membrane to mimic the inner surface of blood vessels and thus inhibits platelet and bacterial adhesion (C). Reproduced with permission from the cited references [275-277]. E. Magill, S. Demartis, E. Gavini et al. Advanced Drug Delivery Reviews 199 (2023) 114950 20 Another example of these first-generation drug-eluting stents (- made from non-degradable polymers) is Taxus TM . This PTX-eluting coronary stent system was made from an elastomeric triblock copolymer (SIBS). This implantable device was marketed by Boston Scientific (MA, USA) and was approved by the US FDA between 2003 and 2004 [278]. Although these drug-eluting nondegradable polymeric stents seemed to be very promising, the use of them led to a delayed healing and late thrombosis as potential risks [274,277,279]. In order to avoid the risk of thrombosis, NO has been investigated [277,279]. For instance, some researchers showed the potential of the NO donor S-nitoroso-N- acetylpenicillamine (SNAP)-loaded polyurethane disks (5% and 10% SNAP) released NO at a valuable rate for 9 and 19 days, respectively (Fig. 10C) [277]. For the second-generation of drug-eluting stents more attention was paid to the type of polymeric materials used in their manufacture. These stents are made from biodegradable polymers such as PLA, PLGA, PCL or poly(D,L-lactic acid) (PDLLA), among others, thus avoiding the abovementioned side effects caused by the nondegradable polymeric materials [150,260,280]. One of these second generation drug-eluting stents commercially available is Biomatrix Ò , which used a poly(L-lactic acid) (PLLA) platform for the delivery of biolimus [281,282]. The use of this biodegradable platform showed lower prevalence of adverse cardiac events (15.7%) in comparison with a first generation sirolimus-eluting stent (19%) (LEADERS clinical trial) [150,282]. Moreover, Abbott Vascular (IL, USA) manufactured a bioresorbable everolimus-eluting stent (Absorb TM ), which consisted of a 150- l m-thick bioresorbable PLLA stent with a 7- l m-thick bioresorbable PDLLA coating [150,283]. Absorb TM was the first drug-eluting fully-erodible stent implanted in a human, which also presented a clear reduction in the rate of adverse cardiac events after 12 months (from 14% to 3.3%) when compared to non-drug loaded PLLA-based stents [283,284]. DREAMS from Biotronik AG (Berlin, Germany) comprise a couple drug eluting absorbable metal stents [150,285]. The manufacturer used magnesium-based alloy as the main scaffold for both DREAMS 1G and 2G [150,285]. However, the first generation of these stents was coated with PTX-loaded polylactic-co-glycolic acid (PLGA) layer of 1 l m, while the second generation was coated with PLLA incorporated with sirolimus [285]. Moreover, the clinical trial performed using DREAMS 2G did not report any episode of stent thrombosis after 12 months [285]. Finally, Endeavor (Medtronic CardioVascular Inc., Santa Rosa, CA) is an example of a zotarolimus-eluting stent. This device consisted of a cobalt– chromium alloy as base with a zotarolimus-containing phosphorylcholine (PC) coating [286]. In contrast to other polymeric coatings, PC is able to avoid hypersensitivity and inflammatory reactions, since this coating mimics the cell membrane of red blood cells in the plasma. However, most of the drug (95% of the loaded zotarolimus) is released within first 15 days [287]. In addition, multiple researchers are still studying the use of novel biodegradable polymeric coatings with the aim of sustaining the release of the therapeutic agents, which is a potential approach to solve the problem of late stent thrombosis due to delayed vascular healing Fig. 9. A macroscopic view of the electrospun DIP-eluting SDVG (A) and its electronic cross-section images (B and C). Scanning electron microscope (SEM) images of the electrospun PCL-based SDVGs before and after modification (D) and their cross-sections (E). Scale bars were 10 and 500 l m, respectively. PCL-based 3D-printed SDVGs containing 20% DIP (F), and images of the performed X-ray microcomputed tomography in this study, indicating a homogeneous structure was obtained. (G). PCL-based 3D printed SDVGs with no drug (H) and containing 10% ASA (I), and a SEM image of the surface of the last SDVGs containing 10% ASA (J). Reproduced with permission from the cited references [107,259,262,306]. E. Magill, S. Demartis, E. Gavini et al. Advanced Drug Delivery Reviews 199 (2023) 114950 21 Table 6 Latest findings in the development of second-generation of drug-eluting stents and drug-eluting vascular grafts. Type of implant Material Target Drug Findings Ref Stent Coating of poly(L-lactide-cocaprolactone) (PLCL) on a stainless steel stent. Cardiovascular diseases Atorvastatin and fenofibrate Sustained release of Ator. and Feno. for more than 60 days. Combination of both drugs provided antithrombotic and anti-inflammatory effects and significantly retarded smooth muscle cell proliferation, showing its effectiveness to overcome restenosis. [288] Stent Coating of chitosan (inner surface) and PLGA (outer surface) on a stainless steel stent. Cardiovascular diseases Monoclonal platelet glycoprotein IIIa receptor antibody SZ-21 and docetaxel A sustained release of both bioactive compounds. This novel combination provided antithrombotic effect at earlier period and inhibition of vascular smooth muscle cells proliferation at later period. [289] Stent Coating of PLA on a cobalt chromium alloy stent. Cardiovascular diseases Sirolimus, abciximab and alphalipoic acid (ALA) The combination of these three drugs had synergistic effects showing a superior neointimal and vascular inflammation suppressive effect in comparison to those containing no drugs or only sirolimus. [290] Stent Sirolimus loaded PLGA nanoparticles, phosphatidylglycerol-bivalirudin complex and bare metal stent. Cardiovascular diseases Sirolimus and bivalirudin nanoparticles Superior antiproliferative activity of sirolimus loaded PLGA nanoparticles over native sirolimus in smooth muscle cells. [291] Stent Zein, alginate and stainless steel stent. Cardiovascular diseases Rutin The addition of alginate succeeded in sustaining rutin release profile over 21 days. Moreover, this plantbased coating showed excellent vascular cell biocompatibility. [292] Stent Coating of a blend of PLGA and PLLA on a cobalt chromium alloy stent. Cardiovascular diseases Sirolimus Developed stents in this study were able to prevent stent-induced tissue hyperplasia in the porcine Eustachian tube model. [293] Stent Coating of PDLLA on magnesium–neodymium-zinc- zirconium alloy stent. Cardiovascular diseases Sirolimus The coating performed on this patented alloy prevented smooth muscle cells adhesion and sustain the drug release rate in vitro. [294] Stent Polymeric scaffolds of PLLA/PDLA using a polydopamine (PDA) intermediate layer. Cardiovascular diseases Everolimus The PDA intermediate layer was able to sustain drug release. Therefore, it can be used as a potential approach to prevent complications of the current drug-eluting stents, such as the late-stent thrombosis. [295] Stent Coating of heparin-loaded alginate and atorvastatin calcium-loaded polyurethane on nickel-titanium (Ni-Ti; also known as nitinol) stents. Cardiovascular diseases Heparin and atorvastatin calcium The coating approach provided a sustained release of both drugs. In addition, this approach was biocompatible, hemocompatible, and enhanced human umbilical vein endothelial cells attachment. [296] Stent Coating of tacrolimus (polymer free) on the outer surface and N-doped titanium dioxide (N-TiO 2 ) coating on the inner surface of the cobalt chromium alloy stent. Cardiovascular diseases Tacrolimus The abluminal coating of tacrolimus provided antiinflammatory effects and reduced in-stent restenosis. In addition, the coating on the inner surface (N-TiO 2 ) was useful for increasing re-endothelialisation and preventing thrombosis. [297] Stent The model stent was a silver coated copper wire, which was then coated with poly(n-butyl methacrylate) (PBMA). Cardiovascular diseases Leoligin The authors proposed an inexpensive drug eluting stent model using natural compounds, which have the potential to inhibit intimal hyperplasia and the regrowth of endothelial cells [298] Stent A polymer blend of PLA and EVA Cardiovascular diseases Aspirin The polymers blend coating proposed in this work showed superior mechanical properties and controlled release of aspirin. [299] Stent Coating of Poly 3-Hydroxybutyrate 4-Hydroxybutyrate (P34HB) on a stainless steel stent. Cardiovascular diseases Sirolimus The polymer coating of this work showed the ability of sustaining release rate. [300] Stent Coating of a PLGA/PEVA on a nickel-titanium alloy stent. Cardiovascular diseases Paclitaxel The coating composite approach of this work was able to sustain the PXL release for at least 30 days, showing a zero-order release profile after initial burst release. [301] Stent Coating of a PC-based copolymer on a PLLA-based biodegradable stent. Cardiovascular diseases Sirolimus This novel biodegradable coating approach showed a sustained sirolimus release profile as well as the potential to inhibit neointimal hyperplasia in a porcine artery injury model in vivo. [302] Stent Coating of a citric acid solution on on nickeltitanium alloy stent Cardiovascular diseases Citric acid The use of citric acid was able to promote endothelial adhesion, migration, and proliferation in vitro on the stent surfaces. However, to support these claims about citric acid for vascular healing, in vivo studies should be performed. [303] Vascular graft PCL and decellularized rat aorta (DRA) Cardiovascular diseases Sirolimus Hybrid tissue-engineered vascular graft showed a sustained sirolimus release, thus preventing intimal hyperplasia. Moreover, these grafts had superior mechanical properties compared to DRA, showing a great clinical translational potential. [304] E. Magill, S. Demartis, E. Gavini et al. Advanced Drug Delivery Reviews 199 (2023) 114950 22 and re-endothelialization in patients following first-generation drug-eluting stents implantation. The latest and most relevant studies addressing this issue are shown in Table 6. Despite their unquestionable advantages, biodegradable polymers have shown weaker mechanical properties compared with the alloys used in the non-degradable drug-eluting stents [260]. Therefore, more research is needed to enhance the mechanical properties of the biodegradable-based drug eluting stents. 4.6.2. Drug loaded vascular grafts Surgical bypass grafting is another valuable strategy for the treatment of some specifics CVD. IDDS have been successfully used to replace large blood vessels, however, some risks of thrombus formation and neointimal hyperplasia can occur when replacing when used to replace SDVGs (greater than6 mm internal diameter). Therefore, the combination of vascular grafts with some therapeutic agents such as heparin, CIL, DIP, acetylsalicylic acid or NO is a simple way to prevent these complications. Different techniques including electrospinning, mould-casting and 3D printing [257,308] can be used for the manufacture of drug-eluting SDVGs. The use of electrospinning has been extensively reported in the literature. Moreover, PCL is one the most common biodegradable polymers used for this purpose. For instance, electrospun PCL-based fibers or nanofibers have been loaded with rapamycin [304], CIL [305], heparin and dexamethasone (Fig. 9D-E)[306], ASA [264] or even fibrin [309]. Overall, these works showed a potential anticoagulant ability and/or the capacity to inhibit intimal hyperplasia. Additionally, other biodegradable polymers such as poly(D,L-lactic acid-co-glycolic acid) (PDLLGA), poly(L-lactic acid-co-e-caprolactone) (P(LLA-CL)) or biodegradable elastic polyurethane (BPU) were successfully used to prepare electrospun tubular scaffolds as a vascular drug-delivery grafts loaded with vancomycin [310], heparin and VEGF [311] and DIP (Fig. 9A- Table 6 (continued) Type of implant Material Target Drug Findings Ref Vascular graft PCL and Pluronic 123 Cardiovascular diseases Cilostazol The addition of Pluronic 123 improved tensile properties of electrospun fibres and increased the cilostazol release rate, however, significantly reduced the cell viability when compared to more hydrophobic PCL formulation. [305] Vascular graft PCL, Polyethyleneimine (PEI) and epigallocatechin gallate (EGCG) Cardiovascular diseases Dexamethasone and heparin A coating of PEI and Hep. in combination with EGCG and Dex. was used to functionalize the electrospun PCL vascular grafts. This coating provided a sustained release. In addition, this system prolonged anticoagulant and anti-inflammatory properties as well as the anti-fibrinogen denaturation ability of the vascular grafts. [306] Vascular graft TPU Cardiovascular diseases Dipyridamole and rifampicin Vascular grafts developed in this study were able to sustain the release of RIF, thus preventing vascular graft infections. Moreover, dual extrusion FDM 3D printing technology enabled to manufacture grafts containing the two different drugs. These grafts were cytocompatible and hemocompatible. [273] Vascular graft PCL Cardiovascular diseases Dipyridamole This 3D printed drug SDVGs were able to provide a sustained and linear drug release for at least 30 days, as well as a significant antithrombotic effect. These grafts were cytocompatible and hemocompatible. [259] Vascular graft TPU Cardiovascular diseases Dipyridamole Drug-eluting SDVGs showed a sustained DIP release for at least 30 days and comparable mechanical properties than natural blood vessels. Moreover, the outcomes of this work suggested that the drug load and also the surface properties were decisive for platelet adhesion. [307] Fig. 10. A) Optical and scanning electron microscopy (SEM) image of the two-layer mesh and nanoporous membrane NICHE. B) Cell and drug reservoir sites of NICHE and SEM image of nanoporous membrane. C) Design of synthetic hydrogel macroencapsulation device. Reproduced with permission from the cited references [328,329,332]. E. Magill, S. Demartis, E. Gavini et al. Advanced Drug Delivery Reviews 199 (2023) 114950 23 C) [107], respectively. The former device achieved a local and sustainable delivery of antimicrobial compound, thus, it could be used for preventing infections when grafts are implanted, while the last two studies showed excellent anticoagulant properties, hemocompatibility and the potential to promote rapid endothelialisation. More recently, some authors have proven that 3D printing technology can be successfully used for the manufacture of drugeluting SDVGs. For this purpose, a combination of two types of PCL (50 kDa and 550 Da) and DIP was achieved without using any solvent by using a centrifugal laboratory mixer prior to the loading the mixture into a semi-solid extrusion 3D-printer [259]. Moreover, the same procedure was used to combine PCL and ASA [262].Fig. 9F-J shows representative images of the resulting 3D- printed vascular grafts containing DIP and ASA. Both studies suggested that the amount of antithrombotic agents in the material surface was more important than the amount of released drug to avoid the platelet adhesion to the surfaces of the 3D printed SDVGs. Additionally, the authors of one of the aforementioned studies [262] showed the possibility of loading more than one therapeutic agent (ASA and RIF), and thus multiple complications could be avoided. In this regard, a different study also explored the use of dual extrusion FDM printer to prepare nonbiodegradable TPU-based drug-eluting SDVGs containing DIP and RIF [273]. Moreover, FDM technology was used by Dominguez- Robles et al. to obtain antiplatelet SDVGs [307]. In this case TPU was combined with DIP (up to 20% w/w) using hot melt extrusion. Subsequently, FDM was used to print SDVGs. Interestingly, SDVGs containing lower DIP content (5%) showed better antiplatelet activity than grafts containing higher drug loading (10 and 20%) [307]. This was mainly due to surface properties of the resulting grafts [307]. Moreover, FDM is a better option than semi-solid extrusion for the development of medical devices due to its higher resolution. The latest and most relevant studies designing and developing drug-eluting vascular grafts by using electrospinning and 3D print- Table 7 Recent studies describing cell encapsulation in IDDS. Type of implant Material Target Findings Ref 3D printed Neovascularized Implantable Cell Homing and Encapsulation Polyamide, resin, polyethersulfone (PES), nylon, silicone and hydrogrel Type 1 diabetes Allogeneic islets transplanted from prevascularized NICHE led to functional engraftment, revascularization, reverting diabetes in rats for over 5 months. [328] 3D printed Neovascularized Implantable Cell Homing and Encapsulation Polyamide, nylon, silicone, hydrogel Type 1 diabetes NICHE, preloaded with mesenchymal stem cells (MSCs), subcutaneously implanted, integrated in situ pre-vascularization and local immunosuppression. [329] Nanofibrous tube encapsulation of insulinproducing islets and stem cell-derived beta (SC-b) cells Alginate hydrogel Type 1 diabetes Long-term cell engraftment, corrects diabetes in mice in vivo for up to 399 days. [341] Semipermeable encapsulation system containing a gas-permeable, liquid-impermeable silicone membrane Alginate hydrogel/ silicone membrane Type 1 diabetes Transports nutrients, O2 and the delivery of insulin but blocks the infiltration of immune effector cells for several months without intervention. [331] Speedy Oxygenation Network for Islet Constructs insulin releasing scaffold Alginate hydrogel Type 1 diabetes Improves cell survival under hypoxic conditions in immunocompetent diabetic mice for over 6 months. [342] Macroencapsulation device for insulin-secreting bcells Acrylic sheet - poly(methyl methacrylate) Type 1 diabetes Enhances the survival and insulin secreting function of the cells in vivo, improves glucose tolerance, and reduces fibrosis. [343] Islet-encapsulation device to secrete