Castleberry Steven A, Golberg Alexander, Sharkh Malak Abu, Khan Saiqa, Almquist Benjamin D, Austen William G, Yarmush Martin L, Hammond Paula T
Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA; Koch Institute of Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA; Institute for Soldier Nanotechnologies, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA; Harvard-MIT Division of Health Sciences and Technology, Cambridge, MA, 02139, USA.
Center for Engineering in Medicine, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, and the Shriners Burns Hospital, Boston, MA, 02114, USA; Porter School of Environmental Studies, Tel Aviv University, Ramat-Aviv, Tel Aviv, Israel.
Biomaterials. 2016 Jul;95:22-34. doi: 10.1016/j.biomaterials.2016.04.007. Epub 2016 Apr 14.
Wound healing is an incredibly complex biological process that often results in thickened collagen-enriched healed tissue called scar. Cutaneous scars lack many functional structures of the skin such as hair follicles, sweat glands, and papillae. The absence of these structures contributes to a number of the long-term morbidities of wound healing, including loss of function for tissues, increased risk of re-injury, and aesthetic complications. Scar formation is a pervasive factor in our daily lives; however, in the case of serious traumatic injury, scars can create long-lasting complications due to contraction and poor tissue remodeling. Within this report we target the expression of connective tissue growth factor (CTGF), a key mediator of TGFβ pro-fibrotic response in cutaneous wound healing, with controlled local delivery of RNA interference. Through this work we describe both a thorough in vitro analysis of nanolayer coated sutures for the controlled delivery of siRNA and its application to improve scar outcomes in a third-degree burn induced scar model in rats. We demonstrate that the knockdown of CTGF significantly altered the local expression of αSMA, TIMP1, and Col1a1, which are known to play roles in scar formation. The knockdown of CTGF within the healing burn wounds resulted in improved tissue remodeling, reduced scar contraction, and the regeneration of papillary structures within the healing tissue. This work adds support to a number of previous reports that indicate CTGF as a potential therapeutic target for fibrosis. Additionally, we believe that the controlled local delivery of siRNA from ultrathin polymer coatings described within this work is a promising approach in RNA interference that could be applied in developing improved cancer therapies, regenerative medicine, and fundamental scientific research.
伤口愈合是一个极其复杂的生物学过程，通常会形成富含胶原蛋白的增厚愈合组织，即瘢痕。皮肤瘢痕缺乏皮肤的许多功能结构，如毛囊、汗腺和乳头。这些结构的缺失导致了伤口愈合的许多长期并发症，包括组织功能丧失、再次受伤风险增加以及美学并发症。瘢痕形成在我们的日常生活中是一个普遍因素；然而，在严重创伤的情况下，瘢痕可能由于收缩和不良的组织重塑而产生长期并发症。在本报告中，我们通过可控的局部RNA干扰递送，靶向结缔组织生长因子（CTGF）的表达，CTGF是皮肤伤口愈合中TGFβ促纤维化反应的关键介质。通过这项工作，我们描述了对纳米层涂层缝线进行全面的体外分析，以可控地递送siRNA，并将其应用于改善大鼠三度烧伤诱导的瘢痕模型中的瘢痕结局。我们证明，CTGF的敲低显著改变了αSMA、TIMP1和Col1a1的局部表达，已知这些基因在瘢痕形成中起作用。在愈合的烧伤伤口中敲低CTGF可改善组织重塑、减少瘢痕收缩，并使愈合组织内的乳头结构再生。这项工作为之前的一些报告提供了支持，这些报告表明CTGF是纤维化的潜在治疗靶点。此外，我们认为，本工作中描述的从超薄聚合物涂层可控地局部递送siRNA是RNA干扰中的一种有前途的方法，可应用于开发改进的癌症治疗、再生医学和基础科学研究。
