Sustained Regeneration of Soft Tissue Defects

临床没有将大型软组织缺损恢复到正常组织结构和功能的选择。脂质酸盐和脂肪转移提供了一些好处，但体积的保留和避免重复手术是大缺陷的主要问题，如手术和创伤造成的缺陷。因此，持续的（在体内重塑过程中体积保持到正常的组织恢复状态）软组织重建是一个主要的未满足的临床需求，起源于疾病、手术和创伤。所有目前的临床方法，包括外科皮瓣、人工填充物和游离脂肪移植，都存在明显的局限性。特别是，这些选择无法在较长时间内恢复原始组织的大小、形状和功能；手术后三个月内体积减少。因此，迫切需要在该领域找到新的选择，在组织整合和体内再生过程中，以保留体积的方式恢复大型软组织缺损至少一年。为了满足这一需求，我们提出了一种3D多孔丝基蛋白质生物材料支架系统与抽脂剂的结合。该系统的独特之处包括：能够在体内稳定使用超过一年的丝蛋白基质，并随着时间的推移实现完全的天然组织再生；能够支持细胞并促进脂肪生成和血管生成；支架系统的机械稳健性能够随着时间的推移支持组织结构和体积；以及在此过程中使用生物相容性，FDA批准的生物材料（丝）。我们的假设是，可以设计一种生物材料系统来满足软组织重建的需要，在血管化脂肪形成过程中，植入部位的大小和形状可以保持至少一年，并且随着时间的推移，可以与原生组织完全整合，完全重塑。我们全面的初步数据支持该计划的可行性，目的是在为期三个月的小鼠体内研究中展示最佳的前进路径。我们将评估细胞粘附位点（RGD）的变量，以及抽脂在这一过程中的作用。未播种的对照支架也将被研究。结果将包括对其他通常认为的可生物降解聚合物材料（胶原蛋白、PLGA、PCL）的评估：(a)在体内大小和形状保持3个月，(b)支架中血管化脂肪组织的分布，以及(c)与周围组织的整合。在研究结束时，我们希望能够进行长期的大型动物研究，然后进行人体临床试验。

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.