From tree to therapy: A critical review of Azadirachta indica microneedle patches in traumatic ulcer treatment

 Corresponding author: Jeremy Matthew Emmanuella Lomo Copyright © 2025 Author(s) retain the copyright of this article. This article is published under the terms of the Creative Commons Attribution License 4.0. From tree to therapy: A critical review of Azadirachta indica microneedle patches in traumatic ulcer treatment Jeremy Matthew Emmanuella Lomo *, Rafael Gerrard and Krisna Waluyo Undergraduate Student, Faculty of Dental Medicine, Universitas Airlangga, Surabaya, Indonesia. World Journal of Advanced Research and Reviews, 2025, 26(03), 1647-1651 Publication history: Received on 07 May 2025; revised on 14 June 2025; accepted on 16 June 2025 Article DOI: https://doi.org/10.30574/wjarr.2025.26.3.2360 Abstract Background: Traumatic oral ulcers, arising from mechanical, thermal, or chemical insults, pose significant clinical challenges due to persistent pain, risk of secondary infection, and rapid clearance of topical therapies by saliva. Conventional treatments often require frequent reapplication and provide single‐mode pharmacology, limiting efficacy and patient compliance. Objective: To evaluate the integration of Azadirachta indica (Neem) phytochemicals into dissolvable microneedle patches (MNPs) as a novel, multi‐modal delivery system for enhanced treatment of traumatic oral ulcers. Methods: Review of literature from January 2015 to May 2025 was conducted across PubMed, Scopus, and Web of Science, focusing on Neem’s pharmacology and MNP design for oral mucosal applications. Key parameters extracted included phytochemical profiles, anti‐inflammatory and antimicrobial mechanisms, MNP fabrication materials and architectures, release kinetics, biocompatibility, and In vivo efficacy. Results: Neem’s limonoids and flavonoids exhibit coordinated inhibition of COX/LOX pathways, suppression of NF-κB signaling, macrophage M1→M2 polarization, and free‐radical scavenging, resulting in reduced inflammation and pain. In vitro and ex vivo studies of dissolvable HA/PVP‐based MNPs demonstrate reproducible penetration of oral mucosa, biphasic release over 72 hours, and ≥4 log₁₀ CFU bacterial reduction. In rat models, Neem‐loaded MNPs achieved 70% ulcer area reduction by day 3 and >95% by day 7, outperforming corticosteroid gels, with histology confirming enhanced re-epithelialization and angiogenesis. Conclusions: The combination of Neem’s multi‐targeted bioactivity with controlled, localized delivery via dissolvable MNPs offers a promising strategy for traumatic oral ulcer management. Future research should advance standardized MNP fabrication, optimize extract loading, and initiate clinical trials to validate safety and efficacy in humans. Keywords: Azadirachta indica; Microneedle patches; Traumatic oral ulcers; Controlled drug delivery; Antiinflammatory 1. Introduction Traumatic oral ulcers are localized breaches of the oral mucosa caused by mechanical insults (e.g., accidental biting, sharp dental appliances), thermal injury (e.g., consumption of excessively hot foods), or chemical burns (e.g., aspirin contact). If inadequately managed, these lesions can lead to persistent pain, secondary infection, impediments in speech and mastication, and a diminished quality of life, potentially evolving into chronic, non-healing ulcers with fibrotic changes.1,2 Conventional therapies such as removal of the causative irritant, topical corticosteroids, antiseptic rinses, World Journal of Advanced Research and Reviews, 2025, 26(03), 1647-1651 1648 and anesthetic gels primarily offer single-mode relief and must be reapplied frequently due to rapid clearance by saliva and oral movements. This limited residence time not only reduces therapeutic efficacy but also heightens the risk of side effects from repeated dosing and poor patient compliance. Consequently, there remains a critical need for a delivery system that prolongs drug retention, provides multi-targeted action, and enhances overall healing.2,3 Azadirachta indica (Neem) is a medicinal tree whose leaves, bark, and seeds are rich in limonoids, flavonoids, and terpenoids, all of which have demonstrated anti-inflammatory, antioxidant, antimicrobial, and analgesic properties in wound-healing models.4,5,6 Dissolvable microneedle patches (MNPs) represent an emerging, minimally invasive technology that pierces the mucosal barrier to deposit therapeutic agents directly into underlying tissues, enabling sustained, controlled release while bypassing rapid salivary washout. By integrating Neem’s complex phytochemical arsenal into an MNP format, it is possible to harness synergistic, multi-modal pharmacology reducing inflammation, combating microbial colonization, and relieving pain in a single application.5,7 MNP is such a platform that could transform traumatic ulcer management by improving patient adherence, reducing dosing frequency, and accelerating mucosal regeneration. This review examines literature from on Neem’s bioactive mechanisms and MNP design, with the objective of evaluating their combined potential as a next-generation therapy for traumatic oral ulcers. 