Van Cleve Cardiac Regenerative Medicine Program, Center for Regenerative Medicine, Mayo Clinic, Rochester, MN, USA.
Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.
Theranostics. 2021 Apr 30;11(13):6616-6631. doi: 10.7150/thno.57701. eCollection 2021.
With over seven million infections and $25 billion treatment cost, chronic ischemic wounds are one of the most serious complications in the United States. The controlled release of bioactive factor enriched exosome from finbrin gel was a promising strategy to promote wound healing. To address this unsolved problem, we developed clinical-grade platelets exosome product (PEP), which was incorporate with injectable surgical fibrin sealant (TISSEEL), to promote chronic wound healing and complete skin regeneration. The PEP characterization stimulated cellular activities and rabbit ischemic wound healing capacity of TISSEEL-PEP were performed and analyzed. PEP, enriched with transforming growth factor beta (TGF-β), possessed exosomal characteristics including exosome size, morphology, and typical markers including CD63, CD9, and ALG-2-interacting protein X (Alix). , PEP significantly promoted cell proliferation, migration, tube formation, as well as skin organoid formation. Topical treatment of ischemic wounds with TISSEEL-PEP promoted full-thickness healing with the reacquisition of hair follicles and sebaceous glands. Superior to untreated and TISSEEL-only treated controls, TISSEEL-PEP drove cutaneous healing associated with collagen synthesis and restoration of dermal architecture. Furthermore, PEP promoted epithelial and vascular cell activity enhancing angiogenesis to restore blood flow and mature skin function. Transcriptome deconvolution of TISSEEL-PEP versus TISSEEL-only treated wounds prioritized regenerative pathways encompassing neovascularization, matrix remodeling and tissue growth. This room-temperature stable, lyophilized exosome product is thus capable of delivering a bioactive transforming growth factor beta to drive regenerative events.
慢性缺血性创面是美国最严重的并发症之一，感染人数超过 700 万，治疗费用达 250 亿美元。纤维连接蛋白凝胶中富含生物活性因子的外泌体的控释是促进伤口愈合的一种很有前途的策略。为了解决这一未解决的问题，我们开发了临床级血小板外泌体产品（PEP），它与可注射外科纤维蛋白密封剂（TISSEEL）结合，以促进慢性伤口愈合和完全皮肤再生。PEP 的特征刺激了细胞活性，进行了 TISSEEL-PEP 对兔缺血性伤口愈合能力的研究和分析。PEP 富含转化生长因子-β（TGF-β），具有外泌体的特征，包括外泌体大小、形态和典型标志物，如 CD63、CD9 和 ALG-2 相互作用蛋白 X（Alix）。PEP 显著促进了细胞增殖、迁移、管状形成以及皮肤类器官的形成。TISSEEL-PEP 对缺血性创面的局部治疗促进了全层愈合，重新获得了毛囊和皮脂腺。与未治疗和仅 TISSEEL 治疗的对照组相比，TISSEEL-PEP 促进了与胶原蛋白合成和真皮结构恢复相关的皮肤愈合。此外，PEP 促进了上皮和血管细胞的活性，增强了血管生成，以恢复血流和成熟皮肤的功能。TISSEEL-PEP 与仅 TISSEEL 治疗的伤口的转录组去卷积优先考虑了包含新生血管形成、基质重塑和组织生长的再生途径。这种室温稳定、冻干的外泌体产品能够递送生物活性转化生长因子-β以驱动再生事件。
