{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,22]],"date-time":"2025-12-22T19:33:35Z","timestamp":1766432015985,"version":"build-2065373602"},"reference-count":79,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2025,5,27]],"date-time":"2025-05-27T00:00:00Z","timestamp":1748304000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Bioengineering"],"abstract":"<jats:p>Epidermolysis bullosa (EB) is a debilitating genetic skin disorder characterized by extreme fragility, chronic wounds, and severe complications, particularly in its most severe form, recessive dystrophic EB (RDEB). Current treatments focus on symptomatic relief through wound care and pain management, with recent FDA approvals of Vyjuvek and Filsuvez providing new but limited therapeutic options. However, emerging research highlights the potential of extracellular vesicles (EVs) derived from mesenchymal stem cells as a promising approach to address both the symptoms and underlying pathology of EB. EVs function as carriers of bioactive molecules, modulating inflammation, promoting tissue regeneration, and even delivering functional type VII collagen to RDEB patient cells. Unlike whole-cell therapies, EVs are non-immunogenic, have greater stability, and avoid risks such as graft-versus-host disease or tumorigenic transformation. Additionally, EVs offer diverse administration routes, including topical application, local injection, and intravenous delivery, which could extend their therapeutic reach beyond skin lesions to systemic manifestations of EB. However, challenges remain, including standardization of EV production, scalability, and ensuring consistent therapeutic potency. Despite these hurdles, EV-based therapies represent a transformative step toward addressing the complex pathology of EB, with the potential to improve wound healing, reduce fibrosis, and enhance patient quality of life.<\/jats:p>","DOI":"10.3390\/bioengineering12060574","type":"journal-article","created":{"date-parts":[[2025,5,28]],"date-time":"2025-05-28T08:12:47Z","timestamp":1748419967000},"page":"574","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Towards Extracellular Vesicles in the Treatment of Epidermolysis Bullosa"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2377-2815","authenticated-orcid":false,"given":"Aaron Gabriel W.","family":"Sandoval","sequence":"first","affiliation":[{"name":"Harvard Medical School, Boston, MA 02115, USA"},{"name":"Aegle Therapeutics, Woburn, MA 01801, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Evangelos V.","family":"Badiavas","sequence":"additional","affiliation":[{"name":"Aegle Therapeutics, Woburn, MA 01801, USA"},{"name":"Dr. Phillip Frost Department of Dermatology and Cutaneous Surgery, University of Miami Miller School of Medicine, Miami, FL 33136, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.jaad.2009.03.052","article-title":"Extracutaneous Manifestations and Complications of Inherited Epidermolysis Bullosa: Part I. Epithelial Associated Tissues","volume":"61","author":"Fine","year":"2009","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1111\/bjd.18921","article-title":"Consensus Reclassification of Inherited Epidermolysis Bullosa and Other Disorders with Skin Fragility","volume":"183","author":"Has","year":"2020","journal-title":"Br. J. Dermatol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"275","DOI":"10.2147\/CCID.S54681","article-title":"Dystrophic Epidermolysis Bullosa: A Review","volume":"8","author":"Shinkuma","year":"2015","journal-title":"Clin. Cosmet. Investig. Dermatol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41572-020-0210-0","article-title":"Epidermolysis Bullosa","volume":"6","author":"Bardhan","year":"2020","journal-title":"Nat. Rev. Dis. Primer"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1186\/s13023-021-01811-7","article-title":"A Systematic Literature Review of the Disease Burden in Patients with Recessive Dystrophic Epidermolysis Bullosa","volume":"16","author":"Tang","year":"2021","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_6","first-page":"41","article-title":"Recessive Dystrophic Epidermolysis Bullosa","volume":"8","author":"Soro","year":"2015","journal-title":"J. Clin. Aesthetic Dermatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"20406223211055920","DOI":"10.1177\/20406223211055920","article-title":"New Perspectives on the Treatment of Hidradenitis Suppurativa","volume":"12","author":"Vilarrasa","year":"2021","journal-title":"Ther. Adv. Chronic Dis."