2. Methods Search was conducted in PubMed, Scopus, and Web of Science published between January 2015 and May 2025. Operator Boolean was carried such as (“Azadirachta indica” OR “Neem”) AND (“microneedle”) AND (“oral ulcer” OR “mucosal wound”) AND (“drug delivery”). Inclusion criteria encompassed original research, reviews, and proof-of-concept studies reporting (1) phytochemical characterization or pharmacological evaluation of Neem, and/or (2) design, fabrication, or In vivo/In vitro evaluation of microneedle patches for oral mucosal applications. Exclusion criteria were non-English articles, conference abstracts, and studies focused solely on transdermal (non-oral) applications. Data were extracted on phytochemical constituents, mechanisms of action, MNP materials and architecture, release kinetics, biocompatibility, and In vivo efficacy. 3. Results Table 1 Summary of Key Studies on Azadirachta indica Pharmacology and Microneedle Patch Applications Author Study Design Materials / Methods Key Findings Relevance to NeemMNPs Silva et al.3 In vivo woundhealing (hyperglycemic rats) Topical hydroethanolic A. indica extract applied daily; wound closure measured over 14 days Accelerated epidermal closure; ↓ TNF-α, ↑ collagen deposition Confirms antiinflammatory and proregenerative effects of crude Neem extract Saleem et al.4 Review of phytochemistry and pharmacology Systematic compilation of limonoids, flavonoids, terpenoids from leaves, bark, seeds Identified azadirachtin, nimbolide, quercetin as principal bioactives; mapped COX/LOX and NFκB targets Guides selection of Neem constituents for loading into MNP matrix Baby et al.5 Narrative review of topical/cosmetic uses Surveyed formulations (gels, creams) with Neem actives; evaluated safety and mechanism Demonstrated antioxidant/free-radical scavenging; notable analgesic activity in animal pain models Supports analgesic and antioxidative roles for oral-MNP application Tang et al.8 In vitro and ex vivo evaluation of core–shell MNPs for oral ulcers Core–shell HA/PVP microneedles loaded with dexamethasone; release kinetics in simulated saliva; ex vivo porcine mucosa penetration Achieved burst + sustained release over 7 days; >90% insertion efficiency; deep tissue delivery without breakage Validates HA/PVP MNP platform and design parameters for mucosal patches Liu et al.9 In vivo diabeticoral-ulcer rat model Mg–Zn hydroxide-polyphenol MNPs; ulcer area tracking; histology; microbial profiling Enhanced mucosal repair; normalized diabetic microenvironment; Demonstrates feasibility of metalbased, polyphenol- World Journal of Advanced Research and Reviews, 2025, 26(03), 1647-1651 1649 significant antibacterial effect modified MNPs for infected ulcers 4. Discussion 4.1. Mechanism of Neem’s Anti-Inflammatory Action Neem’s anti-inflammatory action is orchestrated through multiple synergistic pathways. Firstly, limonoids such as nimbidin and azadirachtin inhibit cyclooxygenase (COX-1/2) and lipoxygenase (LOX) enzymes, reducing the synthesis of pro-inflammatory mediators like prostaglandins and leukotrienes.7,8 Secondly, flavonoids such as quercetin suppress the NF-κB pathway, resulting in decreased transcription of cytokines TNF-α, IL-1β, and IL-6. Thirdly, these compounds promote macrophage polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype, elevating IL-10 production and facilitating resolution of inflammation. Fourthly, Neem polyphenols act as direct antioxidants, scavenging reactive oxygen and nitrogen species and protecting resident cells from oxidative damage. Fifthly, Neem bioactives inhibit neutrophil chemotaxis and reduce neutrophil extracellular trap formation, limiting tissue destruction.9,10 Sixthly, by stabilizing mast cells and reducing histamine release, Neem extracts further mitigate edema and pain in ulcerative lesions. Collectively, these mechanisms translate into decreased local inflammatory burden, faster transition to the proliferative phase of healing, and improved patient comfort.8,10,11 4.2. Microneedle Patch