Three-dimensional printing as a cutting-edge, versatile and personalizable vascular stent manufacturing procedure: Toward tailor-made medical devices

International Journal of Bioprinting Volume 9 Issue 2 (2023) https://doi.org/10.18063/ijb.v9i2.664 219 REVIEW ARTICLE Three-dimensional printing as a cutting-edge, versatile and personalizable vascular stent manufacturing procedure: Toward tailor-made medical devices Fatima Garcia-Villen1,2,3*, Fernando López-Zárraga4, Cesar Viseras5,6, Sandra Ruiz-Alonso1,2,3, Fouad Al-Hakim1,2,3, Irene Diez-Aldama1, Laura Saenz-del-Burgo1,2,3, Denis Scaini7*, Jose Luis Pedraz1,2,3 1NanoBioCel Group, School of Pharmacy, University of the Basque Country (UPV/EHU), 01006, Vitoria-Gasteiz, Spain 2Biomedical Research Networking Center in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), 01006, Vitoria-Gasteiz, Spain 3Bioaraba, NanoBioCel Research Group, 01009, Vitoria-Gasteiz, Spain 4Department of Vascular and Interventional Radiology, Álava University Hospital, Integrated Health Organization of Álava (Osakidetza), Spain 5Department of Pharmacy and Pharmaceutical Technology, School of Pharmacy, University of Granada (UGR), Campus of Cartuja, 18071 s/n, Granada, Spain 6Andalusian Institute of Earth Sciences, CSIC-University of Granada, Avda. de Las Palmeras 4, 18100, Armilla, Granada, Spain 7Joint Research Laboratory (JRL). School of Pharmacy, University of the Basque Country (UPV/ EHU), 01006, Vitoria-Gasteiz, Spain (This article belongs to the Special Issue: 3D Tissue Engineering and Bioprinting for Emerging Applications) Abstract Vascular stents (VS) have revolutionized the treatment of cardiovascular diseases, as evidenced by the fact that the implantation of VS in coronary artery disease (CAD) patients has become a routine, easily approachable surgical intervention for the treatment of stenosed blood vessels. Despite the evolution of VS throughout the years, more efficient approaches are still required to address the medical and scientific challenges, especially when it comes to peripheral artery disease (PAD). In this regard, three-dimensional (3D) printing is envisaged as a promising alternative to upgrade VS by optimizing the shape, dimensions and stent backbone (crucial for optimal mechanical properties), making them customizable for each patient and each stenosed lesion. Moreover, the combination of 3D printing with other methods could also upgrade the final device. This review focuses on the most recent studies using 3D printing techniques to produce VS, both by itself and in combination with other techniques. The final aim is to provide an overview of the possibilities and limitations of 3D printing in the manufacturing of VS. Furthermore, the current situation of CAD and PAD pathologies is also addressed, thus highlighting the main weaknesses of the already existing VS and identifying research gaps, possible market niches and future directions. Keywords: Stent; Three-dimensional printing; Endovascular prosthesis; Atherosclerosis; Peripheral artery disease; Coronary artery disease *Corresponding authors: Fatima Garcia-Villen ([email protected]) Denis Scaini ([email protected]) Citation: Garcia-Villen F, LópezZárraga F, Viseras C, et al., 2023, Three-dimensional printing as a cutting-edge, versatile and personalizable vascular stent manufacturing procedure: Toward tailor-made medical devices. Int J Bioprint, 9(2): 664. https://doi.org/10.18063/ijb.v9i2.664 Received: August 09, 2022 Accepted: October 11, 2022 Published Online: January 9, 2023 Copyright: © 2023 Author(s). This is an Open Access article distributed under the terms of the Creative Commons Attribution License, permitting distribution and reproduction in any medium, provided the original work is properly cited. Publisher’s Note: Whioce Publishing remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. International Journal of Bioprinting Coronary and peripheral artery disease. State of the art. Volume 9 Issue 2 (2023) https://doi.org/10.18063/ijb.v9i2.664 220 1. Introduction Atherosclerosis and thrombosis are vascular conditions that represent one of the major causes of death worldwide[1-3], thus placing a substantial medical and economic burden to society. The progressive and chronic accumulation of fat in artery walls, which is initially asymptomatic, can ultimately lead to the production of atheroma that blocks the vessel lumen, thus jeopardizing blood circulation. Moreover, atheroma plaques can also suffer from ruptures, causing local problems such as thrombosis, arterial wall ulcers, and dissection. If atherosclerosis happens in coronary arteries (coronary artery disease [CAD]), the blockage of the blood flow could lead to myocardial infarction and ultimately, death. If stenosis is located in other blood vessels of the peripheral circulatory system, it is known as peripheral artery disease (PAD). Even if PAD can affect any blood vessel, it is more common in the lower extremities than in the arms. It is also worth to clarify that PAD and CAD could have different causes, but atherosclerosis remains one of the most common causes. Different medical approaches can be performed depending on the risk, age, stage of the condition, type of lesion, etc. Normally, when the artery blockage is severe, cardiologits resort to endovascular procedures or open vascular reconstruction. Regarding endovascular procedures, balloon angioplasty or endovascular stent are the most extended methods for treating the complications of atherosclerosis. Up to 42% of CAD patients have PAD, and half of those patients are asymptomatic[4]. According to Bauersachs etal., “worldwide data showed approximately 5%–8% prevalence of CAD and 10%–20% prevalence of PAD, dependent on the study design, average age, gender, and geographical location”[5]. Another recent report from the American Heart Association states that the lifetime risk of PAD has been estimated between 19% and 30% depending on the race, from white to black people, respectively[6]. Chronic ulceration is one of the major problems of PAD, which could ultimately lead to amputation. Ulceration in these patients is related to disturbed microcirculation, swelling and edema[7]. Due to the silent nature of atherosclerosis, it is very common for patients to suffer from cardiovascular events, thus needing hospitalization, surgery, and pharmacological treatments. Both CAD and PAD have demonstrated to be a significant economic burden on different health systems (Figure 1A). In particular, PAD represents a higher economic expense than CAD, especially due to a worse prognosis. In patients with PAD, cardiac complications are the major cause of morbidity and mortality. Moreover, the peripheral lesions are more complex and vaster than coronary ones[8]. According to a recent market study made by IMARC Group Company, they expect the vascular stent (VS) market to steadily grow in the coming years. They ascribe this growth to the increasing trend of geriatric population as well as to a rise in the incidence rate of PAD, aortic aneurysm and ischemic heart disease[9]. Nevertheless, if we look into the global VS market by product type, it is also clear that the majority of the efforts are centered on coronary stents (Figure 1B), relegating peripheral stents to a secondary place, despite being the condition with the most economic expenditure. In view of the above, Figure 1. (A) Economic burden caused by CAD and PAD in France, Germany, and Canada. Left: average cumulative 1-year and 2-year direct medical costs associated with hospitalization/patient for both CAD and PAD (H stands for “hospitalization”). Extracted from Smolderen etal.[145] Right: Average hospitalization and annual medication costs per patient in Canada. Extracted from Bauersachs etal.