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"904","DOI":"10.1016\/j.jaad.2012.01.016","article-title":"A Consensus Approach to Wound Care in Epidermolysis Bullosa","volume":"67","author":"Pope","year":"2012","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_9","unstructured":"(2023, June 06). FDA FDA Approves First Topical Gene Therapy for Treatment of Wounds in Patients with Dystrophic Epidermolysis Bullosa, Available online: https:\/\/www.fda.gov\/news-events\/press-announcements\/fda-approves-first-topical-gene-therapy-treatment-wounds-patients-dystrophic-epidermolysis-bullosa."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2281","DOI":"10.1056\/NEJMe2213203","article-title":"Topical Gene Therapy for Epidermolysis Bullosa","volume":"387","author":"Payne","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2211","DOI":"10.1056\/NEJMoa2206663","article-title":"Trial of Beremagene Geperpavec (B-VEC) for Dystrophic Epidermolysis Bullosa","volume":"387","author":"Guide","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_12","unstructured":"Xiao, A., Sathe, N.C., and Tsuchiya, A. (2025). Epidermolysis Bullosa Acquisita. StatPearls, StatPearls Publishing."},{"key":"ref_13","unstructured":"(2025, February 20). Dosing & Administration. Available online: https:\/\/www.vyjuvek.com\/starting-vyjuvek\/."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13023-019-1279-y","article-title":"The Challenges of Living with and Managing Epidermolysis Bullosa: Insights from Patients and Caregivers","volume":"15","author":"Bruckner","year":"2020","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1001\/jamadermatol.2023.5857","article-title":"Estimated Spending on Beremagene Geperpavec for Dystrophic Epidermolysis Bullosa","volume":"160","author":"Raymakers","year":"2024","journal-title":"JAMA Dermatol."},{"key":"ref_16","unstructured":"Travagin, C. (2025, February 19). Chiesi Global Rare Diseases Receives FDA Approval for FILSUVEZ\u00ae (Birch Triterpenes) Topical Gel for the Treatment of Epidermolysis Bullosa. Available online: https:\/\/chiesirarediseases.com\/media\/fda-approval-for-filsuvez-topical-gel."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Ebeling, S., Naumann, K., Pollok, S., Wardecki, T., Vidal-y-Sy, S., Nascimento, J.M., Boerries, M., Schmidt, G., Brandner, J.M., and Merfort, I. (2014). From a Traditional Medicinal Plant to a Rational Drug: Understanding the Clinically Proven Wound Healing Efficacy of Birch Bark Extract. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0086147"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1093\/bjd\/ljac001","article-title":"Efficacy and Safety of Oleogel-S10 (Birch Triterpenes) for Epidermolysis Bullosa: Results from the Phase III Randomized Double-Blind Phase of the EASE Study","volume":"188","author":"Kern","year":"2023","journal-title":"Br. J. Dermatol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1111\/jdv.13953","article-title":"The Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI): Grading Disease Severity and Assessing Responsiveness to Clinical Change in Epidermolysis Bullosa","volume":"31","author":"Jain","year":"2017","journal-title":"J. Eur. Acad. Dermatol. Venereol."},{"key":"ref_20","unstructured":"Shesteen, H. (2025, February 20). Amryt\u2019s Rare Skin Disease (Epidermolysis Bullosa) Treatment Rejected by FDA. Available online: https:\/\/www.biospace.com\/fda-declines-approval-for-epidermolysis-bullosa-treatment."},{"key":"ref_21","unstructured":"(2025, February 28). FILSUVEZ\u00ae (Birch Triterpenes) Topical Gel | Prescribing FILSUVEZ. Available online: https:\/\/www.filsuvez.com\/hcp\/dosage-and-administration\/prescribing-filsuvez."