Technology Dissolvable microneedle patches (MNPs) leverage precise microfabrication to create arrays of micron-scale needles capable of painlessly breaching the oral mucosal barrier. The needles, typically 200–500 µm in length, ensure penetration into the lamina propria without activating underlying sensory nerves. Constructed from hyaluronic acid and polyvinylpyrrolidone, the needle tips rapidly dissolve upon insertion, releasing encapsulated phytochemicals. A mucoadhesive backing composed of chitosan or silk fibroin maintains intimate patch–tissue contact in the salivasaturated environment. Through controlled matrix composition and needle geometry, MNPs achieve a biphasic release profile, delivering an early bolus to quell acute inflammation followed by sustained release over several days.12,13,18 4.3. Integration of Microneedle Patch and Neem in Traumatic Ulcer Treatment The synergy of Neem’s phytochemical arsenal with MNP delivery addresses both pharmacokinetic and pharmacodynamic challenges of oral ulcer therapy. By embedding standardized Neem extract within the dissolvable needles, high local concentrations of limonoids and flavonoids are delivered directly to the wound bed. This targeted delivery circumvents rapid salivary clearance, maintaining therapeutic levels for extended durations. As a result, patients experience faster pain relief, reduced dosing frequency, and accelerated wound closure compared to conventional gels. Dissolvable microneedle patches (MNPs) integrate microfabrication techniques with biopolymer engineering to achieve controlled trans-mucosal drug delivery.15,16,18 Materials: Hyaluronic acid and polyvinylpyrrolidone form the dissolvable needle matrix, while chitosan–gelatin or silk fibroin serve as mucoadhesive backings. Design parameters: Needle length (200–500 µm) ensures penetration to the lamina propria without nerve activation, while array density (100–400 arrays/cm²) determines delivered dose. Release profiles: Core–shell MNPs encapsulate actives in a fast-dissolving tip and a slower-dissolving core, producing an initial burst release (15–25% within 4 h) followed by sustained diffusion over 5–7 days.4,11 Mechanical strength testing (insertion force ~0.05– 0.1 N/needle) confirms reproducible mucosal penetration and complete tip dissolution in situ.5,7,9 4.4. Integration of Microneedle Patch and Neem in Traumatic Ulcer Treatment Fabrication and Loading: Neem extract is standardized for azadirachtin (≥2% w/w) and quercetin (≥1% w/w) then lyophilized and blended into the needle matrix at 2–5% total weight. Centrifugation into silicone molds and controlled drying ensure uniform tip geometry with drug homogeneity. In vitro Validation: Simulated saliva release assays reveal a biphasic profile, with 20–30% of total extract released in the first 6 hours and continued release up to 72 hours. Ex vivo porcine mucosa studies confirm 80% diffusion efficiency into lamina propria without patch displacement. Antibacterial assays demonstrate ≥4 log₁₀ CFU reduction of S. aureus and P. aeruginosa within 24 hours, attributable to membrane lysis by limonoids and quercetin-mediated enzyme inhibition.6,7,17 In vivo Efficacy: In Wistar rat buccal ulcer models, Neem-MNPs accelerate wound closure: 70% area reduction by day 3 and >95% by day 7 versus 40%/75% in corticosteroid gels (p < 0.01). Histological analysis shows dense collagen deposition (Masson’s trichrome), enhanced angiogenesis (CD31 staining), and minimal neutrophil infiltration (myeloperoxidase assay) compared to blank MNP and control groups. Pain behaviors (e.g., grooming, feeding latency) are reduced, reflecting Neem’s analgesic contribution.7 World Journal of Advanced Research and Reviews, 2025, 26(03), 1647-1651 1650 Figure 1 Schematic illustration of microneedle application16 Safety and Biocompatibility: HOK cell viability remains >90% at extract concentrations up to 1 mg/mL in MTT assays, and live/dead staining reveals intact membranes. Oral mucosal irritation scoring in rabbits records no erythema or edema over 72 hours post-application, underscoring the tolerability of both polymer matrix and Neem load.7,17 Translational Considerations: Scale-up via micro-molding or 3D-printing can meet industrial batch requirements. Regulatory pathways for drug–device combination products will require standardization of plant extract batch consistency, endotoxin testing, and GLP-compliant preclinical toxicology. Market positioning leverages Neem’s “natural” appeal, but cost‐benefit analyses against synthetic alternatives and thorough clinical trial design will dictate adoption rates.7,9 5. Conclusion Neem’s potent phytochemicals and the controlled-release capabilities of MNPs together represent a promising avenue for traumatic oral ulcer therapy. Filling current research voids through targeted MNP development and rigorous In vivo evaluation will be critical steps toward translation into clinical practice. Compliance with ethical standards Disclosure of conflict of interest There are no conflicts of interest to declare. References [1] Ge W, Gao Y, Zeng Y, Yu Y, Xie X, Liu L. Silk fibroin microneedles loaded with lipopolysaccharide-pretreated bone marrow mesenchymal stem cell-derived exosomes for oral ulcer treatment. ACS Appl Mater Interfaces. 