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Abstract：
Regenerative endodontic therapy is a promising approach to restore the vitality of necrotic teeth, however, pulp regeneration in mature permanent teeth remains a substantial challenge due to insufficient developmental signals. The dentin is embryologically and histologically similar to the pulp, which contains a cocktail of pulp-specific structural proteins and growth factors, thus we proposed an optimizing strategy to obtain dentin matrix extracted proteins (DMEP) and engineered a DMEP functionalized double network hydrogel, whose physicochemical property was tunable by adjusting polymer concentrations to synchronize with regenerated tissues. In vitro models showed that the biomimetic hydrogel with sustained release of DMEP provided a beneficial microenvironment for the encapsulation, propagation and migration of human dental pulp stem cells (hDPSCs). The odontogenic and angiogenic differentiation of hDPSCs were enhanced as well. To elicit the mechanism hidden in the microenvironment to guide cell fate, RNA sequencing was performed and 109 differential expression of genes were identified, the majority of which enriched in cell metabolism, cell differentiation and intercellular communications. The involvement of ERK, p38 and JNK MAPK signaling pathways in the process was confirmed. Of note, in vivo models showed that the injectable and in situ photo-crosslinkable hydrogel was user-friendly for root canal systems and was capable of inducing the regeneration of highly organized and vascularized pulp-like tissues in root segments that subcutaneously implanted into nude mice. Taken together, this study reported a facile and efficient way to fabricate a cell delivery hydrogel with pulp-specific developmental cues, which exhibited promising application and translation potential in future regenerative endodontic fields.
摘要：
再生牙髓治疗是恢复坏死牙齿活力的一种有前途的方法，然而,由于发育信号不足，成熟恒牙的牙髓再生仍然是一个巨大的挑战。牙本质在胚胎和组织学上与牙髓相似，其中含有纸浆特异性结构蛋白和生长因子的混合物，因此，我们提出了一种优化策略来获得牙本质基质提取蛋白（DMEP），并设计了DMEP功能化的双网络水凝胶，其物理化学性质可通过调节聚合物浓度与再生组织同步来调节。体外模型表明，缓释DMEP的仿生水凝胶为封装提供了有益的微环境，人牙髓干细胞(hDPSC)的增殖和迁移。hDPSC的牙源性和血管生成分化也得到增强。为了引出隐藏在微环境中指导细胞命运的机制，进行了RNA测序，鉴定了109个差异表达基因，其中大部分富含细胞代谢，细胞分化和细胞间通讯。ERK的参与,p38和JNK一MAPK信号通路在此过程中被证实。值得注意的是，体内模型表明，可注射和原位可光交联的水凝胶对于根管系统是用户友好的，并且能够诱导皮下植入裸鼠的根段中高度组织和血管化的牙髓样组织的再生。一起来看,这项研究报道了一种简单而有效的方法来制造具有纸浆特异性发育线索的细胞递送水凝胶，在未来的再生牙髓领域显示出很有希望的应用和翻译潜力。
