Oxo-M and 4-PPBP Delivery via Multi-Domain Peptide Hydrogel Toward Tendon Regeneration.
Oxo-M and 4-PPBP Delivery via Multi-Domain Peptide Hydrogel Toward Tendon Regeneration.
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DOI：
10.3389/fbioe.2022.773004
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发表时间：
2022
影响因子：
5.7
通讯作者：
Lee CH
中科院分区：
文献类型：
--
作者：
Park GY;Tarafder S;Eyen SL;Park S;Kim R;Siddiqui Z;Kumar V;Lee CH
我们最近发现了新型小分子 Oxo-M 和 4-PPBP，它们可以特异性刺激内源性肌腱干/祖细胞 (TSC)，从而实现完全横断肌腱的潜在再生愈合。在这里，我们研究了一种可注射的多域肽（MDP）水凝胶，它可以控制小分子的递送，从而促进肌腱再生愈合。我们研究了 MDP 水凝胶中 Oxo-M 和 4-PPBP 的释放动力学以及 MDP 释放的小分子对 TSC 肌腱分化和体内肌腱愈合的影响。在体外，MDP 显示出 Oxo-M 和 4-PPBP 的持续释放，并且降解速度比纤维蛋白慢。此外，与纤维蛋白释放相比，MDP释放的Oxo-M和4-PPBP在TSC中的肌腱基因表达显着增加。在体内，MDP 释放的 Oxo-M 和 4-PPBP 显着改善肌腱愈合，这可能与 Oxo-M 和 4-PPBP 对 M1 巨噬细胞的抑制和 M2 巨噬细胞的促进的长期作用有关。包括组织形态学、数字图像处理和纳米压痕模量映射在内的综合分析一致表明，与基于纤维蛋白的递送相比，通过 MDP 递送的 Oxo-M 和 4-PPBP 进一步改善了肌腱愈合。总之，用 Oxo-M 和 4-PPBP 递送的 MDP 可以作为原位肌腱再生和愈合的有效再生治疗剂。
We have recently identified novel small molecules, Oxo-M and 4-PPBP, which specifically stimulate endogenous tendon stem/progenitor cells (TSCs), leading to potential regenerative healing of fully transected tendons. Here, we investigated an injectable, multidomain peptide (MDP) hydrogel providing controlled delivery of the small molecules for regenerative tendon healing. We investigated the release kinetics of Oxo-M and 4-PPBP from MDP hydrogels and the effect of MDP-released small molecules on tenogenic differentiation of TSCs and in vivo tendon healing. In vitro, MDP showed a sustained release of Oxo-M and 4-PPBP and a slower degradation than fibrin. In addition, tenogenic gene expression was significantly increased in TSC with MDP-released Oxo-M and 4-PPBP as compared to the fibrin-released. In vivo, MDP releasing Oxo-M and 4-PPBP significantly improved tendon healing, likely associated with prolonged effects of Oxo-M and 4-PPBP on suppression of M1 macrophages and promotion of M2 macrophages. Comprehensive analyses including histomorphology, digital image processing, and modulus mapping with nanoindentation consistently suggested that Oxo-M and 4-PPBP delivered via MDP further improved tendon healing as compared to fibrin-based delivery. In conclusion, MDP delivered with Oxo-M and 4-PPBP may serve as an efficient regenerative therapeutic for in situ tendon regeneration and healing.