glucose, insulin, and IgG Alginate hydrogel Type 1 diabetes Improves glycemic control without immunosuppressants. [344] Nanofiber Integrated Cell Encapsulation device for the safe delivery of insulin-producing cells Thermoplastic silicone polycarbonate urethane and alginate hydrogel Type 1 diabetes Enables long term delivery of insulin producing cells including human stem cell derived b(SC-b) cells. [330] Encapsulation device augmented with controlled release of amino acids (alanine and glutamine) PCL nanoporous and nonporous films Type 1 diabetes Improves the survival of encapsulated stem cellderived insulin-producing cells in the poorly vascularized subcutaneous space for several weeks [345] 3D bioprinted construct insulin-secreting bcells Alginate/ PCL Type 1 diabetes Enables proliferation and insulin release normally, proposing a better alternative to portal vein islet transplantation. [346] 3D printed scaffolds carrying human umbilical mesenchymal stem cells (HUCMSCs) Collagen/silk fibroin Spinal cord injury Has the potential to become a novel and safer treatment for SCI repair. [333] 3D printed scaffold integrated with the brainderived neurotrophic factor (3D-CC-BDNF) and Human umbilical cord mesenchymal stem cells (HUCMSCs) Collagen/chitosan Spinal cord injury Accelerates neural regeneration after SCI, thus could be a potential therapeutic method for clinical treatment of SCI. [334] 3D bioprinted nerve scaffold composed of rat Schwann cells Gelatin/alginate hydrogel Neurodegenerative diseases Improves cell adhesion and related factor expression. [347] 3D-printed scaffold loaded with Mesenchymal stem cells PCL/methacrylated alginate Cartilage repair Demonstrates a potential for enhanced cartilage tissue engineering. [335] 3D bioprinted construct with bone marrow mesenchymal stem cells Silk fibroin/ decellularized extracellular matrix Cartilage repair Releases TGF-b3, promoting chondrogenic differentiation of BMSCs and provides a good cartilage repair environment. [336] Electrospun Microtube Array Membranes (MTAMs) encapsulated with Hybridoma cells Polysulfone/ PEG Cancer Treatment Provides a continuous secretion of antibodies which suppressed the cancer cell line A549, MDAMB-468 throughout the entire 21 days of in vitro experiment. [337] Porous microneedle patch that accommodates CAR T cells and allows in situ penetrationmediated seeding of CAR T cells Ethacryloyl chloride modified 4-arm-PLGA/andtriethylene glycol diacetate/CaCO3 microparticles Cancer Treatment Augments T cell infiltration within the solid tumor, preventing local tumor recurrence and potential metastatic dissemination. [348] E. Magill, S. Demartis, E. Gavini et al. Advanced Drug Delivery Reviews 199 (2023) 114950 24 ing techniques are shown in Table 6 The advent and the continuous development of 3D-printing technologies during the last years could make possible a different approach towards the manufacture of drug-eluting SDVGs personalised to each individual. Such a concept provides benefits for patients and physicians. In this way SDVG can be produced on demand adapting the geometry of the device to the anatomy of the patient [259,262,273,312]. 4.7. Implantable devices for cell encapsulation Therapeutic transplanted cells are in shortage, and they need lifelong immunosuppression to prevent their rejection from the body, limiting the widespread application of islet or cell transplantation [313]. The main objective of encapsulated devices is to provide a protected environment that increases cells’ survival rate, providing an immunoisolation barrier to avoid rejection and maintain their sustenance and functions [314]. The most critical factors of materials for cell encapsulation are stability, biocompatibility, flexibility, permeability and maintaining the survival of encapsulated cells [315]. Advanced preparation methodologies for these devices include water and oil systems, microfluidic systems, conformal coating, 3D printing and bioprinting [316-318]. Cell encapsulation devices come in various designs, such as tubular hollow fibers, tubular ultra-filtrate chambers and planar devices [319,320]. These systems acts as diffusion chamber enveloping a large transplant mass within a single well-defined 3D-device, allowing for device retrievability in case of adverse reaction or failure [314]. These devices allow for greater control over membrane parameters, such as pore size and porosity, but have limited mass transportation of nutrients, oxygen, and waste products, leading to necrosis in the middle of the capsule [321]. Some researchers have described a combined approach using microencapsulation devices loaded with microcapsules containing cells [320]. Nanoencapsulation system offers advanced control of uniform capsule thickness and pore size to enhance permeation selectivity and increase oxygen delivery [322]. Currently, basic, and clinical research focuses on encapsulation materials, transplantation sites and methods to improve immune modulation and neovascularization. One of these studies is the encapsulation of Mesenchymal Stem Cells (MSCs) for bone tissue engineering [323]. Recent progress and clinical trials in the world of cell encapsulation that have been conducted or are ongoing to cure many diseases, mainly focused on diabetes [324]. Stem cells are used in these systems to tackle diabetes and many other diseases such as hyperlipidemia, osteoporosis, heart disease, brain tumors, and hemophilia [325,326]. The ongoing exploration under in vitro and in vivo studies mostly treating type 1 diabetes, spinal cord injury (SCI), cartilage regeneration and cancer as summarized in Table 7. The refillable neovascularized implantable cell homing and encapsulation (NICHE) cell reservoir produced by nanoporous membranes, promotes vascularization and independently delivery of two different drugs locally [327]. This NICHE device has been licensed by NanoG- land LLC and is undergoing first levels of the FDA regulatory aspects while keeps being studied more in-depth. A recent study about implantable NICHE device has showed localized immunosuppression, thus preventing islet transplant rejection for type 1 diabetes treatment (Fig. 10A) [328]. Another study applying the same encapsulation platform, showed a local immunosuppressant delivery of neovascularized allogeneic cell transplantation (Fig. 10B) [329]. Also, for type 1 diabetes treatment, the Nanofiber Integrated Cell Encapsulation (NICE) device, enables safe and longterm delivery of insulin-producing cells [330]. Additionally, a semipermeable encapsulation system containing gas-permeable, liquid-impermeable alginate hydrogel/silicone membrane leads to nutrients and O 2 transport and insulin delivery, blocking the infiltration of immune effector cells for several months without intervention [331].Fig. 10C shows another example of hydrogelbased device for islet transplantation [332]. Many more studies in the literature about insulin producing cell encapsulation systems, which can also incorporate growth factors, can be seen in the Table 7. 3D printed scaffolds from collagen, silk fibroin or chitosan, carrying cells and growth factors have been proposed as a potential therapeutic method for clinical treatment of SCI, accelerating neural regeneration [333,334]. Studies have also demonstrated the potential of enhanced cartilage repair tissue engineering devices, promoting chondrogenic differentiation of stem cells [335,336]. The Electrospun Microtube Array Membranes (MTAMs) encapsulated systems have shown the potential for cancer treatment, providing a continuous secretion of antibodies which suppress the cancer cells [337]. Despite these significant advances, extensive efforts have recently focused on investigating the ideal cell encapsulation approach, selecting the suitable material and site of transplantation, and investigating the cell behaviour after encapsulation [338]. Given the donor shortage, stem cells have the potential to be a replenishable source. Further work is necessary, however, to find an effective strategy and develop better methods for generating stem cells with all the necessary characteristics in a sufficient number, showing higher production yield, and without the risk of teratogenicity [339]. The current drawbacks of immune system activation, hypoxia, fibrotic overgrowth and poor clinical response still create obstacles [340]. Future success is promised with the continuous incorporation of material design, nanotechnology and immunomodulation. 4.8. MNs-assisted delivery of IDDS Microneedles (MNs) are minimally invasive devices that bypass the skin’s stratum corneum(SC) barrier with a painless and bloodless insertion [349,350]. MNs, which range in height from 10 to 900 l m and are manufactured using microfabrication in a variety of geometries and materials, have been extensively investigated for enhanced transdermal drug and vaccine delivery [351].As MN array is inserted into the skin, it creates pathways for drug molecules to diffuse through the SC and through the other layers of the skin for localized or systemic drug delivery [352]. Therefore, when compared to conventional oral and injectable administration, this approach offers a number of benefits, including prevention of gastrointestinal degradation, avoidance of first-pass hepatic metabolism, improved bioavailability, painless application, reduced infection danger and the ease of self-administered by the patient [353]. Recently, MNs have received great attention as they are the minimally-invasive devices that can bypass the skin’s SC barrier for the delivery long-acting drug delivery systems. Because of the tunable features of biodegradable polymers, controlled drug delivery can be achieved by using polymeric MN [354]. There are several types of implantable MNs, and the mechanism of delivery described in the literature as seen in Fig. 11A and 11D, including nano/microparticles loaded dissolving MN, fast separable solid implantable MN, hydrogel-forming MN [355,356]. 4.8.1. Implantable nano/microparticles combined with MNs Polymeric micro/nanoparticles (MPs/NPs) are promising carriers have been extensively studied for a wide variety of drug deliv- E. Magill, S. Demartis, E. Gavini et al. Advanced Drug Delivery Reviews 199 (2023) 114950 25 [6] E. Larrañeta, R.E.M. Lutton, A.D. Woolfson, R.F. Donnelly, Microneedle arrays as transdermal and intradermal drug delivery systems: Materials science, manufacture and commercial development, Mater. Sci. Eng. R Reports. 104 (2016) 1–32, https://doi.org/10.1016/j.mser.2016.03.001. [7] S. Stewart, J. Domínguez-Robles, V. McIlorum, E. Mancuso, D. Lamprou, R. Donnelly, E. Larrañeta, Development of a Biodegradable Subcutaneous Implant for Prolonged Drug Delivery Using 3D Printing, Pharmaceutics. 12 (2020) 105, https://doi.org/10.3390/pharmaceutics12020105. [8] Eneko Larrañeta; Thakur Raghu Raj Singh and Ryan F. Donnelly, Long-Acting Drug Delivery Systems Pharmaceutical, Clinical, and Regulatory Aspects, 1st ed., 2021. 10.1016/C2019-0-03097-X. [9] K. Higashi, G. Medic, K.J. Littlewood, T. Diez, O. Granstrom, M. De Hert, Medication adherence in schizophrenia: factors influencing adherence and consequences of nonadherence, a systematic literature review, Ther. Adv. Psychopharmacol. 3 (2013) 200–218, https://doi.org/10.1177/ 2045125312474019 [doi]. [10] P.M. Haddad, C. Brain, J. Scott, Nonadherence with antipsychotic medication in schizophrenia: challenges and management strategies, Patient Relat. Outcome Meas. 5 (2014) 43–62, https://doi.org/10.2147/PROM.S42735 [doi]. [11] R. Deanesly, A.S. Parkes, Testosterone, BMJ 1 (1936) 527–528, https://doi.org/ 10.1136/bmj.1.3923.527. [12] P.M.F. Bishop, Clinical Experiment in Oestrin Therapy, BMJ 1 (1938) 939–941, https://doi.org/10.1136/bmj.1.4034.939. [13] W. Trupti, N. Smita, O. Sumant, Implantable Drug Delivery Devices Market by Material (Silicon and Others), Product Type (Implantable Drug Eluting Stents, Implantable Contraceptive Drug Delivery Devices, Implantable Intraocular Drug Delivery Devices, Implantable Brachytherapy Seeds Devic, Pune, 2020. https://www.alliedmarketresearch.com/implantable-drug-delivery-devices- market#::text=The global implantable drug delivery,enable site specific drug administration. [14] K. Zhi, J. Wang, H. Zhao, X. Yang, Self-assembled small molecule natural product gel for drug delivery: a breakthrough in new application of small molecule natural products, Acta Pharm. Sin. B. 10 (2020) 913–927, https:// doi.org/10.1016/j.apsb.2019.09.009. [15] E. Larrañeta, J.R. Isasi, Self-assembled Supramolecular Gels of Reverse Poloxamers and Cyclodextrins, Langmuir 28 (2012) 12457–12462, https:// doi.org/10.1021/la3024452. [16] J.H. Lee, Injectable hydrogels delivering therapeutic agents for disease treatment and tissue engineering, Biomater. Res. 22 (2018) 27, https://doi. org/10.1186/s40824-018-0138-6. [17] C.I. Nkanga, A. Fisch, M. Rad-Malekshahi, M.D. Romic, B. Kittel, T. Ullrich, J. Wang, R.W.M. Krause, S. Adler, T. Lammers, W.E. Hennink, F. Ramazani, Clinically established biodegradable long acting injectables: An industry perspective, Adv. Drug Deliv. Rev. 167 (2020) 19–46, https://doi.org/10.1016/ j.addr.2020.11.008. [18] D.H. Surve, A.B. Jindal, Recent advances in long-acting nanoformulations for delivery of antiretroviral drugs, J. Control. Release. 324 (2020) 379–404, https://doi.org/10.1016/j.jconrel.2020.05.022. [19] Y. Hua, Z. Wang, D. Wang, X. Lin, B. Liu, H. Zhang, J. Gao, A. Zheng, Key Factor Study for Generic Long-Acting PLGA Microspheres Based on a Reverse Engineering of Vivitrol Ò , Molecules 26 (2021) 1247, https://doi.org/ 10.3390/molecules26051247. [20] E. Utomo, S.A. Stewart, C.J. Picco, J. Domínguez-Robles, E. Larrañeta, Classification, material types, and design approaches of long-acting and implantable drug delivery systems, in: Long-Acting Drug Deliv. Syst., Elsevier, 2022: pp. 17–59. 10.1016/B978-0-12-821749-8.00012-4. [21] G. Bruno, N. Di Trani, R.L. Hood, E. Zabre, C.S. Filgueira, G. Canavese, P. Jain, Z. Smith, D. Demarchi, S. Hosali, A. Pimpinelli, M. Ferrari, A. Grattoni, Unexpected behaviors in molecular transport through size-controlled nanochannels down to the ultra-nanoscale, Nat. Commun. 9 (2018) 1682, https://doi.org/10.1038/s41467-018-04133-8. [22] C.Y.X. Chua, P. Jain, A. Ballerini, G. Bruno, R.L. Hood, M. Gupte, S. Gao, N. Di Trani, A. Susnjar, K. Shelton, L.R. Bushman, M. Folci, C.S. Filgueira, M.A. Marzinke, P.L. Anderson, M. Hu, P. Nehete, R.C. Arduino, J.K. Sastry, A. Grattoni, Transcutaneously refillable nanofluidic implant achieves sustained level of tenofovir diphosphate for HIV pre-exposure prophylaxis, J. Control. Release. 286 (2018) 315–325, https://doi.org/10.1016/j.jconrel.2018.08.010. [23] N. Di Trani, A. Silvestri, A. Sizovs, Y. Wang, D.R. Erm, D. Demarchi, X. Liu, A. Grattoni, Electrostatically gated nanofluidic membrane for ultra-low power controlled drug delivery, Lab Chip. 20 (2020) 1562–1576, https://doi.org/ 10.1039/D0LC00121J. [24] A. Kumar, J. Pillai, Implantable drug delivery systems, in: Nanostructures Eng. Cells, Tissues Organs, Elsevier, 2018, pp. 473–511, https://doi.org/10.1016/ B978-0-12-813665-2.00013-2. [25] S.E. Olsson, Contraception with subdermal implants releasing levonorgestrel. A clinical and pharmacological study., Acta Obstet, Gynecol. Scand. Suppl. 142 (1987) 1–45. http://www.ncbi.nlm.nih.gov/pubmed/3116821. [26] D.A. Bernards, K.D. Lance, N.A. Ciaccio, T.A. Desai, Nanostructured Thin Film Polymer Devices for Constant-Rate Protein Delivery, Nano Lett. 12 (2012) 5355–5361, https://doi.org/10.1021/nl302747y. [27] S.A. Stewart, J. Domínguez-Robles, V.J. McIlorum, Z. Gonzalez, E. Utomo, E. Mancuso, D.A. Lamprou, R.F. Donnelly, E. Larrañeta, Poly(caprolactone)-Based Coatings on 3D-Printed Biodegradable Implants: A Novel Strategy to Prolong Delivery of Hydrophilic Drugs, Mol. Pharm. 17 (2020) 3487–3500, https://doi. org/10.1021/acs.molpharmaceut.0c00515. [28] L.M. Johnson, S.A. Krovi, L. Li, N. Girouard, Z.R. Demkovich, D. Myers, B. Creelman, A. van der Straten, Characterization of a Reservoir-Style Implant for Sustained Release of Tenofovir Alafenamide (TAF) for HIV Pre-Exposure Prophylaxis (PrEP), Pharmaceutics. 11 (2019) 315, https://doi.org/10.3390/ pharmaceutics11070315. [29] C.J. Picco, J. Domínguez-Robles, E. Utomo, A.J. Paredes, F. Volpe-Zanutto, D. Malinova, R.F. Donnelly, E. Larrañeta, 3D-printed implantable devices with biodegradable rate-controlling membrane for sustained delivery of hydrophobic drugs, Drug Deliv. 29 (2022) 1038–1048, https://doi.org/ 10.1080/10717544.2022.2057620. [30] W. Whyte, E.T. Roche, C.E. Varela, K. Mendez, S. Islam, H. O’Neill, F. Weafer, R. N. Shirazi, J.C. Weaver, N.V. Vasilyev, P.E. McHugh, B. Murphy, G.P. Duffy, C.J. Walsh, D.J. Mooney, Sustained release of targeted cardiac therapy with a replenishable implanted epicardial reservoir, Nat. Biomed. Eng. 2 (2018) 416– 428, https://doi.org/10.1038/s41551-018-0247-5. [31] P.A. Campochiaro, D.M. Marcus, C.C. Awh, C. Regillo, A.P. Adamis, V. Bantseev, Y. Chiang, J.S. Ehrlich, S. Erickson, W.D. Hanley, J. Horvath, K.F. Maass, N. Singh, F. Tang, G. Barteselli, The Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration, Ophthalmology 126 (2019) 1141–1154, https://doi.org/10.1016/j.ophtha.2019.03.036. [32] J.C. Wright, Critical Variables Associated with Nonbiodegradable Osmotically Controlled Implants, AAPS J. 12 (2010) 437–442, https://doi.org/10.1208/ s12248-010-9199-8. [33] F.P. Pons-Faudoa, A. Ballerini, J. Sakamoto, A. Grattoni, Advanced implantable drug delivery technologies: transforming the clinical landscape of therapeutics for chronic diseases, Biomed. Microdevices. 21 (2019) 47, https://doi.org/10.1007/s10544-019-0389-6. [34] L.A. Villarruel Mendoza, N.A. Scilletta, M.G. Bellino, M.F. Desimone, P.N. Catalano, Recent Advances in Micro-Electro-Mechanical Devices for Controlled Drug Release Applications, Front. Bioeng. Biotechnol. 