[5]. Bars numbers correspond to amount in euros. (B) Global vascular stents market share by product type. EVAR stands for “endovascular aortic repair.” Values extracted from[9]. International Journal of Bioprinting Coronary and peripheral artery disease. State of the art. Volume 9 Issue 2 (2023) https://doi.org/10.18063/ijb.v9i2.664 221 small improvements in PAD treatment could bring about significant differences not only for the patients, but also for the entire health care system. Angioplasty, also known as percutaneous transluminal coronary angioplasty (PTCA) or percutaneous transluminal angioplasty in peripheral circulation, is an interventional procedure to open narrowed vessels. Balloon angioplasty involves opening the stenosed vessel by inflating a catheter-balloon in the stenosed area. Once the catheter reaches the desired zone, the attached balloon inflates to flatten the atheroma plaque against the artery walls. Subsequently, the device (balloon and catheter) is withdrawn and the vascular vessel remains opened. Balloon angioplasty provides short-term benefits with some improvements in patency. In stent procedure, on the other hand, VS is placed in the treated area after the flattening of atheroma. VS are cylindrical medical devices acting as endoprothesis. VS implantation aims to support the walls of a blood vessel during a certain period of time and prevent restenosis. Once the VS is implanted in the desired position, its final scope is to exert permanent pressure against the vessel walls, acting as a scaffold to keep the artery or vein open until the risk of full closure finishes. VS can also be used as flow diversion devices to treat aneurysm. In this procedure, the stent redirects the blood flow and eliminates the pressure on the aneurysm, reducing the rupture risk. Disregarding the type of intervention, the ultimate objective against atherosclerosis complications is to guarantee blood circulation in the long term after the vessel opening, also referred to as patency. The patency is the state or quality of being open, unblocked, or unobstructed. Even as it seems simple, full patency after angioplasty is still a challenge. Although VS is an innovation in cardiology that has helped saving millions of lives worldwide, they still have some drawbacks and weak points in peripheral vascular disease that require attention. The present review focuses on the most recent studies using three-dimensional (3D) printing techniques to produce VS, both by itself and in combination with other techniques. Due to the complexity of both disease and treatments/medical devices used, the first part of the review is devoted to the most common types of VS, their characteristics, and production techniques. The paper also focuses on the use of 3D printing (3DP) by reviewing the most recent studies that have approached this technique for the manufacturing of VS. The ultimate aim of this review is to offer a rational overview of the strengths and weaknesses of 3DP in the development of these medical devices, identifying research gaps, possible market niches, and feasible future directions. 1.1. Types of vascular stents and their features VS have been in use since 1977[10]. From that moment onward, different aspects concerning VS, such as the type of materials used and the implantation and production technology, have significantly evolved. Any innovation in VS field comes with new challenges arise, either in the manufacturing process or in the final performance of the medical device. The joint effort of the scientific community in the search for the full-patency VS has given rise to the development of a wide variety of cardiovascular stents, which are currently available in the market (Table 1). Figure 2A represents different types of VS depending on their permanence in the human body, the implantation methodology and the therapeutic activity together with their relative presence in the current market (Figure 2B). Permanent stents or non-resorbable stents are made of materials that do not suffer degradation under physiological conditions. The first VS were bare metal stents (BMS), which were made of stainless steel and nickel-titanium alloy (firstgeneration stents). It is possible to find cobalt, chromium, platinum/iridium and platinum/chromium, or tantalum BMS[11]. One of the main inconveniences of BMS are the long-term side effects: although they help to maintain the angioplasty result and they possess excellent mechanical properties, the remaining of the medical device within the vascular vessel could lead to vascular injury, inflammation, thrombosis, and other cardiovascular complications, such as in-stent restenosis in the long term[8,12]. According to Uhlemann etal., BMS have approximately a 30% chance of restenosis within 6 months[13]. Moreover, their permanent presence may interfere with future cardiac interventions. The corrosion of metallic VS might accelerate or trigger atherosclerosis as well as release some toxic ions causing long-term inflammatory responses[14]. BMS can be coated with different substances, aiming to modify their superficial properties and improve their mechanical, biological, and therapeutic performance. Stent surface coating has been used to improve VS biocompatibility and mitigate toxicity. Bearing in mind that the internal part of the stent is in intimate contact with blood flow, they must be fully biocompatible and able to avoid platelet, protein, and other molecules adhesion while maximizing the adherence of specific cells such as endothelial cells. Coating process enables to control and reduce corrosion (oxidation) and the release of undesirable elements or chemicals[15,16]. The category “coated stents” usually overlaps with “drug-eluting stents” (DES), since organic coatings (mainly polymers such as poly(ethylene), polyurethane, polylactides…) can act as drug reservoirs with controlled drug release properties. International Journal of Bioprinting Coronary and peripheral artery disease. State of the art. Volume 9 Issue 2 (2023) https://doi.org/10.18063/ijb.v9i2.664 222 Table 1. Some of the commercialized VS for cardiovascular system classified by material (polymer or metallic) and other important features Commercial name of the stent Polymeric Metallic Other features Blood vessel type SE DES BRS Coronary Peripheral Aorta Vascuflex®5 and 6 F ✓ ✓ ✓ Vascuflex® 2-LOC ✓ ✓ ✓ Vascuflex® 3-LOC ✓ ✓ ✓ Resistant and RESISTANT XL ✓ ✓ ✓ ✓ XoloTM ✓ ✓ ✓ Easy Flype ✓ ✓ ✓ Easy HiFlype ✓ ✓ ✓ Easyflex ✓ ✓ Heliflex TI ✓ ✓ ✓ ✓ ChampionirTM ✓ ✓ ✓ PMSX ✓ ✓ ✓ S.M.A.R.T. ControlTM ✓ ✓ ✓ Neuroform Atlas ✓ ✓ ✓ E-XL ✓ ✓ Acclino® Flex Stent ✓ ✓ ✓ Zeus SX ✓ ✓ ✓ Jaguar ✓ ✓ ✓ Discovery 5FTM ✓ ✓ ✓ Sinus XL ✓ ✓ ✓ MC-Peripheral 6F ✓ ✓ ✓ Finebent ✓ ✓ ✓ LVISTM ✓ ✓ ✓ P64 ✓ ✓ ✓ Biomimics 3DTM ✓ ✓ ✓ SilkenflexTM Iliac ✓ ✓ ✓ Facile ✓ ✓ CGUARDTM ✓ ✓ MERES 100TM ✓ ✓ ✓ ✓ MER ✓ ✓ ✓ Accero® ✓ ✓ ✓ CMCP001 ✓ ✓ Eucalimus ✓ ✓ ✓ ✓ ITRIXII ✓ ✓ ✓ ✓ DesolveTM ✓ ✓ ✓ Advanta V12 ✓ ✓ ✓ Fantom® ✓ ✓ ✓ ✓ NeovasTM Sirolimus-eluting ✓ ✓ ✓ ✓ Gureater® ✓ ✓ ✓ Partner® ✓ ✓ ✓ Coroflex® ISAR Neo ✓ ✓ ✓ (Continued) International Journal of Bioprinting Coronary and peripheral artery disease. State of the art. Volume 9 Issue 2 (2023) https://doi.org/10.18063/ijb.v9i2.664 223 Commercial name of the stent Polymeric Metallic Other features Blood vessel type SE DES BRS Coronary Peripheral Aorta Coroflex® Blue Neo ✓ ✓ Coroflex® Blue Ultra ✓ ✓ EurolimusTM ✓ ✓ ✓ E-Magic® PLUS ✓ ✓ ✓ Biomatrix AlphaTM ✓ ✓ ✓ Biomatrix ✓ ✓ ✓ ✓ ✓ NeoflexTM ✓ ✓ ✓ ✓ CRE8TMEVO ✓ ✓ ✓ DES-CRE8TM ✓ ✓ ✓ Titan Optimax ✓ ✓ ✓ Helios LD ✓ ✓ ✓ ✓ BiomimeTM ✓ ✓ ✓ ✓ ✓ EVERPRO ✓ ✓ ✓ ✓ ✓ MOVYRAP ✓ ✓ ✓ ✓ ✓ TWINRAP ✓ ✓ ✓ ✓ ✓ AVIPLUS ✓ ✓ ✓ ✓ ✓ Xlimus Series ✓ ✓ ✓ ✓ ✓ Orsiro ✓ ✓ ✓ ✓ ✓ Zilver® PTX® ✓ ✓ ✓ ✓ DynamxTM ✓ ✓ ✓ ✓ ✓ Firehawk® ✓ ✓ ✓ ✓ ✓ AbraxTM ✓ ✓ ✓ ✓ Angiolite BTK ✓ ✓ ✓ ✓ Bioss Expert ✓ ✓ ✓ ✓ ✓ SequenceTM ✓ ✓ ✓ ✓ ✓ Yukon® Choice PC ✓ ✓ ✓ ✓ Decent S ✓ ✓ ✓ ✓ ✓ Pronova ✓ ✓ ✓ ✓ ✓ IntrepideTM ✓ ✓ ✓ Xplosion+TM ✓ ✓ ✓ ✓ ✓ Nile® PAX ✓ ✓ ✓ Inspiron ✓ ✓ ✓ ✓ ✓ Cygnus II ✓ ✓ SvelteTM ✓ ✓ Arthospico ✓ ✓ Cronus Plus ✓ ✓ Besmooth ✓ ✓ Mgruard prime ✓ ✓ ChromaTM ✓ ✓ CCFlex ✓ ✓ (Continued) International Journal of Bioprinting Coronary and peripheral artery disease. State of the art. Volume 9 Issue 2 (2023) https://doi.org/10.18063/ijb.v9i2.664 224 Commercial name of the stent Polymeric Metallic Other features Blood vessel type SE DES BRS Coronary Peripheral Aorta NexgenTM ✓ ✓ Twinflex ✓ ✓ Andrastent ✓ ✓ BMS ✓ ✓ Renatural M ✓ ✓ ✓ ✓ Renatural P ✓ ✓ ✓ ✓ Magmaris ✓ ✓ ✓ Amaranth FortitudeTM ✓ ✓ ✓ BiofreedomTM Ultra ✓ ✓ ✓ Cobra PZFTM ✓ ✓ CataniaTM ✓ ✓ ✓ Propass ✓ ✓ Nano+TM ✓ ✓ ✓ Eluvia™ ✓ ✓ ✓ Epic™ ✓ ✓ ✓ Express™ LD Express™ SD ✓ ✓ Innova™ ✓ ✓ ✓ Promus PREMIER™ ✓ ✓ ✓ ✓ Promus ELITE™ ✓ ✓ ✓ ✓ SYNERGY™ ✓ ✓ ✓ ✓ ✓ REBEL™ ✓ ✓ SYNERGY™ XD ✓ ✓ ✓ ✓ ✓ SYNERGY MEGATRON™ ✓ ✓ ✓ ✓ ✓ Zilver® ✓ ✓ ✓ Zilver® Vena TM ✓ ✓ ✓ Zilver® PTX® ✓ ✓ ✓ Magmaris® RMS ✓ ✓ ✓ ✓ ✓ Orsiro Mission ✓ ✓ ✓ ✓ ✓ PRO-Kinetic Energy ✓ ✓ PK Papyrus ✓ ✓ Astron ✓ ✓ ✓ Astron Pulsar ✓ ✓ ✓ Pulsar-18 ✓ ✓ ✓ Pulsar 18 T13 ✓ ✓ ✓ Pulsar-35 ✓ ✓ ✓ Dynamic ✓ ✓ Dynetic®-35 ✓ ✓ Dynamic renal ✓ ✓ iVolution ✓ ✓ ✓ Restorer ✓ ✓ SS, stainless steel; SE, self-expandable; DES, drug-eluting stent; BRS, bioresorbable. Table 1. Continued International Journal of Bioprinting Coronary and peripheral artery disease. State of the art. Volume 9 Issue 2 (2023) https://doi.org/10.18063/ijb.v9i2.664 225 Bioresorbable (BRS) VS are made of biodegradable materials, which can be degraded over time under physiologic conditions until total disappearance. For a proper functioning, total BRS VS degradation must occur at a desirable, predictable rate, leaving behind a native vascular vessel fully repaired[15,17]. In fact, the control and prediction of their biodegradation rate is still the main challenge in the production and improvement of this group of VS. Despite some exceptions such as BRS metallic stents made of Mg, Ti, and Zn, biodegradability is a property usually associated to substances and molecules with poorer mechanical properties than metals (polymers). This means that the major part of the ingredients used for the production of BRS VS undertake poorer mechanical support when compared with BMS[12]. DES are VS that carry active substances in their structure, which are progressively released to obtain a certain therapeutic effect. DES prevent or reduce some of the BMS side effects: thrombosis, neointimal scar tissue formation, restenosis, etc. In addition to the main active substances loaded into DES, other substances also include antithrombotic drugs (heparin), antiproliferative (paclitaxel, actinomycin D), immunosuppressive (sirolimus) and anti-inflammatory (dexamethasone) drugs[18]. The use of paclitaxel has been particularly useful in the prevention of in-stent restenosis according to [8]. Recently, the review of Beshchasna et al. has reported that nanoparticles and genes can also be loaded into DES[15]. Therefore, DES are considered Modified Drug Delivery Systems (MDDS) since they must protect, carry, and control drug release toward the vessel walls or the bloodstream. These medical devices are commonly made of drug–polymer coating or direct drug immobilization on the stent surface[15,18]. The most common techniques to load drugs on stent struts are spray coating and dip coating. Regarding spray coating, a nozzle, which creates droplets of approximately 10 μm in diameter, sprays the drug solution or drug/polymer composite solution over the stent struts. For dip coating, the whole stent is dipped into the drug or drug/polymer solution in repeated occasions. The excess of material over the stent is then removed by spinning or other techniques[19]. DES can be differentiated into first and second generation or third generation, with the former one including non-bioresorbable DES and the latter one belonging to BRS DES[15]. Figure 2. (A) Classification of VS based on their degradability, type of blood vessel (to treat CAD or PAD) and implantation methodology. (B) Relative amount of VS commercially available in the market. BRS stands for “bioresorbable stents,” SS “stainless steel,” SE “self-expandable stent,” and DES “drug-eluting stent.” The sector graph is drawn according to the information available in Table 1. International Journal of Bioprinting Coronary and peripheral artery disease. State of the art. Volume 9 Issue 2 (2023) https://doi.org/10.18063/ijb.v9i2.664 226 Stents can also be differentiated by the implantation procedure, which is designed depending on the particularities of the stent itself. Balloon expandable stents are transported to the desired zone mounted around an inflatable device called “balloon.” Once in the desired area, the balloon is inflated until a certain point, forcing the stent to expand to the desired dimensions and guaranteeing the opening of the vessel (Figure 3, top). The corresponding counterpart are self-expandable stents, which are also transported with a catheter to the desired area. Nonetheless, in this particular case, the stent is crimped inside a thin tube that deploys it once in the correct position (Figure 3, bottom). That is, self-expandable stents are able to expand on their own, due to their high radial force, whereas balloon-expandable stents must be dilated to be implanted. Each placement strategy demands different stent mechanical properties and geometries. As stated by Krankenberg et al., “whereas self-expanding stents are of high elasticity but apply low radial outward force, balloon-expandable stents are rigid but support high radial outward force and allow to be placed with greater precision”[20]. Finally, VS can also be differentiated based on the type of blood vessel: peripheral or coronary (Figure 2A). The significant success of coronary stenting has encouraged the translation of this technology to the treatment of PAD Figure 3. Schematic representation of VS implantation procedures. Top: balloon-mediated stent delivery; bottom: self-expanding stent delivery. International Journal of Bioprinting Coronary and peripheral artery disease. State of the art. Volume 9 Issue 2 (2023) https://doi.org/10.18063/ijb.v9i2.664 227 that affects peripheral blood vessels, such as femoral, iliac or popliteal arteries, among others[21]. In fact, the endovascular treatment of PAD still yields unsatisfactory patency rates[22] or no significant differences between stenting and percutaneous transluminal angioplasty (PTA) in the lower extremities[23]. Among subjects with diabetes, the risk of PAD is often severe and associated with extensive arterial calcification, thus leading to a particular type of lesion that could complicate the stenting procedure. Definitely, PAD and CAD respond differently toward the same pathology and intervention, due to differential features and characteristics summarized in Table 2. The differential anatomy of coronary and peripheral arteries (size, bifurcations, elasticity, and curvature) influences the shear stress and blood turbulences, indicating the need to adjust the VS to the idiosyncrasy of each vessel. The blood flow and blood pressure and perfusion is better regulated in the heart due to excellent autoregulation mechanisms of these vessels, thus guaranteeing optimal blood flow[24]; on the other hand, other organs such as skeletal muscle and splanchnic circulations show moderate autoregulation[25]. If blood pressure drops to below the autoregulatory range due to pathologies such as stenosis, the distal vessels will be maximally dilated in an attempt to guarantee proper blood flow, thus causing further pressure reductions. When stenting peripheral blood vessels, the moderated autoregulation of blood pressure and flow could hinder the function of the vessel in maintaining the open lumen. Because of this, stents with better radial force are desirable for PAD. Another factor to bear in mind is blood oxygenation of the tissues in the distal region of the stenosed vessel. When it comes to the heart, the flow is tightly coupled to oxygen demand (when cardiac O2 consumption increases, there is an increase in coronary blood flow)[24], indicating that it is more easily compensated in CAD. In the case of PAD, the moderated pressure autoregulation of the peripheral tissues could lead to oxygen-starvation of the distal tissues as well as inflammation, hypoxia, edema, ulceration, and, ultimately, amputation in the long term. The lower blood oxygenation in PAD worsens the prognosis of the treatments, including stenting. Another factor to consider when designing and implanting a stent is the extent of the stenosed lesion: in CAD, normally the size of the stenosed area is smaller and more localized (always with exceptions), while in PAD, the lesions can be much longer and usually located between muscle and bone tissue. The lesion size and its location imply that the stent will be subjected to higher level of movements and stresses (e.g., displacement, fracture, crushing). Therefore, more flexible VS are preferred for PAD, while the VS is allowed to be a little stiffer for CAD because it will not be subjected to so much movements. 