I-Corps: Injectable Cellulosic Hydrogels for Intervertebral Disc Repair

椎间盘退变是下背部疼痛最常见的诊断，这是一种使人衰弱的疾病，影响了美国15-30%的人口，相关的年成本为1000亿美元。IVD的退变常引起椎间盘突出，这是一种组织从椎间盘间隙突出并冲击附近神经的情况。腰椎间盘切除术是椎间盘突出最常见的手术治疗方法，在此过程中，切除部分椎间盘组织以减压受损的神经根。然而，这种治疗有很高的复发率（5-15%），通常需要二次干预。对于严重退变的椎间盘，通常采用脊柱融合术。然而，随着时间的推移，该手术限制了活动能力并对邻近椎间盘造成损伤。一些用于椎间盘组织置换的产品正在开发中，包括Newcleus （Zimmer）和NucleoFix (Replication Medical)，但在美国都没有被批准使用。这些装置的临床应用受到限制，因为它们会向椎间盘外移位、磨损碎片形成以及周围组织的疲劳或断裂失效。因此，目前的手术治疗方案不足以长期治疗疾病，现有的商业植入物不能充分恢复椎间盘的结构和功能。用可注射的椎间盘样材料替代椎间盘组织可能有助于恢复IVD的机械功能并限制疾病进展。这个项目的重点是利用可注射的植物基凝胶，在椎间盘内空间形成，以取代切除的IVD组织。该技术代表了对转化生物材料研究的重要贡献，并有可能显著影响患者的健康和生活质量。I-Corps团队开发了一种基于可注射的交联羧甲基纤维素（CMC）水凝胶的技术，用于工程椎间盘（IVD）组织。CMC是一种植物衍生的带负电荷的多糖，类似于天然圆盘中的多糖，与惰性聚合物（如聚环氧乙烷）相比，它提供了一个更有利于膨胀、营养物质运输和细胞外基质组织的环境。作为纤维素（地球上最丰富的天然有机化合物）的衍生物，CMC本质上是可再生的，是用于软骨组织修复的合成聚合物、动物源性蛋白质和多糖的“绿色”替代品。此外，CMC比目前用于类似应用的其他多糖（即硫酸软骨素和透明质酸）更具成本效益，并且避免了与动物或细菌副产品相关的风险。此外，共价交联的CMC凝胶是稳定的，不容易被人类的粘多糖酶（即透明质酸酶）酶降解，因为多糖只能被纤维素酶裂解，而纤维素酶在人类中是不存在的。对这些原位形成水凝胶的评估表明，在动物外植体模型中，损伤椎间盘的力学功能得到了恢复，其力学特性（即平衡杨氏模量）与天然人类椎间盘组织的力学特性相匹配。因此，这些可注射的纤维素植入物有潜力显著影响相当大的患有与IVD损伤和变性相关的病理状况的患者群体。水凝胶还显示出可调节的材料特性和细胞相容性，扩展了椎间盘置换以外的可能应用，如软组织填充物或再生疗法的细胞载体。

Intervertebral disc (IVD) degeneration is the most common diagnosis for lower back pain, a debilitating condition that affects 15-30% of the United States population, with associated annual costs of $100 billion. Degeneration of the IVD often causes disc herniation, a condition in which tissue is extruded from the disc space and impinges on nearby nerves. Lumbar discectomy is the most frequent surgical treatment for herniated discs, during which portions of the disc tissue are resected to decompress affected nerve roots. However, this treatment has a high recurrence rate (5-15%), and often requires secondary intervention. For heavily degenerated discs, spinal fusion is typically employed. However, this procedure limits mobility and produces damage to adjacent discs over time. Several products are under development for disc tissue replacement including Newcleus (Zimmer) and NucleoFix (Replication Medical), with none approved for use in the United States. Clinical application of these devices has been limited due to migration out of the disc space, wear debris formation, and fatigue or fracture failure of the surrounding tissues. Thus, current surgical treatment options are inadequate for long-term disease management, and existing commercial implants do not sufficiently restore disc structure and function. Replacing the disc tissue with an injectable disc-like material may help restore IVD mechanical functionality and limit disease progression. This project is centered on the utilization of injectable plant-based gels that form in the intradiscal space to replace resected IVD tissue. The technology represents an important contribution to translational biomaterials research, and has the potential to significantly impact patient health and quality of life.This I-Corps team has developed a technology based on the use of injectable, crosslinked carboxymethylcellulose (CMC) hydrogels for engineering intervertebral disc (IVD) tissue. CMC is a plant-derived, negatively-charged polysaccharide similar to those found in the native disc, which provides an environment more conducive to swelling, nutrient transport and extracellular matrix organization in comparison to inert polymers, such as poly(ethylene oxide). As a derivative of cellulose, the most abundant naturally occurring organic compound on the planet, CMC is inherently renewable and a "green" alternative to synthetic polymers and animal-derived proteins and polysaccharides used for the repair of cartilaginous tissues. Further, CMC is more cost-effective than other polysaccharides (i.e., chondroitin sulfate and hyaluronic acid) currently used for similar applications, and obviates risks associated with animal or bacterial by-products. In addition, the covalently crosslinked CMC gels are stable and not susceptible to enzymatic degradation by mucopolysaccharidases in humans (i.e., hyaluronidase), as the polysaccharide can only be cleaved by cellulase, an enzyme absent in humans. Evaluation of these in situ-forming hydrogels has demonstrated restoration of the mechanical function of injured discs in an animal explant model, and the mechanical properties (i.e., equilibrium Young's modulus) have been found to match those of native human disc tissue. Thus, these injectable cellulosic implants have the potential to significantly impact a sizable patient population suffering from pathological conditions associated with IVD injury and degeneration. The hydrogels have also been shown to exhibit tunable material properties and cytocompatibility, extending the possible applications beyond disc replacement, for uses such as soft tissue fillers or as cell carriers for regenerative therapies.