Biomolecule releasing adhesive for cell-mediated labral repair

摘要 肩袖唇是一种纤维软骨性结构，位于肩关节的肩袖边缘。 肩袖撕裂或病变可发生在几个不同的位置(前、上或后)， 形态不同(脱离骨骼或实体内)并与慢性肩部相关 疼痛和/或不稳定。虽然通常需要手术干预才能将受损的唇部重新连接到 关节突骨或直接修复实体内撕裂的下唇，反复出现肩关节不稳和疼痛 据报道，唇裂手术修复后的死亡率高达30%。这种持续的残疾伴随着 治疗与阴唇愈合能力差是一致的。目前的唇部修复通常涉及 使用锚钉和缝线来恢复唇部和肩部的稳定，但很少能促进实际 受伤的唇骨再生。尽管细胞疗法和组织工程学方法已被用于 改善软骨和骨愈合，这些方法还没有被探索来促进肩袖唇愈合。 要解决这一不足的治疗，这是至关重要的是提高我们的认识。 唇裂相关组织损伤的过程及辅助唇裂的新治疗方法 组织再生和功能恢复。在我们的实验室，在这方面已经取得了实质性的进展。 简单地说，合成了基于点击化学的粘合剂，这些粘合剂具有良好的组织结构 附着性、细胞/组织相容性和原位生长因子释放特性。同样重要的是，我们的学习 在人类和大鼠的唇部组织中发现了丰富的祖细胞来源，这些细胞可以被招募 刺激产生丰富的细胞外基质蛋白，加速唇部愈合。 在活体关节唇撕裂大鼠模型中进行评估时，仅应用生物粘附剂就足以 减少90%的炎细胞浸润和~70%的唇部组织侵蚀。通过激发祖细胞反应 (募集、增殖和细胞外基质生产)，生长因子释放粘合剂支架的应用 发现可促进唇部愈合(与50%的唇部相比，6周后唇部撕裂完全再生 在不处理对照中退化/丢失)。这些令人兴奋的发现支持了两个假设。首先，一种粘合剂 可以被制造成作为支架基质，以桥接和密封撕裂的唇骨内的间隙，并且优先 招募和刺激内源性唇祖细胞到损伤部位修复和再生损伤 嘴唇组织。第二，唇部撕裂伤介导的滑膜炎症反应和炎性细胞浸润 撕裂部位及其周围的细胞会导致唇部组织侵蚀。这些假设将通过3- 一系列研究。拟议工作的成功完成将大大提高我们的理解 并导致创建一种新的治疗方法，以促进 唇部再生补充目前应用缝线锚定修复唇裂的手术方法。

Summary The glenoid labrum is a fibrocartilaginous structure that lines the edge of the glenoid rim of the shoulder joint. Glenoid labral tears, or lesions, can occur in several distinct locations (anterior, superior, or posterior) with variable morphology (detachment from bone or intrasubstance) and have been associated with chronic shoulder pain and/or instability. While operative intervention is typically needed to re-attach the damaged labrum to the glenoid bone or to directly repair an intrasubstance tear of the labrum, recurrent shoulder instability and pain following surgical repair of the labrum has been reported to be as high as 30%. This continued disability following treatment is consistent with the poor healing capacity of the labrum. Current labral repair typically involves the use of anchors and sutures to restore stability of the labrum and shoulder, but rarely promotes actual regeneration of the injured labrum. Although cell therapy and tissue engineering approaches have been used to improve cartilage and bone healing, these approaches have not been explored to improve glenoid labrum healing. To address this deficiency in the treatment of glenoid labral injuries, it is essential to improve our knowledge of the process of labral tear associated tissue injury and to develop a new treatment method assisting in labral tissue regeneration and functional recovery. In our laboratory, substantial progress has been made on this front. Briefly, click-chemistry based adhesives have been synthesized and these adhesives possess good tissue attachment, cell/tissue compatibility, and in situ growth factor releasing property. Equally important, our studies have uncovered an abundant source of progenitor cells in human and rat labrum tissue, which can be recruited to the injured sites and stimulated to produce abundant extracellular matrix protein for accelerated labrum healing. When evaluated in an in vivo glenoid labrum tear rat model, the application of bioadhesive alone suffices to reduce 90% inflammatory cell infiltration and ~70% labral tissue erosion. By eliciting progenitor cell responses (recruitment, proliferation, and ECM production), the application of growth factor-releasing adhesive scaffold was found to enhance labral healing (with complete labral tear regeneration by 6 weeks vs. 50% labral degeneration/lost in no treatment control). These exciting findings support two hypotheses. First, an adhesive can be fabricated to serve as a scaffold matrix to bridge and seal the gap within the torn labrum, and preferentially recruit and stimulate endogenous labral progenitor cells to the injury site for repairing and regenerating damaged labral tissue. Second, labral tear injury mediated synovial inflammatory responses and infiltration of inflammatory cells in and around the tear site cause labral tissue erosion. These hypotheses will be investigated through 3- series of studies. The successful completion of the proposed work will significantly improve our understanding of labral tear-associated tissue damage and lead to the creation of a new treatment approach for promoting labrum regeneration complementing current surgical labral repair of torn labrum with suture anchor strategies.