Mechanobiology and Regenerative Medicine

重建缺失或受伤组织和器官的再生医学方法包括使用支架、细胞和生物活性分子。使用细胞植入的生物支架是一种常见的方法，并且已经成功地将其应用于临床医学，包括下尿路、胃肠道、肌肉肌腱和真皮皮肤再生。指导组织重塑和再生的原理只被部分理解，但生物力学载荷对重塑过程的影响被认为是一个重要的变量。然而，几乎完全缺乏系统的、定量的研究来确定这一可控因素对组织重塑的影响，特别是具有平滑肌壁成分的组织。本提案寻求支持进行一项定量的、假设驱动的研究，以确定机械负荷对体外和体内平滑肌表型的影响，以及支架结构的相关变化。由猪膀胱细胞外基质（ECM）衍生的生物支架将植入来自不同来源的平滑肌细胞：血管壁、膀胱和食道。这些器官特定的机械负荷方案对重塑过程的影响以及通过改变机械负荷模式来调节重塑过程的能力将被研究。其中描述了两个具体目标：1)用三种不同类型的平滑肌播种的ECM将受到精心选择的机械负荷方案的影响，对细胞表型和基质组织的影响将进行定量评估；2)在器官培养模型（大鼠膀胱壁）中使用的ECM将评估两种平滑肌细胞类型，以评估相邻正常组织细胞存在时细胞和ECM重塑的影响。一个由生物力学工程师、组织工程师、医生和病理学家组成的经验丰富的跨学科团队已经被召集起来进行这些研究。两位顾问，包括再生医学领域的一位领导者和一位统计学家，将支持这项工作。提供了完成这些研究的时间表、推动具体目标的假设、完成工作的替代方法和成功的定量标准。

Regenerative medicine approaches for the reconstitution of missing or injured tissues and organs involves the use of scaffolds, cells, and bioactive molecules. The use of biologic scaffolds seeded with cells is a common approach and several applications have been successfully translated to clinical medicine including lower urinary tract, gastrointestinal tract, musculotendinous, and dermal skin regeneration. The principles that guide tissue remodeling and regeneration are only partially understood but the influence of biomechanical loading upon the remodeling process is accepted as an important variable. However, there is an almost complete absence of systematic, quantitative studies to determine the effect of this controllable factor upon tissue remodeling, especially tissues with a smooth muscle wall component. The present proposal seeks support to conduct a quantitative, hypothesis driven study that determines the effects of mechanical loading upon smooth muscle phenotype in vitro and in vivo and the related changes to the architecture of the scaffold upon which they are seeded. A biologic scaffold derived from the extracellular matrix (ECM) of a porcine urinary bladder will be seeded with smooth muscle cells derived from different sources: the vascular wall, urinary bladder, and esophagus. The influence of those organ specific mechanical loading regimens upon the remodeling process and the ability to modulate the remodeling process by changing the mechanical loading pattern will be investigated. Two specific aims are described in which: 1) ECM seeded with the three different types of smooth muscle will be subjected to carefully selected mechanical loading regimens and the effect upon cell phenotype and matrix organization will be quantitatively evaluated and 2) two smooth muscle cells types will be evaluated upon ECM used within an organ culture model (rat bladder wall) to evaluate the effect of cellular and ECM remodeling when adjacent normal tissue cells are present. An experienced interdisciplinary team consisting of biomechanical engineers, tissue engineers, physicians, and pathologists has been assembled to conduct these studies. Two consultants, including a leader in the field of regenerative medicine and a statistician, will support this effort. A timeline for completion of these studies, hypotheses to drive the specific aims, alternative approaches for completion of the work, and quantitative criteria for success are provided.