Rotator cuff repair using hyaluronan enriched fascia extracellular matrix

描述（由申请人提供）：肩袖撕裂影响40%或更多的60岁以上的人，每年给美国经济造成约30亿美元的损失。高达90%的大型肩袖撕裂修复后再次撕裂，导致长期肩关节残疾。肩袖修复后的高再撕裂率取决于可能损害患者内在愈合能力的机械因素和生物因素。因此，迫切需要提供足够强度以及刺激和增强患者愈合潜力的修复策略。我们研究项目的长期目标是设计有效的策略，成功修复大型慢性肩袖撕裂。本申请的目的是确定筋膜细胞外基质（ECM）（经生物增强和未经生物增强）可改善肩袖修复的功能结局的程度。我们的中心假设是，生物富集增强了宿主对筋膜的反应，因此使用工程化筋膜增强肩袖修复将改善修复结果，优于传统的仅缝合修复或使用自体筋膜增强。我们的基本原理是为骨科医生提供一种机械坚固的天然支架，促进功能性肌腱-骨桥接，从而改善肩袖修复患者的结局。该项目的具体目的是：1）确定最大化细胞浸润筋膜ECM的生物治疗水平; 2）减少与筋膜ECM相关的慢性炎症; 3）使用筋膜ECM改善肩袖修复结局。实验方法将使用体外细胞培养模型研究腱细胞浸润到工程化筋膜中，以建立使细胞浸润到ECM中最大化的治疗。随后，将在大鼠腹壁缺损模型中定量工程化筋膜调节慢性炎症的能力，如通过持续淋巴细胞和浆细胞的数量所定义的。最后，将研究工程化筋膜ECM改善大型动物肩袖损伤和修复模型结果的能力。在这项工作的结论，我们希望已经开发出一种新的策略，肩袖修复-工程筋膜ECM-这是机械上合适的和生物学上有益的。通过最终评估我们的方法在相关的临床前动物模型中增强肩袖修复结果的能力，可以做出关于将这种修复策略转化为人类患者的判断。重要的是，这些研究还将为评估任何数量的改良或替代治疗方法提供基本范例。成功治疗大型慢性肩袖撕裂患者的策略将大大减少长期困扰许多老年人的衰弱性疼痛，肩关节功能下降和虚弱的发生率，而不是让他们在晚年保持健康，积极的生活方式。

DESCRIPTION (provided by applicant): Rotator cuff tears affect 40% or more of those over age 60 and cost the US economy approximately $3 billion per year. As many as 90% of large rotator cuff tears that are repaired re-tear, resulting in long-term shoulder disability. High re-tear rates following rotator cuff repair depend on mechanical factors and biologic factors that may compromise the patients' intrinsic capacity to heal. Hence, there is a critical need for repair strategies that provide adequate strength as well as stimulate and enhance the patients' healing potential. The long-term goal of our research program is to design effective strategies for successful repair of large, chronic rotator cuff tears. The objective of this application is to establish the extent to which fascia extracellular matrix (ECM), engineered with and without biologic enhancement, can improve the functional outcomes of rotator cuff repair. Our central hypothesis is that biologic enrichment enhances the host response to fascia such that augmenting rotator cuff repairs with engineered fascia will improve repair outcomes over conventional suture only repair or augmentation with native fascia. Our rationale is to provide the orthopaedic surgeon with a mechanically robust, natural scaffold that will foster functional tendon-bone bridging and thereby improve outcomes in rotator cuff repair patients. The specific aims of this project are to 1) identify the biologic treatment level that maximizes cell infiltration into fascia ECM 2) reduce chronic inflammation associated with fascia ECM, 3) improve rotator cuff repair outcomes using fascia ECM. The experimental approach will be to investigate tenocyte infiltration into engineered fascia using an in vitro cell culture model, in order to establish the treatment that maximizes cell infiltration into the ECM. Subsequently, the ability of engineered fascia to modulate chronic inflammation, as defined by the number of persisting lymphocytes and plasma cells, will be quantified in a rat abdominal wall defect model. Finally, the ability of engineered fascia ECM to improve outcomes in a large animal rotator cuff injury and repair model will be investigated. At the conclusion of this work, we expect to have developed a novel strategy for rotator cuff repair--engineered fascia ECM-- that is both mechanically suitable and biologically beneficial. By ultimately assessing the ability of our approach to enhance rotator cuff repair outcomes in a relevant, pre-clinical, animal model, judgments regarding the translation of this repair strategy to human patients can be made. Importantly, these studies will also provide the foundational paradigm for evaluating any number of modified or alternate therapeutic approaches to rotator cuff repair. Strategies to successfully treat patients with large, chronic rotator cuff tears will dramatically reduce the incidence of debilitating pain, reduced shoulder function and weakness that chronically plague many elderly individuals, instead allowing them to maintain a healthy, active lifestyle in later years.