8 (2020), https://doi.org/10.3389/fbioe.2020.00827. [35] A.B. Bußmann, L.M. Grünerbel, C.P. Durasiewicz, T.A. Thalhofer, A. Wille, M. Richter, Microdosing for drug delivery application—A review, Sensors Actuators A Phys. 330 (2021), https://doi.org/10.1016/j.sna.2021.112820. [36] N. Di Trani, A. Silvestri, G. Bruno, T. Geninatti, C.Y.X. Chua, A. Gilbert, G. Rizzo, C.S. Filgueira, D. Demarchi, A. Grattoni, Remotely controlled nanofluidic implantable platform for tunable drug delivery, Lab Chip. 19 (2019) 2192– 2204, https://doi.org/10.1039/C9LC00394K. [37] G. Bruno, G. Canavese, X. Liu, C.S. Filgueira, A. Sacco, D. Demarchi, M. Ferrari, A. Grattoni, The active modulation of drug release by an ionic field effect transistor for an ultra-low power implantable nanofluidic system, Nanoscale 8 (2016) 18718–18725, https://doi.org/10.1039/C6NR06235K. [38] A.E.M. Eltorai, On-demand antibiotic-eluting microchip for implanted spinal screws, J. Orthop. 14 (2017) 565–570, https://doi.org/10.1016/j. jor.2017.07.012. [39] R. Farra, N.F. Sheppard, L. McCabe, R.M. Neer, J.M. Anderson, J.T. Santini, M.J. Cima, R. Langer, First-in-Human Testing of a Wirelessly Controlled Drug Delivery Microchip, Sci. Transl. Med. 4 (2012), https://doi.org/10.1126/ scitranslmed.3003276. [40] S. Liu, Z. Jia, F. Yang, T. Ning, X. Gu, X. Niu, Y. Fan, Flexible Transient Bioelectronic System Enables Multifunctional Active-Controlled Drug Delivery, Adv. Funct. Mater. 33 (2023) 2215034, https://doi.org/10.1002/ adfm.202215034. [41] J. Moohan, S.A. Stewart, E. Espinosa, A. Rosal, A. Rodríguez, E. Larrañeta, R.F. Donnelly, J. Domínguez-Robles, Cellulose Nanofibers and Other Biopolymers for Biomedical Applications. A Review, Appl. Sci. 10 (2019) 65, https://doi.org/ 10.3390/app10010065. [42] R. Mohammadinejad, H. Maleki, E. Larrañeta, A.R. Fajardo, A.B. Nik, A. Shavandi, A. Sheikhi, M. Ghorbanpour, M. Farokhi, P. Govindh, E. Cabane, S. Azizi, A.R. Aref, M. Mozafari, M. Mehrali, S. Thomas, J.F. Mano, Y.K. Mishra, V. K. Thakur, Status and future scope of plant-based green hydrogels in biomedical engineering, Appl. Mater. Today. 16 (2019) 213–246, https:// doi.org/10.1016/j.apmt.2019.04.010. [43] X. Tang, S.K. Thankappan, P. Lee, S.E. Fard, M.D. Harmon, K. Tran, X. Yu, Polymeric Biomaterials in Tissue Engineering and Regenerative Medicine, in: Nat. Synth. Biomed. Polym., Elsevier (2014) 351–371, https://doi.org/ 10.1016/B978-0-12-396983-5.00022-3. [44] D.-H. Kim, D.C. Martin, Sustained release of dexamethasone from hydrophilic matrices using PLGA nanoparticles for neural drug delivery, Biomaterials 27 (2006) 3031–3037, https://doi.org/10.1016/j.biomaterials.2005.12.021. [45] D.H. Shastri, S.T. Prajapati, L.D. Patel, Design and Development of Thermoreversible Ophthalmic In Situ Hydrogel of Moxifloxacin HCl, (n.d.). [46] A. Sionkowska, Current research on the blends of natural and synthetic polymers as new biomaterials: Review, Prog. Polym. Sci. 36 (2011) 1254– 1276, https://doi.org/10.1016/j.progpolymsci.2011.05.003. [47] S.-B. Park, E. Lih, K.-S. Park, Y.K. Joung, D.K. Han, Biopolymer-based functional composites for medical applications, Prog. Polym. Sci. 68 (2017) 77–105, https://doi.org/10.1016/j.progpolymsci.2016.12.003. [48] M. Xeroudaki, M. Thangavelu, A. Lennikov, A. Ratnayake, J. Bisevac, G. Petrovski, P. Fagerholm, M. Rafat, N. Lagali, A porous collagen-based hydrogel and implantation method for corneal stromal regeneration and sustained local drug delivery, Sci. Rep. 10 (2020) 16936, https://doi.org/10.1038/ s41598-020-73730-9. [49] J. Liu, T. Tagami, T. Ozeki, Fabrication of 3D-Printed Fish-Gelatin-Based Polymer Hydrogel Patches for Local Delivery of PEGylated Liposomal E. Magill, S. Demartis, E. Gavini et al. Advanced Drug Delivery Reviews 199 (2023) 114950 32 Doxorubicin, Mar. Drugs. 18 (2020) 325, https://doi.org/10.3390/ md18060325. [50] M.C. Echave, R. Hernáez-Moya, L. Iturriaga, J.L. Pedraz, R. Lakshminarayanan, A. Dolatshahi-Pirouz, N. Taebnia, G. Orive, Recent advances in gelatin-based therapeutics, Expert Opin. Biol. Ther. 19 (2019) 773–779, https://doi.org/ 10.1080/14712598.2019.1610383. [51] P. Bhattacharjee, B. Kundu, D. Naskar, H.-W. Kim, T.K. Maiti, D. Bhattacharya, S.C. Kundu, Silk scaffolds in bone tissue engineering: An overview, Acta Biomater. 63 (2017) 1–17, https://doi.org/10.1016/j.actbio.2017.09.027. [52] A.J. Wolfe, J.S. Guasto, F.G. Omenetto, D.L. Kaplan, Silk Reservoir Implants for Sustained Drug Delivery, ACS Appl. Bio Mater. 4 (2021) 869–880, https://doi. org/10.1021/acsabm.0c01382. [53] B. Yavuz, L. Chambre, D.L. Kaplan, Extended release formulations using silk proteins for controlled delivery of therapeutics, Expert Opin. Drug Deliv. 16 (2019) 741–756, https://doi.org/10.1080/17425247.2019.1635116. [54] W. Xu, K. Yagoshi, T. Asakura, M. Sasaki, T. Niidome, Silk Fibroin as a Coating Polymer for Sirolimus-Eluting Magnesium Alloy Stents, ACS Appl. Bio Mater. 3 (2020) 531–538, https://doi.org/10.1021/acsabm.9b00957. [55] S.M. Coulter, S. Pentlavalli, L.K. Vora, Y. An, E.R. Cross, K. Peng, K. McAulay, R. Schweins, R.F. Donnelly, H.O. McCarthy, G. Laverty, Enzyme-Triggered <scp>l</scp> - a / <scp>d</scp> -Peptide Hydrogels as a Long-Acting Injectable Platform for Systemic Delivery of HIV/AIDS Drugs, Adv. Healthc. Mater. (2023) 2203198. 10.1002/adhm.202203198. [56] A. Gonella, S. Grizot, F. Liu, A. López Noriega, J. Richard, Long-acting injectable formulation technologies: challenges and opportunities for the delivery of fragile molecules, Expert Opin. Drug Deliv. 19 (2022) 927–944, https://doi. org/10.1080/17425247.2022.2105318. [57] D.-K. Ho, C. LeGuyader, S. Srinivasan, D. Roy, V. Vlaskin, T.E.J. Chavas, C.L. Lopez, J.M. Snyder, A. Postma, J. Chiefari, P.S. Stayton, Fully synthetic injectable depots with high drug content and tunable pharmacokinetics for long-acting drug delivery, J. Control. Release. 329 (2021) 257–269, https:// doi.org/10.1016/j.jconrel.2020.11.030. [58] L.S. Nair, C.T. Laurencin, L.S. Nair, C.T. Laurencin, Biodegradable polymers as biomaterials, Prog. Polym. Sci. 32 (2007) 762–798. [59] K. Ginjupalli, G.V. Shavi, R.K. Averineni, M. Bhat, N. Udupa, P. Nagaraja Upadhya, Poly( a -hydroxy acid) based polymers: A review on material and degradation aspects, Polym. Degrad. Stab. 144 (2017) 520–535, https://doi. org/10.1016/j.polymdegradstab.2017.08.024. [60] H. Ueda, Y. Tabata, Polyhydroxyalkanonate derivatives in current clinical applications and trials, Adv. Drug Deliv. Rev. 55 (2003) 501–518, https://doi. org/10.1016/S0169-409X(03)00037-1. [61] V.R. Sinha, K. Bansal, R. Kaushik, R. Kumria, A. Trehan, Poly- e -caprolactone microspheres and nanospheres: an overview, Int. J. Pharm. 278 (2004) 1–23, https://doi.org/10.1016/j.ijpharm.2004.01.044. [62] A. Rodriguez-Galan, L. Franco, J. Puiggali, Degradable Poly(ester amide)s for Biomedical Applications, Polymers (Basel). 3 (2010) 65–99, https://doi.org/ 10.3390/polym3010065. [63] T. Steinbach, F.R. Wurm, Poly(phosphoester)s: A New Platform for Degradable Polymers, Angew. Chemie Int. Ed. 54 (2015) 6098–6108, https://doi.org/ 10.1002/anie.201500147. [64] J. Wang, H.-Q. Mao, K.W. Leong, A Novel Biodegradable Gene Carrier Based on Polyphosphoester, J. Am. Chem. Soc. 123 (2001) 9480–9481, https://doi.org/ 10.1021/ja016062m. [65] N. Goonoo, R. Jeetah, A. Bhaw-Luximon, D. Jhurry, Polydioxanone-based biomaterials for tissue engineering and drug/gene delivery applications, Eur. J. Pharm. Biopharm. 97 (2015) 371–391, https://doi.org/10.1016/j. ejpb.2015.05.024. [66] J. Zhu, H.-C. Dang, W.-T. Wang, X.-L. Wang, Y.-Z. Wang, Cellulose Diacetate-g- poly(p-dioxanone) Co-polymer: Synthesis, Properties and Microsphere Preparation, J. Biomater. Sci. Polym. Ed. 22 (2011) 981–999, https://doi.org/ 10.1163/092050610X497863. [67] G.-Y. Liu, Y.-L. Zhai, X.-L. Wang, W.-T. Wang, Y.-B. Pan, X.-T. Dong, Y.-Z. Wang, Preparation, characterization, and in vitro drug release behavior of biodegradable chitosan-graft-poly(1, 4-dioxan-2-one) copolymer, Carbohydr. Polym. 74 (2008) 862–867, https://doi.org/10.1016/ j.carbpol.2008.05.002. [68] L. Zhang, Y. Feng, H. Tian, C. Shi, M. Zhao, J. Guo, Controlled release of doxorubicin from amphiphilic depsipeptide–PDO–PEG-based copolymer nanosized microspheres, React. Funct. Polym. 73 (2013) 1281–1289, https://doi.org/10.1016/j.reactfunctpolym.2013.06.012. [69] S. Miyazaki, K. Ishii, K. Sugibayashi, Y. Morimoto, M. Takada, Antitumor effect of ethylene-vinyl acetate copolymer matrices containing 5-fluorouracil on Ehrlich ascites carcinoma in mice, Chem. Pharm. Bull. 30 (1982) 3770–3775, https://doi.org/10.1248/cpb.30.3770. [70] M.B. Yang, R.J. Tamargo, H. Brem, Controlled delivery of 1,3-bis(2- chloroethyl)-1-nitrosourea from ethylene-vinyl acetate copolymer, Cancer Res. 49 (1989) 5103–5107. http://www.ncbi.nlm.nih.gov/pubmed/2766281. [71] T.R. Pasic, E.W. Rubel, Rapid changes in cochlear nucleus cell size following blockade of auditory nerve electrical activity in gerbils, J. Comp. Neurol. 283 (1989) 474–480, https://doi.org/10.1002/cne.902830403. [72] L.K. Fung, W.M. Saltzman, Polymeric implants for cancer chemotherapy, Adv. Drug Deliv. Rev. 26 (1997) 209–230, https://doi.org/10.1016/S0169-409X(97) 00036-7. [73] D. Mansour, Nexplanon<SUP> Ò </SUP>: what Implanon<SUP> Ò </SUP> did next, J. Fam. Plan. Reprod. Heal. Care. 36 (2010) 187–189, https://doi.org/ 10.1783/147118910793048629. [74] F.E. Kane, K.E. Green, Ocular Pharmacokinetics of Fluocinolone Acetonide Following Iluvien Implantation in the Vitreous Humor of Rabbits, J. Ocul. Pharmacol. Ther. 31 (2015) 11–16, https://doi.org/10.1089/jop.2014.0100. [75] D.J. Kelsey, G.S. Springer, S.B. Goodman, Composite Implant for Bone Replacement, J. Compos. Mater. 31 (1997) 1593–1632, https://doi.org/ 10.1177/002199839703101603. [76] S. Verma, N. Sharma, S. Kango, S. Sharma, Developments of PEEK (Polyetheretherketone) as a biomedical material: A focused review, Eur. Polym. J. 147 (2021), https://doi.org/10.1016/j.eurpolymj.2021.110295. [77] A. Rahimi, A. Mashak, Review on rubbers in medicine: natural, silicone and polyurethane rubbers, Plast. Rubber Compos. 42 (2013) 223–230, https://doi. org/10.1179/1743289811Y.0000000063. [78] Y. Fu, W.J. Kao, Drug release kinetics and transport mechanisms of nondegradable and degradable polymeric delivery systems, Expert Opin. Drug Deliv. 7 (2010) 429–444, https://doi.org/10.1517/17425241003602259. [79] H. Maeda, M. Brandon, A. Sano, Design of controlled-release formulation for ivermectin using silicone, Int. J. Pharm. 261 (2003) 9–19, https://doi.org/ 10.1016/S0378-5173(03)00293-X. [80] J. Power, R. French, F.M. Cowan, Subdermal implantable contraceptives versus other forms of reversible contraceptives or other implants as effective methods for preventing pregnancy, Cochrane Database Syst. Rev. (2007), https://doi.org/10.1002/14651858.CD001326.pub2. [81] J.A. Lyndon, B.J. Boyd, N. Birbilis, Metallic implant drug/device combinations for controlled drug release in orthopaedic applications, J. Control. Release. 179 (2014) 63–75, https://doi.org/10.1016/j.jconrel.2014.01.026. [82] Y.E. Saleh, M.A. Gepreel, N.K. Allam, Functional Nanoarchitectures For Enhanced Drug Eluting Stents, Sci. Rep. 7 (2017) 40291, https://doi.org/ 10.1038/srep40291. [83] K. Prasad, O. Bazaka, M. Chua, M. Rochford, L. Fedrick, J. Spoor, R. Symes, M. Tieppo, C. Collins, A. Cao, D. Markwell, K. Ostrikov, K. Bazaka, Metallic biomaterials: Current challenges and opportunities, Materials (Basel). 10 (2017) 1–33, https://doi.org/10.3390/ma10080884. [84] H. Warlimont, Ceramics, in (2018) 445–488, https://doi.org/10.1007/978-3- 319-69743-7_17. [85] E. Larraneta, T.R.R. Singh, R.F. Donnelly, Long-Acting Drug Delivery Systems, (2022). [86] W. Paul, C.P. Sharma, Ceramic Drug Delivery: A Perspective, J. Biomater. Appl. 17 (2003) 253–264, https://doi.org/10.1177/0885328203017004001. [87] P. Diaz-Rodriguez, M. Sánchez, M. Landin, Drug-Loaded Biomimetic Ceramics for Tissue Engineering, Pharmaceutics. 10 (2018) 272, https://doi.org/ 10.3390/pharmaceutics10040272. [88] J. Spałek, P. Ociepa, P. Deptuła, E. Piktel, T. Daniluk, G. Król, S. Góz ´dz ´, R. Bucki, S. Okła, Biocompatible Materials in Otorhinolaryngology and Their Antibacterial Properties, Int. J. Mol. Sci. 23 (2022) 2575, https://doi.org/ 10.3390/ijms23052575. [89] C. Petit, L. Montanaro, P. Palmero, Functionally graded ceramics for biomedical application: Concept, manufacturing, and properties, Int. J. Appl. Ceram. Technol. 15 (2018) 820–840, https://doi.org/10.1111/ijac.12878. [90] J.R. Henstock, L.T. Canham, S.I. Anderson, Silicon: The evolution of its use in biomaterials, Acta Biomater. 11 (2015) 17–26, https://doi.org/10.1016/j. actbio.2014.09.025. [91] S. Punj, J. Singh, K. Singh, Ceramic biomaterials: Properties, state of the art and future prospectives, Ceram. Int. 47 (2021) 28059–28074, https://doi.org/ 10.1016/j.ceramint.2021.06.238. [92] A.R. Johnson, S.P. Forster, D. White, G. Terife, M. Lowinger, R.S. Teller, S.E. Barrett, Drug eluting implants in pharmaceutical development and clinical practice, Expert Opin. Drug Deliv. 18 (2021) 577–593, https://doi.org/ 10.1080/17425247.2021.1856072. [93] K. Ganesh, S. Yang, S. Schillace, V. Vita, Y. Wang, K.F. Ehmann, P. Guo, A review of manufacturing techniques for subcutaneous drug delivery implants, Procedia CIRP. 110 (2022) 329–334, https://doi.org/10.1016/j. procir.2022.06.059. [94] M. Maniruzzaman, J.S. Boateng, M.J. Snowden, D. Douroumis, A Review of Hot-Melt Extrusion: Process Technology to Pharmaceutical Products, ISRN Pharm. 2012 (2012) 1–9, https://doi.org/10.5402/2012/436763. [95] M. Jivraj, L.G. Martini, C.M. Thomson, I.I. Jivraj, L.G. Martini, C.M. Thomson, An overview of the different excipients useful for the direct compression of tablets, Pharm. Sci. Technolo. Today. 3 (2000) 58–63, https://doi.org/10.1016/ S1461-5347(99)00237-0. [96] S.L. Fialho, A. da Silva Cunha, Manufacturing Techniques of Biodegradable Implants Intended for Intraocular Application, Drug Deliv. 12 (2005) 109– 116, https://doi.org/10.1080/10717540590921432. [97] E. Utomo, J. Domínguez-Robles, N. Moreno-Castellanos, S.A. Stewart, C.J. Picco, Q.K. Anjani, J.A. Simón, I. Peñuelas, R.F. Donnelly, E. Larrañeta, Development of intranasal implantable devices for schizophrenia treatment, Int. J. Pharm. 624 (2022), https://doi.org/10.1016/j. ijpharm.2022.122061. [98] A. Korelidou, J. Domínguez-Robles, E. Magill, M. Eleftheriadou, V.A. Cornelius, R.F. Donnelly, A. Margariti, E. Larrañeta, 3D-printed reservoir-type implants containing poly(lactic acid)/poly(caprolactone) porous membranes for sustained drug delivery, Biomater, Adv. (2022), https://doi.org/10.1016/j. bioadv.2022.213024. [99] C.J. Picco, E. Utomo, A. McClean, J. Domínguez-Robles, Q. Kurnia Anjani, F. Volpe-Zanutto, P.E. McKenna, J. Acheson, D. Malinova, R.F. Donnelly, E. Larrañeta, Development of 3D-printed subcutaneous implants using E. Magill, S. Demartis, E. Gavini et al. Advanced Drug Delivery Reviews 199 (2023) 114950 33 concentrated polymer/drug solutions, Int. J. Pharm. (2022), https://doi.org/ 10.1016/j.ijpharm.2022.122477. [100] L. Zema, G. Loreti, A. Melocchi, A. Maroni, A. Gazzaniga, Injection Molding and its application to drug delivery, J. Control. Release. 159 (2012) 324–331, https://doi.org/10.1016/j.jconrel.2012.01.001. [101] A. Rothen-Weinhold, K. Besseghir, E. Vuaridel, E. Sublet, N. Oudry, F. Kubel, R. Gurny, Injection-molding versus extrusion as manufacturing technique for the preparation of biodegradable implants, Eur. J. Pharm. Biopharm. 48 (1999) 113–121, https://doi.org/10.1016/S0939-6411(99)00034-X. [102] A. Luraghi, F. Peri, L. Moroni, Electrospinning for drug delivery applications: A review, J. Control. Release. 334 (2021) 463–484, https://doi.org/10.1016/j. jconrel.2021.03.033. [103] H. Lian, Z. Meng, Melt electrospinning vs. solution electrospinning: A comparative study of drug-loaded poly ( e -caprolactone) fibres, Mater. Sci. Eng. C. 74 (2017) 117–123, https://doi.org/10.1016/j.msec.2017.02.024. [104] O.S. Fenton, K.N. Olafson, P.S. Pillai, M.J. Mitchell, R. Langer, Advances in Biomaterials for Drug Delivery, Adv. Mater. 30 (2018) 1705328, https://doi. org/10.1002/adma.201705328. [105] G. Kuang, Z. Zhang, S. Liu, D. Zhou, X. Lu, X. Jing, Y. Huang, Biphasic drug release from electrospun polyblend nanofibers for optimized local cancer treatment, Biomater. Sci. 6 (2018) 324–331, https://doi.org/10.1039/ C7BM01018D. [106] E.A. Tawfik, D.Q.M. Craig, S.A. Barker, Dual drug-loaded coaxial nanofibers for the treatment of corneal abrasion, Int. J. Pharm. 581 (2020), https://doi.org/ 10.1016/j.ijpharm.2020.119296. [107] P. Punnakitikashem, D. Truong, J.U. Menon, K.T. Nguyen, Y. Hong, Electrospun biodegradable elastic polyurethane scaffolds with dipyridamole release for small diameter vascular grafts, Acta Biomater. 10 (2014) 4618–4628, https:// doi.org/10.1016/j.actbio.2014.07.031. [108] A. Balaji, S.K. Jaganathan, A.F. Ismail, R. Rajasekar, Fabrication and hemocompatibility assessment of novel polyurethane-based bionanofibrous dressing loaded with honey and Carica papaya extract for the management of burn injuries, Int. J. Nanomedicine. 11 (2016) 4339–4355. [109] T. Tracy, L. Wu, X. Liu, S. Cheng, X. Li, 3D printing: Innovative solutions for patients and pharmaceutical industry, Int. J. Pharm. 631 (2023), https://doi. org/10.1016/j.ijpharm.2022.122480. [110] A. Konta, M. García-Piña, D. Serrano, Personalised 3D Printed Medicines: Which Techniques and Polymers Are More Successful?, Bioengineering 4 (2017) 79, https://doiorg/10.3390/bioengineering4040079. [111] R. Davis, A. Singh, M.J. Jackson, R.T. Coelho, D. Prakash, C.P. Charalambous, W. Ahmed, L.R.R. da Silva, A.A. Lawrence, A comprehensive review on metallic implant biomaterials and their subtractive manufacturing, Int. J. Adv. Manuf. Technol. 120 (2022) 1473–1530, https://doi.org/10.1007/s00170-022-08770- 8. [112] F. Mangano, L. Chambrone, R. van Noort, C. Miller, P. Hatton, C. Mangano, Direct Metal Laser Sintering Titanium Dental Implants: A Review of the Current Literature, Int. J. Biomater. 