2. Desirable stent features In general, the perfect VS has the ability to be crimped in agreement with the implantation methodology (balloon or self-expansion), and has good expandability ratio with enough radial strength and minimal recoil. VS must also be flexible and fully biocompatible, as well as able to prevent or avoid thrombosis and restenosis after implantation[26]. These desirable properties and features are intimately related to the stent raw materials, their combinations, and the intrinsic features of each of them as well as the manufacturing process and post-processes. Nevertheless, the geometry and design of the VS are likewise important to control the final properties of the medical device, including the mechanical properties[27]. Under these circumstances, the study of the geometry and dimensions of VS is a field of study on its own due to the myriad of possibilities. In this sense, computational studies have proven themselves as useful tools to analyze and predict the influence of stent design on the final performance. Good expandability is the property of a material to expand (active expansion or self-expandability) or to be expanded (passive expansion). VS implanted with a balloon are passively expanded by the inflation of the balloon. Therefore, the materials used for the manufacturing of balloon-expandable stents need to be more plastic than elastic. On the contrary, self-expandability of VS refers to the ability of the medical device to expand without the use of an external force and to retain the final shape. This can Table 2. Differential properties and features of peripheral and coronary blood vessels influencing the patency of PAD and CAD stenting Differential characteristic Coronary blood vessels Peripheral blood vessels Blood flow Excellent autoregulation (60–200 mm Hg) to maintain normal blood flow under aortic pressure changes[24]. Moderate autoregulation (50–70 mmHg). Stenosis could reduce distal pressures below the autoregulatory range causing maximally dilated vessels and further pressure reductions[25] Blood oxygenation Flow tightly coupled to oxygen demand due to high basal oxygen consumption by heart[24]. Moderate pressure autoregulation could lead to tissue hypoxia. Extent of the stenosed lesion Smaller, localized lesions. Much longer lesions, usually located between muscle and bone. International Journal of Bioprinting Coronary and peripheral artery disease. State of the art. Volume 9 Issue 2 (2023) https://doi.org/10.18063/ijb.v9i2.664 234 Other MEX-based studies have also been reported feasible methodologies for printing VS, even if these techniques depend on semisolid-like materials. Some plastic materials can be dissolved in certain solvents that left behind a solid structure after evaporation. Particularly, PCL, PLGA, and polyethylene glycol (PEG) were dissolved, extruded and subsequently coated with sirolimus by means of ultrasonic spray method[69]. This 3DP methodology enables the production of a helical, biocompatible BRS and DES with successful results in vivo and in vitro. Sirolimuscoated BRS was able to reduce neointimal hyperplasia in male pigs for 4 weeks compared to the corresponding counterpart without sirolimus, together with reduced thrombosis and inflammation. This effectiveness has been related to the controlled release of sirolimus for 31 days. It is also worth to mention that the in vivo stent implantation was performed without much complications, proving that 3DP stents are suitable for real treatments. MEX 3DP has Figure 6. (A) Tilted structures printed (scale bar: 1 cm). (B) Steps of in vitro deployment testing. Different frames, from (a) to (d), show the shape memory effect of PGDA after photocrosslinking and thermal curing. Effective deployment inside a compressed silicone tube. (C) Results of in vivo studies in mouse aorta; (a) images after implantation and (b) after 14 days; (c), (d), (e), and (f) correspond to different staining techniques of middle/inner (c and e) and outer layers (d and f) of newly formed tissue after 14 days of VS implantation. Black arrows indicate inner elastin layer and green arrows indicate outer elastin layer; (g) endothelial cells stained with VE-cadherin antibody (green) and cell nuclei stained with DAPI (blue); (h) myofibroblasts (red) and nuclei stained with DAPI (blue). Reproduced with permission from [64] 2021, Acta Biomaterialia. International Journal of Bioprinting Coronary and peripheral artery disease. State of the art. Volume 9 Issue 2 (2023) https://doi.org/10.18063/ijb.v9i2.664 235 enabled the production of patient-specific polymer-carbon BRS[70]. This study proves that patient-specific stenting process based on MEX 3DP is feasible and promising. Fibrin-directed radio-opaque contrast helps to obtain the mold and shape of the lesion, from which the 3D design of the stent is prepared. The extrusion-based printing process of the BRS was carried out as a flat rectangular slab that was subsequently folded and successfully deployed into a pig heart. Lee etal. have recently produced a BRS with pneumatic-based 3DP[14]. The electronic microscopy revealed that all of the PLA strands were smooth, uniform and clearly connected without surface damage (Figure 8A), guaranteeing absence of trauma and structural stability during implantation. To enhance biocompatibility and anti-coagulation activity, heparin was introduced through surface modification with polydopamine (PDA) and polyethyleneimine (PEI) as intermediates. This coating allows for not only a higher hydrophilicity, but also the crosslinking of heparin carboxyl groups with amino groups of PEI in the stent surface[14]. Successful in vivo studies were reported, with inhibited neointima hyperplasia and absence of thrombosis. These performances can be entirely Figure 7. (A) Pulling platform for deposition process over the sacrificial mold obtained by means of 3DP. (B) Shaped nitinol wires to be used in the final stent. (C) Final aspect of aortic metal-PU stents with different shapes (branched and straight). Reproduced with permission from [68] 2020, Medical Engineering and Physics. Figure 8. (A) Scanning electron microscopy of printed PLA stents: (a) full PLA stent; (b) entire surface image; (c) exterior connection; (d) interior connection. (B) Confocal laser scanning microscopy (CLSM) of smooth muscle cells (SMC, red) and endothelial cells (EC, green) seeded over the produced stents. PLA stands for pure PLA stents; PLADP stands for PLA stents after PEI immobilization; PLADPH refers to stents loaded with heparin after surface modification. Bar charts represent the percentage of cellular proliferation (both SMC and EC) at day 1 and day 3, thus demonstrating significant differences between samples. Reproduced with permission from [14] 2019, Chemical Engineering. International Journal of Bioprinting Coronary and peripheral artery disease. State of the art. Volume 9 Issue 2 (2023) https://doi.org/10.18063/ijb.v9i2.664 236 ascribed to the presence and control release of heparin. On the other hand, the functional groups in the stent surface did influence the medical device interaction with cells and mechanical properties. The amine-rich surface of the stent with PDA and immobilized PEI promoted rapid smooth muscle cells (SMC) proliferation, while the opposite happened for the heparin-loaded stent (Figure8B). On the other hand, heparin-loaded stent increased endothelial cells (EC) proliferation (Figure 8B) and nitric oxide generation, which is desirable for a good patency. The combination of PLA, PDA, and PEI enhanced segmental compression, bending and foreshortening tests. Even if the addition of heparin weakened the mechanical performance, it enhanced the stent flexibility[14]. More recently, a MEX 3D printer has been used to obtain a BRS, photocurable, shape memory cyclodextrin-PCL-paclitaxel (βCD-PCL-PTX) stent, which has appropriate tensile strength, elasticity, and bursting pressure[71]. More recently, SC-3DP has also been proposed for the production of VS medical devices. As previously emphasized, SC-3DP is considered a PBF or MEX 3DP, depending on the ingredients and the printing process. Singh etal. used this technique to obtain a PCL-carbonyl iron powder (CIP) stent-like structures[72], meaning that they worked with a polymeric base dissolved in an organic solvent that evaporated as extruded. No sintering is required and debinding occurs by evaporation of the organic solvent. The authors highlighted the fact that no other previous studies have ever reported the use of this 3DP process as a VS manufacturing technique. Nevertheless, no VS 3D constructs were produced, but the attention was focused on the effect of CIP as a PCL reinforcement as well as on the final biological performance of the printed composite. The role, properties and potential usefulness of CIP will be addressed in later sections. 