Injectable collagen crosslink augmentation for degenerative disc disease

描述（由申请人提供）：就患病率和社会成本而言，腰痛几乎没有同行。随着患者人数超过1500万/年，社会成本估计为1000亿美元/年。目前对这种疾病的治疗选择显示出有限的成功，包括物理治疗，药物治疗和手术。该提案涉及一种新颖的、非手术的、具有成本效益的组织再生方法，该方法有望治疗机械和营养挑战的组织，如椎间盘。之前的体外和体内研究已经证明了可注射胶原交联增强在稳定脊柱关节、减少负荷下椎间盘膨出、增加组织的强度、抗撕裂性和耐久性方面的有效性，同时还改善了这些大部分无血管组织的营养流。I期试验使用机械、热和蛋白酶消化试验成功表征了7种候选药物在椎间盘纤维环（AF）组织中的交联作用。确定至少一种优选的试剂，并优化浓度、pH、调节和缓冲以使交联效率和机械效应最大化。最近，已经进行了体外测定以确定试剂和缓冲液的生物相容性。拟议的II期试验将为监管备案和首次人体临床试验提供必要的数据。将彻底研究试剂输送、渗透、反应动力学、持久性（作用持续时间）和储存要求（有效期）。将进行急性、功能性生物相容性和神经毒性研究，以量化动物模型中的预期和最差情况治疗效应。将使用不同的人类AF组织亚组（年龄、组成、变性的变化）确定交联效应的进一步表征。通过将这种开创性的治疗方法带到临床试验的门口，SBIR资金将在实现最终目标方面发挥至关重要的作用，即在与腰痛和残疾的斗争中提供一种新颖，具有成本效益的治疗方法。 公共卫生相关性：与脊柱退化和不稳定相关的背痛和残疾仍然是当今美国最昂贵和最普遍的健康问题之一。随着患者人数超过1500万/年，社会成本估计为1000亿美元/年。由于目前治疗方案的成功有限，因此有理由期待有效的非手术解决方案可以彻底改变这种流行病的临床护理。

DESCRIPTION (provided by applicant): With regard to prevalence and cost to society, low-back pain has few peers. With a patient population in excess of 15 million/year, the societal cost is estimated to be in the realm of $100 billion/year. Current treatment options for this disease have shown limited success, including physical therapy, medication and surgery. This proposal involves a novel, nonsurgical and cost-effective, tissue revitalization approach which shows promise for treatment of mechanically and nutritionally challenged tissues like the spinal disc. Previous in vitro and in vivo studies have demonstrated the efficacy of Injectable collagen crosslink augmentation in stabilizing spinal joints, decreasing disc bulge under load, increasing the strength, tear resistance, and durability of the tissue, while also improving nutritional flow to these largely avascular tissues. Phase I testing was successful in characterizing the crosslinking effects of seven candidate agents in disc annulus fibrosis (AF) tissue using mechanical, thermal and protease digestion assays. At least one preferred agent was identified, and concentration, pH, conditioning, and buffering were optimized to maximize the efficiency of crosslinking and mechanical effect. Recently, in vitro assays have been undertaken to determine agent and buffer biocompatibility. The proposed Phase II testing will provide data necessary for regulatory filings and first-in-man clinical trials. Reagent delivery, penetration, reaction kinetics, permanency (effect duration), and storage requirements (shelf life) will be thoroughly investigated. Acute, functional biocompatibility and neurotoxicity studies will be conducted to quantify expected and worst-case treatment effects in an animal model. Further characterization of crosslinking effects will be determined using different subgroups of human AF tissues (variations in age, composition, degeneration). By bringing this path-breaking treatment to the doorstep of clinical trials, SBIR funding will play a vital role in enabling progress towards the ultimate goal of providing a novel, cost-effective treatment in the struggle against low back pain and disability. PUBLIC HEALTH RELEVANCE: Back pain and disability associated with spinal degeneration and instability remains among the most costly and prevalent health problems in the US today. With a patient population in excess of 15 million/year, the societal cost is estimated to be in the realm of $100 billion/year. Due to the limited success of current treatment options, it is reasonable to expect that an effective nonsurgical solution could revolutionize clinical care for this pandemic.