2014 (2014) 1–11, https://doi.org/ 10.1155/2014/461534. [113] A.M. Baracu, L.A. Dinu Gugoasa, Review—Recent Advances in Microfabrication, Design and Applications of Amperometric Sensors and Biosensors, J. Electrochem. Soc. 168 (2021), https://doi.org/10.1149/1945- 7111/abe8b6. [114] S. Rowlands, S. Searle, Contraceptive implants: current perspectives, Open Access, J. Contracept. (2014) 73, https://doi.org/10.2147/OAJC.S55968. [115] G. Benagiano, H. Gabelnick, M. Farris, Contraceptive devices: subcutaneous delivery systems, Expert Rev. Med. Devices. 5 (2008) 623–637, https://doi. org/10.1586/17434440.5.5.623. [116] L.W. Kleiner, J.C. Wright, Y. Wang, Evolution of implantable and insertable drug delivery systems, J. Control. Release. 181 (2014) 1–10, https://doi.org/ 10.1016/j.jconrel.2014.02.006. [117] F. Rafiei, H. Tabesh, S. Farzad, F. Farzaneh, M. Rezaei, F. Hosseinzade, K. Mottaghy, Development of Hormonal Intravaginal Rings: Technology and Challenges, Geburtshilfe Frauenheilkd. 81 (2021) 789–806, https://doi.org/ 10.1055/a-1369-9395. [118] Z.-L. Farmer, J. Domínguez-Robles, C. Mancinelli, E. Larrañeta, D.A. Lamprou, Urogynecological surgical mesh implants: New trends in materials, manufacturing and therapeutic approaches, Int. J. Pharm. 585 (2020), https://doi.org/10.1016/j.ijpharm.2020.119512. [119] H. Croxatto, Progestin implants, Steroids 65 (2000) 681–685, https://doi.org/ 10.1016/S0039-128X(00)00124-0. [120] D. Shoupe, D.R. Mishell, Norplant: Subdermal implant system for long-term contraception, Am. J. Obstet. Gynecol. 160 (1989) 1286–1292, https://doi.org/ 10.1016/S0002-9378(89)80014-6. [121] H.B. Croxatt, Progestin implants for female contraception, Contraception 65 (2002) 15–19, https://doi.org/10.1016/S0010-7824(01)00293-1. [122] M. Yan, Y. Zhang, Z. Wu, Y. Li, K. Dou, B. Wang, Y. Wang, Q. Zhou, Recent progress in advanced biomaterials for long-acting reversible contraception, J. Nanobiotechnology. 20 (2022) 138, https://doi.org/10.1186/s12951-022- 01329-5. [123] F.A. Meece, G. Ahmed, H. Nair, B. Santhamma, R.R. Tekmal, C. Zhao, N.E. Pollok, J. Lara, Z. Shaked, K. Nickisch, Esters of levonorgestrel and etonogestrel intended as single, subcutaneous-injection, long-lasting contraceptives, Steroids 137 (2018) 47–56, https://doi.org/10.1016/j. steroids.2018.07.010. [124] J. Cohen, D. Shull, S. Reed, Co-delivery of an HIV prophylactic and contraceptive using PGSU as a long-acting multipurpose prevention technology, Expert Opin. Drug Deliv. 20 (2023) 285–299, https://doi.org/ 10.1080/17425247.2023.2168642. [125] B. Zhu, Y. Chen, W. Lu, Q. Zhang, S. Gao, L. Sun, S. Chen, R. Hu, A biodegradable long-term contraceptive implant with steady levonorgestrel release based on PLGA microspheres embedded in PCL-coated implant, J. Drug Deliv. Sci. Technol. 67 (2022), https://doi.org/10.1016/j.jddst.2021.102955. [126] G. Bao, K. Wang, L. Yang, J. He, B. He, X. Xu, Y. Zheng, Feasibility evaluation of a Zn-Cu alloy for intrauterine devices: In vitro and in vivo studies, Acta Biomater. 142 (2022) 374–387, https://doi.org/10.1016/j.actbio.2022.01.053. [127] K. Wang, G. Bao, Q. Fan, L. Zhu, L. Yang, T. Liu, Z. Zhang, G. Li, X. Chen, X. Xu, X. Xu, B. He, Y. Zheng, Feasibility evaluation of a Cu-38 Zn alloy for intrauterine devices: In vitro and in vivo studies, Acta Biomater. 138 (2022) 561–575, https://doi.org/10.1016/j.actbio.2021.11.006. [128] G. Bao, Q. Fan, D. Ge, K. Wang, M. Sun, Z. Zhang, H. Guo, H. Yang, B. He, Y. Zheng, In vitro and in vivo studies to evaluate the feasibility of Zn-0.1Li and Zn-0.8Mg application in the uterine cavity microenvironment compared to pure zinc, Acta Biomater. 123 (2021) 393–406, https://doi.org/10.1016/j. actbio.2020.12.048. [129] S. Hu, Y. Wang, D. Ke, F. Zhou, G. Cheng, W. Xia, C. Zhu, Antifertility effectiveness of a novel copper-containing intrauterine device material and its influence on the endometrial environment in rats, Mater. Sci. Eng. C. 89 (2018) 444–455, https://doi.org/10.1016/j.msec.2018.04.025. [130] M. Bertuola, C.A. Grillo, M. Fernández Lorenzo de Mele, Eradication of burst release of copper ions from copper-bearing IUDs by a phytocompound-based electropolymeric coating, Mater. Lett. 252 (2019) 317–320. 10.1016/ j.matlet.2019.06.009. [131] Q. Bao, S. Fanse, X. (James) Lu, D.J. Burgess, Impact of drug loading on release from levonorgestrel intrauterine systems, Int. J. Pharm. 631 (2023) 122532. 10.1016/j.ijpharm.2022.122532. [132] S. Fanse, Q. Bao, Y. Zou, Y. Wang, D.J. Burgess, Impact of polymer crosslinking on release mechanisms from long-acting levonorgestrel intrauterine systems, Int. J. Pharm. 612 (2022), https://doi.org/10.1016/j.ijpharm.2021.121383. [133] S. Fanse, Q. Bao, Y. Zou, Y. Wang, D.J. Burgess, Effect of crosslinking on the physicochemical properties of polydimethylsiloxane-based levonorgestrel intrauterine systems, Int. J. Pharm. 609 (2021), https://doi.org/10.1016/j. ijpharm.2021.121192. [134] Q. Bao, Y. Zou, Y. Wang, S. Choi, D.J. Burgess, Impact of product design parameters on in vitro release from intrauterine systems, Int. J. Pharm. 578 (2020), https://doi.org/10.1016/j.ijpharm.2020.119135. [135] Q. Bao, B. Gu, C.F. Price, Y. Zou, Y. Wang, D. Kozak, S. Choi, D.J. Burgess, Manufacturing and characterization of long-acting levonorgestrel intrauterine systems, Int. J. Pharm. 550 (2018) 447–454, https://doi.org/ 10.1016/j.ijpharm.2018.09.004. [136] D.J. Murphy, Y.H. Dallal Bashi, C.F. McCoy, P. Boyd, L. Brown, F. Martin, N. McMullen, K. Kleinbeck, B. Dangi, P. Spence, B. Hansraj, B. Devlin, R.K. Malcolm, In vitro drug release, mechanical performance and stability testing of a custom silicone elastomer vaginal ring releasing dapivirine and levonorgestrel, Int. J. Pharm. X. 4 (2022), https://doi.org/10.1016/j. ijpx.2022.100112. [137] Y.H. Dallal Bashi, D.J. Murphy, C.F. McCoy, P. Boyd, L. Brown, M. Kihara, F. Martin, N. McMullen, K. Kleinbeck, B. Dangi, P. Spence, B. Hansraj, B. Devlin, R.K. Malcolm, Silicone elastomer formulations for improved performance of a multipurpose vaginal ring releasing dapivirine and levonorgestrel, Int. J. Pharm. X. 3 (2021), https://doi.org/10.1016/j.ijpx.2021.100091. [138] Y.H. Dallal Bashi, C.F. McCoy, D.J. Murphy, P. Boyd, P. Spence, K. Kleinbeck, B. Devlin, R.K. Malcolm, Towards a dapivirine and levonorgestrel multipurpose vaginal ring: Investigations into the reaction between levonorgestrel and addition-cure silicone elastomers, Int. J. Pharm. 569 (2019), https://doi.org/ 10.1016/j.ijpharm.2019.118574. [139] I. Koutsamanis, S. Eder, M. Beretta, A. Witschnigg, A. Paudel, K. Nickisch, M. Friedrich, K. Eggenreich, E. Roblegg, Formulation and processability screening for the rational design of ethylene-vinyl acetate based intra-vaginal rings, Int. J. Pharm. 564 (2019) 90–97, https://doi.org/10.1016/j.ijpharm.2019.04.041. [140] J. Fu, X. Yu, Y. Jin, 3D printing of vaginal rings with personalized shapes for controlled release of progesterone, Int. J. Pharm. 539 (2018) 75–82, https:// doi.org/10.1016/j.ijpharm.2018.01.036. [141] J. Domínguez-Robles, C. Mancinelli, E. Mancuso, I. García-Romero, B.F. Gilmore, L. Casettari, E. Larrañeta, D.A. Lamprou, 3D Printing of Drug- Loaded Thermoplastic Polyurethane Meshes: A Potential Material for Soft Tissue Reinforcement in Vaginal Surgery, Pharmaceutics. 12 (2020) 63, https://doi.org/10.3390/pharmaceutics12010063. [142] N. Mangır, C.J. Hillary, C.R. Chapple, S. MacNeil, Oestradiol-releasing Biodegradable Mesh Stimulates Collagen Production and Angiogenesis: An Approach to Improving Biomaterial Integration in Pelvic Floor Repair, Eur. Urol. Focus. 5 (2019) 280–289, https://doi.org/10.1016/j.euf.2017.05.004. [143] Z.-L. Farmer, E. Utomo, J. Domínguez-Robles, C. Mancinelli, E. Mathew, E. Larrañeta, D.A. Lamprou, 3D printed estradiol-eluting urogynecological mesh implants: Influence of material and mesh geometry on their mechanical properties, Int. J. Pharm. 593 (2021), https://doi.org/10.1016/j.ijpharm.2020. 120145. [144] M. Qin, J. Jin, Q. Saiding, Y. Xiang, Y. Wang, F. Sousa, B. Sarmento, W. Cui, X. Chen, In situ inflammatory-regulated drug-loaded hydrogels for promoting pelvic floor repair, J. Control. Release. 322 (2020) 375–389, https://doi.org/ 10.1016/j.jconrel.2020.03.030. [145] Medical gallery of Blausen Medical 2014, WikiJournal Med. 1 (2014). 10.15347/wjm/2014.010. E. Magill, S. Demartis, E. Gavini et al. Advanced Drug Delivery Reviews 199 (2023) 114950 34 [146] L. Carson, R. Merkatz, E. Martinelli, P. Boyd, B. Variano, T. Sallent, R.K. Malcolm, The Vaginal Microbiota, Bacterial Biofilms and Polymeric Drug- Releasing Vaginal Rings, Pharmaceutics. 13 (2021) 751, https://doi.org/ 10.3390/pharmaceutics13050751. [147] N.S. Whaley, A.E. Burke, Intrauterine Contraception, Women’s Heal. 11 (2015) 759–767, https://doi.org/10.2217/whe.15.77. [148] A. Nelson, N. Massoudi, MPH, New developments in intrauterine device use: focus on the US, Open Access J. Contracept. 7 (2016) 127–141, https://doi.org/ 10.2147/OAJC.S85755. [149] D.M. Bastidas, B. Valdez, M. Schorr, J.M. Bastidas, Corrosion of copper intrauterine devices: review and recent developments, Corros. Rev. 37 (2019) 307–320, https://doi.org/10.1515/corrrev-2019-0012. [150] J.C. Quarterman, S.M. Geary, A.K. Salem, Evolution of drug-eluting biomedical implants for sustained drug delivery, Eur. J. Pharm. Biopharm. 159 (2021) 21– 35, https://doi.org/10.1016/j.ejpb.2020.12.005. [151] D.J. Murphy, P. Boyd, C.F. McCoy, S. Kumar, J.D.S. Holt, W. Blanda, A.N. Brimer, R.K. Malcolm, Controlling levonorgestrel binding and release in a multipurpose prevention technology vaginal ring device, J. Control. Release. 226 (2016) 138–147, https://doi.org/10.1016/j.jconrel.2016.02.020. [152] J.T. Jensen, A.B. Edelman, B.A. Chen, D.F. Archer, K.T. Barnhart, M.A. Thomas, A.E. Burke, C.L. Westhoff, L.S. Wan, R. Sitruk-Ware, N. Kumar, B. Variano, D.L. Blithe, Continuous dosing of a novel contraceptive vaginal ring releasing Nestorone Ò and estradiol: pharmacokinetics from a dose-finding study, Contraception 97 (2018) 422–427, https://doi.org/10.1016/ j.contraception.2018.01.012. [153] P. Smith, G. Heimer, M. Lindskog, U. Ulmsten, Oestradiol-releasing vaginal ring for treatment of postmenopausal urogenital atrophy, Maturitas 16 (1993) 145–154, https://doi.org/10.1016/0378-5122(93)90059-Q. [154] J. Loganathan, A. Fayyad, M. Abdel-Fattah, Continence surgery at the time of pelvic organ prolapse repair: a review of the literature, Obstet. Gynaecol. 21 (2019) 21–26, https://doi.org/10.1111/tog.12533. [155] M. Abdel-fattah, A. Familusi, S. Fielding, J. Ford, S. Bhattacharya, Primary and repeat surgical treatment for female pelvic organ prolapse and incontinence in parous women in the UK: a register linkage study, BMJ Open 1 (2011) e000206–e, https://doi.org/10.1136/bmjopen-2011-000206. [156] E. Mironska, C. Chapple, S. MacNeil, Recent advances in pelvic floor repair, F1000Research. 8 (2019) 778. 10.12688/f1000research.15046.1. [157] F. Corduas, D.A. Lamprou, E. Mancuso, Next-generation surgical meshes for drug delivery and tissue engineering applications: materials, design and emerging manufacturing technologies, Bio-Design Manuf. 4 (2021) 278–310, https://doi.org/10.1007/s42242-020-00108-1. [158] N. Mangir, C.R. Chapple, S. MacNeil, Synthetic Materials Used in the Surgical Treatment of Pelvic Organ Prolapse: Problems of Currently Used Material and Designing the Ideal Material, in: Pelvic Floor Disord., InTech, 2018. 10.5772/ intechopen.76671. [159] K.O. Lillehei, S.N. Kalkanis, L.M. Liau, D.E. Mydland, J. Olson, N.A. Paleologos, T. Ryken, T. Johnson, E. Scullin, Rationale and design of the 500-patient, 3-year, and prospective Vigilant ObservatIon of GlIadeL WAfer ImplaNT registry, CNS Oncol. 7 (2018) CNS08. 10.2217/cns-2017-0036. [160] R. Li, Y. Song, P. Fouladian, M. Arafat, R. Chung, J. Kohlhagen, S. Garg, Threedimensional printing of curcumin-loaded biodegradable and flexible scaffold for intracranial therapy of glioblastoma multiforme, Pharmaceutics. 13 (2021), https://doi.org/10.3390/pharmaceutics13040471. [161] T. Shapira-Furman, R. Serra, N. Gorelick, M. Doglioli, V. Tagliaferri, A. Cecia, M. Peters, A. Kumar, Y. Rottenberg, R. Langer, H. Brem, B. Tyler, A.J. Domb, Biodegradable wafers releasing Temozolomide and Carmustine for the treatment of brain cancer, J. Control. Release. 295 (2019) 93–101, https:// doi.org/10.1016/j.jconrel.2018.12.048. [162] T. Jones, B. Zhang, S. Major, A. Webb, All-trans retinoic acid eluting poly(diol citrate) wafers for treatment of glioblastoma, J. Biomed. Mater. Res. - Part B Appl. Biomater. 108 (2020) 619–628, https://doi.org/10.1002/jbm.b.34416. [163] A. Kefayat, S. Vaezifar, Biodegradable PLGA implants containing doxorubicinloaded chitosan nanoparticles for treatment of breast tumor-bearing mice, Int. J. Biol. Macromol. 136 (2019) 48–56, https://doi.org/10.1016/j. ijbiomac.2019.06.055. [164] Y. Wang, L. Sun, Z. Mei, F. Zhang, M. He, C. Fletcher, F. Wang, J. Yang, D. Bi, Y. Jiang, P. Liu, 3D printed biodegradable implants as an individualized drug delivery system for local chemotherapy of osteosarcoma, Mater. Des. 186 (2020), https://doi.org/10.1016/j.matdes.2019.108336. [165] Y. Yang, X. Qiao, R. Huang, H. Chen, X. Shi, J. Wang, W. Tan, Z. Tan, E-jet 3D printed drug delivery implants to inhibit growth and metastasis of orthotopic breast cancer, Biomaterials 230 (2020), https://doi.org/10.1016/j. biomaterials.2019.119618. [166] H.P. Dang, A. Shafiee, C.A. Lahr, T.R. Dargaville, P.A. Tran, Local Doxorubicin Delivery via 3D-Printed Porous Scaffolds Reduces Systemic Cytotoxicity and Breast Cancer Recurrence in Mice, Adv. Ther. 3 (2020), https://doi.org/ 10.1002/adtp.202000056. [167] P. Ahangar, E. Akoury, A.S.R.G. Luna, A. Nour, M.H. Weber, D.H. Rosenzweig, Nanoporous 3D-printed scaffolds for local doxorubicin delivery in bone metastases secondary to prostate cancer, Materials (Basel). 11 (2018), https://doi.org/10.3390/ma11091485. [168] Y. Jiang, X. Pan, M. Yao, L. Han, X. Zhang, Z. Jia, J. Weng, W. Chen, L. Fang, X. Wang, Y. Zhang, R. Duan, F. Ren, K. Wang, X. Chen, X. Lu, Bioinspired adhesive and tumor microenvironment responsive nanoMOFs assembled 3D-printed scaffold for anti-tumor therapy and bone regeneration, Nano Today 39 (2021), https://doi.org/10.1016/j.nantod.2021.101182. [169] N. Yang, H. Chen, H. Han, Y. Shen, S. Gu, Y. He, S. Guo, 3D printing and coating to fabricate a hollow bullet-shaped implant with porous surface for controlled cytoxan release, Int. J. Pharm. 552 (2018) 91–98, https://doi.org/ 10.1016/j.ijpharm.2018.09.042. [170] X. Li, Y. He, J. Hou, G. Yang, S. Zhou, A Time-Programmed Release of Dual Drugs from an Implantable Trilayer Structured Fiber Device for Synergistic Treatment of Breast Cancer, Small 16 (2020), https://doi.org/10.1002/ smll.201902262. [171] M. Gawley, L. Almond, S. Daniel, S. Lastakchi, S. Kaur, A. Detta, G. Cruickshank, R. Miller, S. Hingtgen, K. Sheets, C. McConville, Development and in vivo evaluation of Irinotecan-loaded Drug Eluting Seeds (iDES) for the localised treatment of recurrent glioblastoma multiforme, J. Control. Release. 324 (2020) 1–16, https://doi.org/10.1016/j.jconrel.2020.05.012. [172] H.-C. Liu, D.I. Viswanath, F. Pesaresi, Y. Xu, L. Zhang, N. Di Trani, J. Paez- Mayorga, N. Hernandez, Y. Wang, D.R. Erm, J. Ho, A. Susnjar, X. Liu, S. Demaria, S.-H. Chen, B.S. Teh, E.B. Butler, C.Y. Xuan Chua, A. Grattoni, Potentiating Antitumor Efficacy Through Radiation and Sustained Intratumoral Delivery of Anti-CD40 and Anti-PDL1, Int. J. Radiat. Oncol. 110 (2021) 492–506, https://doi.org/10.1016/j.ijrobp.2020.07.2326. [173] H. Liu, D. Davila Gonzalez, D.I. Viswanath, R.S. Vander Pol, S.Z. Saunders, N. Di Trani, Y. Xu, J. Zheng, S. Chen, C.Y.X. Chua, A. Grattoni, Sustained Intratumoral Administration of Agonist CD40 Antibody Overcomes Immunosuppressive Tumor Microenvironment in Pancreatic Cancer, Adv. Sci. 10 (2023) 2206873, https://doi.org/10.1002/advs.202206873. [174] D. Di Mascolo, A.L. Palange, R. Primavera, F. Macchi, T. Catelani, F. Piccardi, R. Spanò, M. Ferreira, R. Marotta, A. Armirotti, A.L. Gallotti, R. Galli, C. Wilson, G. A. Grant, P. Decuzzi, Conformable hierarchically engineered polymeric micromeshes enabling combinatorial therapies in brain tumours, Nat. Nanotechnol. 16 (2021) 820–829, https://doi.org/10.1038/s41565-021- 00879-3. [175] H. Brem, S. Piantadosi, E. Hospital, H. Brem, Placebo-controlled trial of safety and efficacy of intraoperative controlled delivery by biodegradable polymers of chemotherapy for recurrent gliomas Departments of Neurological Surgery (Prof H Brem MD), Oncology (Prof, n.d. [176] S. Valtonen, L. Tim, P. Toivanen, H. Kalimo, L. Kivipelto, G. Unsgaard, T.O. Kuurne, CLIN ICA L STUDIES Interstitial Chemotherapy with Carmustineloaded Polymers for High-grade Gliom as: A Randomized Double-blind Study, n.d. [177] F.J. Attenello, D. Mukherjee, G. Datoo, M.J. McGirt, E. Bohan, J.D. Weingart, A. Olivi, A. Quinones-Hinojosa, H. Brem, Use of Gliadel (BCNU) wafer in the surgical treatment of malignant glioma: A 10-year institutional experience, Ann. Surg. Oncol. 15 (2008) 2887–2893, https://doi.org/10.1245/s10434-008- 0048-2. [178] B.D. Weinberg, H. Ai, E. Blanco, J.M. Anderson, J. Gao, Antitumor efficacy and local distribution of doxorubicin via intratumoral delivery from polymer millirods, J. Biomed. Mater. Res. - Part A. 81 (2007) 161–170, https://doi.org/ 10.1002/jbm.a.30914. [179] J.E. Belz, R. Kumar, P. Baldwin, N.C. Ojo, A.S. Leal, D.B. Royce, D. Zhang, A.L. van de Ven, K.T. Liby, S. Sridhar, Sustained Release Talazoparib Implants for Localized Treatment of BRCA1 -deficient Breast Cancer, Theranostics. 