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Niti, A., Koliakos, G., and Michopoulou, A. (2023). Stem Cell Therapies for Epidermolysis Bullosa Treatment. Bioengineering, 10.","DOI":"10.3390\/bioengineering10040422"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1038\/nature24487","article-title":"Regeneration of the Entire Human Epidermis by Transgenic Stem Cells","volume":"551","author":"Hirsch","year":"2017","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2264","DOI":"10.1056\/NEJMoa2108544","article-title":"Transgenic Epidermal Cultures for Junctional Epidermolysis Bullosa\u20145-Year Outcomes","volume":"385","author":"Kueckelhaus","year":"2021","journal-title":"N. Engl. J. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1016\/j.jid.2018.11.036","article-title":"Gene Therapy for Epidermolysis Bullosa","volume":"139","author":"Marinkovich","year":"2019","journal-title":"J. Investig. Dermatol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1808","DOI":"10.1001\/jama.2016.15588","article-title":"Safety and Wound Outcomes Following Genetically Corrected Autologous Epidermal Grafts in Patients With Recessive Dystrophic Epidermolysis Bullosa","volume":"316","author":"Siprashvili","year":"2016","journal-title":"JAMA"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1186\/s13023-022-02546-9","article-title":"Long-Term Safety and Efficacy of Gene-Corrected Autologous Keratinocyte Grafts for Recessive Dystrophic Epidermolysis Bullosa","volume":"17","author":"So","year":"2022","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_28","unstructured":"(2025, May 09). Little Abeona Gets Big Setback with FDA Clinical Hold on Pivotal Phase 3 | Fierce Biotech. Available online: https:\/\/www.fiercebiotech.com\/biotech\/little-abeona-gets-a-big-setback-fda-clinical-hold-pivotal-phase-3."},{"key":"ref_29","unstructured":"Dunleavy, K. (2025, May 09). FDA Rejects Abeona\u2019 Therapeutics\u2019 Topical Gene Therapy Pz-Cel. Available online: https:\/\/www.fiercepharma.com\/pharma\/another-delay-abeonas-topical-gene-therapy-pz-cel-fda-sends-out-crl."},{"key":"ref_30","unstructured":"(2025, May 04). U.S. FDA Approves ZEVASKYNTM (Prademagene Zamikeracel), the First and Only Cell-Based Gene Therapy for Patients with Recessive Dystrophic Epidermolysis Bullosa (RDEB). Available online: https:\/\/investors.abeonatherapeutics.com\/press-releases\/detail\/303\/u-s-fda-approves-zevaskyn-prademagene-zamikeracel."},{"key":"ref_31","unstructured":"Abeona Therapeutics, Inc. (2022). VIITAL: A Phase 3 Study of EB-101 for the Treatment of Recessive Dystrophic Epidermolysis Bullosa (RDEB)."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e126243","DOI":"10.1172\/jci.insight.126243","article-title":"Safety and Early Efficacy Outcomes for Lentiviral Fibroblast Gene Therapy in Recessive Dystrophic Epidermolysis Bullosa","volume":"4","author":"Lwin","year":"2019","journal-title":"JCI Insight"},{"key":"ref_33","unstructured":"Bautz, D. (2025, May 04). 3 min ABEO: ZevaskynTM Approved by FDA. Raising Valuation to $11\u2026. Available online: https:\/\/finance.yahoo.com\/news\/abeo-zevaskyn-approved-fda-raising-100500085.html."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1002\/jcp.10260","article-title":"Participation of Bone Marrow Derived Cells in Cutaneous Wound Healing","volume":"196","author":"Badiavas","year":"2003","journal-title":"J. Cell. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1167","DOI":"10.1182\/blood-2008-06-161299","article-title":"Amelioration of Epidermolysis Bullosa by Transfer of Wild-Type Bone Marrow Cells","volume":"113","author":"Tolar","year":"2009","journal-title":"Blood"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1996","DOI":"10.4049\/jimmunol.1400914","article-title":"Transplanted Bone Marrow\u2013Derived Circulating PDGFR\u03b1+ Cells Restore Type VII Collagen in Recessive Dystrophic Epidermolysis Bullosa Mouse Skin Graft","volume":"194","author":"Iinuma","year":"2015","journal-title":"J. Immunol. Author Choice"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1111\/pde.15591","article-title":"Bone Marrow Transplantation and Bone Marrow-Derived Mesenchymal Stem Cell Therapy in Epidermolysis Bullosa: A Systematic Review","volume":"41","author":"Agustin","year":"2024","journal-title":"Pediatr. Dermatol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1056\/NEJMe1004319","article-title":"Systemic Therapy for a Genetic Skin Disease","volume":"363","year":"2010","journal-title":"N. Engl. J. Med."