Sustained Regeneration of Soft Tissue Defects

描述(由申请人提供)：摘要：临床上没有将大的软组织缺损恢复到正常组织结构和功能的选择。脂肪和脂肪转移提供了一些好处，但保留容量和避免重复手术是大缺陷的主要问题，如手术和创伤。因此，持续的(体内重建过程中的体积保持到正常恢复的组织状态)软组织重建是临床上尚未满足的主要需求，起源于疾病、手术和创伤。目前所有的临床方法，包括外科皮瓣、人工填充物和游离脂肪移植，都会有很大的局限性。特别是，这些选择无法在较长的时间内恢复自然组织的大小、面积和功能；在手术后三个月内失去容量。因此，在活体组织整合和再生过程中，迫切需要一种新的方法来修复大的软组织缺损区，使其体积保持至少一年。为了满足这一需求，我们提出了一种结合吸脂剂的三维多孔丝蛋白生物材料支架系统。该系统的独特功能包括能够稳定体内使用一年以上的丝蛋白基质，并随着时间的推移实现完全的自然组织再生，支持细胞并促进脂肪生成和血管生成的能力，支架系统的机械稳定性以随时间支持组织结构和体积，以及在此过程中使用FDA批准的生物兼容性生物材料(丝绸)。假设生物材料系统可以设计用于软组织重建的需求，其中植入部位的大小和形状可以在血管化脂肪形成期间保持至少一年，并允许随着时间的推移与自然组织完全整合并完全重塑。我们全面的初步数据支持该计划的可行性，目的是在三个月的活体小鼠研究中展示前进的最佳路径。我们将评估细胞黏附部位(RGD)的变量，以及吸脂剂在这一过程中的作用。非种子型控制支架也将被研究。结果将包括对其他通常认为可生物降解的聚合物材料(胶原、PLGA、PCL)的评估：(A)大小和形状在体内保留3个月，(B)血管脂肪组织在支架中的分布，以及(C)与周围组织的整合。在研究结束时，我们预计能够进行长期的大型动物研究，然后进行人类临床试验。 公共卫生相关性：由于严重创伤、癌症和外科手术等疾病，对稳定的软组织重建的需求很大，而且还在不断增长。然而，目前的临床选择有限。拟议的计划将满足这一需求，并填补目前在可用临床选择方面的空白，即在组织再生过程中保留缺损处的体积和形状。

DESCRIPTION (provided by applicant): Summary There is no clinical option to restore large soft tissue defects to normal tissue structure and function. Lipoaspriates and fat transfers offer some benefits, but retention of volume and avoidance of recurring repeats of the surgeries is a major problem for large defects, such as those from surgery and trauma. Thus, sustained (retention of volume during remodeling in vivo to normal restored tissue states) soft tissue reconstruction is a major unmet clinical need, with origins in disease, surgeries and trauma. All current clinical approaches, including surgical flaps, artificial fillers, and free fat transplant ll present significant limitations. In particular, these options fail to restore native tissue size, sape and function over extended time frames; losing volume within three months of surgery. Therefore there is a critical need for new options in the field that would restore large soft tissu defects in terms of retention of volume for at least one year during tissue integration and regeneration in vivo. To address this need, we propose to implement a 3D porous silk-based protein biomaterial scaffold system in combination with lipoaspirate. The unique features of the system include the ability to stabilize the silk protein matrix used in vivo for more than a year yt achieve full native tissue regeneration over time, the ability to support cells and promote adipogenesis and vasculogenesis, the mechanical robustness of the scaffold system to support tissue structure and volume over time, and the use of a biocompatible, FDA approved, biomaterial (silk) in the process. The hypothesis is that a biomaterial system can be designed for soft tissue reconstruction needs where size and shape at the implant site can be retained for at least one year during vascularized adipose formation, and allow full integration with native tissue with complete remodeling over time. Our comprehensive preliminary data support the feasibility of the plan and the aim is designed to demonstrate the best path forward in a three month in vivo mouse study. We will assess variables of cell adhesion sites (RGD), and the role of lipoaspirate in the process. Unseeded control scaffolds will also be studied. Outcomes will include assessments against other commonly considered biodegradable polymeric materials (collagen, PLGA, PCL): (a) retention of size and shape for 3 months in vivo, and (b) vascularized adipose tissue distribution in the scaffold, and (c) integration with surrounding tissue. At the end of the study we anticipate being in a position to pursue long term large animal studies and then human clinical trials. PUBLIC HEALTH RELEVANCE: The need for stable soft tissue reconstruction is large and growing due to severe trauma, diseases such as cancer and surgery. However, current clinical options are limited. The proposed program will address this need and fill the current gap in available clinical options in terms of retention of volume and shape of the defect site during tissue regeneration.