4.2. Vat photopolymerization 3DP as vascular stent manufacturing technique As previously mentioned, VPP 3DP techniques work with a liquid raw material that undergoes solidification by different mechanisms, depending on both the material itself and the specific 3DP methodology used. For the production of VS, photocrosslinkable resins and polyesters are able to provide suitable mechanical properties after curing; therefore, they can be used as vascular endoprothesis. Micro-continuous liquid interface printing (micro CLIP) is a technique that works with a similar principle to that of DLP. The speed, reproducibility, and fidelity of this 3DP possess a high potential in the production of in situ, tailor-made BRS. Van Lith etal. used a customized micro CLIP for the production of a photocurable, antioxidant and bioresorbable metacrylated biomaterial (poly(1,12dodecamethylene citrate), mPDC) by mixing citric acid and 1,12-dodecanediol, THF[73]. The photocuring process transforms the initial material into a bioresorbable one, which can be used as a biomaterial ink for the production of VS and shows in vitro degradation of 25% (PBS, 37°C) within 6 months. Upon deployment, the fabricated stent was able to self-expand properly, reaching the original diameter in just 3 min. This self-expansion was reported to be faster than the expansion of other commercial BRS, taking time from 3 to 8 min. Moreover, the final mechanical properties of these 3D-printed BRS were comparable to bare-metal nitinol stents, making them a feasible formulation for the production of customizable, personalized BRS. Later, authors reported an in-process calibration method for the same micro CLIP printing process, aiming to reduce the total fabrication time from 70min to 20-11 min depending on the layer slicing thickness of the stent[74]. They also optimized the ingredients and concentrations during the printing process by including two photoinitiators: irgacure and ethyl 4-dimethylamino benzoate (EDAB). This combination enabled greater crosslinking and made possible strut geometries. Photocrosslinkable, elastomeric polyesters such as metacrylated poly(dodecanediol citrate) (mPDC) can be used as raw materials for the production of 3D constructs by means of DLP. mPDC polymer has proven to be biodegradable and biocompatible and possess elastic behavior, making it suitable for the production of selfexpandable BRS[75,76]. Oliveira etal. developed a BRS, DES based on mPDC and nitric oxide, and used DLP as 3DP technology to produce a small diameter VS (Figure 9A)[75]. With respect to other active substances, nitric oxide has proven to be more advantageous for stents in terms of cellular proliferation, biocompatibility and restenosis. Moreover, nitric oxide is beneficial to maintain the muscular tonus of the vasculature under treatment, control blood pressure and inhibit platelet adhesion. Although the authors proposed this approach for a coronary stent, its translation into a peripheral one could be more beneficial if blood pressure and muscle tone of the peripheral vessels are lower with respect to coronary arteries. Moreover, it has recently been demonstrated that the nitric oxide system and its regulators are compromised in PAD[77]. Nitric oxide release was achieved by the S-nitrosation of N-acetyl-d-penicillamine (SNAP) of the 3D-printed construct via liquid adsorption[75]. The self-expanding properties of the stent were confirmed due to good elastic response up to 50% strain. In fact, the stent completely recovered its initial dimensions after being collapsed and crimped (Figure 9C). Nevertheless, the authors stated that an optimal cure is needed for the mechanical properties to be maximized, meaning that the DLP printing process International Journal of Bioprinting Coronary and peripheral artery disease. State of the art. Volume 9 Issue 2 (2023) https://doi.org/10.18063/ijb.v9i2.664 237 (Figure 9B) must be previously optimized. The release of nitric oxide from mPDC/SNAP BRS is directly related to the surface in contact with the aqueous biological medium, suggesting that the modulation of the final stent geometry can be an important variable to control the nitric oxide release[75]. This can be interpreted as follows: 3DP enables the production of customized VS in terms of not only dimensions, but also particular therapeutic needs when it comes to DES. 4.3. Material jetting 3DP as vascular stent manufacturing technique MJT 3DP is based on the deposition of liquid droplets. It is complicated to obtain intricate, high-resolution structures such as those required for the production of VS by this 3DP technique. Moreover, the manufacturing of MJTprinted constructs depends on the rapid solidification or instantaneous curing (such as photo-crosslinking) of the droplets as they are deposited, in an attempt to minimize the liquid ink to flow over the previously deposited layer. Under these circumstances, MJT is a challenging technique when it comes to VS. Nonetheless, it can be of great usefulness in combination with other methods. In an attempt to improve the drug coating process of stent struts, Scoutaris etal. referred MJT 3DP to as a reliable, robust, and reproducible technique in controlling and guaranteeing the proper drug-coating of an intravascular Figure 9. (A) Photographs and scanning electron microscopy of mDPC-SNAP stent. (B) Schematic representation of the DLP printer used. (C) Stress– strain compression curves for uncured and post-cured mPDC stents at different times and with different diameters (a and b). Photographs frames of a stent of 6 mm diameter during stress–strain compression test (c–e). Reproduced with permission from [75] 2021, Bioprinting. International Journal of Bioprinting Coronary and peripheral artery disease. State of the art. Volume 9 Issue 2 (2023) https://doi.org/10.18063/ijb.v9i2.664 238 stent[19]. The quality of stent drug-coating is crucial for two main reasons: (i) it influences the drug release rate, and (ii) it affects the superficial texture of the VS as an irregular coating could lead to rough surfaces. Therefore, a smooth stent surface would minimize the injury of blood vessels during the implantation of the medical device. They aimed to improve the traditional stent drug-coating procedures, thereby reducing the time required and material waste. Thus, they MJT-printed PLA/simvastatin and PLA/ paclitaxel solutions over different already-existing BMS (PresillionTM and CypherTM stents) by means of a piezodriven dispenser. The authors reported that “tips with 300 pL aqueous droplet volume are suitable for stent coating (…) while smaller volumes (100 pL) resulted in clogging of the nozzle”[19]. Another important factor to bear in mind is the voltage used, since an inadequate voltage could lead to bubble formation inside the ink tip, jeopardizing the printability. The comparison between the final coating of two commercial stents with different geometries indicates the need for MJT drug-coating optimization according to the shape of each medical device to avoid irregular drugcoating. The in vitro drug release profiles of simvastatin and paclitaxel, separately, revealed burst release for the first 5 days, followed by a first-order release until day 30 in both cases. A successful implantation in male Wistar rats was reported, without