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"801","DOI":"10.1177\/0963689719837897","article-title":"The Pros and Cons of Mesenchymal Stem Cell-Based Therapies","volume":"28","author":"Kot","year":"2019","journal-title":"Cell Transplant."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1353","DOI":"10.1007\/s00018-013-1462-6","article-title":"Natural History of Mesenchymal Stem Cells, from Vessel Walls to Culture Vessels","volume":"71","author":"Murray","year":"2014","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e151922","DOI":"10.1172\/jci.insight.151922","article-title":"Clinical Trial of ABCB5+ Mesenchymal Stem Cells for Recessive Dystrophic Epidermolysis Bullosa","volume":"6","author":"Kiritsi","year":"2021","journal-title":"JCI Insight"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1038\/nbt.2816","article-title":"Mesenchymal Stem Cells: Immune Evasive, Not Immune Privileged","volume":"32","author":"Ankrum","year":"2014","journal-title":"Nat. Biotechnol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1002\/stem.1118","article-title":"Analysis of Tissues Following Mesenchymal Stromal Cell Therapy in Humans Indicates Limited Long-Term Engraftment and No Ectopic Tissue Formation","volume":"30","author":"Batsis","year":"2012","journal-title":"Stem Cells"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1038\/s41419-021-03839-w","article-title":"Short Lifespan of Syngeneic Transplanted MSC Is a Consequence of in Vivo Apoptosis and Immune Cell Recruitment in Mice","volume":"12","author":"Preda","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1016\/j.cmet.2015.09.019","article-title":"Beyond Hit-and-Run: Stem Cells Leave a Lasting Memory","volume":"22","author":"Ng","year":"2015","journal-title":"Cell Metab."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1622","DOI":"10.1016\/j.jid.2017.04.021","article-title":"Extracellular Vesicles as Biomarkers and Therapeutics in Dermatology: A Focus on Exosomes","volume":"137","author":"McBride","year":"2017","journal-title":"J. Investig. Dermatol."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Bray, E.R., Oropallo, A.R., Grande, D.A., Kirsner, R.S., and Badiavas, E.V. (2021). Extracellular Vesicles as Therapeutic Tools for the Treatment of Chronic Wounds. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13101543"},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Clos-Sansalvador, M., Mongui\u00f3-Tortajada, M., Roura, S., Franquesa, M., and Borr\u00e0s, F.E. (2022). Commonly Used Methods for Extracellular Vesicles\u2019 Enrichment: Implications in Downstream Analyses and Use. Eur. J. Cell Biol., 101.","DOI":"10.1016\/j.ejcb.2022.151227"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"20417314231174609","DOI":"10.1177\/20417314231174609","article-title":"Comparison of Extracellular Vesicle Isolation Processes for Therapeutic Applications","volume":"14","author":"Williams","year":"2023","journal-title":"J. Tissue Eng."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2403199","DOI":"10.1002\/adma.202403199","article-title":"Immunogenicity of Extracellular Vesicles","volume":"36","author":"Xia","year":"2024","journal-title":"Adv. Mater."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.biocel.2016.03.018","article-title":"Loss of Interactions between P53 and Survivin Gene in Mesenchymal Stem Cells after Spontaneous Transformation in Vitro","volume":"75","author":"He","year":"2016","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Vizoso, F.J., Eiro, N., Cid, S., Schneider, J., and Perez-Fernandez, R. (2017). Mesenchymal Stem Cell Secretome: Toward Cell-Free Therapeutic Strategies in Regenerative Medicine. