Division of Bioengineering, College of Life Sciences and Bioengineering, Incheon National University, Incheon 22012, Republic of Korea.
Department of Veterinary Surgery, College of Veterinary Medicine and Institute of Veterinary Science, Kangwon National University, Chuncheon 24341, Republic of Korea.
J Control Release. 2020 Nov 10;327:284-295. doi: 10.1016/j.jconrel.2020.08.002. Epub 2020 Aug 5.
Exogenous dual delivery of progenitor cell population and therapeutic growth factors (GFs) is one of alternative tissue engineering strategies for osteochondral tissue regeneration. In the present study, an implantable dual delivery platform was developed using coacervates (Coa) (i.e., a tertiary complex of poly(ethylene argininylaspartate diglyceride) (PEAD) polycation, heparin, and cargo insulin-like growth factor-1 (IGF-1), in thiolated gelatin (gelatin-SH)/ poly(ethylene glycol) diacrylate (PEGDA) interpenetrating network (IPN) hydrogels. Since Coa is able to protect cargo GF and maintain its long-term bioactivity, it is speculated that Coa-mediated delivery of chondrogenic factor IGF-1 with the aid of adipose-derived stem cells (ADSCs) would synergistically facilitate osteochondral tissue repair during physiological regeneration process. Our results indicate that gelatin-SH/PEGDA IPN hydrogels demonstrated biocompatibility and mechanical properties for a possible long-term transplantation, and PEAD-base Coa exhibited a sustained release of bioactive IGF-1 over 3 weeks. Subsequently, released IGF-1 from Coa could effectively induce chondrogenic differentiation of embedded ADSCs in the hydrogel, by showing enhanced glycosaminoglycan deposition and expression of chondrogenesis-associated genes. More importantly, at 12 weeks post-implantation in a rabbit full thickness osteochondral defect model, the quality of regenerative tissues in both chondral and subchondral layers was significantly improved in dual delivery of ADSC and IGF-1 in Coa encapsulated in gelatin-SH/PEGDA IPN hydrogels, as compared with a single delivery of ADSC only and a dual delivery without Coa. Therefore, we conclude that our Coa-embedded composite hydrogel platform could effectively augment osteochondral tissue regeneration holds promise for a feasible osteoarthritis therapeutic application.
外源性祖细胞群体和治疗性生长因子 (GFs) 的双重递呈是骨软骨组织再生的替代组织工程策略之一。在本研究中，使用凝聚物 (Coa)（即聚（精氨酸天冬氨酸二甘油酯）（PEAD）聚阳离子、肝素和货物胰岛素样生长因子-1 (IGF-1) 的三级复合物）开发了一种可植入的双重递呈平台，在巯基化明胶 (gelatin-SH)/聚乙二醇二丙烯酸酯 (PEGDA) 互穿网络 (IPN) 水凝胶中。由于 Coa 能够保护货物 GF 并保持其长期生物活性，因此推测 Coa 介导的携带软骨形成因子 IGF-1 的递呈，在脂肪来源的干细胞 (ADSCs) 的辅助下，将在生理再生过程中协同促进骨软骨组织修复。我们的结果表明，gelatin-SH/PEGDA IPN 水凝胶具有生物相容性和机械性能，可能适合长期移植，PEAD 基 Coa 表现出生物活性 IGF-1 的持续释放超过 3 周。随后，从 Coa 释放的 IGF-1 可以有效地诱导水凝胶中嵌入的 ADSC 向软骨分化，表现为糖胺聚糖沉积增加和软骨形成相关基因的表达增强。更重要的是，在兔全层骨软骨缺损模型中植入 12 周后，与单独递送 ADSC 和没有 Coa 的双重递送相比，在 gelatin-SH/PEGDA IPN 水凝胶中包封 Coa 的 ADSC 和 IGF-1 的双重递送显著改善了软骨和软骨下层再生组织的质量。因此，我们得出结论，我们的 Coa 嵌入式复合水凝胶平台可以有效地增强骨软骨组织再生，为可行的骨关节炎治疗应用提供了希望。
