Repair of Soft Tissue Defects with Engineered Fat Grafts

描述（由申请人提供）：本研究的长期目标是开发一种临床可翻译的策略来修复由癌症、创伤、先天性异常和感染引起的软组织缺损。组织工程脂肪移植修复软组织缺损是一种理想的解决方案，可以消除目前重建手术中的许多局限性。然而，工程脂肪移植物如何存活的基本问题在很大程度上仍然没有答案。本提案的直接目标是解决阻碍脂肪组织工程进展的三个基本问题。我们假设工程脂肪的成功移植与移植物的细胞组成有关，并对移植物受体部位的微环境进行了测试。三个具体目的是利用综合的多学科方法来研究这一假设。目的1侧重于定义注射器抽吸人体脂肪的细胞组成，作为用于处理用于植入的收获脂肪的技术的功能。流式细胞术用于鉴定和定量细胞群。在目的2中，我们确定了工程脂肪移植体积与局部血供的关系。这一关键的设计参数是通过定量组织形态计量学和异种移植模型来阐明的，异种移植模型包含了具有自身蒂血供应的脂肪结构。目的3集中于确定驻地脂肪前体和干细胞募集的必要作用。工程脂肪移植的发展将广泛影响与癌症、创伤、先天性异常和感染引起的软组织缺损相关的医疗保健。了解参与脂肪移植的细胞群和脂肪移植对血液供应的依赖是影响工程脂肪移植设计的关键机制。此外，脂肪移植部位的常驻成脂细胞的参与可能会调节脂肪移植的存活。这些基本问题一旦被理解，就有可能模拟或调节这些活动，以实现新的生物启发技术。

DESCRIPTION (provided by applicant): The long-term objective of this research is to develop a clinically translatable strategy to repair soft tissue defects resulting from cancer, trauma, congenital abnormalities, and infections. Repair of soft tissue defects with tissue engineered fat grafts are the ideal solution to obviate many current limitations in reconstructive surgery. However, the fundamental question of how engineered fat grafts survive remains largely unanswered. The immediate objective of this proposal is to address three fundamental issues that hinder the progress of adipose tissue engineering. We hypothesize that successful grafting of engineered fat is linked to the cellular composition of the graft and the microenvironment of the graft's recipient site is tested. Three specific aims investigate this hypothesis utilizing an integrated, multidisciplinary approach. Aim 1 focuses on defining the cellular composition of syringe-aspirated human fat as a function of the techniques used to process harvested fat for implantation. Flow cytometry is employed to identify and quantify cell populations. In Aim 2, we determine the relationship between engineered fat graft volume and local blood supply. This critical design parameter is elucidated using quantitative histomorphometry and a xenograft model that incorporates a fat construct possessing its own pedicled blood supply. Aim 3 concentrates on determining the requisite role of the recruitment of resident fat precursor and stem cells. The development of an engineered fat graft will broadly impact health care related to soft tissue defects caused by cancer, trauma, congenital abnormalities, and infections. Understanding the cell populations involved in fat grafting and blood supply dependence of fat grafts are critical mechanisms that affect the design of an engineered fat graft. Moreover, the involvement of resident adipogenic cells at the site of fat grafting may modulate the survival of fat grafting. These fundamental issues, once understood, offer the potential to mimic or modulate these activities for novel bioinspired technologies.