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18091852"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1016\/j.jcyt.2022.11.006","article-title":"Impact of Storage Conditions and Duration on Function of Native and Cargo-Loaded Mesenchymal Stromal Cell Extracellular Vesicles","volume":"25","author":"Levy","year":"2023","journal-title":"Cytotherapy"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1186\/s13287-022-02806-2","article-title":"Engineering Strategies for Customizing Extracellular Vesicle Uptake in a Therapeutic Context","volume":"13","author":"Esmaeili","year":"2022","journal-title":"Stem Cell Res. Ther."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"(2025, May 08). Inflammation in Chronic Wounds. Available online: https:\/\/www.mdpi.com\/1422-0067\/17\/12\/2085.","DOI":"10.3390\/ijms17122085"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"105689","DOI":"10.1016\/j.intimp.2019.105689","article-title":"Comparison of the Effects of Adipose Tissue Mesenchymal Stromal Cell-Derived Exosomes with Conditioned Media on Neutrophil Function and Apoptosis","volume":"74","author":"Mahmoudi","year":"2019","journal-title":"Int. Immunopharmacol."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"(2025, May 08). MSC-Derived Exosome Promotes M2 Polarization and Enhances Cutaneous Wound Healing-He-2019-Stem Cells International-Wiley Online Library. Available online: https:\/\/onlinelibrary.wiley.com\/doi\/full\/10.1155\/2019\/7132708.","DOI":"10.1155\/2019\/7132708"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1007\/s00125-015-3808-0","article-title":"Human Mesenchymal Stem Cells and Derived Extracellular Vesicles Induce Regulatory Dendritic Cells in Type 1 Diabetic Patients","volume":"59","author":"Favaro","year":"2016","journal-title":"Diabetologia"},{"key":"ref_59","unstructured":"(2025, May 08). Microvesicles from Human Adipose Stem Cells Promote Wound Healing by Optimizing Cellular Functions via AKT and ERK Signaling Pathways | Stem Cell Research & Therapy. Available online: https:\/\/link.springer.com\/article\/10.1186\/s13287-019-1152-x."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1002\/sctm.19-0446","article-title":"The Emerging Antioxidant Paradigm of Mesenchymal Stem Cell Therapy","volume":"9","author":"Stavely","year":"2020","journal-title":"Stem Cells Transl. Med."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"(2025, May 08). Concise Review: Intercellular Communication Via Organelle Transfer in the Biology and Therapeutic Applications of Stem Cells | Stem Cells | Oxford Academic. Available online: https:\/\/academic.oup.com\/stmcls\/article-abstract\/37\/1\/14\/6423871.","DOI":"10.1002\/stem.2922"},{"key":"ref_62","doi-asserted-by":"crossref","unstructured":"Narauskait\u0117, D., Vydmantait\u0117, G., Rusteikait\u0117, J., Sampath, R., Rudaityt\u0117, A., Sta\u0161yt\u0117, G., Aparicio Calvente, M.I., and Jekabsone, A. (2021). Extracellular Vesicles in Skin Wound Healing. Pharmaceuticals, 14.","DOI":"10.20944\/preprints202108.0004.v1"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1724","DOI":"10.1111\/exd.14411","article-title":"Immunological Mechanisms Underlying Progression of Chronic Wounds in Recessive Dystrophic Epidermolysis Bullosa","volume":"30","author":"Huitema","year":"2021","journal-title":"Exp. Dermatol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.biochi.2018.04.007","article-title":"Dual Mechanism of Type VII Collagen Transfer by Bone Marrow Mesenchymal Stem Cell Extracellular Vesicles to Recessive Dystrophic Epidermolysis Bullosa Fibroblasts","volume":"155","author":"McBride","year":"2018","journal-title":"Biochimie"},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Lv, K., Wang, Y., Lou, P., Liu, S., Zhou, P., Yang, L., Lu, Y., Cheng, J., and Liu, J. (2022). Extracellular Vesicles as Advanced Therapeutics for the Resolution of Organ Fibrosis: Current Progress and Future Perspectives. