SBIR Phase I: An Injectable Treatment for the Repair of Damaged Tendons and Ligaments

这项小企业创新研究（SBIR）第一阶段项目的广泛影响将是改善生活质量，降低与肌腱和韧带损伤相关的医疗成本。众所周知，肌腱和韧带损伤很难愈合，而且愈合缓慢，使数百万美国人失去了多年的生产力。肌腱和韧带损伤对老年人、活动者或从事体力要求高的职业的人来说尤其严重。受伤的韧带（如前十字韧带）或肌腱（如跟腱）需要数月的康复，可能需要长达一年的时间才能痊愈。在老年人中，肩袖损伤是有害的，普遍的和难以治疗的。在美国，每年有1300亿美元花费在与肌肉骨骼损伤相关的医疗访问上，其中60%是肌腱和韧带损伤。肌腱和韧带损伤导致美国每年损失2.88亿个工作日，经济损失达500亿美元。尽管经过了几十年的努力，这些损伤的愈合速度和质量都没有什么提高。所提出的注射修复系统可缩短修复时间，提高修复质量。通过人体细胞工程大幅降低原材料成本的计划将使治疗方案普遍负担得起。拟议的项目将确定一种全新的肌腱和韧带修复方法的可行性，该方法基于胶原单体在体内的输送和组装进入力的路径。该方法是最近两项创新的衍生物，将在四个目标中结合起来，生产一种可注射的胶原蛋白溶液，旨在加速受损结缔组织（即韧带和肌腱）的修复，这是一个重大的医学挑战。第一个创新是使用CRISPR/CAS9技术，该技术将用于加速人类成纤维细胞产生胶原蛋白。目的1将优化CRISPR工艺，并通过分离和扩增接受增强胶原蛋白生产的细胞来扩大其规模。目标2将利用第二项重大创新——液晶胶原蛋白加工技术，开发一种货架稳定的高密度颗粒注射溶液，有望为受伤的结缔组织提供大量胶原蛋白。目的3将证明可注射修复液在体外可递送胶原蛋白修复损伤，目的4将在体内应用该方法，证明外源性胶原蛋白递送可加速受损活肌腱的修复。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

The broader impact of this Small Business Innovation Research (SBIR) Phase I project will be improvement of quality of life and reduction of healthcare costs associated with tendon and ligament injuries which are notoriously difficult and slow to heal, depriving millions of Americans years of productivity. Tendon and ligament injuries are especially debilitating for the aged, the active or those with physically demanding professions. Injured ligaments (e.g. anterior cruciate ligament) or tendons (e.g. Achilles) require months of rehabilitation and can take up to a year to heal. In the elderly, rotator cuff injuries are pernicious, prevalent and refractory to treatment. Every year in the US, $130 billion is spent on musculoskeletal injury-related medical visits, 60% of which are tendon and ligament injuries. Tendon and ligament injuries result in 288 million lost work days costing the US economy $50 billion annually. In spite of decades of effort, there has been very little improvement in either the rate or the quality of healing for these injuries. The injectable repair system proposed could reduce healing time and improve repair quality. The proposed plan to drastically reduce the cost of the raw materials through human cell engineering will make the treatment solution universally affordable.The proposed project will determine the feasibility of an entirely new approach to tendon and ligament repair based upon the in vivo delivery and assembly of collagen monomers into the path of force. The approach is derivative of two recent innovations that will be combined in four objectives to produce an injectable collagen-based solution designed to accelerate the repair of damaged connective tissues (i.e. ligaments and tendons) the healing of which presents a significant medical challenge. The first innovation is the use of CRISPR/CAS9 technology which will be used to accelerate the production of collagen by human fibroblasts. Objective 1 will to optimize the CRISPR process and scale it up through isolation and expansion of cells receptive to enhanced collagen production. Objective 2 will leverage the second major innovation, liquid crystal collagen processing technology, to develop a shelf stable injectable solution of highly-dense particulates that is expected to donate large amounts of collagen to injured connective tissue. Objective 3 will demonstrate that the injectable repair solution will deliver collagen to repair damage in vitro and Objective 4 will apply the approach in vivo, to demonstrate that exogenous collagen delivery can speed the repair of damaged, living tendon.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.