7 (2017) 4340–4349, https://doi.org/10.7150/thno.18563. [180] M. Hrynyk, J.P. Ellis, F. Haxho, S. Allison, J.A.M. Steele, S. Abdulkhalek, R.J. Neufeld, M.R. Szewczuk, Therapeutic designed poly (lactic-co-glycolic acid) cylindrical oseltamivir phosphate-loaded implants impede tumor neovascularization, growth and metastasis in mouse model of human pancreatic carcinoma, Drug Des. Devel. Ther. 9 (2015) 4573–4586, https:// doi.org/10.2147/DDDT.S90170. [181] O. Jonas, H.M. Landry, J.E. Fuller, J.T. Santini, J. Baselga, R.I. Tepper, M.J. Cima, R. Langer, An implantable microdevice to perform high-throughput in vivo drug sensitivity testing in tumors, Sci. Transl. Med. 7 (2015), https://doi.org/ 10.1126/scitranslmed.3010564. [182] Y.Y. Tseng, Y.C. Huang, T.C. Yang, S.T. Yang, S.C. Liu, T.M. Chang, Y.C. Kau, S.J. Liu, Concurrent Chemotherapy of Malignant Glioma in Rats by Using Multidrug-Loaded Biodegradable Nanofibrous Membranes, Sci. Rep. 6 (2016), https://doi.org/10.1038/srep30630. [183] F.P. Seib, D.L. Kaplan, Doxorubicin-loaded silk films: Drug-silk interactions and in vivo performance in human orthotopic breast cancer, Biomaterials 33 (2012) 8442–8450, https://doi.org/10.1016/j.biomaterials.2012.08.004. [184] R. Staupe-Delgado, O. Rubin, Living through and with the global HIV/AIDS pandemic: Distinct ‘pandemic practices’ and temporalities, Soc. Sci. Med. 296 (2022), https://doi.org/10.1016/j.socscimed.2022.114809. [185] A. Shaikh, K.S. Nisar, V. Jadhav, S.K. Elagan, M. Zakarya, Dynamical behaviour of HIV/AIDS model using Fractional Derivative with Mittag-Leffler Kernel, Alexandria Eng. J. 61 (2022) 2601–2610, https://doi.org/10.1016/j. aej.2021.08.030. [186] O.O. Apenteng, P.P. Osei, N.A. Ismail, A. Chiabai, Analysing the impact of migration on HIV/AIDS cases using epidemiological modelling to guide policy makers, Infect. Dis. Model. 7 (2022) 252–261, https://doi.org/10.1016/j. idm.2022.01.002. [187] Y. Sang, S. Han, S. Han, C. Pannecouque, E. De Clercq, C. Zhuang, F. Chen, Follow on-based optimization of the biphenyl-DAPYs as HIV-1 nonnucleoside reverse transcriptase inhibitors against the wild-type and mutant strains, Bioorg. Chem. 89 (2019), https://doi.org/10.1016/j.bioorg.2019.102974. [188] D.A. Solomon, P.E. Sax, Current state and limitations of daily oral therapy for treatment, Curr. Opin. HIV AIDS. 10 (2015) 219–225, https://doi.org/10.1097/ COH.0000000000000165. E. Magill, S. Demartis, E. Gavini et al. Advanced Drug Delivery Reviews 199 (2023) 114950 35 [189] L. Li, G.J. Gatto, R.M. Brand, S.A. Krovi, M.L. Cottrell, C. Norton, A. van der Straten, L.M. Johnson, Long-acting biodegradable implant for sustained delivery of antiretrovirals (ARVs) and hormones, J. Control. Release. 340 (2021) 188–199, https://doi.org/10.1016/j.jconrel.2021.10.021. [190] T.G. Kebede, M.B. Seroto, R.C. Chokwe, S. Dube, M.M. Nindi, Adsorption of antiretroviral (ARVs) and related drugs from environmental wastewaters using nanofibers, J. Environ. Chem. Eng. 8 (2020), https://doi.org/10.1016/ j.jece.2020.104049. [191] F.P. Pons-Faudoa, A. Sizovs, N. Di Trani, J. Paez-Mayorga, G. Bruno, J. Rhudy, M. Manohar, K. Gwenden, C. Martini, C.Y.X. Chua, G. Varchi, M.A. Marzinke, A. Grattoni, 2-Hydroxypropyl-b-cyclodextrin-enhanced pharmacokinetics of cabotegravir from a nanofluidic implant for HIV pre-exposure prophylaxis, J. Control. Release. 306 (2019) 89–96, https://doi.org/10.1016/j. jconrel.2019.05.037. [192] D. Karunakaran, S.M. Simpson, J.T. Su, E. Bryndza-Tfaily, T.J. Hope, R. Veazey, G. Dobek, J. Qiu, D. Watrous, S. Sung, J.E. Chacon, P.F. Kiser, Design and Testing of a Cabotegravir Implant for HIV Prevention, J. Control. Release. 330 (2021) 658–668, https://doi.org/10.1016/j.jconrel.2020.12.024. [193] A.J. Paredes, F. Volpe-Zanutto, L.K. Vora, I.A. Tekko, A.D. Permana, C.J. Picco, H. O. McCarthy, R.F. Donnelly, Systemic delivery of tenofovir alafenamide using dissolving and implantable microneedle patches, Mater. Today Bio. 13 (2022), https://doi.org/10.1016/j.mtbio.2022.100217. [194] P. Maturavongsadit, R. Shrivastava, C. Sykes, M.L. Cottrell, S.A. Montgomery, A.D.M. Kashuba, S. Rahima Benhabbour, Biodegradable polymeric solid implants for ultra-long-acting delivery of single or multiple antiretroviral drugs, Int. J. Pharm. 605 (2021), https://doi.org/10.1016/j. ijpharm.2021.120844. [195] L. Li, L.M. Johnson, S.A. Krovi, Z.R. Demkovich, A. van der Straten, Performance and Stability of Tenofovir Alafenamide Formulations within Subcutaneous Biodegradable Implants for HIV Pre-Exposure Prophylaxis (PrEP), Pharm. 12 (2020), https://doi.org/10.3390/pharmaceutics12111057. [196] J.W. McBride, P. Boyd, N. Dias, D. Cameron, R.E. Offord, O. Hartley, V.L. Kett, R. K. Malcolm, Vaginal rings with exposed cores for sustained delivery of the HIV CCR5 inhibitor 5P12-RANTES, J. Control. Release. 298 (2019) 1–11, https://doi.org/10.1016/j.jconrel.2019.02.003. [197] M.J. Keller, L. Wood, J.M. Billingsley, L.L. Ray, J. Goymer, S. Sinclair, P. Aileen, Tenofovir disoproxil fumarate intravaginal ring for HIV pre-exposure prophylaxis in sexually active women: a phase 1, single-blind, randomised, controlled trial, Lancet HIV. 6 (2019) e498–e508. [198] E. Schlesinger, D. Johengen, E. Luecke, G. Rothrock, I. McGowan, A. van der Straten, T. Desai, A. Tunable, Biodegradable, Thin-Film Polymer Device as a Long-Acting Implant Delivering Tenofovir Alafenamide Fumarate for HIV Preexposure Prophylaxis, Pharm. Res. 33 (2016) 1649–1656, https://doi.org/ 10.1007/s11095-016-1904-6. [199] A. Nel, N. van Niekerk, B. Van Baelen, M. Malherbe, W. Mans, A. Carter, J. Steytler, E. van der Ryst, C. Craig, C. Louw, T. Gwetu, Z. Mabude, P. Kotze, R. Moraba, H. Tempelman, K. Gill, S. Kusemererwa, L.G. Bekker, B. Devlin, Z. Rosenberg, Safety, adherence, and HIV-1 seroconversion among women using the dapivirine vaginal ring (DREAM): an open-label, extension study, Lancet HIV. 8 (2021) e77–e86, https://doi.org/10.1016/S2352-3018(20) 30300-3. [200] Y.A. Han, M. Singh, B.B. Saxena, Development of vaginal rings for sustained release of nonhormonal contraceptives and anti-HIV agents, Contraception 76 (2007) 132–138, https://doi.org/10.1016/j.contraception.2007.04.006. [201] K. Ridgeway, E.T. Montgomery, K. Smith, K. Torjesen, A. van der Straten, S.L. Achilles, J.B. Griffin, Vaginal ring acceptability: A systematic review and meta-analysis of vaginal ring experiences from around the world, Contraception 106 (2022) 16–33, https://doi.org/10.1016/ j.contraception.2021.10.001. [202] S.A. Krovi, L.M. Johnson, E. Luecke, S.L. Achilles, A. van der Straten, Advances in long-acting injectables, implants, and vaginal rings for contraception and HIV prevention, Adv. Drug Deliv. Rev. 176 (2021), https://doi.org/10.1016/j. addr.2021.113849. [203] S.R. Ugaonkar, A. Wesenberg, J. Wilk, S. Seidor, O. Mizenina, L. Kizima, A. Rodriguez, S. Zhang, K. Levendosky, J. Kenney, M. Aravantinou, N. Derby, B. Grasperge, A. Gettie, J. Blanchard, N. Kumar, K. Roberts, M. Robbiani, J.A. Fernández-Romero, T.M. Zydowsky, A novel intravaginal ring to prevent HIV- 1, HSV-2, HPV, and unintended pregnancy, J. Control. Release. 213 (2015) 57– 68, https://doi.org/10.1016/j.jconrel.2015.06.018. [204] J.A. Moss, I. Butkyavichene, S.A. Churchman, M. Gunawardana, R. Fanter, C.S. Miller, F. Yang, J.T. Easley, M.A. Marzinke, C.W. Hendrix, T.J. Smith, M.M. Baum, Combination pod-intravaginal ring delivers antiretroviral agents for HIV prophylaxis: Pharmacokinetic evaluation in an ovine model, Antimicrob. Agents Chemother. 60 (2016) 3759–3766, https://doi.org/10.1128/ AAC.00391-16. [205] S.M. Fetherston, P. Boyd, C.F. McCoy, M.C. McBride, K.L. Edwards, S. Ampofo, R.K. Malcolm, A silicone elastomer vaginal ring for HIV prevention containing two microbicides with different mechanisms of action, Eur. J. Pharm. Sci. 48 (2013) 406–415, https://doi.org/10.1016/j.ejps.2012.12.002. [206] J.W. Romano, M.M. Baum, Z.R. Demkovich, F. DIana, C. Dobard, P.L. Feldman, J. G. Garcia-Lerma, A. Grattoni, M. Gunawardana, D.K. Ho, T.J. Hope, I. Massud, M. Milad, J.A. Moss, F.P. Pons-Faudoa, S. Roller, A. Van Der Straten, S. Srinivasan, R.S. Veazey, D. Zane, Tenofovir Alafenamide for HIV Prevention: Review of the Proceedings from the Gates Foundation Long-Acting TAF Product Development Meeting, AIDS Res. Hum. Retroviruses. 37 (2021) 409– 420. 10.1089/aid.2021.0028. [207] J.M. Baeten, T. Palanee-Phillips, N.M. Mgodi, A.J. Mayo, D.W. Szydlo, G. Ramjee, B. Gati Mirembe, F. Mhlanga, P. Hunidzarira, L.E. Mansoor, S. Siva, V. Govender, B. Makanani, L. Naidoo, N. Singh, G. Nair, L. Chinula, U.M. Parikh, J. W. Mellors, I.C. Balán, K. Ngure, A. van der Straten, R. Scheckter, M. Garcia, M. Peda, K. Patterson, E. Livant, K. Bunge, D. Singh, C. Jacobson, Y. Jiao, C.W. Hendrix, Z.M. Chirenje, C. Nakabiito, T.E. Taha, J. Jones, K. Torjesen, A. Nel, Z. Rosenberg, L.E. Soto-Torres, S.L. Hillier, E.R. Brown, D. Aanyu, J. Abima, J. Abullarade, P. Agarwal, S. Ahluwalia, S.A. Akasiima, C.A. Akello, S. Albert, M. Alphale, C. Alphonse, L. Apeduno, S. Aranda, O. Aridor, S. Arnolds, P. Asiimwe, M. Atujuna, D. Atwebembere, L. Baboolall, K. Badana, J.M. Baeten, D. Balamusani, I.C. Balán, G. Banda, T.W. Banda, J. Baugh, J.A. Baziira, M. Beamer, S.A. Bebeza, L.G. Bekker, I. Bell, M. Bemer, R. Berman, J. Berthiaume, L. Bezak, Y. Bhagwandin, H.A. Bhayat, N. Bhengu, S. Bhengu, A. Bhoola, F.A. Biira, D. Bittoni, R. Black, N.J. Blose, P. Boks, S.G. Bolton, P. Botya, A. Brown, E. Brown, H. Brown, R.H. Bruce, L.E. Bukenya, A. Bukirwa, L. Bunts, F. Buthelezi, M.W. Buthelezi, S.D. Buthelezi, R. Byogero, S. Byroo, R. Byuma, J.A. Carstens, A. Carter, N. Cassim, B. Cebekhulu, B. Cele, D.J. Cele, P. Cele, S. Cele, S. Cele, M. Chadza, N. Chakhtoura, C. Chapdu, G.T. Chareka, C. Chasakara, M. Chatani- Gada, D. Chetty, M. Chidanyika, T.T.L. Chifambi, E. Chihota, S. Chikono, A. Chikonyora, B.D. Chikukwa, C. Chin, M. Chindevu, T.B. Chinyanda, T.H. Chirenda, Z.M. Chirenje, C. Chirisa, P. Chisale, A. Chishanga, T. Chitambo, F. Chitema, F. Chithila, T.H. Chitowa, C. Chitsinde, G. Chitsulo, M. Chitukuta, S. Chiveso, N. Chome, P.F. Chonco, E. Christopher, K. Chunderduri, V. Cibi, N. Cleland, T. Coba, M.R. Cobbing, C. Collins, K. Comer, S. Cozzi, D. Crida, S. Dadabhai, T. Daki, N. Danster, R. Dassaye, R. David, J.M. Davis, S. Dawood, P. Deb, L. Degnam, T.S. Derrick, B.T. Devlin, C. Dezzutti, P.M. Dhlakama, L. Dias, J. C. Dimairo, E. Dinnie, A. Dlabanta, M. Dladla, T.I. Dladla, A.P. Dlungele, C. Dolezal, K. Donaty, C. Dott, J. Dubbs, V. Dubula-Majola, P. Dukwe, C.I. Duma, P. I.M. Duma, P. Duma, V.K. Duncan, L. Duran, L. Dyabeni, A. Edwards, R. Etikala, J. Etima, L. Fairlie, H. Fischer, J. Fitzpatrick, L. Fleurs, M.G. Fowler, L. Freeman, Z. Gaffoor, L. Gama, A. Garg, V.M. Gatsi, C. Gcwensa, E.L. Gebashe, S. Geduld, J. Gelant, D. Germuga, J. Ggita, R. Giguere, L. Godo, B.J. Goetz, L. Gogo, E. Goliati, D.K. Gondwe, K.C. Gordon, R. Goreraza, J. Gounden, D. Govender, J.S. Govender, N. Govender, S. Govender, N.N. Gqwara, A. (Tracy) Gravelle, P. Guga, V. Guma, D.Z. Gumede, S. Gumede, T. Gumede, T.W. Gumede, O. Gundani, R. Gunnam, R. Gupta, M. Gwande, X. Gxako, K. Hall, W. Hall, P. Hargrave, I. Harkoo, T. Harrell, A.L. Heaps, S.L. Hendricks, B. Hlabisa, L.B. Hlabisa, K. Hlahla, T.M. Hlela, T. Hobongwana, E. Horn, R. Howard, H. Huang, P. Hunidzairia, N. Hurbans, M. Husnik, T.D. Hwehwe, R. Imamdin, A. Ismail, E. Jacobs, A.C. Jacques, J. Jamabya, G. James, K. Janse van Rensburg, Z.N. Jaya, N. Jeenarain, L. Jennings, H. Jiang, N. Jiang, N.L. Jijana, G. Jokoniya, M. Kabasonga, D.K. Kabenge, S. Kabwigu, E. Kachale, L. Kachenjera, F. Kachingamire, E. Kachipapa, M. Kadiwa, M. Kadyamusuma, B. Kafufu, M.M. Kagwa, C. Kajura- Manyindo, B.C. Kakayi, V. Kaliwo, D.J. Kalonji, N.E. Kamanga, B. Kamira, Z. Kampangire, G. Kamwana, J. Kamya, L.D. Kapa, P. Karugaba, K. Kasambara, P. Kassim, S. Kassim, M. Katana, F. Katongole, S. Katongole, A. Katsis, C. Katumbi, A.W.K. Katz, E. Kawanje, C.N. Kawuma, S. Kayongo, E. Kekana, D. Kemigisha, S. Khanyile, N.H. Khanyisile, B. Khaya, N. Khiya, N.N. Khoza, T. Khumalo, C. Khwela, Z. Khwela, E. Kibiribiri, I. Kibirige, B. Kiiza, F.S. Kikonyogo, M. Kin, C. Kirkwood, G. Kistnasami, F.M. Kiweewa, M. Kiweewa, D. Konatham, L. Kubheka, T. Kufakunesu, P. Kumwenda, W.W.I. Kumwenda, M. Kush, B.A. Kutner, N. Kwatsha, R. Kwedza, E. Kyomukama, D. Lands, P.N. Langa, K. Lebeta, C. Lentz, B.T. Leremi, M. Leszczewski, L. Levy, T. Livant, I. Lukas, L.P. Mabanga, N. Mabaso, V. Machisa, T.M. Maddox, B. Madlala, N. Magobiane, M. Magolela, F. Maguramhinga, P.D. Magwaza, K. Maharaj, F. Mahed, T.V. Mahlase, M.L. Maila, Y. Makala, P. Makamure, K.P. Makgoka, P. Makhamba, N. Makhanya, R. Makondo, R. Makoni, H. Makooka, J. Makunganya, S. Makwenda, G. Malan, A. Malemia, M. Malherbe, F. Malunga, T. Mamba Nhassengo, M. Mampa, T.K. Mamvura, E. Manengamambo, L.Z. Mangove, N.T. Mangxilana, T.P. Manjera, W.E. Mans, L. Mansoor, M. Maoko, A. Mapfunde, N. Y. Maphumulo, F.E.A. Martinson, A. Maruwo, E.Y. Marx, M.A. Marzinke, M. Masango, M.N. Mashego, G.T.R. Mashinini, S.I. Masuko, K.V. Matambanadzo, F.T. Mathebula, M. Mathipa, J.M. Matsa, E.A. Matta, A.T. Matubu, A.C. Mavundla, S. Mavundla, B. Mawindo, J. Mayani, E. Mayanja, N. Mayekiso, N. P. Mayisela, A.J. Mayo, M.S. Mbabali, N.M.G. Mbanjwa, C.S. Mbatha, N.J. Mbatha, D. Mbewe, T. Mbichila, Y.R. Mbilizi, S. Mbokazi, M. Mbwerera, Z. Mchunu, L. McKinstry, B. Mdlongwa, J.W. Mellors, S.P. Meyiwa, N.M. Mgodi, E.S. Mhizha, N.S. Mhlanga, B.G. Mirembe, D. Mirembe, F. Mkandawire, N.H. Mkhabela, B. Mkhize, P.H. Mkhize, Z. Mkhize, E.G. Mlangeni, M. Mlingo, B. Mngqebisa, N. Mngxekeza, A. Mninzi, N. Mnqonywa, M. Mogkoro, T.W. Mogodiri, R.F. Mohuba, M.C. Mokoena, N. Mona, D. Montoya, W. Monyethabeng, J. Moodley, J. Moodley, K. Moodley, S. Moonsamy, N.S. Morar, S.N. Morudu, A. Mpekula, G.T. Mphisa, J. Mpofu, H.T. Mposula, A. Mqadi, E. Msiska, L. Msumba, N. Mtambo, E.S. Mthalane, T.S. Mthembu, Z. Mthethi, M.J. Mthethwa, N.Z. Mthethwa, S.S. Mthimkhulu, I. Mtlokoa, M.C. Mubiru, M. Mudavanhu, A.Z. Mufumisi, A.M. Mugagga, J. Muganga, M. Mugava, M. Mugenyi, C. Mugocha, F. Mugodhi, N. Mugwagwa, F.G.S. Muhlanga, S. Mukaka, D. Mukasa, R. Mukasa, M. Mukatipa, S. Mukova, S. Mulebeke, J. Mulima, J. Muller, F. Mulumba, T. Mupamombe, C. Murandu, T. Murefu, F. Murewa, K. Muringayi, C. Murombedzi, P. Musara, J.N. Musisi, M. M. Musisi, P. Musoke, J. Mutebo, P. Mutero, K.S. Mutiti, S. Mutizira, S. Mutsvunguma, N. Muungani, T. Muvunzi, R. Muwawu, S. Mvelase, P.P. Mvinjelwa, G.Z. Mvuyane, L. Mwafulirwa, P. Mwagomba, T.G. Mwakhwawa, D. Mwebaza, W.L. Mwenda, N. Myeni, A.D.N. Mzolo, R.B. Nabatanzi, J. Nabisere, J. Nabukeera, C.V. Nagawa, C. Naicker, K. Naicker, V. Naicker, I. Naidoo, J. Naidoo, J. Naidoo, K. Naidoo, R. Naidoo, S. Naidoo, N. Naidu, G.L. E. Magill, S. Demartis, E. Gavini et al. Advanced Drug Delivery Reviews 199 (2023) 114950 36 Nair, S. Nakacwa, J.G. Nakakande, R. Nakalega, M.G. Nakalema, J. Nakibuka, T. Nakyanzi, J. Nakyeyune, S. Nalusiba, R. Namakula, F. Namalueso, P.M. Namayanja, C.T. Nampala, S.N. Nampiira, A. Namuddu, N. Nandundu, W. Nansamba, S. Nanyonga, S.C. Nanziri, Z.N. Nassoma, D.E. Ncube, E. Ncube, S. Ncube, P. Ndadziyira, P.P. Ndamase, W.S.T. Nderecha, Z. Ndhlovu-Forde, T.C. Ndimande, B. Ndlovu, G. Ndlovu, J. Ndlovu, N.H. Ndlovu, T.N. Ndlovu, Z. Ndlovu, M. Ndovie, B. Nemasango, B. Neradilek, S. Ngani, N.Q. Ngcebethsha, L. Ngcobela, N. Ngcobo, N. Ngcobo, S.P. Ngcobo, N. Ngcukana, J. Ngo, N. Ngqabe, S. Ngqame, M.D. Ngubane, N.N. Ngwenya, M. Nhkoma, B.N. Nhlapho, S. Nhleko, H. Nkwanyana, H. Noble, L.L. Nobula, M. Nolan, M. Nompondwana, B. Notshokovu, V.S. Ntanzi, N. Nursaye, J.P. Nutall, O. Nyabadza, E. Nyaka, S. Nyakudya, E.C. Nyakura, S. Nyamadzawo, T. Nyamuzihwa, Z. Nyanzi, A.T. Nyathi, F. Nyirenda, M. Nyirenda, M. Nyirenda, S.C. Nzama, L.S. Nzuza, B. O’Byrne, F. Okello, E. Okumu, E. Oluka, F. Onen, C.P. Onyango, K. Ostbye, K. Padayachee, V. Palichina, Z. Pan, C. Pappajohn, L. Paramanund, U.M. Parikh, N. Pearce, K.J. Penrose, B.M. Phahlamohlaka, N.R. Phidane, O. Pillay, A. Premrajh, N. Prosad, L. Rabe, A. Rajman, K.M. Rampai, H.S. Rampyapedi, A. Randhawa, S. Rasmeni, D. Rausch, A. Reddy, I. Reddy, J. Reddy, K. Reddy, V.H. Rees, A. Repetto, C. Richards, S. Riddler, N. Rini, B. Roeber, L. Rohan, Z. Romer, M. Rose, Z.F. Rosenberg, L. Rossi, A. Ruch, C. Rullo, S. Runeyi, O. Rupemba, C. Rushwaya, M. Russell, P.S. Ruzive, G. Rwanzogyera, M.N. Saava, T.J. Sagela, R. Sakwa, F. Sayed, J. Schille, N. Scotch, W. Scott, C. Scoville, R. Sebagala, E. Sebastian, N.T. Sedze, N.H. Seedat, J. Semakula, T. Senn, F. Serugo, L. Seyama, B.K. Shabalala, C.P. Shangase, P.C. Shanhinga, J. Shaver, H. Shen, M.C. Shogole, R. Shonhiwa, C. Shozi, M. Sibanda, S.S. Sibeko, N.T. Sibisi, S.S. Sibisi, B.Z. Sibiya, H. Sibiya, D. Sichali, P.Y. Sikosana, C. Silva, A.P. Simelane, M. Simon, T. Sing, H.V. Sithole, E. Sitima, A. Siyasiya, V. Sizane, B. Siziba, E. Slezinger, D. Smolinski, K. Snapinn, O. Sogoni, D. Soko, L.N. Solai, M. Somga, M. Song, X. Song, D. Soobryan, L. Soto- Torres, P.L. Spence, E. Spooner, V. Sseguya, A. Ssentongo, M. Ssenyonga, L.L. Sseremba, M. Stais, J. Steytler, S. Stockton, J. Stofel, T.R. Stuurman, S. Sukazi, J. L. Sukdao, K. Swarna, D. Szydlo, C. Tagliaferri Rael, D.R. Taguta, T. Taha, E. Tahuringana, J. Tamale, P. Tambama, E. Taulo, F. Taulo, T.T. Tauya, G. Tegha, S. L. Tembe, T. Tembo, C.L. Thatelo, P.M. Thobela, A. Thom, C. Thompson, M. Thompson, L. Thusi, L. Tock, T. Tofile, C. Tranfaglia, J. Tseng, T. Tshabalala, N. Tshongoyi, M. Tsidya, W.R. Tsikiwa, N.C. Tuswa-Haynes, B.O. Tutshana, A.P. Twala, A.V. Udith, C. Unten, N. van Niekerk, A. Varela, N. Vatsha, G. Vijayendran, A.C. Vuma, D.O. Wabwire, M. Walani, B. Wanda, L. Wasberg, R. R. White, K.M. Windle, K. Woeber, D. Wright, T. Wright, T.N. Xaba, M.J.S. Yambira, N. Yola, S.L. Zaca, A. Zalwango, J. Zemanek, C. Zimba, T. Zinyengere, M. Zinyongo, T.G. Zondi, C. Zou, J. Zuma, N.P. Zungu, N. Zungu, Safety, uptake, and use of a dapivirine vaginal ring for HIV-1 prevention in African women (HOPE): an open-label, extension study, Lancet HIV. 8 (2021) e87–e95. 10.1016/S2352-3018(20)30304-0. [208] G.A. Peyman, E.M. Lad, D.M. Moshfeghi, Intravitreal injection of therapeutic agents, Retina 29 (2009) 875–912, https://doi.org/10.1097/ IAE.0b013e3181a94f01. [209] T. Walters, M. Endl, T.R. Elmer, J. Levenson, P. Majmudar, S. Masket, Sustained-release dexamethasone for the treatment of ocular inflammation and pain after cataract surgery, J. Cataract Refract. Surg. 41 (2015) 2049– 2059, https://doi.org/10.1016/j.jcrs.2015.11.005. [210] M.J. Ibach, L. Zimprich, D.D. Wallin, C. Olevson, K. Puls-Boever, V. Thompson, In Clinic Optometrist Insertion of Dextenza (Dexamethasone Ophthalmic Insert 0.4mg) Prior to Cataract Surgery: The PREPARE Study, Clin. Ophthalmol. 