Drew Seymour

Background: Type II diabetic wounds represent a major and growing clinical challenge due to impaired self-healing, chronic inflammation, diminished angiogenesis, and increased susceptibility to infection. Diabetic foot ulcers affect millions of individuals globally and remain a leading cause of non-traumatic lower-extremity amputation. Current standard therapies, including glycemic control, debridement, pressure offloading, infection management, and advanced dressings, frequently fail to restore a regenerative wound microenvironment or address the underlying molecular drivers of impaired healing. Recent regenerative approaches have focused on extracellular vesicle (EV) and exosome-based therapies because of their ability to deliver pro-angiogenic growth factors, cytokines, lipids, and regulatory microRNAs capable of modulating inflammation and promoting tissue repair. However, limitations in therapeutic delivery, including poor transdermal penetration, rapid degradation, and the invasiveness of repeated injections, have restricted the clinical translation of these therapies. Dissolvable microneedle-based delivery systems have emerged as a promising strategy to overcome these barriers through sustained and minimally invasive transdermal administration.

Objective: This narrative literature review evaluated recent advances in extracellular vesicle-based therapies and dissolvable microneedle delivery systems for the treatment of type II diabetic wounds, with emphasis on translational strategies capable of restoring angiogenesis, reducing chronic inflammation, and improving tissue regeneration.

Search Methods: A literature search was conducted using the PubMed database for studies published between 2021 and 2024. Search terms included “type II diabetic wounds,” “diabetic foot ulcers,” “extracellular vesicles,” “exosomes,” “microneedles,” “angiogenesis,” “VEGF,” “PI3K/Akt,” and “wound healing.” Primary studies and review articles emphasizing mechanisms of impaired diabetic wound healing, extracellular vesicle therapeutics, transdermal drug delivery systems, and regenerative biomaterials were selected for inclusion.

Results: Recent studies demonstrated that extracellular vesicles derived from platelets and stem cells possess significant regenerative potential through delivery of angiogenic and immunomodulatory biomolecules. These therapies promoted endothelial migration, fibroblast proliferation, collagen synthesis, and macrophage polarization toward anti-inflammatory M2 phenotypes. Dissolvable microneedle systems provided superior dermal retention and sustained release of extracellular vesicles compared with topical or injectable administration while avoiding limitations associated with poor penetration and repeated invasive treatments. Cao et al. developed a dissolvable microneedle-based dressing composed of methacrylated acellular dermal matrix hydrogel capable of continuously delivering platelet-derived exosomes within diabetic wound models. This platform significantly accelerated wound closure, enhanced angiogenesis, improved collagen deposition, and promoted re-epithelialization through activation of PI3K/Akt/HIF-1α signaling pathways. Additional mechanistic research identified XB130 as a negative regulator of diabetic wound healing through disruption of PI3K/Akt signaling, suggesting future opportunities for combining pathway-targeted therapies with extracellular vesicle delivery systems.

Conclusion: Dissolvable microneedle-based extracellular vesicle delivery systems represent a promising translational strategy for overcoming the complex biological barriers associated with type II diabetic wound healing impairments. By integrating sustained transdermal delivery with bioactive exosome therapeutics, these platforms can modulate chronic inflammation, enhance angiogenesis, and improve tissue regeneration while minimizing invasiveness. Continued investigation into impaired molecular signaling pathways within the diabetic wound microenvironment may further optimize these therapies and support future human clinical trials focused on chronic wound management and regenerative medicine.

Work Cited 

1. Armstrong DG, Tan TW, Boulton AJM, Bus SA. Diabetic Foot Ulcers: A Review. JAMA. 2023 Jul 3;330(1):62-75. doi: 10.1001/jama.2023.10578.
2. Uberoi A, McCready-Vangi A, Grice EA. The wound microbiota: microbial mechanisms of impaired wound healing and infection. Nature Reviews Microbiology. 2024;22:507–521.
3. Mo R, Zhang H, Xu Y, et al. Transdermal drug delivery via microneedles to mediate wound microenvironment. Advanced Drug Delivery Reviews. 2023;195:114753.
4. Cao Y, Chen B, Liu Q, et al. Dissolvable microneedle-based wound dressing transdermally and continuously delivers anti-inflammatory and pro-angiogenic exosomes for diabetic wound treatment. Bioactive Materials. 2024;42:32–51.
5. Zhu XL, Hu DY, Zeng ZX, et al. XB130 inhibits healing of diabetic skin ulcers through the PI3K/Akt signaling pathway. World Journal of Diabetes. 2023;14(9):1369–1384.
6. Wu J, Piao Y, Liu Q, Yang X. Platelet-rich plasma-derived extracellular vesicles: A superior alternative in regenerative medicine? Cell Proliferation. 2021;54:e13123.