inflammatory and cytotoxicity response within 7 days. Therefore, MJT-printing for stent drug-coating can be used to optimize and maximize the performance of DES. 4.4. Powder bed fusion 3DP as vascular stent manufacturing technique PBF 3DP is usually associated to strong, hard materials. In fact, metal powders are most frequently used in PBF 3DP techniques to obtain metallic VS. Despite the long-term complications and disadvantages of permanent metallic stents, they are the most widely used (Table 1, Figure 2). Nevertheless, in terms of cutting-edge technologies and research, the efforts are centered on BRS, DES, which means that the number of studies dealing with PBF 3DP techniques is scarce. Laser-cutting and braiding are the most commonly used manufacturing techniques for the production of metallic VS. When it comes to 3DP, PBF is commonly used to print metallic materials. Demir and Previtali demonstrated the feasibility and convenience of PBF and the subsequent electrochemical polishing to produce a CoCr stent with respect to the conventional manufacturing cycles (microtube production followed by laser-cutting)[37]. In this technique, different scan strategies can be followed (parallel or concentric scanning), giving rise to different results. The authors highlighted the importance of a proper stent design and manufacturing orientation together with some basic rules during PBF printing process. With PBF printing, layer plane supports are needed when angles smaller than 45° are created; overhanging regions up to 1 mm can be built without supports; minimum gaps of 0.3mm are recommended between separate features, etc.[37] According to these requirements, they designed a stent with hexagonal, zig-zag pattern forming a closed cell without flex-connectors (Figure 10A). This geometry avoided the requirements of support structures during PBF 3DP. Their attention was clearly centered on the optimization of the 3DP manufacturing, not in the final properties of the final stent, so the tensile strength, recoil and fatigue resistance were not characterized in this study. Depending on the laser scanning pattern, the laser pulse duration and peak power must be optimized. They also concluded that increased peak power and pulse duration reduced surface roughness. For the particular geometrical design of this VS, the parallel strategy gave rise to irregular geometry, thickness, and surface roughness, thus highlighting the inadequacy of this strategy for the production of micro-geometries (Figure 10C). On the contrary, concentric scanning and higher printability were achieved (Figure 10C). Additionally, PBF 3DP produces items with very rough surfaces, implying that post-processing techniques such electro-polishing are compulsory to reduce harm during stent implantation (Figure 10B)[37]. Despite the fact that metallic substrates are the most frequent in PBF, there are also some exceptions. For instance, some years ago, Flege et al. adapted the PBF 3DP technique to produce a BRS vascular stent made of PLLA and PCL[78]. Since this 3DP technique requires powdery raw materials for the printing process, PLLA and PCL polymers were subjected to solvent-evaporation processes to obtain homogeneous, small particles so that they could then be used in PBF; both PCL and PLLA particles possessed good flowability, regular spherical shape, narrow particle size distribution, and high density. Moreover, the laser of the PBF printer was adapted by adding a power attenuator. The attention of this study was therefore centered on the ability to produce stents from these raw materials and to monitor the stability of the resultant ingredients after the PBF printing and gammairradiation sterilization. The biocompatibility of the stents and the materials was assessed using human arterial smooth muscle cells (haSMCs), human umbilical vein endothelial cells (HUVECs), and endothelial progenitor cells (EPCs). First, the manufacturing of PCL and PLLA powder particles did not jeopardize their biocompatibility, unlike the printing process, which reduced metabolic activity of the EPCs. The authors ascribed this result to the presence of polymerization initiators in stent International Journal of Bioprinting Coronary and peripheral artery disease. State of the art. Volume 9 Issue 2 (2023) https://doi.org/10.18063/ijb.v9i2.664 239 surfaces. Gamma-irradiation was an effective sterilization procedure, although it also affected the structure of the polymers and their biological performance. haSMCs proliferation and metabolic activity were inhibited due to surface modifications of the polymers during sterilization, while EPCs were unaffected. Flege etal. highlighted this result as a positive one, since it “might favor the prevention of neointimal hyperplasia in stented vessels”[78]. This study demonstrated the versatility of 3DP techniques to be adapted to print a wide variety of materials, meaning that none of them can be dismissed as useful ally in the production of medical devices in future. 5. Computational studies and 3D printing Several studies have demonstrated that stent design features are of great importance for a successful treatment due to correlations with thrombosis and in-restenosis risk[33,79,80]. For better clarity and understanding of this section, a schematic representation of the most important stent parts and their nomenclature are included in Figure 11A. The implanted VS induces disturbances in blood flow and alters shear stress of wall vessels at the strut level. These factors highly influence the pathophysiological mechanisms leading to VS complications[81]. Focusing on the structural and geometrical design of VS, the first manufactured stents could be classified into slotted geometries and coil geometries. The former ones possessed higher radial strength but lacked flexibility, as compared to their coil counterparts. Afterward, VS geometries have greatly evolved and changed, with more complicated and perfected geometries included, and are adapted to their final scope (Table 3). Nowadays, coil stent geometries are more commonly used for non-vascular stents, being more frequent to find helical spiral designs for VS. Woven (braided or knitted) designs can be made of more than one strand (made of different materials) and they are traditionally used for the production of self-expandable VS, although balloon-expandable examples can also be found. VS with individual rings frequently use zig-zag wire (struts) that should be attached to one another to form the final stent or vascular prosthesis. If individual rings are connected to each other with a certain consistent pattern, the stent possesses the so-called “sequential ring connection.” In this occasion, the zig-zag struts are connected through “bridges,” “hinges,” or “nodes,” placed in every strut inflection point (regular connection), in a subset of inflection points alternating with unconnected ones (periodic connection) or they can be placed to join the outer radii (peak-peak bridging elements) or to join inner radii with outer radii (peak-valley bridging elements). The stent bridges can have different shapes such as V, L, N, W, S shapes, etc., as well as multiple shapes all combined in the same structure (Figure 11C). These connections play an important role in the optimization of the final performance of the stent, especially in their Figure 10. (A) Digital stent prototype optimized for PBF 3DP. (B) Scanning electron microscopy images of printed VS after electrochemical polishing; images at the upper panel belong to VS produced by hatching PBF scanning, whereas images at the lower panel correspond to a stent produced with concentric scanning PBF. (C) Scanning electron microscopy images of 3DP CoCr VS produced by hatching (top) or concentric strategy laser scanning (bottom) and their differences. Laser pulse duration is indicated in each case. Reproduced with permission from [37] 2019, Materials & Design. International Journal of Bioprinting Coronary and peripheral artery disease. State of the art. Volume 9 Issue 2 (2023) https://doi.org/10.18063/ijb.v9i2.664 240 mechanical properties, as recently reviewed by Pan etal.