16 (2022) 2609–2615, https://doi.org/10.2147/OPTH.S374405. [211] M. Gavidia, Novel Port Delivery System With Ranibizumab Approved in Wet AMD, AJMC News. (2021). [212] N.M. Holekamp, P.A. Campochiaro, M.A. Chang, D. Miller, D. Pieramici, A.P. Adamis, C. Brittain, E. Evans, D. Kaufman, K.F. Maass, S. Patel, S. Ranade, N. Singh, G. Barteselli, C. Regillo, Archway Randomized Phase 3 Trial of the Port Delivery System with Ranibizumab for Neovascular Age-Related Macular Degeneration, Ophthalmology 129 (2022) 295–307, https://doi.org/10.1016/ j.ophtha.2021.09.016. [213] F. (2022 Kansteiner, Roche recalls new eye therapy Susvimo on leakage fears, aims for market return ‘‘within a year or so,” Fierce Pharma. (2022). https:// www.fiercepharma.com/manufacturing/roche-recalls-susvimo-implant- lucentis-leakage-fears-return-market-expected-within. [214] J. Wang, A. Jiang, M. Joshi, J. Christoforidis, Drug Delivery Implants in the Treatment of Vitreous Inflammation, Mediators Inflamm. 2013 (2013) 1–8, https://doi.org/10.1155/2013/780634. [215] C.C. Patel, N. Mandava, S.C.N. Oliver, R. Braverman, H. Quiroz-Mercado, J.L. Olson, TREATMENT OF INTRACTABLE POSTERIOR UVEITIS IN PEDIATRIC PATIENTS WITH THE FLUOCINOLONE ACETONIDE INTRAVITREAL IMPLANT (RETISERT), Retina 32 (2012) 537–542, https://doi.org/10.1097/ IAE.0b013e31822058bb. [216] F.E. Kane, J. Burdan, A. Cutino, K.E. Green, Iluvien TM : a new sustained delivery technology for posterior eye disease, Expert Opin. Drug Deliv. 5 (2008) 1039–1046, https://doi.org/10.1517/17425247.5.9.1039. [217] I. Testi, C. Pavesio, Preliminary evaluation of YUTIQ TM (fluocinolone acetonide intravitreal implant 0.18 mg) in posterior uveitis, Ther. Deliv. 10 (2019) 621– 625, https://doi.org/10.4155/tde-2019-0051. [218] S.S. Lee, P. Hughes, A.D. Ross, M.R. Robinson, Biodegradable Implants for Sustained Drug Release in the Eye, Pharm. Res. 27 (2010) 2043–2053, https:// doi.org/10.1007/s11095-010-0159-x. [219] K. Cholkar, K. City, Ocular drug delivery systems : An overview, World, J Pharmacol. 2 (2015) 47–64, https://doi.org/10.5497/wjp.v2.i2.47. [220] M. Shirley, Bimatoprost Implant: First Approval, Drugs Aging. 37 (2020) 457– 462, https://doi.org/10.1007/s40266-020-00769-8. [221] A.-I. Cocarta, R. Hobzova, J. Sirc, T. Cerna, J. Hrabeta, K. Svojgr, P. Pochop, M. Kodetova, J. Jedelska, U. Bakowsky, J. Uhlik, Hydrogel implants for transscleral drug delivery for retinoblastoma treatment, Mater. Sci. Eng. C. 103 (2019), https://doi.org/10.1016/j.msec.2019.109799. [222] R. Hobzova, M. Kodetova, P. Pochop, J. Uhlik, K. Dunovska, K. Svojgr, J. Hrabeta, B. Feriancikova, A.-I. Cocarta, J. Sirc, Hydrogel implants for transscleral diffusion delivery of topotecan: In vivo proof of concept in a rabbit eye model, Int. J. Pharm. 606 (2021), https://doi.org/10.1016/j. ijpharm.2021.120832. [223] C. Zhou, A. Singh, G. Qian, N. Wolkow, C.H. Dohlman, D.G. Vavvas, J. Chodosh, E.I. Paschalis, Microporous Drug Delivery System for Sustained Anti-VEGF Delivery to the Eye, Transl. Vis. Sci. Technol. 9 (2020) 5, https://doi.org/ 10.1167/tvst.9.8.5. [224] N. Nagai, E. Koyanagi, Y. Izumida, J. Liu, A. Katsuyama, H. Kaji, M. Nishizawa, N. Osumi, M. Kondo, H. Terasaki, Y. Mashima, T. Nakazawa, T. Abe, Long-Term Protection of Genetically Ablated Rabbit Retinal Degeneration by Sustained Transscleral Unoprostone Delivery, Investig. Opthalmology Vis. Sci. 57 (2016) 6527, https://doi.org/10.1167/iovs.16-20453. [225] H. Kojima, B. Raut, L.-J. Chen, N. Nagai, T. Abe, H. Kaji, A 3D Printed Self- Sustainable Cell-Encapsulation Drug Delivery Device for Periocular Transplant-Based Treatment of Retinal Degenerative Diseases, Micromachines 11 (2020) 436, https://doi.org/10.3390/mi11040436. [226] Y. Sato, N. Nagai, T. Abe, H. Kaji, A multilayered sheet-type device capable of sustained drug release and deployment control, Biomed. Microdevices. 21 (2019) 60, https://doi.org/10.1007/s10544-019-0411-z. [227] N. Nagai, Z.K. Nezhad, R. Daigaku, S. Saijo, Y. Song, K. Terata, A. Hoshi, M. Nishizawa, T. Nakazawa, H. Kaji, T. Abe, Transscleral sustained ranibizumab delivery using an episcleral implantable device: Suppression of laser-induced choroidal neovascularization in rats, Int. J. Pharm. 567 (2019), https://doi.org/ 10.1016/j.ijpharm.2019.118458. [228] D. Waite, Y. Wang, D. Jones, A. Stitt, T.R. Raj Singh, Posterior drug delivery via periocular route: challenges and opportunities, Ther. Deliv. 8 (2017) 685– 699, https://doi.org/10.4155/tde-2017-0097. [229] S. Raghava, M. Hammond, U.B. Kompella, Periocular routes for retinal drug delivery, Expert Opin. Drug Deliv. 1 (2004) 99–114, https://doi.org/10.1517/ 17425247.1.1.99. [230] S.R. Chennamaneni, C. Mamalis, B. Archer, Z. Oakey, B.K. Ambati, Development of a novel bioerodible dexamethasone implant for uveitis and postoperative cataract inflammation, J. Control. Release. 167 (2013) 53–59, https://doi.org/10.1016/j.jconrel.2013.01.007. [231] Y. Agban, S.S. Thakur, O.O. Mugisho, I.D. Rupenthal, Depot formulations to sustain periocular drug delivery to the posterior eye segment, Drug Discov. Today. 24 (2019) 1458–1469, https://doi.org/10.1016/j.drudis.2019.03.023. [232] J. Okabe, H. Kimura, N. Kunou, K. Okabe, A. Kato, Y. Ogura, Biodegradable Intrascleral Implant for Sustained Intraocular Delivery of Betamethasone Phosphate, Investig. Opthalmology Vis. Sci. 44 (2003) 740, https://doi.org/ 10.1167/iovs.02-0375. [233] T. Kawashima, N. Nagai, H. Kaji, N. Kumasaka, H. Onami, Y. Ishikawa, N. Osumi, M. Nishizawa, T. Abe, A scalable controlled-release device for transscleral drug delivery to the retina, Biomaterials 32 (2011) 1950–1956, https://doi.org/10.1016/j.biomaterials.2010.11.006. [234] H. Onami, N. Nagai, H. Kaji, M. Nishizawa, Y. Sato, N. Osumi, T. Nakazawa, T. Abe, Transscleral Sustained Vasohibin-1 Delivery by a Novel Device Suppressed Experimentally-Induced Choroidal Neovascularization, PLoS One 8 (2013) e58580. [235] N. Nagai, S. Yamada, J. Kawasaki, E. Koyanagi, S. Saijo, H. Kaji, M. Nishizawa, T. Nakazawa, T. Abe, Pharmacokinetic and Safety Evaluation of a Transscleral Sustained Unoprostone Release Device in Monkey Eyes, Investig. Opthalmology Vis. Sci. 59 (2018) 644, https://doi.org/10.1167/iovs.17-22429. [236] World Health Organization, Schizophrenia, Fact Sheets - WHO. (2019). [237] Harvard Helth Publishing, Harvard Medical School, Schizophrenia. (2019). [238] A. Tessier, L. Boyer, M. Husky, F. Baylé, P.-M. Llorca, D. Misdrahi, Medication adherence in schizophrenia: The role of insight, therapeutic alliance and perceived trauma associated with psychiatric care, Psychiatry Res. 257 (2017) 315–321, https://doi.org/10.1016/j.psychres.2017.07.063. [239] M.S. Turner, J.M. Kane, Partial Adherence to Antipsychotic Medication Impacts the Course of Illness in Patients With Schizophrenia: A Review, Prim. Care Companion J. Clin. Psychiatry. 11 (2009) 148–155, https://doi.org/ 10.4088/PCC.08r00612. [240] E. Parellada, M. Bioque, Barriers to the Use of Long-Acting Injectable Antipsychotics in the Management of Schizophrenia, CNS Drugs 30 (2016) 689–701, https://doi.org/10.1007/s40263-016-0350-7. [241] J. Hong, C. Reed, D. Novick, J.M. Haro, J. Aguado, Clinical and economic consequences of medication non-adherence in the treatment of patients with a manic/mixed episode of bipolar disorder: Results from the European Mania in Bipolar Longitudinal Evaluation of Medication (EMBLEM) Study, Psychiatry Res. 190 (2011) 110–114, https://doi.org/10.1016/j.psychres.2011.04.016. [242] J.F.M. Van Boven, N.H. Chavannes, T. Van Der Molen, M.P.M.H. Rutten-Van Mölken, M.J. Postma, S. Vegter, Clinical and economic impact of nonadherence in COPD: A systematic review, Respir. Med. 108 (2014) 103–113, https://doi.org/10.1016/j.rmed.2013.08.044. [243] S.C. Ho, H.Y. Chong, N. Chaiyakunapruk, B. Tangiisuran, S.A. Jacob, Clinical and economic impact of non-adherence to antidepressants in major depressive E. Magill, S. Demartis, E. Gavini et al. Advanced Drug Delivery Reviews 199 (2023) 114950 37 disorder: A systematic review, J. Affect. Disord. 193 (2016) 1–10, https://doi. org/10.1016/j.jad.2015.12.029. [244] D. Lin, P. Thompson-Leduc, I. Ghelerter, H. Nguyen, M.H. Lafeuille, C. Benson, P. Mavros, P. Lefebvre, Real-World Evidence of the Clinical and Economic Impact of Long-Acting Injectable Versus Oral Antipsychotics Among Patients with Schizophrenia in the United States: A Systematic Review and Meta- Analysis, CNS Drugs 35 (2021) 469–481, https://doi.org/10.1007/s40263- 021-00815-y. [245] S. Brissos, M.R. Veguilla, D. Taylor, V. Balanzá-Martinez, The role of longacting injectable antipsychotics in schizophrenia: a critical appraisal, Ther. Adv. Psychopharmacol. 4 (2014) 198–219, https://doi.org/10.1177/ 2045125314540297. [246] I. Clark, D. Taylor, Newer Formulations of Risperidone: Role in the Management of Psychotic Disorders, CNS Drugs 34 (2020) 841–852, https://doi.org/10.1007/s40263-020-00735-3. [247] SBIR.gov, Risperidone Subcutaneous Implant, (2017). [248] Delpor, Delpor PROZOR, (n.d.). [249] inc. Delpor, Implant device, (n.d.). [250] C. Rabin, Y. Liang, R.S. Ehrlichman, A. Budhian, K.L. Metzger, C. Majewski- Tiedeken, K.I. Winey, S.J. Siegel, In vitro and in vivo demonstration of risperidone implants in mice, Schizophr. Res. 98 (2008) 66–78, https://doi. org/10.1016/j.schres.2007.08.003. [251] H.R.O. de Almeida, B.F. de Carvalho Patricio, Y. do Anjos Garcia, T.G. da Silva, D.B. Pereira, M.A. Sarcinelli, H.V.A. Rocha, R.H. Mendonça, Production of biodegradable rods of polycaprolactone/olanzapine for potential application in treatment of Schizophrenia, J. Appl. Polym. Sci. 138 (2021) 1–11. 10.1002/ app.50944. [252] X. Yan, S. Wang, K. Sun, Long-Acting Risperidone Dual Control System: Preparation, Characterization and Evaluation In Vitro and In Vivo, Pharmaceutics. 13 (2021) 1210, https://doi.org/10.3390/ pharmaceutics13081210. [253] R. Dammerman, S. Kim, M. Adera, A. Schwarz, Pharmacokinetics and Safety of Risperidone Subcutaneous Implants in Stable Patients With Schizophrenia, Clin. Pharmacol. Drug Dev. 7 (2018) 298–310, https://doi.org/10.1002/ cpdd.428. [254] J.A. Simón, E. Utomo, F. Pareja, M. Collantes, G. Quincoces, A. Otero, M. Ecay, J. Domínguez-Robles, E. Larrañeta, I. Peñuelas, Radiolabeled Risperidone microSPECT/CT Imaging for Intranasal Implant Studies Development, Pharmaceutics. 15 (2023) 843, https://doi.org/10.3390/ pharmaceutics15030843. [255] G. Manini, S. Benali, A. Mathew, S. Napolitano, J.-M. Raquez, J. Goole, Paliperidone palmitate as model of heat-sensitive drug for long-acting 3D printing application, Int. J. Pharm. 618 (2022), https://doi.org/10.1016/j. ijpharm.2022.121662. [256] G. Manini, M. Deldime, S. Benali, J.-M. Raquez, J. Goole, Long-acting implantable dosage forms containing paliperidone palmitate obtained by 3D printing, Int. J. Pharm. 603 (2021), https://doi.org/10.1016/j. ijpharm.2021.120702. [257] H. Cui, S. Miao, T. Esworthy, X. Zhou, S. Lee, C. Liu, Z. Yu, J.P. Fisher, M. Mohiuddin, L.G. Zhang, 3D bioprinting for cardiovascular regeneration and pharmacology, Adv. Drug Deliv. Rev. 132 (2018) 252–269, https://doi.org/ 10.1016/j.addr.2018.07.014. [258] G.A. Mensah, G.A. Roth, V. Fuster, The Global Burden of Cardiovascular Diseases and Risk Factors, J. Am. Coll. Cardiol. 74 (2019) 2529–2532, https:// doi.org/10.1016/j.jacc.2019.10.009. [259] J. Domínguez-Robles, T. Shen, V.A. Cornelius, F. Corduas, E. Mancuso, R.F. Donnelly, A. Margariti, D.A. Lamprou, E. Larrañeta, Development of drug loaded cardiovascular prosthesis for thrombosis prevention using 3D printing, Mater. Sci. Eng. C. 129 (2021), https://doi.org/10.1016/j. msec.2021.112375. [260] J.C.K. Ng, D.W.Y. Toong, V. Ow, S.Y. Chaw, H. Toh, P.E.H. Wong, S. Venkatraman, T.T. Chong, L.P. Tan, Y.Y. Huang, H.Y. Ang, Progress in drugdelivery systems in cardiovascular applications: stents, balloons and nanoencapsulation, Nanomedicine (2022), https://doi.org/10.2217/nnm- 2021-0288. [261] F.O. Obiweluozor, G.A. Emechebe, D.-W. Kim, H.-J. Cho, C.H. Park, C.S. Kim, I.S. Jeong, Considerations in the Development of Small-Diameter Vascular Graft as an Alternative for Bypass and Reconstructive Surgeries: A Review, Cardiovasc, Eng. Technol. 11 (2020) 495–521, https://doi.org/10.1007/ s13239-020-00482-y. [262] J. Domínguez-Robles, L. Diaz-Gomez, E. Utomo, T. Shen, C.J. Picco, C. Alvarez- Lorenzo, A. Concheiro, R.F. Donnelly, E. Larrañeta, Use of 3D Printing for the Development of Biodegradable Antiplatelet Materials for Cardiovascular Applications, Pharmaceuticals. 14 (2021) 921, https://doi.org/10.3390/ ph14090921. [263] M. Rychter, A. Baranowska-Korczyc, B. Milanowski, M. Jarek, B.M. Maciejewska, E.L. Coy, J. Lulek, Cilostazol-Loaded Poly( e -Caprolactone) Electrospun Drug Delivery System for Cardiovascular Applications, Pharm. Res. 35 (2018) 32, https://doi.org/10.1007/s11095-017-2314-0. [264] C. Del Gaudio, E. Ercolani, P. Galloni, F. Santilli, S. Baiguera, L. Polizzi, A. Bianco, Aspirin-loaded electrospun poly( e -caprolactone) tubular scaffolds: potential small-diameter vascular grafts for thrombosis prevention, J. Mater. Sci. Mater. Med. 24 (2013) 523–532, https://doi.org/10.1007/s10856-012- 4803-3. [265] R.A. Hoshi, R. Van Lith, M.C. Jen, J.B. Allen, K.A. Lapidos, G. Ameer, The blood and vascular cell compatibility of heparin-modified ePTFE vascular grafts, Biomaterials 34 (2013) 30–41, https://doi.org/10.1016/j. biomaterials.2012.09.046. [266] D. Kim, J.J. Chung, Y. Jung, S.H. Kim, The effect of Substance P/Heparin conjugated PLCL polymer coating of bioinert ePTFE vascular grafts on the recruitment of both ECs and SMCs for accelerated regeneration, Sci. Rep. 9 (2019) 17083, https://doi.org/10.1038/s41598-019-53514-6. [267] M. Bosiers, K. Deloose, J. Verbist, H. Schroë, G. Lauwers, W. Lansink, P. Peeters, Heparin-bonded expanded polytetrafluoroethylene vascular graft for femoropopliteal and femorocrural bypass grafting: 1-year results, J. Vasc. Surg. 43 (2006) 313–318, https://doi.org/10.1016/j.jvs.2005.10.037. [268] B. Scheller, C. Hehrlein, W. Bocksch, W. Rutsch, D. Haghi, U. Dietz, M. Böhm, U. Speck, Treatment of Coronary In-Stent Restenosis with a Paclitaxel-Coated Balloon Catheter, N. Engl. J. Med. 355 (2006) 2113–2124, https://doi.org/ 10.1056/NEJMoa061254. [269] D. Sun, Y. Zheng, T. Yin, C. Tang, Q. Yu, G. Wang, Coronary drug-eluting stents: From design optimization to newer strategies, J. Biomed. Mater. Res. Part A. 102 (2014) 1625–1640, https://doi.org/10.1002/jbm.a.34806. [270] M. Adhami, N.K. Martin, C. Maguire, A.J. Courtenay, R.F. Donnelly, J. Domínguez-Robles, E. Larrañeta, Drug loaded implantable devices to treat cardiovascular disease, Expert Opin. Drug Deliv. (2023), https://doi.org/ 10.1080/17425247.2023.2190580. [271] F. Picard, S. Doucet, A.W. Asgar, Contemporary use of drug-coated balloons in coronary artery disease: Where are we now?, Arch Cardiovasc. Dis. 110 (2017) 259–272, https://doi.org/10.1016/j.acvd.2017.01.005. [272] S. Borhani, S. Hassanajili, S.H. Ahmadi Tafti, S. Rabbani, Cardiovascular stents: overview, evolution, and next generation, Prog. Biomater. 7 (2018) 175–205, https://doi.org/10.1007/s40204-018-0097-y. [273] N.K. Martin, J. Domínguez-Robles, S.A. Stewart, V.A. Cornelius, Q.K. Anjani, E. Utomo, I. García-Romero, R.F. Donnelly, A. Margariti, D.A. Lamprou, E. Larrañeta, Fused deposition modelling for the development of drug loaded cardiovascular prosthesis, Int. J. Pharm. 595 (2021), https://doi.org/10.1016/j. ijpharm.2021.120243. [274] J.D. Häner, L. Räber, S. Windecker, Biodegradable vs. permanent polymer drug-eluting stents: the need for a new nomenclature to classify drug-eluting stent technology, Eur. Heart J. 40 (2019) 2616–2619, https://doi.org/10.1093/ eurheartj/ehz330. [275] R. Du, Y. Wang, Y. Huang, Y. Zhao, D. Zhang, D. Du, Y. Zhang, Z. Li, S. McGinty, G. Pontrelli, T. Yin, G. Wang, Design and testing of hydrophobic core/ hydrophilic shell nano/micro particles for drug-eluting stent coating, NPG Asia Mater. 10 (2018) 642–658, https://doi.org/10.1038/s41427-018-0064-z. [276] J. Bukala, P.P. Buszman, J. Małachowski, L. Mazurkiewicz, K. Sybilski, Experimental Tests, FEM Constitutive Modeling and Validation of PLGA Bioresorbable Polymer for Stent Applications, Materials (Basel). 13 (2020) 2003, https://doi.org/10.3390/ma13082003. [277] L.-C. Xu, M.E. Meyerhoff, C.A. Siedlecki, Blood coagulation response and bacterial adhesion to biomimetic polyurethane biomaterials prepared with surface texturing and nitric oxide release, Acta Biomater. 84 (2019) 77–87, https://doi.org/10.1016/j.actbio.2018.11.035. [278] J. Canfield, H. Totary-jain, 40 Years of Percutaneous Coronary Intervention : History and Future Directions, J. Pers. Med. 8 (2018) 1–9, https://doi.org/ 10.3390/jpm8040033. [279] Y. Wo, E.J. Brisbois, R.H. Bartlett, M.E. Meyerhoff, Recent advances in thromboresistant and antimicrobial polymers for biomedical applications: just say yes to nitric oxide (NO), Biomater. Sci. 4 (2016) 1161–1183, https:// doi.org/10.1039/C6BM00271D. [280] H. Hermawan, Updates on the research and development of absorbable metals for biomedical applications, Prog. Biomater. 7 (2018) 93–110, https:// doi.org/10.1007/s40204-018-0091-4. [281] D. Hou, B. Huibregtse, K. Dawkins, J. Donnelly, K. Roy, J.P. Chen, A. Akinapelli, Current State of Bioabsorbable Polymer-Coated Drug-Eluting Stents, Curr. Cardiol. Rev. 13 (2017), https://doi.org/10.2174/1573403X1266616122 2155230. [282] J. Wykrzykowska, P. Serruys, P. Buszman, A. Linke, T. Ischinger, V. Klauss, F. Eberli, R. Corti, W. Wijns, M.-C. Morice, C. Di Mario, R.-J. Van Geuns, G.