I-Corps: Injectable Cellulosic Hydrogels for Intervertebral Disc Repair

椎间盘（IVD）退变是下背痛最常见的诊断，这是一种影响15-30%美国人口的衰弱性疾病，相关的年成本为1000亿美元。椎间盘退行性变通常会导致椎间盘突出，这种情况下组织从椎间盘间隙中挤出并撞击附近的神经。腰椎间盘切除术是最常见的手术治疗椎间盘突出，在此期间，椎间盘组织的部分被切除到椎间盘受累的神经根。然而，这种治疗具有高复发率（5-15%），并且通常需要二次干预。 对于严重退变的椎间盘，通常采用脊柱融合术。然而，这种手术限制了活动性，并随着时间的推移对相邻椎间盘造成损伤。几种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），但在美国没有批准使用。这些器械的临床应用受到了限制，原因是从椎间隙中移出、磨损碎屑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进行长期的疾病管理，现有的商业植入物不能充分恢复椎间盘结构和功能。用可注射盘状材料替换椎间盘组织可能有助于恢复IVD机械功能并限制疾病进展。 该项目的重点是利用可注射的植物基凝胶，在椎间盘间隙中形成，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交联羧甲基纤维素（CMC）水凝胶用于工程椎间盘（IVD）组织的技术。 CMC是一种植物来源的带负电荷的多糖，类似于天然椎间盘中发现的那些多糖，与惰性聚合物如聚（环氧乙烷）相比，其提供了更有利于溶胀、营养转运和细胞外基质组织的环境。作为地球上最丰富的天然有机化合物纤维素的衍生物，CMC具有固有的可再生性，是用于修复软骨组织的合成聚合物和动物源性蛋白质和多糖的“绿色”替代品。 此外，CMC比其他多糖（即，硫酸软骨素和透明质酸），并且避免了与动物或细菌副产物相关的风险。 此外，共价交联的CMC凝胶是稳定的，并且不易受人体中粘多糖酶的酶促降解（即，透明质酸酶），因为多糖只能被纤维素酶切割，纤维素酶是人体中不存在的酶。对这些原位形成水凝胶的评价已经证明了在动物外植体模型中损伤椎间盘的机械功能的恢复，以及机械性能（即，平衡杨氏模量）与天然人椎间盘组织的那些相匹配。因此，这些可注射纤维素植入物有可能显著影响患有与IVD损伤和变性相关的病理状况的相当大的患者群体。水凝胶还显示出可调节的材料特性和细胞相容性，将可能的应用扩展到椎间盘置换之外，用于诸如软组织填充物或作为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.