[82] Within these stents, it is possible to differentiate between “closed cells” and “open cells” (Table 3)[28]. Nowadays, it is also possible to find commercial stents with different strut width in the same device, such as NIRxcellTM stent system (Figure 11B) and others with non-uniform cell sizes and shapes (Figure 11D). The preparation of different stent designs and the experimental study of their correlation with stent performance and future complications is not feasible from an experimental point of view due to the milieu of possible designs (Table 3), dimensions, materials, hemodynamics, etc., together with the long-term studies and the number of replicates. For example, some authors and manufacturers advocate for stents with thinner struts to improve and aid re-endothelialization[83,84], but this can significantly influence the VS deliverability, flexibility, friction, amount of vessel wall coverage, and drug delivery, if applicable. In this regard, computational studies or in silico studies are of great usefulness, enabling digital simulations to predict the final properties and performance of a particular stent. From a medical point of view, 3DP is an especially robust, versatile technique for the manufacturing of personalized, in situ VS prior to the surgical intervention and adapted to the particular type of lesion and blood vessel. From the research point of view, 3DP is also useful in the production of stents with different geometries enabling the study of the influence that each design would be upgraded to as a medical device. Therefore, 3DP is the perfect method for rapidly confirming or denying computational studies. Misra et al. used computational studies to explore different PCL-GR geometries and simulate the deformation of the stent during crimping and expansion[70]. The simulations helped to discern the most optimal stent design, thus accelerating the production of the CAD model for 3DP. In a similar way, Cabrera etal. used computational studies to translate the results into a physical polymer prototype through FDM 3DP[85]. The idea was to fabricate a stent with a flexible, BRS thermoplastic co-polyester elastomer (TPC) having physical properties similar to that of a commercially available nitinol stent, including self-expanding ability. Computational studies enabled the anticipation and adjustment of the final stent performance by changing the width, thickness, and strut number. After selecting the desirable stent parameters, dimensions and geometry as well as obtaining adequate crimping and crush computational results, the TPC stent was printed with FDM. The experimental mechanical studies were in agreement with the computational models, confirming the ability of computational simulations to build realistic prototypes. Figure 11. (A) Schematic representation of stent parts and nomenclature. (B) Geometrical design of commercial NIRxcell stent, which possesses different strut widths within the same structure. (C) Some examples of strut connections. (D) Non-uniform Poisson’s ratio stent 2D structure. Reproduced with permission from [82] 2021, Micromachines. International Journal of Bioprinting Coronary and peripheral artery disease. State of the art. Volume 9 Issue 2 (2023) https://doi.org/10.18063/ijb.v9i2.664 241 6. The importance of ingredients for the manufacturing of vascular stents In the development of cardiovascular grafts and stents, the use of material such as nanocomposites has greatly evolved throughout the years. A nanocomposite is a material of heterogeneous composition (organic, inorganic or hybrids) including ingredients mixed at the nanometer scale. Usually, nanocomposites are made of a polymericlike matrix hosting another ingredient with functional activity (therapeutic, crosslinking, reinforcing, etc.). Apart from the composition and ingredient concentration, the production methodology is also important for the successful nanocomposite performance, including production technique, type of ingredients, reactions/interactions between the nanocomposite components, among others[86]. Clays, carbon, metals and glass ingredients have proven their usefulness as nanocomposite reinforcing or fillers, enabling not only the carriage and delivery of therapeutic ingredients, but also the improvement of mechanical features and rheology. When it comes to medical devices, the biocompatibility of the nanocomposite is crucial to guarantee their safety after implantation. In the particular case of cardiovascular medical devices (vascular grafts and VS), carbon-based ingredients (carbon nanotubes, graphene, etc.) have proven their biocompatibility[86]. Graphite, graphene, and carbon nanotubes are allotropic carbon forms, which differ from each other by spatial disposition. Graphene is a monolayer of carbon atoms linked to each other forming a hexagonal honeycomb lattice. Graphite, on the other hand, occurs when graphene layers are stacked in the z-plane and held together by van der Waals forces. Carbon nanotubes (CNT) are tubular graphene sheets. Depending on the number of tubular sheets, CNT can be divided into single-walled CNT (typically abbreviated as SWCNT) or multi-walled CNT, which is when more than two layers are combined (MWCNT). The main interest of these synthetic materials lies in their biocompatibility. Vellayappan etal. reviewed the usefulness of these materials in the development of vascular grafts and stents[86]. Carbon-based materials are useful as anticoagulant ingredients and can promote cellular growth Table 3. Classification and features of most frequently used VS designs and geometries Geometry Scheme Strengths Weaknesses Helical spiral • High flexibility (minimal internal connection points) • Can be subjected to elongation and compression during delivery • Lack of longitudinal support Woven (braided, knitted) • Offer remarkable coverage of the stenosed region • Frequent recoil events after expansion • Radial strength dependent on axial fixation of their ends Individual rings • Useful as vascular grafts • Easy to produce • Highly flexible • Versatile • Require additional support or connection with other pieces/rings Sequential rings Closed cells (peak-to-peak connections) • Regular bridging elements lead to improved strength • Optimal scaffolding and support • Flex connectors (with different shapes) allow for higher flexibility due to plastic deformation of the bridging element during implantation • Generally less flexible than opened structures, especially if too much bridging, rigid connections are used Open cells (peak-to-peak, peak-to-valley, myriad of hybrid combinations). • Longitudinal flexibility thanks to unconnected struts regions • Peak-to-valley connections optimize scaffolding due to higher alignment • Peak-to-valley sacrifices strength with respect to peak-to-peak connections Table constructed based on the review of Stoeckel etal.[28]. International Journal of Bioprinting Coronary and peripheral artery disease. State of the art. Volume 9 Issue 2 (2023) https://doi.org/10.18063/ijb.v9i2.664 242 and mechanical properties of polymers such as a PLGA, PCL, PCLA (poly(L-lactide-co-ε-caprolactone))[87-92]. For the particular case of mechanical reinforcement, the homogeneous dispersion of carbon nanotubes is crucial to ascertain optimal mechanical strength[92]. Consequently, there is no direct relationship between the amount of CNT and the mechanical improvement, since very high concentration could lead to heterogeneous dispersion, which hinders the mechanical performance of the nanocomposite. Graphene (GR) has demonstrated to be a useful ingredient to improve both mechanical properties of VS and control drug release from drug-eluting VS. The literature regarding 3DP and GR is currently scarce, but there are clear indications of the usefulness of graphene as an ingredient to improve the mechanical and biological properties of stents. Carbon is one of the materials with higher hemocompatibility due to chemical inertness, minimal platelet activation and favorable conformational changes[93]. Coating is the most common strategy to add GR to VS[94-96]. Nitinol VS coated with GR had improved biological properties compared to its counterpart[94]. Briefly, GR coating inhibited platelet activation and