-A. Van Es, P. Juni, S. Windecker, The three year follow-up of the randomised ‘‘allcomers” trial of a biodegradable polymer biolimus-eluting stent versus permanent polymer sirolimus-eluting stent (LEADERS), EuroIntervention 7 (2011) 789–795, https://doi.org/10.4244/EIJV7I7A125. [283] J.A. Ormiston, P.W. Serruys, E. Regar, D. Dudek, L. Thuesen, M.W. Webster, Y. Onuma, H.M. Garcia-Garcia, R. McGreevy, S. Veldhof, A bioabsorbable everolimus-eluting coronary stent system for patients with single de-novo coronary artery lesions (ABSORB): a prospective open-label trial, Lancet 371 (2008) 899–907, https://doi.org/10.1016/S0140-6736(08)60415-8. [284] H. Tamai, K. Igaki, E. Kyo, K. Kosuga, A. Kawashima, S. Matsui, H. Komori, T. Tsuji, S. Motohara, H. Uehata, Initial and 6-Month Results of Biodegradable Polyl -Lactic Acid Coronary Stents in Humans, Circulation 102 (2000) 399– 404, https://doi.org/10.1161/01.CIR.102.4.399. [285] M. Haude, H. Ince, A. Abizaid, R. Toelg, P.A. Lemos, C. von Birgelen, E.H. Christiansen, W. Wijns, F.-J. Neumann, C. Kaiser, E. Eeckhout, S.T. Lim, J. Escaned, Y. Onuma, H.M. Garcia-Garcia, R. Waksman, Sustained safety and performance of the second-generation drug-eluting absorbable metal scaffold in patients with de novo coronary lesions: 12-month clinical results and angiographic findings of the BIOSOLVE-II first-in-man trial, Eur. Heart J. 37 (2016) 2701–2709, https://doi.org/10.1093/eurheartj/ehw196. [286] K. Waseda, A. Miyazawa, J. Ako, T. Hasegawa, I. Tsujino, R. Sakurai, P.G. Yock, Y. Honda, D.E. Kandzari, M.B. Leon, P.J. Fitzgerald, Intravascular Ultrasound E. Magill, S. Demartis, E. Gavini et al. Advanced Drug Delivery Reviews 199 (2023) 114950 38 Results From the ENDEAVOR IV Trial, JACC Cardiovasc. Interv. 2 (2009) 779– 784, https://doi.org/10.1016/j.jcin.2009.05.015. [287] Y. Huang, H.C.A. Ng, X.W. Ng, V. Subbu, Drug-eluting biostable and erodible stents, J. Control. Release. 193 (2014) 188–201, https://doi.org/10.1016/j. jconrel.2014.05.011. [288] P. Roopmani, S. Satheesh, D.C. Raj, U.M. Krishnan, Development of Dual Drug Eluting Cardiovascular Stent with Ultrathin Flexible Poly(<scp>l</scp> - lactideco -caprolactone) Coating, ACS Biomater. Sci. Eng. 5 (2019) 2899– 2915, https://doi.org/10.1021/acsbiomaterials.9b00303. [289] J. Wang, Y. Ren, Y. Huang, R. Du, Y. Xi, T. Yin, Y. Wang, D. Zhang, J. Chen, G. Wang, An asymmetrical dual coating on the stent prepared by ultrasonic atomization, J. Biomed. Mater. Res. Part B Appl. Biomater. 107 (2019) 825– 837, https://doi.org/10.1002/jbm.b.34179. [290] J.-K. Park, S.S. Kim, H.K. Kim, J.-W. Nah, H.B. Kim, I.H. Bae, D.S. Park, J.W. Shim, M.Y. Lee, J.S. Kim, B.-S. Koo, K.-J. Jeong, Y.B. Jin, S.-U. Kim, S.-R. Lee, J.-Y. Na, D. S. Sim, Y.J. Hong, K.S. Lim, M.H. Jeong, Poly-l-lactide Polymer-Based Triple Drug-Eluting Stent with Abciximab, Alpha-Lipoic Acid and Sirolimus in Porcine Coronary Restenosis Model, Macromol. Res. 28 (2020) 9–14, https:// doi.org/10.1007/s13233-020-8004-5. [291] M. Sane, V. Dighe, R. Patil, P.A. Hassan, S. Gawali, V. Patravale, Bivalirudin and sirolimus co-eluting coronary stent: Potential strategy for the prevention of stent thrombosis and restenosis, Int. J. Pharm. 600 (2021), https://doi.org/ 10.1016/j.ijpharm.2021.120403. [292] M. Lenzuni, G. Suarato, D. Miele, R. Carzino, M. Ruggeri, R. Bertorelli, G. Sandri, A. Athanassiou, Development of biodegradable zein-based bilayer coatings for drug-eluting stents, RSC Adv. 11 (2021) 24345–24358, https:// doi.org/10.1039/D1RA03748J. [293] J.M. Kang, S.H. Kim, Y.J. Choi, Y. Park, D.S. Ryu, W.S. Kang, J.-H. Park, H.J. Park, Sirolimus-eluting cobalt–chrome alloy stent suppresses stent-induced tissue hyperplasia in a porcine Eustachian tube model, Sci. Rep. 12 (2022) 3436, https://doi.org/10.1038/s41598-022-07471-2. [294] J. Zhu, X. Zhang, J. Niu, Y. Shi, Z. Zhu, D. Dai, C. Chen, J. Pei, G. Yuan, R. Zhang, Biosafety and efficacy evaluation of a biodegradable magnesium-based drugeluting stent in porcine coronary artery, Sci. Rep. 11 (2021) 7330, https://doi. org/10.1038/s41598-021-86803-0. [295] M.A. Jumat, P. Chevallier, D. Mantovani, S. Saidin, Everolimus immobilisation using polydopamine intermediate layer on poly(l-lactic acid)/poly(d-lactic acid) scaffold for sustainable anti-proliferative drug release, Mater. Today Commun. 31 (2022), https://doi.org/10.1016/j.mtcomm.2022.103720. [296] T. Ebrahimi-Nozari, R. Imani, M. Haghbin-Nazarpak, A. Nouri, Multimodal effects of asymmetric coating of coronary stents by electrospinning and electrophoretic deposition, Int. J. Pharm. 630 (2023), https://doi.org/10.1016/ j.ijpharm.2022.122437. [297] D.S. Park, I.-H. Bae, M.H. Jeong, K.-S. Lim, Y.J. Hong, J.W. Shim, J.U. Kim, M.K. Kim, J.H. Kim, D.Y. Hyun, J.-K. Park, H.C. Lim, H.B. Kim, I.-S. Kim, D.S. Sim, Anti-restenotic and anti-thrombotic effect of polymer-free N-TiO2 film-based tacrolimus-eluting stent in a porcine model, Mater. Today Commun. 22 (2020), https://doi.org/10.1016/j.mtcomm.2019.100777. [298] L. Czollner, E. Papaplioura, T. Linder, R. Liu, Y. Li, A.G. Atanasov, V.M. Dirsch, M. Schnürch, M.D. Mihovilovic, A silver-coated copper wire as inexpensive drug eluting stent model: determination of the relative releasing properties of leoligin and derivatives, Monatshefte Für Chemie - Chem. Mon. (2020), https://doi.org/10.1007/s00706-020-02677-4. [299] N. Ishaque, N. Naseer, M.A. Abbas, F. Javed, S. Mushtaq, N.M. Ahmad, M.F.A. Khan, N. Ahmed, A. Elaissari, Optimize PLA/EVA Polymers Blend Compositional Coating for Next Generation Biodegradable Drug-Eluting Stents, Polymers (Basel). 14 (2022) 3547, https://doi.org/10.3390/ polym14173547. [300] Y. Jian, Y. Zhu, Drug Release Property of Poly 3-Hydroxybutyrate 4- Hydroxybutyrate (P34HB) as Drug-Eluting Coatings on Metal Coronary Stents, Polymers (Basel). 14 (2022) 3018, https://doi.org/10.3390/ polym14153018. [301] B.S. Jang, E. Kim, M.A. Gwak, S.A. Park, W.H. Park, Fabrication and application of drug eluting stent for peripheral artery disease, Korean J. Chem. Eng. 40 (2023) 361–368, https://doi.org/10.1007/s11814-022-1286-x. [302] J. Liu, J. Wang, Y. Xue, T. Chen, D. Huang, Y. Wang, K. Ren, Y. Wang, G. Fu, J. Ji, Biodegradable phosphorylcholine copolymer for cardiovascular stent coating, J. Mater. Chem. B. 8 (2020) 5361–5368, https://doi.org/10.1039/D0TB00813C. [303] M. Ceresnakova, D. Murray, K.D. McGourty, J. Butler, J. Neilan, T. Soulimane, S. P. Hudson, Citric acid functionalized nitinol stent surface promotes endothelial cell healing, J. Biomed. Mater. Res. Part A. 109 (2021) 1549– 1559, https://doi.org/10.1002/jbm.a.37150. [304] Y. Yang, D. Lei, H. Zou, S. Huang, Q. Yang, S. Li, F.-L. Qing, X. Ye, Z. You, Q. Zhao, Hybrid electrospun rapamycin-loaded small-diameter decellularized vascular grafts effectively inhibit intimal hyperplasia, Acta Biomater. 97 (2019) 321–332, https://doi.org/10.1016/j.actbio.2019.06.037. [305] M. Rychter, B. Milanowski, B.F. Grzes ´kowiak, M. Jarek, M. Kempin ´ski, E.L. Coy, S. Borysiak, A. Baranowska-Korczyc, J. Lulek, Cilostazol-loaded electrospun three-dimensional systems for potential cardiovascular application: Effect of fibers hydrophilization on drug release, and cytocompatibility, J. Colloid Interface Sci. 536 (2019) 310–327, https://doi.org/10.1016/j.jcis.2018.10.026. [306] Y. Wang, B. Ma, A. Yin, B. Zhang, R. Luo, J. Pan, Y. Wang, Polycaprolactone vascular graft with epigallocatechin gallate embedded sandwiched layer-by- layer functionalization for enhanced antithrombogenicity and antiinflammation, J. Control. Release. 320 (2020) 226–238, https://doi.org/ 10.1016/j.jconrel.2020.01.043. [307] J. Domínguez-Robles, E. Utomo, V.A. Cornelius, Q.K. Anjani, A. Korelidou, Z. Gonzalez, R.F. Donnelly, A. Margariti, M. Delgado-Aguilar, Q. Tarrés, E. Larrañeta, TPU-based antiplatelet cardiovascular prostheses prepared using fused deposition modelling, Mater. Des. 220 (2022), https://doi.org/10.1016/ j.matdes.2022.110837. [308] F.M. Mwema, E.T. Akinlabi, Basics of Fused Deposition Modelling (FDM), in: 2020: pp. 1–15. 10.1007/978-3-030-48259-6_1. [309] L. Zhao, X. Li, L. Yang, L. Sun, S. Mu, H. Zong, Q. Li, F. Wang, S. Song, C. Yang, C. Zhao, H. Chen, R. Zhang, S. Wang, Y. Dong, Q. Zhang, Evaluation of remodeling and regeneration of electrospun PCL/fibrin vascular grafts in vivo, Mater. Sci. Eng. C. 118 (2021), https://doi.org/10.1016/j.msec.2020.111441. [310] S.-J. Liu, K.-S. Liu, C.-H. Lee, Y.-C. Wang, Sustained release of vancomycin from novel biodegradable nanofiber-loaded vascular prosthetic grafts: in vitro and in vivo study, Int. J. Nanomedicine. (2015) 885, https://doi.org/10.2147/IJN. S78675. [311] X. Chen, J. Wang, Q. An, D. Li, P. Liu, W. Zhu, X. Mo, Electrospun poly(l-lactic acid-co-e-caprolactone) fibers loaded with heparin and vascular endothelial growth factor to improve blood compatibility and endothelial progenitor cell proliferation, Colloids Surfaces B Biointerfaces. 128 (2015) 106–114, https:// doi.org/10.1016/j.colsurfb.2015.02.023. [312] A.J. Melchiorri, N. Hibino, C.A. Best, T. Yi, Y.U. Lee, C.A. Kraynak, L.K. Kimerer, A. Krieger, P. Kim, C.K. Breuer, J.P. Fisher, 3D-Printed Biodegradable Polymeric Vascular Grafts, Adv. Healthc. Mater. 5 (2016) 319–325, https://doi.org/ 10.1002/adhm.201500725. [313] J. Stanekzai, E.R. Isenovic, S.A. Mousa, Treatment options for diabetes: potential role of stem cells, Diabetes Res. Clin. Pract. 98 (2012) 361–368. [314] M. Farina, J.F. Alexander, U. Thekkedath, M. Ferrari, A. Grattoni, Cell encapsulation: Overcoming barriers in cell transplantation in diabetes and beyond, Adv. Drug Deliv. Rev. 139 (2019) 92–115, https://doi.org/10.1016/j. addr.2018.04.018. [315] B.L. Strand, A.E. Coron, G. Skjak-Braek, Current and future perspectives on alginate encapsulated pancreatic islet, Stem Cells Transl. Med. 6 (2017) 1053–1058, https://doi.org/10.1002/sctm.16-0116. [316] C. Villa, V. Manzoli, M.M. Abreu, C.A. Verheyen, M. Seskin, M. Najjar, R.D. Molano, Y. Torrente, C. Ricordi, A.A. Tomei, Effects of composition of alginatepolyethylene glycol microcapsules and transplant site on encapsulated islet graft outcomes in mice, Transplantation 101 (2017) 1025–1035, https://doi. org/10.1097/TP.0000000000001454. [317] A.A. Stock, V. Manzoli, T. De Toni, M.M. Abreu, Y.C. Poh, L. Ye, A. Roose, F.W. Pagliuca, C. Thanos, C. Ricordi, A.A. Tomei, Conformal Coating of Stem Cell- Derived Islets for bCell Replacement in Type 1 Diabetes, Stem Cell Rep. 14 (2020) 91–104, https://doi.org/10.1016/j.stemcr.2019.11.004. [318] O.M. Sabek, M. Farina, D.W. Fraga, S. Afshar, A. Ballerini, C.S. Filgueira, U.R. Thekkedath, A. Grattoni, A.O. Gaber, Three-dimensional printed polymeric system to encapsulate human mesenchymal stem cells differentiated into islet-like insulin-producing aggregates for diabetes treatment, J. Tissue Eng. 7 (2016), https://doi.org/10.1177/2041731416638198. [319] T.A. Desai, T. West, M. Cohen, T. Boiarski, A. Rampersaud, Nanoporous microsystems for islet cell replacement, 2004. [320] L. Saenz del Burgo, J. Ciriza, A. Espona-Noguera, X. Illa, E. Cabruja, G. Orive, R. M. Hernández, R. Villa, J.L. Pedraz, M. Alvarez, 3D Printed porous polyamide macrocapsule combined with alginate microcapsules for safer cell-based therapies, Sci. Rep. 8 (2018) 8512, https://doi.org/10.1038/s41598-018- 26869-5. [321] K.G. Maxwell, J.R. Millman, Applications of iPSC-derived beta cells from patients with diabetes, Cell Reports Med. 2 (2021), https://doi.org/10.1016/j. xcrm.2021.100238. [322] S.C. Wiggins, N.J. Abuid, K.M. Gattás-Asfura, S. Kar, C.L. Stabler, Nanotechnology Approaches to Modulate Immune Responses to Cell-based Therapies for Type 1 Diabetes, J. Diabetes Sci. Technol. 14 (2020) 212–225, https://doi.org/10.1177/1932296819871947. [323] S.H. Kim, J.E. Kim, S.H. Kim, Y. Jung, Substance P/dexamethasoneencapsulated PLGA scaffold fabricated using supercritical fluid process for calvarial bone regeneration, J. Tissue Eng. Regen. Med. 11 (2017) 3469–3480, https://doi.org/10.1002/term.2260. [324] E. de Klerk, M. Hebrok, Stem Cell-Based Clinical Trials for Diabetes Mellitus, Front. Endocrinol. (Lausanne). 12 (2021), https://doi.org/10.3389/ fendo.2021.631463. [325] V.H. Pérez-Luna, O. González-Reynoso, Encapsulation of biological agents in hydrogels for therapeutic applications, Gels. 4 (2018), https://doi.org/ 10.3390/gels4030061. [326] R. Krishnan, M. Alexander, L. Robles, C.E. Foster, J.R.T. Lakey, Islet and stem cell encapsulation for clinical transplantation, Rev. Diabet. Stud. 11 (2014) 84–101, https://doi.org/10.1900/RDS.2014.11.84. [327] M. Farina, C.Y.X. Chua, A. Ballerini, U. Thekkedath, J.F. Alexander, J.R. Rhudy, G. Torchio, D. Fraga, R.R. Pathak, M. Villanueva, C.S. Shin, J.A. Niles, R. Sesana, D. Demarchi, A.G. Sikora, G.S. Acharya, A.O. Gaber, J.E. Nichols, A. Grattoni, Transcutaneously refillable, 3D-printed biopolymeric encapsulation system for the transplantation of endocrine cells, Biomaterials 177 (2018) 125–138, https://doi.org/10.1016/j.biomaterials.2018.05.047. [328] J. Paez-Mayorga, J.N. Campa-Carranza, S. Capuani, N. Hernandez, H.-C. Liu, C. Y.X. Chua, F.P. Pons-Faudoa, G. Malgir, B. Alvarez, J.A. Niles, L.B. Argueta, K.A. Shelton, S. Kezar, P.N. Nehete, D.M. Berman, M.A. Willman, X.C. Li, C. Ricordi, J.E. Nichols, A.O. Gaber, N.S. Kenyon, A. Grattoni, Implantable niche with local immunosuppression for islet allotransplantation achieves type 1 diabetes E. Magill, S. Demartis, E. Gavini et al. Advanced Drug Delivery Reviews 199 (2023) 114950 39 reversal in rats, Nat. Commun. 13 (2022) 7951, https://doi.org/10.1038/ s41467-022-35629-z. [329] J. Paez-Mayorga, S. Capuani, N. Hernandez, M. Farina, C.Y.X. Chua, R. Blanchard, A. Sizovs, H.-C. Liu, D.W. Fraga, J.A. Niles, H.F. Salazar, B. Corradetti, A.G. Sikora, M. Kloc, X.C. Li, A.O. Gaber, J.E. Nichols, A. Grattoni, Neovascularized implantable cell homing encapsulation platform with tunable local immunosuppressant delivery for allogeneic cell transplantation, Biomaterials 257 (2020), https://doi.org/10.1016/j. biomaterials.2020.120232. [330] X. Wang, K.G. Maxwell, K. Wang, D.T. Bowers, J.A. Flanders, W. Liu, L.-H. Wang, Q. Liu, C. Liu, A. Naji, Y. Wang, B. Wang, J. Chen, A.U. Ernst, J.M. Melero- Martin, J.R. Millman, M. Ma, A nanofibrous encapsulation device for safe delivery of insulin-producing cells to treat type 1 diabetes, Sci. Transl. Med. 13 (2021), https://doi.org/10.1126/scitranslmed.abb4601. [331] L.-H. Wang, A.U. Ernst, J.A. Flanders, W. Liu, X. Wang, A.K. Datta, B. Epel, M. Kotecha, K.K. Papas, M. Ma, An inverse-breathing encapsulation system for cell delivery, Sci. Adv. 7 (2021), https://doi.org/10.1126/sciadv.abd5835. [332] J.D. Weaver, D.M. Headen, M.D. Hunckler, M.M. Coronel, C.L. Stabler, A.J. García, Design of a vascularized synthetic poly(ethylene glycol) macroencapsulation device for islet transplantation, Biomaterials 172 (2018) 54–65, https://doi.org/10.1016/j.biomaterials.2018.04.047. [333] C. Chen, H.-H. Xu, X.-Y. Liu, Y.-S. Zhang, L. Zhong, Y.-W. Wang, L. Xu, P. Wei, Y.-X. Chen, P. Liu, C.-R. Hao, X.-L. Jia, N. Hu, X.-Y. Wu, X.-S. Gu, L.-Q. Chen, X.- H. Li, 3D printed collagen/silk fibroin scaffolds carrying the secretome of human umbilical mesenchymal stem cells ameliorated neurological dysfunction after spinal cord injury in rats, Regen. Biomater. 9 (2022), https://doi.org/10.1093/rb/rbac014. [334] X.-Y. Liu, C. Chen, H.-H. Xu, Y. Zhang, L. Zhong, N. Hu, X.-L. Jia, Y.-W. Wang, K.- H. Zhong, C. Liu, X. Zhu, D. Ming, X.-H. Li, Integrated printed BDNF/collagen/chitosan scaffolds with low temperature extrusion 3D printer accelerated neural regeneration after spinal cord injury, Regen. Biomater. 8 (2021), https://doi.org/10.1093/rb/rbab047. [335] Y. Cao, P. Cheng, S. Sang, C. Xiang, Y. An, X. Wei, Z. Shen, Y. Zhang, P. Li, Mesenchymal stem cells loaded on 3D-printed gradient poly( e - caprolactone)/methacrylated alginate composite scaffolds for cartilage tissue engineering, Regen. Biomater. 8 (2021), https://doi.org/10.1093/rb/ rbab019. [336] X. Zhang, Y. Liu, C. Luo, C. Zhai, Z. Li, Y. Zhang, T. Yuan, S. Dong, J. Zhang, W. Fan, Crosslinker-free silk/decellularized extracellular matrix porous bioink for 3D bioprinting-based cartilage tissue engineering, Mater. Sci. Eng. C. 118 (2021), https://doi.org/10.1016/j.msec.2020.111388. [337] C.H. Chew, C.-W. Lee, W.-T. Huang, L.-W. Cheng, A. Chen, T.-M. Cheng, Y.-L. Liu, C.-C. Chen, Microtube Array Membrane (MTAM)-Based Encapsulated Cell Therapy for Cancer Treatment, Membranes (Basel). 10 (2020) 80, https://doi. org/10.3390/membranes10050080. [338] S. Kuncorojakti, S. Srisuwatanasagul, K. Kradangnga, C. Sawangmake, Insulin- Producing Cell Transplantation Platform for Veterinary Practice, Front. Vet. Sci. 7 (2020), https://doi.org/10.3389/fvets.2020.00004. [339] N. Dimitrioglou, M. Kanelli, E. Papageorgiou, T. Karatzas, D. Hatziavramidis, Paving the way for successful islet encapsulation, Drug Discov. Today. 24 (2019) 737–748, https://doi.org/10.1016/j.drudis.2019.01.020. [340] A. Mooranian, M. Jones, C.M. Ionescu, D. Walker, S.R. Wagle, B. Kovacevic, J. Chester, T. Foster, E. Johnston, J. Kuthubutheen, D. Brown, M. Mikov, H. Al- Salami, Artificial cell encapsulation for biomaterials and tissue bionanoengineering: History, achievements, limitations, and future work for potential clinical applications and transplantation, J. Funct. Biomater. 12 (2021), https://doi.org/10.3390/jfb12040068. [341] W. Liu, J.A. Flanders, L. Wang, Q. Liu, D.T. Bowers, K. Wang, A. Chiu, X. Wang, A.U. Ernst, K. Shariati, J.S. Caserto, B. Parker, D. Gao, M.D. Plesser, L.G. Grunnet, C. Rescan, R. Pimentel Carletto, L. Winkel, J.M. Melero-Martin, M. Ma, A Safe, Fibrosis-Mitigating, and Scalable Encapsulation Device Supports Long-Term Function of Insulin-Producing Cells, Small. 18 (2022) 2104899. 10.1002/smll.202104899. [342] L.-H. Wang, A.U. Ernst, D. An, A.K. Datta, B. Epel, M. Kotecha, M. Ma, A bioinspired scaffold for rapid oxygenation of cell encapsulation systems, Nat. Commun. 12 (2021) 5846, https://doi.org/10.1038/s41467-021-26126-w. [343] K. Yang, E.D. O’Cearbhaill, S.S. Liu, A. Zhou, G.D. Chitnis, A.E. Hamilos, J. Xu, M. K.S. Verma, J.A. Giraldo, Y. Kudo, E.A. Lee, Y. Lee, R. Pop, R. Langer, D.A. Melton, D.L. Greiner, J.M. Karp, A therapeutic convection–enhanced macroencapsulation device for enhancing bcell viability and insulin secretion, Proc. Natl. Acad. Sci. 118 (2021), https://doi.org/10.1073/ pnas.2101258118. [344] K. Ajima, N. Tsuda, T. Takaki, S. Furusako, S. Matsumoto, K. Shinohara, Y. Yamashita, S. Amano, C. Oyama, M. Shimoda, A porcine islet-encapsulation device that enables long-term discordant xenotransplantation in immunocompetent diabetic mice, Cell Reports Methods. 