Rotator cuff repair using hyaluronan enriched fascia extracellular matrix

描述（由申请人提供）：60岁以上人群中有40%或更多的人患有肩袖撕裂，每年给美国经济造成约30亿美元的损失。多达90%的大肩袖撕裂可修复后再撕裂，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，迫切需要提供足够的强度以及刺激和增强患者愈合潜力的修复策略。我们的研究计划的长期目标是设计有效的策略，成功修复大，慢性肩袖撕裂。本应用的目的是确定筋膜细胞外基质（ECM），在有或没有生物增强的情况下，能在多大程度上改善肩袖修复的功能结果。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，与传统的缝合修复或天然筋膜修复相比，利用工程筋膜进行肌腱套修复将改善修复效果。我们的基本原理是为骨科医生提供一个机械坚固、天然的支架，以培养功能性肌腱-骨桥，从而改善肩袖修复患者的预后。该项目的具体目标是：1)确定最大限度地提高筋膜外膜细胞浸润的生物治疗水平；2)减少与筋膜外膜细胞浸润相关的慢性炎症；3)改善筋膜外膜修复术的肩袖修复效果。实验方法将是使用体外细胞培养模型来研究细胞浸润到工程筋膜中的情况，以建立最大限度地细胞浸润到ECM中的治疗方法。随后，工程筋膜调节慢性炎症的能力（由持续存在的淋巴细胞和浆细胞的数量定义）将在大鼠腹壁缺损模型中量化。最后，我们将研究工程化筋膜ECM改善大型动物肩袖损伤和修复模型的效果。在这项工作的结论中，我们期望开发出一种新的肌腱套修复策略-工程化筋膜ECM-既适合机械又有益于生物学。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，这些研究也将为评估任何改良或替代的肩袖修复治疗方法提供基础范例。成功治疗大型慢性肩袖撕裂患者的策略将大大减少慢性困扰许多老年人的衰弱性疼痛、肩部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。公共卫生相关性。大约30-40%的60岁以上人口受到肩袖损伤的影响，并对医疗费用和失去工作的天数产生重大影响。该研究将为肩关节外科医生提供一个天然的、坚固的、可再生的肩袖修复支架。成功治疗大型慢性肩袖撕裂患者的策略将大大减少慢性困扰许多老年人的衰弱性疼痛、肩部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. 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.