was fully biocompatible with smooth muscle cells. Likewise, excellent bioand hemocompatibility was reported for a coated stainless steel VS[96]. In this occasion, a coating mixture containing poly(3,4-ethylenedioxythiophene) polystyrene sulfonate (PEDOT:PSS), graphene oxide (GO), and heparin was deposited over the stainless steel VS (SUS316) by electrochemical polymerization. This process gave rise to a stent with high hydrophilic nature, which can prevent platelet adhesion following implantation. GO contributed the most to this effect, while the role of heparin was the minimum. The authors hypothesized that the negative charge of GO created a repulsing force against plasma proteins and platelets (also with a negative net charge)[96]. On the opposite side, GR has also been shown to be a useful coating in BRS stents. Magnesium alloy stents are BRS VS with good mechanical properties. Nonetheless, these stents suffers from a rapid degradation and insufficient biocompatibility. Layer-by-layer deposition method was recently used to coat magnesium alloy VS with GR functionalized with chitosan[95]. The authors stated that the resultant bioactive multilayer coating endowed magnesium alloy with excellent in vitro degradation resistance. Additionally, good blood compatibility (reduced hemolysis and platelet adhesion) and improved expression of vascular endothelial growth factor (VEGF) and nitric oxide were ascribed to the GRbased coating. The study of Misra et al. is one of the few dealing with 3DP, graphene, and VS[70]. A BRS stent made of PCL and graphene and loaded with niclosamide and inositol phosphate reported good anticoagulation and antirestenosis performance. The comparison of the 3D-printed stent with and without graphene helps discern the influence of the inorganic ingredient on the stent performance. The presence of 4% of graphene increased the Young’s modulus of PCL and demonstrated better resistance under artery wall pressure after deployment. By the same token, PCL–graphene stent had a better control of niclosamide and inositol phosphate release. One of the limitations of 3DP for the production of VS lies in the fact that most of the materials used are polymeric, but not all of them are able to be deployed inside the vessels. In this regard, shape memory polymers (SMP), also known as “smart” or “intelligent materials” are currently on the spotlight, not only for 3DP in general[97], but also in the production of VS. In fact, smart materials such as shape memory alloys (such as nitinol) have already been used to fabricate VS, and most of them have been commercialized. SMP are polymeric smart materials with the ability to change their shape while subjected to some triggers such as temperature, electromagnetic fields, photo-activation, electro-activation, contact with water (swelling), pH medium changes, etc. Disregarding the triggering stimulus, all these smart materials are used in a two-step manner[97,98]. The “programming step” is the shape-memory creation process, where the permanent, original shape is changed to a secondary (temporary) one by subjecting the material to external stress forces (mechanical stress). Under these circumstances, the SMP acquires a desirable shape and maintains it after stress removal. Then, after the exposure of the shaped structure to other nonmechanical triggers (e.g., heat, light, pH change), it is able to recover the original, permanent shape by reverting the shape it acquires during the application of mechanical forces. Hence, SMP have the ability to store mechanical stress and release it under non-mechanical stimuli. Depending on the nature of the material, the mechanism of shape modification is different. For the particular case of SMP, they share the presence of “permanent netpoints” or “permanent links” in their internal network structure and “temporary links” or “switches.” The permanent links are responsible for the permanent shape, the so-called “memory effect,” and therefore, these netpoints are not affected by mechanical deformation. On the other hand, switches are formed during mechanical stress due to the conformational freedom of some of the polymer chains. The deformation obtained during the programming step can be stabilized by the formation of these “temporary links” within the polymer structure. When it comes to thermalsensitive polymers, the difference between permanent links and temporary links lies in the existence of more than International Journal of Bioprinting Coronary and peripheral artery disease. State of the art. Volume 9 Issue 2 (2023) https://doi.org/10.18063/ijb.v9i2.664 243 one thermal transition. Those domains with the highest thermal transition (glass transition temperature, Tg or melting temperature, Tm) are responsible for the memory shape or permanent shape, whereas switching domains that possess the second highest thermal transition (Tg or Tm) is responsible for the temporary shape[97,98]. SMP also possesses useful properties, such as lightweight, large elastic modulus and flexibility, as well as biodegradability[97]. A polyurethane SMP was successfully used to obtain a bifurcated stent deployable in just one step[65,66]. When vascular stenosis occurs in a bifurcated vessel (vessel with Y-shaped lumen), two cylindrical stents must be inserted and subsequently joined, which complicates the intervention. Thanks to the intrinsic properties of SMP, Kim et al. were able to fabricate a one-piece, bifurcated stent combining two different geometrical designs: the trunk of the stent (main vessel) possessed a conventional wavy pattern, whereas the bifurcated zone was designed with a “kirigami-like” structure (Figure 12A). Kirigami is a superset of origami with the addition of cutting[66]. For deployment, an intelligent strategy was also applied: the two bifurcated vessels will be folded and fitted with one another (like a puzzle) to form a full, cylindrical piece that is will be taken to the deployment area (Figure 12B). Once there, the folded branches will bifurcate and deployed in both vessels in just one step after the application of temperature as a trigger (Figure 12C)[65,66]. The main drawback of this particular stent was the mismatch between the temperature that triggers the SMP to unfold (55°C–60°C) and the temperature of the human body. A recent study demonstrates the possibility of modifying the glass transition temperature of SMP, bringing it closer to a more physiological temperature range[64]. The authors synthetized biodegradable poly(glycerol dodecanoate (PGD, transition temperature of 22.5°C–43.6°C) and subsequently modified it to obtain poly(glycerol dodecanoate acrylate) (PGDA) through glycerol and docecanedioic polycondensation. The resultant material wa photocurable and showed a final transition temperature of 20°C–37°C, which was much closer to the physiological range. After being printed and photocured with UV light, the PGDA construct was thermally cured at 145°C in an oven. Then, the construct was deformed to create the “crimped state” of the stent. With further heating above the transition temperature (20°C–37°C), the stent recovered its initial state within 8 seconds. Similar mechanical properties between the printed stent and the soft biological tissues at 37°C was found, demonstrating mechanical adaptation Figure 12. Design and real aspect of bifurcated self-expandable stent produced by FMD using a shape memory polymer. The bifurcated branch is able to deform until the formation of a single conduit, thereby allowing implantation. The suitability of this VS for deployment in a bifurcated vessel was tested in a silicon, transparent mold. Scale bars: 20 mm. Reproduced with permission from [66] 2018, Scientific Reports. International Journal of Bioprinting Coronary and peripheral artery disease. State of the art. Volume 9 Issue 2 (2023) https://doi.org/10.18063/ijb.v9i2.664 250 18. Ooi OC, Mullany CJ, Rihal CS, 2007, Revascularization options for ischemic heart disease: Coronary artery bypass grafting and percutaneous coronary intervention, in Cardiovascular Therapeutics: A Companion to Braunwald’s Heart Disease, 3rd ed., E. M. Antman and M. S. 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