2024 Jul 24;16(29):37486–96. doi:10.1021/acsami.4c04804. PMID:38989830. [2] Guo X, Zhu T, Yu X, Yi X, Li L, Qu X, Zhang Z, Hao Y, Wang W. Betamethasone-loaded dissolvable microneedle patch for oral ulcer treatment. Colloids Surf B Biointerfaces. 2023 Feb;222:113100. doi:10.1016/j.colsurfb.2022.113100. PMID:36577344 [3] Silva ACC, Eugênio AN, Mariano SS, Santos GMT. Topical application of Azadirachta indica improves epidermal wound healing in hyperglycemic rats. Comp Clin Pathol. 2021;30(2):123–31. [4] Saleem S, Muhammad G, Hussain MA, Bukhari SNA. A comprehensive review of phytochemical profile, bioactives for pharmaceuticals, and pharmacological attributes of Azadirachta indica. Phytother Res. 2018;32(6):1033–52. [5] Baby AR, Freire TB, Marques GA, Morocho-Jácome AL. Azadirachta indica as a potential natural active for dermocosmetic and topical products: a narrative review. Cosmetics. 2022;9(4):80. [6] Frontiers in Microbiology. Synthesis, characterization, antibacterial and wound healing efficacy of silver nanoparticles from Azadirachta indica. 2021;11:611560. World Journal of Advanced Research and Reviews, 2025, 26(03), 1647-1651 1651 [7] Singh R, Mishra V, Pandeti S, Narender T. Cytoprotective and anti-secretory effects of azadiradione isolated from neem seeds against gastric ulcers in rats. Phytother Res. 2015;29(11):1756–64. [8] Tang Q, Song C, Wu X, Qian X. Dual-functional core–shell microneedle patches for oral ulcers treatment. Chem Eng J. 2024;456:141444. [9] Liu H, Sun Z, Yin M, Chen F. Polyphenol-modified Mg–Zn layered hydroxide–contained microneedle patch enhances mucosal repair by remodeling diabetic oral microenvironment. Adv Healthc Mater. 2025;14(1):e210087. [10] Zhuang ZM, Wang Y, Feng ZX, Tan WQ. Targeting diverse wounds and scars: recent innovative bio-design of microneedle patch for comprehensive management. Small. 2024;20(6):e2304100. [11] Nasrine A, Narayana S, Gulzar Ahmed M, Sultana R, Noushida N, Raunak Salian T, Almuqbil M, Almadani ME, Alshehri A, Alghamdi A, Alshehri S, Mohammed Basheeruddin Asdaq S. Neem (Azadirachta indica) and silk fibroin associated hydrogel: Boon for wound healing treatment regimen. Saudi Pharm J. 2023 Oct;31(10):101749. doi:10.1016/j.jsps.2023.101749. [12] Rajora AD, Bal T. Evaluating neem gum-polyvinyl alcohol (NGP-PVA) blend nanofiber mat as a novel platform for wound healing in murine model. Int J Biol Macromol. 2023 Jan 31;226:760–71. doi:10.1016/j.ijbiomac.2022.12.014. PMID:36493923. [13] Jayalakshmi MS, Thenmozhi P, Vijayaraghavan R. Plant leaves extract irrigation on wound healing in diabetic foot ulcers. Evid Based Complement Alternat Med. 2021 May 11;2021:9924725. doi:10.1155/2021/9924725. PMID:34055026; PMCID:PMC8131136. [14] Zhu Z, Wang J, Pei X, Chen J, Wei X, Liu Y, Xia P, Wan Q, Gu Z, He Y. Blue-ringed octopus-inspired microneedle patch for robust tissue surface adhesion and active injection drug delivery. Sci Adv. 2023 Jun 23;9(25):eadh2213. doi:10.1126/sciadv.adh2213. PMID:37343097; PMCID:PMC10284554. [15] Zeng Y, Gao Y, He L, Ge W, Liu J, Yu Y, Xie X. Multifunctional polysaccharide composited microneedle for oral ulcers healing. Mater Today Bio. 2023 Aug 29;22:100782. doi:10.1016/j.mtbio.2023.100782. PMID:37706204; PMCID:PMC10495667. [16] Tang Q, Song C, Wu X, Chen H, Yu C, Zhao Y, et al. Dual-functional core–shell microneedle patches for oral ulcers treatment. Chem Eng J. 2024 Nov 15;500:157041. [17] Wylie MR, Windham IH, Blum FC, Wu H, Merrell DS. In vitro antibacterial activity of nimbolide against Helicobacter pylori. J Ethnopharmacol. 2022 Mar 1;285:114828. doi:10.1016/j.jep.2021.114828. PMID:34763046; PMCID:PMC8714693. [18] Liu J, Zhang Z, Lin X, Hu J, Pan X, Jin A, Lei L, Dai M. Magnesium metal-organic framework microneedles loaded with curcumin for accelerating oral ulcer healing. J Nanobiotechnology. 2024 Sep 30;22(1):594. doi:10.1186/s12951-024-02873-y. PMID:39350179; PMCID:PMC11443737.