Dong Yixiao, Cui Meihua, Qu Ju, Wang Xuechun, Kwon Sun Hyung, Barrera Janos, Elvassore Nicola, Gurtner Geoffrey C
Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China; Department of Surgery, Stanford University School of Medicine, Stanford, CA, United States; The Charles Institute of Dermatology, School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China.
Acta Biomater. 2020 May;108:56-66. doi: 10.1016/j.actbio.2020.03.040. Epub 2020 Apr 3.
Injury to the skin from severe burns can cause debilitating physical and psychosocial distress to the patients. Upon healing, deep dermal burns often result in devastating hypertrophic scar formation. For many decades, stem cell-based therapies have shown significant potential in improving wound healing. However, current cell delivery methods are often insufficient to maintain cell viability in a harmful burn wound environment to promote skin regeneration. In this study, we developed an enhanced approach to deliver adipose-derived stem cells (ASCs) for the treatment of burn wounds, using an in-situ-formed hydrogel system comprised of a hyperbranched poly(ethylene glycol) diacrylate (HB-PEGDA) polymer, a commercially available thiol-functionalized hyaluronic acid (HA-SH) and a short RGD peptide. Stable hydrogels with tunable swelling and mechanical properties form within five minutes under physiological conditions via the Michael-type addition reaction. Combining with RGD peptide, as a cell adhesion motif, significantly alters the cellular morphology, enhances cell proliferation, and increases the paracrine activity of angiogenesis and tissue remodeling growth factors and cytokines. Bioluminescence imaging of luciferase ASCs indicated that the hydrogel protected the implanted cells from the harmful wound environment in burns. Hydrogel-ASC treatment significantly enhanced neovascularization, accelerated wound closure and reduced the scar formation. Our findings suggest that PEG-HA-RGD-based hydrogel provides an effective niche capable of augmenting the regenerative potential of ASCs and promoting burn wound healing. STATEMENT OF SIGNIFICANCE: Burn injury is one of the most devastating injures, and patients suffer from many complications and post-burn scar formation despite modern therapies. Here, we designed a conformable hydrogel-based stem cell delivery platform that allows rapid in-situ gelation upon contact with wounds. Adipose-derived stem cells were encapsulated into a PEG-HA-RGD hydrogels. Introducing of RGD motif significantly improved the cellular morphology, proliferation, and secretion of angiogenesis and remodeling cytokines. A deep second-degree burn murine model was utilized to evaluate in-vivo cell retention and therapeutic effect of the hydrogel-ASC-based therapy on burn wound healing. Our hydrogel remarkably improved ASCs viability in burn wounds and the hydrogel-ASC treatment enhanced the neovascularization, promoted wound closure, and reduced scar formation.
严重烧伤对皮肤造成的损伤会给患者带来身心上的巨大痛苦。愈合后，深度真皮烧伤常常会导致严重的增生性瘢痕形成。几十年来，基于干细胞的疗法在促进伤口愈合方面显示出巨大潜力。然而，目前的细胞递送方法往往不足以在有害的烧伤伤口环境中维持细胞活力以促进皮肤再生。在本研究中，我们开发了一种增强的方法来递送脂肪来源干细胞（ASC）用于治疗烧伤伤口，使用由超支化聚（乙二醇）二丙烯酸酯（HB-PEGDA）聚合物、市售的硫醇官能化透明质酸（HA-SH）和短RGD肽组成的原位形成水凝胶系统。在生理条件下，通过迈克尔型加成反应，可在五分钟内形成具有可调溶胀和机械性能的稳定水凝胶。与作为细胞粘附基序的RGD肽结合，可显著改变细胞形态、增强细胞增殖，并增加血管生成和组织重塑生长因子及细胞因子的旁分泌活性。荧光素酶ASC的生物发光成像表明，水凝胶可保护植入细胞免受烧伤伤口有害环境的影响。水凝胶-ASC治疗显著增强了新血管形成，加速了伤口闭合，并减少了瘢痕形成。我们的研究结果表明，基于PEG-HA-RGD的水凝胶提供了一个有效的微环境，能够增强ASC的再生潜力并促进烧伤伤口愈合。重要性声明：烧伤是最具毁灭性的损伤之一，尽管有现代治疗方法，患者仍会遭受许多并发症和烧伤后瘢痕形成。在此，我们设计了一种适应性强的基于水凝胶的干细胞递送平台，该平台在与伤口接触时可快速原位凝胶化。脂肪来源干细胞被封装到PEG-HA-RGD水凝胶中。引入RGD基序显著改善了细胞形态、增殖以及血管生成和重塑细胞因子的分泌。利用深度二度烧伤小鼠模型评估基于水凝胶-ASC疗法对烧伤伤口愈合的体内细胞保留和治疗效果。我们的水凝胶显著提高了ASC在烧伤伤口中的活力，水凝胶-ASC治疗增强了新血管形成，促进了伤口闭合，并减少了瘢痕形成。
