Bioengineered Urethral Augmentation

描述（由申请人提供）：尿道功能障碍是糖尿病、脊髓损伤和骨盆创伤的常见并发症。压力性尿失禁（SUI）-继发于尿道括约肌机制受损的非自愿尿失禁-在女性中特别常见，可能由阴道分娩引起。目前有几种方法来治疗SUI，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，包括细胞治疗和组织工程，可能会解决这些局限性。我们相信，利用功能性组织工程尿道包裹物（TEUW）将允许天然尿道保持完整，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增强。在这个R21提案中，我们将探索使用祖细胞作为TEUW的功能成分。具体而言，我们将探讨以下两个假设：i）通过在天然生物基质中适当刺激骨髓来源的祖细胞（BMPC），可以在体外制造活的、功能性的、平滑肌填充的管状结构;和ii）衍生自这些构建体的组织工程尿道包裹物（TEUW）可以成功植入，并将逆转短-在SUI大鼠模型中发现的尿道机械和功能特性的长期变化。我们提出了两个具体的目标来探索这些假设。目的1是从BMPC和适合作为TEUW植入的天然生物基质制造活的、功能性平滑肌填充的管状结构。这将通过确定体外刺激方案来确定，所述体外刺激方案选自产生最佳组织学、功能、生物力学和免疫学特性的机械应变和生物化学品的组合。目的2是评估由特定目的1的BMPC衍生SMC填充构建体组成的TEUW。评估将包括使用组织学、功能、生物力学和免疫学终点进行的体外和体内分析。结果将与正常和患病的天然尿道，以及使用分离的天然尿道SMC构建的TEUW进行比较。成功开发用于尿道扩张机制不足的TEUW可能会缓解SUI和其他尿道疾病。

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.