Developing a SMART scaffold for bladder augmentation

摘要 在美国，每年都有创伤、放射治疗来治疗泌尿系癌症、严重脊椎病例 脊柱裂和间质性膀胱炎导致至少14,000例膀胱隆大肠膀胱成形术。 虽然这是终末期病理性膀胱患者的标准护理，但肠膀胱成形术会导致 由于膀胱组织和肠道之间的解剖和生理差异而引起的许多并发症 用来增加膀胱容量的组织。据报道，有几种策略将取代 肠膀胱成形术和再生膀胱组织，但这些都在临床上失败了。失败的原因包括 系统发育不同的临床前动物模型的常见用途不能准确地代表 人类膀胱或其疾病状态，使用不适当的材料作为细胞生长的支架 在膀胱组织上和再生上，使用经常患病的自体膀胱细胞已经失去了 再生功能性膀胱组织的能力，以及连续监测该组织的能力 再生过程，以便在早期阶段识别潜在问题。因此，目前没有可行的 肠膀胱成形术的替代方法。再生工程是先进技术的汇聚 材料科学、干细胞科学、物理学和临床翻译。这个项目的总体目标是推动 通过STEM集成开发前所未有的再生工程工具和技术 细胞科学、先进生物材料和生物集成电子学，使功能再生成为可能 膀胱组织及其非侵入性的实时评估，以更好地预测结果。为了实现这个目标， 我们已经展示了我们的能力：a)在大鼠膀胱中再生血管和神经支配的膀胱组织 使用骨髓(BM)间充质干细胞(MSCs)组合的增强模型， 造血干/祖细胞(HSPC)和基于柠檬酸盐类抗氧化剂的可生物降解弹性体，b) 6个月后成功应用自体细胞种植的POC支架重建膀胱 狒狒； C)通过生物集成电子应变仪测量大鼠膀胱压力并控制其功能 和光激活的兴奋通道，d)将可伸展的电子设备集成到柠檬酸盐基弹性体中，以及 E)利用生物集成技术实现体内实时生理数据的无线传输 电子产品。就我们的目标而言，该提案的具体目标是：1)设计、制造和表征 生物集成电子设备，通过遥测监测和调节再生膀胱组织的功能， 2)设计和表征拉伸监控高级再生遥测(SMART)支架，用于 以及3)评估膀胱适形可伸展电子设备的安全性和有效性 狒狒膀胱增大模型中的智能支架。

SUMMARY Each year in the United States, trauma, radiation therapy to treat urological cancers, severe cases of spina bifida, and interstitial cystitis contribute to at least 14,000 bladder augmentation enterocystoplasty surgeries. Although it is the standard of care for patients with an end-stage pathologic bladder, enterocystoplasty causes many complications due to anatomical and physiological differences between bladder tissue and the bowel tissue used to augment the bladder’s capacity. Several strategies have been reported to replace enterocystoplasty and regenerate bladder tissue but these have failed clinically. Reasons for the failure include the common use of phylogenetically dissimilar pre-clinical animal models that do not accurately represent the human bladder or its disease condition, the use of inadequate materials to serve as scaffolds for cells to grow on and regenerate bladder tissue, the use of often diseased autologous bladder cells that have lost the capacity to regenerate functional bladder tissue, and an inability to continuously monitor the tissue regeneration process to identify potential problems at an early stage. As a result, there is currently no viable alternative to augmentation enterocystoplasty. Regenerative engineering is a convergence of advanced material science, stem cell science, physics, and clinical translation. The overall goal of this project is to drive the development of unprecedented regenerative engineering tools and technologies via the integration of stem cell science, advanced biomaterials, and bio-integrated electronics to enable the regeneration of functional bladder tissue and the non-invasive, real-time assessment thereof to better predict outcome. Toward this goal, we have demonstrated our ability to: a) regenerate vascularized and innervated bladder tissue in a rat bladder augmentation model using a combination of bone marrow (BM) mesenchymal stem cells (MSCs), hematopoietic stem/progenitor cells (HSPCs), and an antioxidant citrate-based biodegradable elastomer, b) demonstrated successful bladder reconstruction with autologous cell-seeded POC scaffolds at 6 months in baboon; c) measure rat bladder pressure and control its function via a bio-integrated electronic strain gauge and light-activated excitatory channels, d) integrate stretchable electronics into citrate-based elastomers, and e) achieve wireless transmission of real time physiological data obtained in vivo using bio-integrated electronics. Towards our goal, the specific aims of this proposal are to: 1) Design, fabricate, and characterize bio-integrated electronics that monitor and modulate the function of regenerating bladder tissue via telemetry, 2) Engineer and characterize Stretch Monitoring Advanced Regenerative Telemetric (SMART) scaffolds for bladder augmentation, and 3) Assess the safety and efficacy of bladder conformal stretchable electronics and SMART scaffolds in a baboon bladder augmentation model.