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.1042983"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"406","DOI":"10.1186\/s13023-022-02282-0","article-title":"Hand Surgery and Hand Therapy Clinical Practice Guideline for Epidermolysis Bullosa","volume":"17","author":"Box","year":"2022","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_67","first-page":"021903","article-title":"Overview of Extracellular Vesicle Characterization Techniques and Introduction to Combined Reflectance and Fluorescence Confocal Microscopy to Distinguish Extracellular Vesicle Subpopulations","volume":"9","author":"Belder","year":"2022","journal-title":"Neurophotonics"},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Ng, C.Y., Kee, L.T., Al-Masawa, M.E., Lee, Q.H., Subramaniam, T., Kok, D., Ng, M.H., and Law, J.X. (2022). Scalable Production of Extracellular Vesicles and Its Therapeutic Values: A Review. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23147986"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"113961","DOI":"10.1016\/j.addr.2021.113961","article-title":"Dosing Extracellular Vesicles","volume":"178","author":"Gupta","year":"2021","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_70","doi-asserted-by":"crossref","unstructured":"Hindle, J., Williams, A., Kim, Y., Kim, D., Patil, K., Khatkar, P., Osgood, Q., Nelson, C., Routenberg, D.A., and Howard, M. (2024). hTERT-Immortalized Mesenchymal Stem Cell-Derived Extracellular Vesicles: Large-Scale Manufacturing, Cargo Profiling, and Functional Effects in Retinal Epithelial Cells. Cells, 13.","DOI":"10.3390\/cells13100861"},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Soler-Botija, C., Mongui\u00f3-Tortajada, M., Munizaga-Larroud\u00e9, M., G\u00e1lvez-Mont\u00f3n, C., Bayes-Genis, A., and Roura, S. (2022). Mechanisms Governing the Therapeutic Effect of Mesenchymal Stromal Cell-Derived Extracellular Vesicles: A Scoping Review of Preclinical Evidence. Biomed. Pharmacother., 147.","DOI":"10.1016\/j.biopha.2022.112683"},{"key":"ref_72","unstructured":"(2021). C.Regenerative Medicine Advanced Therapy Designation, FDA."},{"key":"ref_73","unstructured":"Commissioner, O. (2025, May 14). of the Rare Pediatric Disease Designation and Priority Review Voucher Programs, Available online: https:\/\/www.fda.gov\/industry\/medical-products-rare-diseases-and-conditions\/rare-pediatric-disease-designation-and-priority-review-voucher-programs."},{"key":"ref_74","unstructured":"Aegle Therapeutics (2025). A Safety Study of the Administration of Mesenchymal Stem Cell Extracellular Vesicles in the Treatment of Dystrophic Epidermolysis Bullosa Wounds."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1038\/s41551-019-0485-1","article-title":"Large-Scale Generation of Functional mRNA-Encapsulating Exosomes via Cellular Nanoporation","volume":"4","author":"Yang","year":"2020","journal-title":"Nat. Biomed. Eng."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1038\/s44222-025-00277-7","article-title":"Extracellular Vesicles for the Delivery of Gene Therapy","volume":"3","author":"Obuchi","year":"2025","journal-title":"Nat. Rev. Bioeng."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1038\/s41551-022-00989-w","article-title":"Intradermally Delivered mRNA-Encapsulating Extracellular Vesicles for Collagen-Replacement Therapy","volume":"7","author":"You","year":"2023","journal-title":"Nat. Biomed. Eng."},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1016\/j.addr.2020.04.004","article-title":"Extracellular Vesicles as Drug Delivery Systems: Why and How?","volume":"159","author":"Elsharkasy","year":"2020","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1016\/j.ymthe.2023.01.021","article-title":"Extracellular Vesicles: The next Generation in Gene Therapy Delivery","volume":"31","author":"Cecchin","year":"2023","journal-title":"Mol. Ther."}],"container-title":["Bioengineering"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2306-5354\/12\/6\/574\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:41:06Z","timestamp":1760031666000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2306-5354\/12\/6\/574"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,27]]},"references-count":79,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["bioengineering12060574"],"URL":"https:\/\/doi.org\/10.3390\/bioengineering12060574","relation":{},"ISSN":["2306-5354"],"issn-type":[{"type":"electronic","value":"2306-5354"}],"subject":[],"published":{"date-parts":[[2025,5,27]]}}}