3 (2023), https:// doi.org/10.1016/j.crmeth.2022.100370. [345] G.S. Chendke, G. Faleo, C. Juang, A.V. Parent, D.A. Bernards, M. Hebrok, Q. Tang, T.A. Desai, Supporting Survival of Transplanted Stem-Cell-Derived Insulin-Producing Cells in an Encapsulation Device Augmented with Controlled Release of Amino Acids, Adv. Biosyst. 3 (2019) 1900086, https:// doi.org/10.1002/adbi.201900086. [346] C.B. Ahn, J.-H. Lee, J.H. Kim, T.H. Kim, H.-S. Jun, K.H. Son, J.W. Lee, Development of a 3D subcutaneous construct containing insulin-producing beta cells using bioprinting, Bio-Design Manuf. 5 (2022) 265–276, https://doi. org/10.1007/s42242-021-00178-9. [347] Z. Wu, Q. Li, S. Xie, X. Shan, Z. Cai, In vitro and in vivo biocompatibility evaluation of a 3D bioprinted gelatin-sodium alginate/rat Schwann-cell scaffold, Mater. Sci. Eng. C. 109 (2020), https://doi.org/10.1016/j. msec.2019.110530. [348] H. Li, Z. Wang, E.A. Ogunnaike, Q. Wu, G. Chen, Q. Hu, T. Ci, Z. Chen, J. Wang, D. Wen, H. Du, J. Jiang, J. Sun, X. Zhang, G. Dotti, Z. Gu, Scattered seeding of CAR T cells in solid tumors augments anticancer efficacy, Natl. Sci. Rev. 9 (2022), https://doi.org/10.1093/nsr/nwab172. [349] A.J. Paredes, F. Volpe-Zanutto, A.D. Permana, A.J. Murphy, C.J. Picco, L.K. Vora, J.A. Coulter, R.F. Donnelly, Novel tip-loaded dissolving and implantable microneedle array patches for sustained release of finasteride, Int. J. Pharm. 606 (2021), https://doi.org/10.1016/j.ijpharm.2021.120885. [350] A.R.J. Hutton, H.L. Quinn, P.J. McCague, C. Jarrahian, A. Rein-Weston, P.S. Coffey, E. Gerth-Guyette, D. Zehrung, E. Larraneta, R.F. Donnelly, Transdermal delivery of vitamin K using dissolving microneedles for the prevention of vitamin K deficiency bleeding, Int. J. Pharm. 541 (2018) 56–63. S0378-5173 (18)30112-1 [pii]. [351] L.K. Vora, P.R. Vavia, E. Larrañeta, S.E.J. Bell, R.F. Donnelly, Novel nanosuspension-based dissolving microneedle arrays for transdermal delivery of a hydrophobic drug, J. Interdiscip. Nanomedicine. 3 (2018) 89– 101, https://doi.org/10.1002/jin2.41. [352] L.K. Vora, A.J. Courtenay, I.A. Tekko, E. Larrañeta, R.F. Donnelly, Pullulanbased dissolving microneedle arrays for enhanced transdermal delivery of small and large biomolecules, Int. J. Biol. Macromol. 146 (2020) 290–298, https://doi.org/10.1016/j.ijbiomac.2019.12.184. [353] L.K. Vora, K. Moffatt, R.F. Donnelly, 9 - Long-lasting drug delivery systems based on microneedles, in: E. Larrañeta, T. Raghu Raj Singh, R.F.B.T.-L.-A.D.D. S. Donnelly (Eds.), Woodhead Publ. Ser. Biomater., Woodhead Publishing, 2022: pp. 249–287. 10.1016/B978-0-12-821749-8.00010-0. [354] L.K. Vora, K. Moffatt, I.A. Tekko, A.J. Paredes, F. Volpe-Zanutto, D. Mishra, K. Peng, R. Raj Singh Thakur, R.F. Donnelly, Microneedle array systems for longacting drug delivery, Eur. J. Pharm. Biopharm. 159 (2021) 44–76. 10.1016/j. ejpb.2020.12.006. [355] E. Larrañeta, L. Vora, Delivery of Nanomedicines Using Microneedles, Microneedles Drug Vaccine Deliv, Patient Monit. (2018) 177–205, https:// doi.org/10.1002/9781119305101.ch6. [356] A.J. Paredes, I.K. Ramöller, P.E. McKenna, M.T.A. Abbate, F. Volpe-Zanutto, L. K. Vora, M. Kilbourne-Brook, C. Jarrahian, K. Moffatt, C. Zhang, I.A. Tekko, R. F. Donnelly, Microarray patches: Breaking down the barriers to contraceptive care and HIV prevention for women across the globe, Adv. Drug Deliv. Rev. 173 (2021) 331–348, https://doi.org/10.1016/j.addr.2021. 04.002. [357] I.A. Tekko, L.K. Vora, F. Volpe-Zanutto, K. Moffatt, C. Jarrahian, H.O. McCarthy, R.F. Donnelly, Novel Bilayer Microarray Patch-Assisted Long-Acting Micro- Depot Cabotegravir Intradermal Delivery for HIV Pre-Exposure Prophylaxis, Adv. Funct. Mater. 32 (2022) 2106999, https://doi.org/10.1002/ adfm.202106999. [358] M.A. Pawar, L.K. Vora, P. Kompella, V.K. Pokuri, P.R. Vavia, Long-acting microspheres of Human Chorionic Gonadotropin hormone: In-vitro and invivo evaluation, Int. J. Pharm. 611 (2022), https://doi.org/10.1016/j. ijpharm.2021.121312. [359] M.T.C. Mc Crudden, E. Larrañeta, A. Clark, C. Jarrahian, A. Rein-Weston, S. Lachau-Durand, N. Niemeijer, P. Williams, C. Haeck, H.O. McCarthy, D. Zehrung, R.F. Donnelly, Design, formulation and evaluation of novel dissolving microarray patches containing a long-acting rilpivirine nanosuspension, J. Control. Release. 292 (2018) 119–129, https://doi.org/ 10.1016/j.jconrel.2018.11.002. [360] M.T.C. Mc Crudden, E. Larrañeta, A. Clark, C. Jarrahian, A. Rein-Weston, B. Creelman, Y. Moyo, S. Lachau-Durand, N. Niemeijer, P. Williams, H.O. McCarthy, D. Zehrung, R.F. Donnelly, Design, Formulation, and Evaluation of Novel Dissolving Microarray Patches Containing Rilpivirine for Intravaginal Delivery, Adv. Healthc. Mater. 8 (2019) 1801510. 10.1002/ adhm.201801510. [361] K. Moffatt, I.A. Tekko, L. Vora, F. Volpe-Zanutto, A.R.J. Hutton, J. Mistilis, C. Jarrahian, N. Akhavein, A.D. Weber, H.O. McCarthy, R.F. Donnelly, Development and Evaluation of Dissolving Microarray Patches for Coadministered and Repeated Intradermal Delivery of Long-acting Rilpivirine and Cabotegravir Nanosuspensions for Paediatric HIV Antiretroviral Therapy, Pharm. Res. (2022), https://doi.org/10.1007/s11095-022-03408-6. [362] S. Rojekar, L.K. Vora, I.A. Tekko, F. Volpe-Zanutto, H.O. McCarthy, P.R. Vavia, R. F. Donnelly, Etravirine-loaded dissolving microneedle arrays for long-acting delivery, Eur. J. Pharm. Biopharm. 165 (2021) 41–51, https://doi.org/10.1016/ j.ejpb.2021.04.024. [363] L.K. Vora, R.F. Donnelly, E. Larrañeta, P. González-Vázquez, R.R.S. Thakur, P.R. Vavia, Novel bilayer dissolving microneedle arrays with concentrated PLGA nano-microparticles for targeted intradermal delivery: Proof of concept, Challenges Adv. Microneedle Technol. 265 (2017) 93–101, https://doi.org/ 10.1016/j.jconrel.2017.10.005. [364] Y.A. Naser, I.A. Tekko, L.K. Vora, K. Peng, Q.K. Anjani, B. Greer, C. Elliott, H.O. McCarthy, R.F. Donnelly, Hydrogel-forming microarray patches with solid dispersion reservoirs for transdermal long-acting microdepot delivery of a hydrophobic drug, J. Control. Release. 356 (2023) 416–433, https://doi.org/ 10.1016/j.jconrel.2023.03.003. [365] A.J. Paredes, A.D. Permana, F. Volpe-Zanutto, M.N. Amir, L.K. Vora, I.A. Tekko, N. Akhavein, A.D. Weber, E. Larrañeta, R.F. Donnelly, Ring inserts as a useful strategy to prepare tip-loaded microneedles for long-acting drug delivery E. Magill, S. Demartis, E. Gavini et al. Advanced Drug Delivery Reviews 199 (2023) 114950 40 with application in HIV pre-exposure prophylaxis, Mater. Des. 224 (2022), https://doi.org/10.1016/j.matdes.2022.111416. [366] L. Yang, Q. Liu, X. Wang, N. Gao, X. Li, H. Chen, L. Mei, X. Zeng, Actively separated microneedle patch for sustained-release of growth hormone to treat growth hormone deficiency, Acta Pharm. Sin. B. 13 (2023) 344–358, https://doi.org/10.1016/j.apsb.2022.04.015. [367] W. Li, J.Y. Chen, R.N. Terry, J. Tang, A. Romanyuk, S.P. Schwendeman, M.R. Prausnitz, Core-shell microneedle patch for six-month controlled-release contraceptive delivery, J. Control. Release. 347 (2022) 489–499, https://doi. org/10.1016/j.jconrel.2022.04.051. [368] K. Peng, L.K. Vora, J. Domínguez-Robles, Y.A. Naser, M. Li, E. Larrañeta, R.F. Donnelly, Hydrogel-forming microneedles for rapid and efficient skin deposition of controlled release tip-implants, Mater. Sci. Eng. C. 127 (2021), https://doi.org/10.1016/j.msec.2021.112226. [369] W. Li, R.N. Terry, J. Tang, M.R. Feng, S.P. Schwendeman, M.R. Prausnitz, Rapidly separable microneedle patch for the sustained release of a contraceptive, Nat. Biomed. Eng. 3 (2019) 220–229, https://doi.org/ 10.1038/s41551-018-0337-4. [370] Y. Lee, W. Li, J. Tang, S.P. Schwendeman, M.R. Prausnitz, Immediate detachment of microneedles by interfacial fracture for sustained delivery of a contraceptive hormone in the skin, J. Control. Release. 337 (2021) 676–685, https://doi.org/10.1016/j.jconrel.2021.08.012. [371] W. Li, J. Tang, R.N. Terry, S. Li, A. Brunie, R.L. Callahan, R.K. Noel, C.A. Rodríguez, S.P. Schwendeman, M.R. Prausnitz, Long-acting reversible contraception by effervescent microneedle patch, Sci. Adv. 5 (2019), https://doi.org/10.1126/sciadv.aaw8145. [372] K. Peng, L.K. Vora, I.A. Tekko, A.D. Permana, J. Domínguez-Robles, D. Ramadon, P. Chambers, H.O. McCarthy, E. Larrañeta, R.F. Donnelly, Dissolving microneedle patches loaded with amphotericin B microparticles for localised and sustained intradermal delivery: Potential for enhanced treatment of cutaneous fungal infections, J. Control. Release. 339 (2021) 361– 380, https://doi.org/10.1016/j.jconrel.2021.10.001. [373] E. McAlister, M. Kirkby, J. Domínguez-Robles, A.J. Paredes, Q.K. Anjani, K. Moffatt, L.K. Vora, A.R.J. Hutton, P.E. McKenna, E. Larrañeta, R.F. Donnelly, The role of microneedle arrays in drug delivery and patient monitoring to prevent diabetes induced fibrosis, Adv. Drug Deliv. Rev. 175 (2021), https://doi.org/ 10.1016/j.addr.2021.06.002. [374] X. Zhao, S. Zhang, G. Yang, Z. Zhou, Y. Gao, Exploring trehalose on the release of levonorgestrel from implantable PLGA microneedles, Polymers (Basel). 12 (2020) 59, https://doi.org/10.3390/polym12010059. [375] A. Than, C. Liu, H. Chang, P.K. Duong, C.M.G. Cheung, C. Xu, X. Wang, P. Chen, Self-implantable double-layered micro-drug-reservoirs for efficient and controlled ocular drug delivery, Nat. Commun. 9 (2018) 1–12, https://doi. org/10.1038/s41467-018-06981-w. [376] M. Li, L.K. Vora, K. Peng, R.F. Donnelly, Trilayer microneedle array assisted transdermal and intradermal delivery of dexamethasone, Int. J. Pharm. (2021), https://doi.org/10.1016/j.ijpharm.2021.121295. [377] I. Menon, P. Bagwe, K.B. Gomes, L. Bajaj, R. Gala, M.N. Uddin, M.J. D’Souza, S. M. Zughaier, Microneedles: A New Generation Vaccine Delivery System, Micromachines 12 (2021) 435, https://doi.org/10.3390/mi12040435. [378] A.J. Najibi, M.O. Dellacherie, T. Shih, E.J. Doherty, D.A. White, T. Bauleth- Ramos, A.G. Stafford, J.C. Weaver, C.D. Yeager, B.T. Seiler, M. Pezone, A.W. Li, B. Sarmento, H.A. Santos, D.J. Mooney, L. Gu, Scaffold Vaccines for Generating Robust and Tunable Antibody Responses, Adv. Funct. Mater. 32 (2022) 2110905, https://doi.org/10.1002/adfm.202110905. [379] J. Myschik, W.T. McBurney, T. Rades, S. Hook, Immunostimulatory lipid implants containing Quil-A and DC-cholesterol, Int. J. Pharm. 363 (2008) 91– 98, https://doi.org/10.1016/j.ijpharm.2008.07.014. [380] M.Z.I. Khan, I.G. Tucker, J.P. Opdebeeck, Cholesterol and lecithin implants for sustained release of antigen: release and erosion in vitro, and antibody response in mice, Int. J. Pharm. 76 (1991) 161–170, https://doi.org/10.1016/ 0378-5173(91)90354-Q. [381] M.-P. Even, S. Bobbala, B. Gibson, S. Hook, G. Winter, J. Engert, Twin-screw extruded lipid implants containing TRP2 peptide for tumour therapy, Eur. J. Pharm. Biopharm. 114 (2017) 79–87, https://doi.org/10.1016/j. ejpb.2016.12.033. [382] K. Amssoms, P.A. Born, M. Beugeling, B. De Clerck, E. Van Gulck, W.L.J. Hinrichs, H.W. Frijlink, N. Grasmeijer, G. Kraus, R. Sutmuller, K. Simmen, L. Baert, Ovalbumin-containing core-shell implants suitable to obtain a delayed IgG1 antibody response in support of a biphasic pulsatile release profile in mice, PLoS One 13 (2018) e0202961. [383] S. Shao, O. Ortega-Rivera, S. Ray, J. Pokorski, N. Steinmetz, A Scalable Manufacturing Approach to Single Dose Vaccination against HPV, Vaccines. 9 (2021) 66, https://doi.org/10.3390/vaccines9010066. [384] O.A. Ortega-Rivera, J.K. Pokorski, N.F. Steinmetz, A. Single-Dose, Implant- Based, Trivalent Virus-like Particle Vaccine against ‘‘Cholesterol Checkpoint” Proteins, Adv. Ther. 4 (2021) 2100014, https://doi.org/10.1002/ adtp.202100014. [385] R.G. Schaut, M.T. Brewer, K. Mendoza, J. Jackman, B. Narasimhan, D.E. Jones, A polyanhydride-based implantable single dose vaccine platform for long-term immunity, Vaccine 36 (2018) 1024–1025, https://doi.org/10.1016/ j.vaccine.2017.11.067. [386] H. Song, P. Huang, J. Niu, G. Shi, C. Zhang, D. Kong, W. Wang, Injectable polypeptide hydrogel for dual-delivery of antigen and TLR3 agonist to modulate dendritic cells in vivo and enhance potent cytotoxic T-lymphocyte response against melanoma, Biomaterials 159 (2018) 119–129, https://doi. org/10.1016/j.biomaterials.2018.01.004. [387] A. Nishiguchi, T. Taguchi, Sustained-immunostimulatory nanocellulose scaffold to enhance vaccine efficacy, J. Biomed. Mater. Res. Part A. 108 (2020) 1159–1170, https://doi.org/10.1002/jbm.a.36890. [388] A. Bansal, X. Wu, V. Olson, M.J. D’Souza, Characterization of rabies pDNA nanoparticulate vaccine in poloxamer 407 gel, Int. J. Pharm. 545 (2018) 318– 328, https://doi.org/10.1016/j.ijpharm.2018.05.018. [389] J.R. Adams, S. Senapati, S.L. Haughney, M.J. Wannemuehler, B. Narasimhan, S. K. Mallapragada, Safety and biocompatibility of injectable vaccine adjuvants composed of thermogelling block copolymer gels, J. Biomed. Mater. Res. Part A. 107 (2019) 1754–1762, https://doi.org/10.1002/jbm.a.36691. [390] R. Chen, H. Zhang, J. Yan, J.D. Bryers, Scaffold-mediated delivery for non-viral mRNA vaccines, Gene Ther. 25 (2018) 556–567, https://doi.org/10.1038/ s41434-018-0040-9. [391] D.I. Viswanath, H.-C. Liu, S. Capuani, R.S. Vander Pol, S.Z. Saunders, C.Y.X. Chua, A. Grattoni, Engineered implantable vaccine platform for continuous antigen-specific immunomodulation, Biomaterials 281 (2022), https://doi. org/10.1016/j.biomaterials.2022.121374. [392] L.A. Silverman, E.K. Neely, G.B. Kletter, K. Lewis, S. Chitra, O. Terleckyj, E.A. Eugster, Long-Term Continuous Suppression With Once-Yearly Histrelin Subcutaneous Implants for the Treatment of Central Precocious Puberty: A Final Report of a Phase 3 Multicenter Trial, J. Clin. Endocrinol. Metab. 100 (2015) 2354–2363, https://doi.org/10.1210/jc.2014-3031. [393] E. Caló, V.V. Khutoryanskiy, Biomedical applications of hydrogels: A review of patents and commercial products, Eur. Polym. J. 65 (2015) 252–267, https:// doi.org/10.1016/j.eurpolymj.2014.11.024. [394] C.L. Stevenson, J.T. Santini, R. Langer, Reservoir-based drug delivery systems utilizing microtechnology, Adv. Drug Deliv. Rev. 64 (2012) 1590–1602, https://doi.org/10.1016/j.addr.2012.02.005. [395] A. McCullough, A Review of Testosterone Pellets in the Treatment of Hypogonadism, Curr. Sex. Heal. Reports. 6 (2014) 265–269, https://doi.org/ 10.1007/s11930-014-0033-7. [396] W. Li, J. Tang, D. Lee, T.R. Tice, S.P. Schwendeman, M.R. Prausnitz, Clinical translation of long-acting drug delivery formulations, Nat. Rev. Mater. (2022), https://doi.org/10.1038/s41578-021-00405-w. [397] R.K. Cavender, M. Fairall, Subcutaneous Testosterone Pellet Implant (Testopel Ò ) Therapy for Men with Testosterone Deficiency Syndrome: A Single-Site Retrospective Safety Analysis, J. Sex. Med. 6 (2009) 3177–3192, https://doi.org/10.1111/j.1743-6109.2009.01513.x. [398] S.A. Stewart, J. Domínguez-Robles, E. Utomo, C.J. Picco, F. Corduas, E. Mancuso, M.N. Amir, M.A. Bahar, S. Sumarheni, R.F. Donnelly, A.D. Permana, E. Larrañeta, Poly(caprolactone)-based subcutaneous implant for sustained delivery of levothyroxine, Int. J. Pharm. 607 (2021), https://doi.org/ 10.1016/j.ijpharm.2021.121011. [399] A. Parikh, U. Anand, M.C. Ugwu, T. Feridooni, E. Massoud, R.U. Agu, Drugeluting nasal implants: formulation, characterization, clinical applications and challenges, Pharmaceutics. 6 (2014) 249–267, https://doi.org/10.3390/ pharmaceutics6020249 [doi]. [400] M. Alomari, P.R. Vuddanda, S.J. Trenfield, C.C. Dodoo, S. Velaga, A.W. Basit, S. Gaisford, Printing T3 and T4 oral drug combinations as a novel strategy for hypothyroidism, Int. J. Pharm. 549 (2018) 363–369, https://doi.org/10.1016/j. ijpharm.2018.07.062. [401] S.A. Stewart, D. Waite, J. Domínguez-Robles, E. McAlister, A.D. Permana, R.F. Donnelly, E. Larrañeta, HPLC method for levothyroxine quantification in longacting drug delivery systems. Validation and evaluation of bovine serum albumin as levothyroxine stabilizer, J. Pharm. Biomed. Anal. 203 (2021), https://doi.org/10.1016/j.jpba.2021.114182. [402] Titan Pharmaceuticals, T3 implant, (2020). [403] E. Mathew, S.A. Stewart, E. Utomo, E. Larrañeta, D.A. Lamprou, Implantable and long-lasting drug delivery systems for infectious, inflammatory, endocrine, and neurodegenerative diseases, in: Long- Acting Drug Deliv. Syst., Elsevier, 2022: pp. 223–248. 10.1016/B978-0- 12-821749-8.00003-3. [404] M. Itzoe, M. Guarnieri, New developments in managing opioid addiction: impact of a subdermal buprenorphine implant, Drug Des. Devel. Ther. 11 (2017) 1429–1437, https://doi.org/10.2147/DDDT.S109331. [405] A. Jhugroo, D. Ellayah, A. Norman, G. Hulse, Naltrexone implant treatment for buprenorphine dependence – Mauritian case series, J. Psychopharmacol. 28 (2014) 800–803, https://doi.org/10.1177/0269881114528592. [406] NIH, Safety, Tolerability, and Pharmacokinetics of Naltrexone Implant (DLP- 160), (2022). https://clinicaltrials.gov/ct2/show/NCT05304364. [407] Delpor, DLP-160, (2019). https://delpor.com/products/dlp-160/ (accessed April 8, 2022). [408] Titan Pharmaceuticals, Probuphine Notice October 2020, (2020). https:// www.titanpharm.com/Probuphine_Notice_October_2020 (accessed April 8, 2022). [409] A. Carnicer-Lombarte, S.-T. Chen, G.G. Malliaras, D.G. Barone, Foreign Body Reaction to Implanted Biomaterials and Its Impact in Nerve Neuroprosthetics, Front. Bioeng. Biotechnol. 9 (2021), https://doi.org/10.3389/ fbioe.2021.622524. [410] C. Li, C. Guo, V. Fitzpatrick, A. Ibrahim, M.J. Zwierstra, P. Hanna, A. Lechtig, A. Nazarian, S.J. Lin, D.L. Kaplan, Design of biodegradable, implantable devices towards clinical translation, Nat. Rev. Mater. 5 (2019) 61–81, https://doi.org/ 10.1038/s41578-019-0150-z. E. Magill, S. Demartis, E. Gavini et al. Advanced Drug Delivery Reviews 199 (2023) 114950 41