Rotator cuff repair using hyaluronan enriched fascia extracellular matrix

描述(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。多达90%的大型肩袖撕裂修复后会再次撕裂，导致长期的肩部残疾。肩袖修复后较高的再撕裂率取决于机械因素和生物因素，这些因素可能会损害患者的内在愈合能力。因此，迫切需要修复策略，以提供足够的力量以及刺激和提高患者的愈合潜力。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。这项应用的目的是确定筋膜细胞外基质(ECM)在多大程度上可以改善肩袖修复的功能结果，无论是否有生物增强。我们的中心假设是，生物丰富增强了宿主对筋膜的反应，因此使用工程筋膜加强肩袖修复将改善修复结果，而不是仅使用传统缝合修复或使用天然筋膜增强修复。我们的理念是为骨科医生提供一种机械坚固的天然支架，这种支架将促进肌腱-骨桥接功能，从而改善肩袖修复患者的预后。该项目的具体目标是：1)确定使细胞最大限度地渗透到筋膜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改善肩袖修复效果。实验方法是使用体外细胞培养模型研究腱细胞在工程筋膜中的渗透，以建立最大限度地使细胞渗透到ECM的治疗方法。随后，工程化筋膜调节慢性炎症的能力将在大鼠腹壁缺损模型中量化，该能力由持续存在的淋巴细胞和浆细胞的数量定义。最后，将研究工程化筋膜ECM在大型动物肩袖损伤和修复模型中改善结果的能力。在这项工作结束时，我们希望开发出一种新的肩袖修复策略--工程化筋膜ECM--既适用于机械上，又有益于生物。通过最终评估我们的方法在相关的临床前动物模型中提高肩袖修复结果的能力，可以判断这种修复策略是否适用于人类患者。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来修复肩袖提供基础范例。成功治疗大型慢性肩袖撕裂患者的策略将极大地减少长期困扰许多老年人的衰弱疼痛、肩部功能下降和虚弱的发生率，使他们能够在晚年保持健康、积极的生活方式。与公共卫生相关。肩袖损伤影响大约30%-40%的60岁以上人口，并对医疗费用和工作损失天数产生重大影响。这项拟议的研究将为肩部外科医生提供一种天然、坚固、可再生的支架，用于肩袖修复。成功治疗大型慢性肩袖撕裂患者的策略将极大地减少长期困扰许多老年人的衰弱疼痛、肩部功能下降和虚弱的发生率，使他们能够在晚年保持健康、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. PUBLIC HEALTH RELEVANCE. Rotator cuff injuries affect approximately 30-40% of the population over age 60 and have a major impact on the cost of medical care and the number of days lost from work. The proposed research will provide the shoulder surgeon with a natural, strong, regenerative scaffold for 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.