Poly(ethylene glycol) (PEG) hydrogels crosslinked with enzyme-cleavable peptides are promising biodegradable vehicles for therapeutic cell delivery. However, peptide synthesis at the level required for bulk biomaterial manufacturing is costly, and fabrication of hydrogels from scalable, low-cost synthetic precursors while supporting cell-specific degradation remains a challenge. Reactive oxygen species (ROS) are cell-generated signaling molecules that can also be used as a trigger to mediate specific in vivo degradation of biomaterials. Here, PEG-based hydrogels crosslinked with ROS-degradable poly(thioketal) (PTK) polymers were successfully synthesized via thiol-maleimide chemistry and employed as a cell-degradable, antioxidative stem cell delivery platform. PTK hydrogels were mechanically robust and underwent ROS-mediated, dose-dependent degradation in vitro, while promoting robust cellular infiltration, tissue regeneration, and bioresorption in vivo. Moreover, these ROS-sensitive materials successfully encapsulated mesenchymal stem cells (MSCs) and maintained over 40% more viable cells than gold-standard hydrogels crosslinked with enzymatically-degradable peptides. The higher cellular survival in PTK-based gels was associated with the antioxidative function of the ROS-sensitive crosslinker, which scavenged free radicals and protected encapsulated MSCs from cytotoxic doses of ROS. Improved MSC viability was also observed in vivo as MSCs delivered within injectable PTK hydrogels maintained significantly more viability over 11 days compared against cells delivered within gels crosslinked with either a PEG-only control polymer or a gold-standard enzymatically-degradable peptide. Together, this study establishes a new paradigm for scalable creation and application of cell-degradable hydrogels, particularly for cell delivery applications.

与酶可裂解肽交联的聚（乙二醇）（PEG）水凝胶是用于治疗性细胞递送的有前途的可生物降解载体。然而，大块生物材料制造所需水平的肽合成成本高昂，并且从可扩展的低成本合成前体制造水凝胶同时支持细胞特异性降解仍然是一个挑战。活性氧 (ROS) 是细胞生成的信号分子，也可用作触发体内特定的介导生物材料的降解。在这里，与 ROS 可降解的聚（硫缩酮）（PTK）聚合物交联的基于 PEG 的水凝胶通过硫醇-马来酰亚胺化学成功合成，并用作细胞可降解的抗氧化干细胞递送平台。PTK 水凝胶机械强度高，在体外经历 ROS 介导的剂量依赖性降解，同时促进体内细胞浸润、组织再生和生物再吸收。此外，这些 ROS 敏感材料成功地封装了间充质干细胞 (MSC)，并且比用酶促降解肽交联的金标准水凝胶多维持了 40% 以上的活细胞。基于 PTK 的凝胶中较高的细胞存活率与 ROS 敏感交联剂的抗氧化功能有关，该交联剂清除自由基并保护封装的 MSC 免受细胞毒性剂量的 ROS 的影响。在体内也观察到改善的 MSC 活力与在凝胶中递送的细胞相比，在可注射 PTK 水凝胶中递送的 MSC 在 11 天内保持了更高的活力，而凝胶中的细胞与仅 PEG 的对照聚合物或金标准酶促降解肽交联。总之，这项研究为细胞可降解水凝胶的可扩展创建和应用建立了新的范例，特别是对于细胞递送应用。