3D Bioprinting of Biomimetic Constructs for Rotator Cuff Augmentation

项目摘要 肩袖肌腱撕裂每年有超过450万人次的医生就诊， 在美国每年进行袖带修复手术。对于巨大的肩袖缺损或慢性 撕裂伴显著牵开和组织缺损，多种策略，包括自体、同种和异种移植物 作为合成植入物，已被用于增加骨-肌腱连接，以提高成功率。 这些严重的肩袖撕裂的愈合尽管目前在组织增强方面取得了进展，但总体而言， 失败率在38%到65%之间。在制定解决办法方面的障碍 解决肌腱-骨愈合的部分原因是（1）目前的增强选项无法模拟多动物 天然肩袖组织的结构;（2）均匀的基质微环境阻碍了异质性 祖细胞/间充质干细胞（MSC）的分化和血管化;（3）知识有限 了解了不同区域间充质干细胞的分化状态和血管化模式 影响肩袖愈合。我们开发了一种新的策略，将3D生物打印技术与 生物纺织技术用于产生具有带状结构和空间生物活性的工程化肩袖结构 因子分布拟议的研究将测试腱骨再生增强的假设 在体外和体内通过脂肪来源的MSC（ADMSC）的空间分化和 在优化的生物打印微环境中预先设计的区域中的血管化程度。具体目标 的研究是（i）确定生物打印的肩袖结构中ADMSC的空间分化 影响腱-骨愈合;以及（ii）确定空间结合的生物活性因子如何调节 ADMSC分化、血管化和肩袖修复。兔冈下肌腱大面积缺损 模型将用于这两个目标。主要结果指标包括炎症， 结构整合、胶原纤维排列、不同区域的胶原类型、肌肉质量和脂肪 渗透和拉伸生物力学。该提案将制定生物扩增战略，以促进 无疤痕愈合我们的方法是更好地了解外源性干细胞和血管系统在肿瘤发生中的作用。 体外和体内肌腱-骨界面再生。

Project Summary Rotator cuff tendon tears account for more than 4.5 million physician visits per year, and over 250,000 rotator cuff repair surgeries are performed annually in the United States. For massive rotator cuff defect or chronic tears with significant retraction and tissue loss, multiple strategies, including auto-, allo- and xenografts as well as synthetic implants, have been used to augment the bone-tendon junction to improve the rates of successful healing of these severe rotator cuff tears. Despite the current advances in tissue augmentation, the overall failure rate has been reported to be between 38% and 65%. Obstacles in the development of approaches to address tendon-to-bone healing are partly because (1) current augmentation options fail to mimic multizoal structure of native rotator cuff tissue; (2) uniform matrix microenvironment impedes the heterogeneous differentiation and vascularization of progenitor cells/mesenchymal stem cells (MSC); (3) limited knowledge has been gained about how MSC differentiation status and vascularization pattern within different zonal region affect rotator cuff healing. We have developed a novel strategy by combining 3D bioprinting technique with biotextile technique to generate engineered rotator cuff constructs with zonal structure and spatial bioactive factor distribution. The proposed studies will test the hypothesis that tendon-to-bone regeneration is enhanced in vitro and in vivo by spatial differentiation of adipose derived MSC (ADMSC) and spatial control of vascularization degree in pre-designed region in the optimized bioprinted microenvironment. The specific aims of the studies are (i) determine how spatial differentiation of ADMSC within bioprinted rotator cuff constructs affect tendon-to-bone healing; and (ii) determine how the spatially incorporated bioactive factors regulate ADMSC differentiation, vascularization and rotator cuff repair. A massive rabbit infraspinatus tendon defect model will be employed for both of the aims. The primary outcome measures will include inflammation, construct integration, collagen fiber alignment, collagen types in different regions, muscle quality and fat infiltration, and tensile biomechanics. This proposal will develop biological augmentation strategies to promote scarless healing. Our approach is to better understand the roles of exogenous stem cells and vasculature on tendon-to-bone interface regeneration in vitro and in vivo.