Bioengineered Urethral Augmentation

描述(申请人提供)：尿路功能障碍是糖尿病、脊髓损伤和骨盆创伤的常见并发症。压力性尿失禁(SUI)是一种继发于尿道括约肌机制受损的继发性尿失禁，在女性中尤其常见，可能是由阴道分娩引起的。目前有几种治疗SUI的方法，所有这些方法都受到无效或后续并发症的限制。再生医学方法，包括细胞疗法和组织工程学，可能会解决这些限制。我们相信，使用功能性组织工程尿道袋(TEUW)将使天然尿路保持完整，同时通过设计的再生修复机制提供增强的机械稳定性和功能加固。在这个R21提案中，我们将探索使用祖细胞作为TEUW的功能组件。具体地说，我们将探索以下两个假设：i)通过在天然生物基质中适当刺激骨髓来源的祖细胞(BMPC)，可以在体外构建一个具有活性、功能和平滑肌肉填充的管状结构；以及ii)由这些结构衍生的组织工程尿道膜(TEUW)可以成功植入，并将逆转在SUI大鼠模型中发现的尿道力学和功能特性的短期变化。我们提出了两个具体的目标来探索这些假设。目的1是用骨髓基质干细胞和天然生物基质构建一种活性的、功能性的、可作为TEUW植入的管状结构。这将通过确定体外刺激方案来确定，该方案从机械应变和生物化学的组合中选择，产生最佳的组织学、功能、生物力学和免疫学特性。目标2是评估由来自特定目标1的BMPC来源的SMC填充的构建物组成的TEUW。评估将包括体外和体内分析，使用组织学、功能、生物力学和免疫学终点。结果将与正常和疾病的自然尿路，以及使用分离的自然尿路SMC构建的TEUW进行比较。成功研制出一种针对不充分的尿路控制机制的TEUW将有可能缓解SUI和其他尿路疾病。

DESCRIPTION (provided by applicant): Urethral dysfunction is a common complication of diabetes mellitus, spinal cord injury and pelvic trauma. Stress urinary incontinence (SUI) - the involuntary loss of urine secondary to a damaged urethral sphincter mechanism - is particularly common in women and can result from vaginal childbirth. There are currently several approaches to treat SUI, all of which are limited by ineffectiveness or subsequent complications. Regenerative medicine approaches, including cell therapy and tissue engineering, could potentially address these limitations. We believe that utilization of a functional tissue engineered urethral wrap (TEUW) will allow the native urethra to remain intact, while providing enhanced mechanical stability'and functional reinforcement through designed regenerative repair mechanisms. In this R21 proposal, we will explore the use of progenitor cells as the functional component of a TEUW. Specifically, we will explore the following two hypothesest: i) a living, functional, smooth muscle-populated tubular construct can be fabricated in-vitro by appropriately stimulating bone marrow derived progenitor cells (BMPCs) within a natural biological matrix; and ii) a tissue engineered urethral wrap (TEUW) derived from these constructs can be successfully implanted and will reverse the short-term changes in mechanical and functional properties of the urethra found in a rat model of SUI. We propose two specific aims to explore these hypotheses. AIM 1 is to fabricate a living, functional smooth muscle populated tubular construct from BMPCs and a natural biological matrix that is suitable for implantation as a TEUW. This will be determined by determining the in-vitro stimulation regimen, chosen from combinations of mechanical strain and biochemicals, that yield optimal histological, functional, biomechanical and immunological properties. AIM 2 is to assess a TEUW composed of the BMPC-derived SMC-populated constructs from specific aim 1. Assessments will include both in vitro and in vivo analyses, using histological, functional, biomechanical, and immunological endpoints. Results will be compared with normal and diseased native urethra, as well as a TEUW constructed using isolated native urethral SMCs. Successful development a TEUW for an insufficient urethral continence mechanism would potentially provide relief from SUI and other urethral disorders.