Creation of the First Nanostructured Synthetic Regenerative Bladder Graft Materia

描述(申请人提供)：膀胱癌是男性第四大常见癌症，女性第七大常见癌症，确诊后的预期寿命仅为五年。要修复这种癌症的中期，需要切除病变区域。然而，令人惊讶的是，尽管最近在开发用于其他组织的再生支架方面取得了进展，但区域性的泌尿生殖系统修复，特别是中期(T2)膀胱癌后的膀胱修复，几乎没有手术选择。对于因任何原因需要切除和替换部分膀胱的患者，最常用的选择是用一段肠道替换切除的区域。切除的组织可能会给患者带来严重的并发症，因为它会将粘液分泌到膀胱中，导致结石形成，并可能导致癌症。正在开发的选择包括种子支架，它可能提供一种替换大部分膀胱的解决方案，但潜在的程序复杂性和费用可能限制其适用于部分/局部修复。脱细胞基质在推向市场时提供了希望，但自那以来一直因缺乏长期机械强度而受到批评。出于这些原因，本项目的目标是开发第一个合成纳米结构再生膀胱移植材料。纳米结构材料因其能够模拟天然组织的表面粗糙度而成为组织工程研究的关键领域。先前的工作已经证明了一种纳米表面控制的机制，可以减缓蛋白质的吸附，驱动细胞的附着和生长，并出人意料地成为一种减少膀胱结石形成的膀胱修复移植材料。建议的产品将利用这些发现来创建简单而优雅的产品解决方案。本提案将通过重点使用纳米结构多层可生物降解聚合物基质来实现这一目标。Nanovis将制备这些移植原型，并在体外评估它们的再生性能，并表征它们的机械和生物兼容性。通过这种方式，建议的具体目标将：(I)由聚氨酯(PU)和聚丙交酯-乙交酯(PLGA)(75：25wt.%PU：PLGA)支架制备分层和分级的多孔纳米结构可生物降解基质并表征其机械和化学性质，(Ii)使用体外模型评估尿路上皮和平滑肌细胞功能以及钙结石或细菌在纳米级PU和PLGA上定植的可能性，以及(Iii)在预算限制的范围内对最佳纳米结构膀胱构建物进行初步体内评估。 公共卫生相关性：膀胱和泌尿系统的外科修复是一种常见的手术，但令人惊讶的是，目前还没有合成的再生移植物材料。Nanovis的建议旨在开发一种合成纳米结构膀胱移植材料，这种材料可以防止膀胱结石的形成，适合帮助每年需要这种手术的5万多名美国患者。

DESCRIPTION (provided by applicant): Bladder cancer is the fourth most common cancer among men and the seventh most common cancer in women with a life expectancy of only five years after diagnosis. Repair of the mid stage of this cancer requires excision of the diseased area. Surprisingly however, regional repair of the genitourinary system and specifically including the repair of the bladder after mid stage (T2) bladder cancer has surprisingly few surgical options despite the recent advances in the development of regenerative scaffolds for other tissues. The most commonly used option for patients requiring resection and replacement of part of their bladder for any reason is the replacement of the resected area with a section of the intestine. The resected tissue can cause serious complications for the patient because it secretes mucus into the bladder, causing stone formation and potentially cancer. Options under development include seeded scaffolds which are likely to offer a solution for replacement of large portions of the bladder but potential procedural complexity and expense may limit their suitability for partial/regional repairs. Acellular matrices offered promise upon introduction to the market but have since been criticized for a lack of long term mechanical strength. For these reasons, the goal of this project is to develop the first synthetic nanostructured regenerative bladder graft material. Nanostructured materials have become a key area of tissue engineering research due to their ability to mimic the roughness and, consequently, the surface energy of natural tissues. Prior work has demonstrated a nanosurface controlled mechanism of moderating protein adsorption driven cell attachment and growth and unexpectedly a bladder repair graft material that reduces bladder stone formation. The proposed product will leverage these findings to create a simple and elegant product solution. The present proposal will reach this goal by focusing on the use of nanostructured multilayered biodegradable polymer matrices. Nanovis will prepare these graft prototypes and evaluate their regenerative properties in vitro and characterize their mechanical and biocompatibility properties. In this manner the specific aims of the proposal will : (i) prepare layered and graded porous nanostructured biodegradable matrices from polyurethane (PU) and poly-lactide-co-glycolide (PLGA) (75:25 wt.% PU:PLGA) scaffolds and characterize its mechanical and chemical properties, (ii) use in vitro models to assess the urothelial and smooth muscle cell functions and the likelihood of calcium stone or bacterial colonization on nanoscale PU and PLGA, and (iii) conduct a preliminary in vivo assessment of the best nanostructured bladder constructs within the budget limitations. PUBLIC HEALTH RELEVANCE: Surgical repair of the bladder and urogential system is a common procedure yet surprisingly a synthetic regenerative graft material is not available. Nanovis' proposal seeks to develop a synthetic nanostructured bladder graft material that is resistant to bladder stone formation suitable to help the over 50,000 U.S. patients per year in need of such a procedure.