Enhanced tendon to bone healing

描述(由候选人提供)： 肌腱到骨骼插入部位的损伤是老年人疼痛和残疾的主要原因 年轻的人群。在肩袖，没有修复技术可以避免反复撕裂，据报道，短期到中期失败率高达94%。同样，屈肌腱插入部位的修复也不能很好地愈合。失败愈合反应的两个关键特征是骨密度丢失和界面上缺乏纤维软骨形成。因此，本研究的总体目标是利用生物工程方法促进骨和纤维软骨的形成，以改善肌腱到骨的修复。我们的组织工程学方法将利用胎儿肌腱到骨的植入作为动力，在我们的两个成熟的动物模型中促进再生愈合反应。骨形态发生蛋白2(BMP-2)和骨形态发生蛋白12的表达 (BMP-12)将被上调，以分别促进骨和纤维软骨的形成。BMP-2与骨胎儿发育有关，并已成功地用于促进成人组织中的骨形成。BMP-12与关节胎儿发育有关，并已被证明在皮下植入时可诱导新生肌腱/纤维软骨的形成。在这项研究中，自体间充质干细胞将被转化为产生感兴趣的因子，并使用胶原基质进行输送。机械负荷环境也与骨的发育和维持有关。胎儿发育和成人愈合研究表明，增加负荷会导致骨的形成，而减少负荷会导致骨的吸收。机械负荷在愈合过程中的作用将通过在一组中移除修复部位的负荷并增强 在第二组中穿过维修现场的装载。在具体目标1中，我们将通过生物(即骨形态发生蛋白-2)和机械(即增加负荷)的方法刺激成骨细胞在愈合的犬屈肌腱骨附着点产生骨。在特定的目标2中，我们将开发生物力学模型来预测肌腱-骨界面处的应力。在具体目标3中，我们将通过生物学手段(即BMP-12)刺激修复部位的细胞在愈合的大鼠棘上肌腱-骨植入处产生纤维软骨。我们研究计划的长期目标是为肌腱到骨骼愈合的临床问题提供治疗性解决方案。候选人在生物工程方面的专业知识将与导师在临床科学和分子生物学方面的优势相结合，形成一个独特且平衡的跨学科团队。

DESCRIPTION (provided by candidate): Tendon to bone insertion site injuries are a leading cause of pain and disability in elderly as well as young populations. At the rotator cuff, where there are no repair techniques that are immune from recurrent tears, short to mid term failure rates have been reported to be as high as 94%. Similarly, flexor tendon insertion site repairs do not heal well. The two key features of the failed healing response are loss of bone mineral density and lack of fibrocartilage formation at the interface. Therefore, the overall objective of this study is to use bioengineering approaches to promote bone and fibrocartilage formation in order to improve the tendon to bone repair. Our tissue engineering approach will use the fetal development of tendon to bone insertions as motivation for promoting a regenerative healing response in our two well established animal models. Specifically, the expression of bone morphogenetic protein 2 (BMP-2) and bone morphogenetic protein 12 (BMP-12) will be upregulated to promote the formation of bone and fibrocartilage, respectively. BMP-2 has been implicated in bone fetal development and has successfully been used to promote bone formation in adult tissues. BMP-12 has been implicated in joint fetal development and has been demonstrated to induce neo-tendon/fibrocartilage formation when implanted subcutaneously. In this study, autologous mesenchymal stem cells will be transformed to produce the factors of interest and delivered using a collagen matrix. The mechanical loading environment has also been implicated in the development and maintenance of bone. Fetal development and adult healing studies have demonstrated that increased loading results in the formation of bone, while decreased loading results in the resorption of bone. The role of mechanical loading during healing will be explored by removing the loading across the repair site in one group and enhancing the loading across the repair site in a second group. In specific aim 1 we will stimulate osteoblasts to produce bone at the healing canine flexor tendon bone insertion site through biologic (i.e., BMP-2) and mechanical (i.e., increased loading) means. In specific aim 2 we will develop biomechanical models to predict the stresses at the tendon to bone interface. In specific aim 3 we will stimulate repair site cells to produce fibrocartilage at the healing rat supraspinatu tendon-bone insertion through biologic (i.e., BMP-12) means. The long term goal of our research program is to provide therapeutic solutions to the clinical problem of tendon to bone healing. The candidate's expertise in bioengineering will be combined with the mentors strengths in clinical science and molecular biology to form a unique and well balanced interdisciplinary team.