Gullbrand Sarah E, Schaer Thomas P, Agarwal Prateek, Bendigo Justin R, Dodge George R, Chen Weiliam, Elliott Dawn M, Mauck Robert L, Malhotra Neil R, Smith Lachlan J
Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, United States; McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA, United States; Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA, United States.
Comparative Orthopaedic Research Laboratory, School of Veterinary Medicine, University of Pennsylvania, Kennett Square, PA, United States.
Acta Biomater. 2017 Sep 15;60:201-209. doi: 10.1016/j.actbio.2017.07.025. Epub 2017 Jul 19.
Degeneration of the intervertebral discs is a progressive cascade of cellular, compositional and structural changes that is frequently associated with low back pain. As the first signs of disc degeneration typically arise in the disc's central nucleus pulposus (NP), augmentation of the NP via hydrogel injection represents a promising strategy to treat early to mid-stage degeneration. The purpose of this study was to establish the translational feasibility of a triple interpenetrating network hydrogel composed of dextran, chitosan, and teleostean (DCT) for augmentation of the degenerative NP in a preclinical goat model. Ex vivo injection of the DCT hydrogel into degenerated goat lumbar motion segments restored range of motion and neutral zone modulus towards physiologic values. To facilitate non-invasive assessment of hydrogel delivery and distribution, zirconia nanoparticles were added to make the hydrogel radiopaque. Importantly, the addition of zirconia did not negatively impact viability or matrix producing capacity of goat mesenchymal stem cells or NP cells seeded within the hydrogel in vitro. In vivo studies demonstrated that the radiopaque DCT hydrogel was successfully delivered to degenerated goat lumbar intervertebral discs, where it was distributed throughout both the NP and annulus fibrosus, and that the hydrogel remained contained within the disc space for two weeks without evidence of extrusion. These results demonstrate the translational potential of this hydrogel for functional regeneration of degenerate intervertebral discs.
The results of this work demonstrate that a radiopaque hydrogel is capable of normalizing the mechanical function of the degenerative disc, is supportive of disc cell and mesenchymal stem cell viability and matrix production, and can be maintained in the disc space without extrusion following intradiscal delivery in a preclinical large animal model. These results support evaluation of this hydrogel as a minimally invasive disc therapeutic in long-term preclinical studies as a precursor to future clinical application in patients with disc degeneration and low back pain.
椎间盘退变是细胞、成分和结构变化的渐进性级联反应，常与腰痛相关。由于椎间盘退变的最初迹象通常出现在椎间盘的中央髓核（NP），通过水凝胶注射增强NP是治疗早期至中期退变的一种有前景的策略。本研究的目的是在临床前山羊模型中确定由葡聚糖、壳聚糖和硬骨鱼（DCT）组成的三重互穿网络水凝胶增强退变NP的转化可行性。将DCT水凝胶体外注射到退变的山羊腰椎运动节段可使运动范围和中性区模量恢复到生理值。为便于对水凝胶的递送和分布进行非侵入性评估，则添加氧化锆纳米颗粒以使水凝胶具有放射性不透明性。重要的是，添加氧化锆不会对体外接种在水凝胶中的山羊间充质干细胞或NP细胞的活力或基质产生能力产生负面影响。体内研究表明，具有放射性不透明性的DCT水凝胶成功递送至退变的山羊腰椎间盘，在那里它分布于整个NP和纤维环，并且水凝胶在椎间盘间隙内保持两周，没有挤出的迹象。这些结果证明了这种水凝胶在退变椎间盘功能再生方面的转化潜力。
这项工作的结果表明，一种具有放射性不透明性的水凝胶能够使退变椎间盘的机械功能正常化，支持椎间盘细胞和间充质干细胞的活力以及基质产生，并且在临床前大型动物模型中进行椎间盘内递送后可在椎间盘间隙内维持而不挤出。这些结果支持在长期临床前研究中评估这种水凝胶作为一种微创椎间盘治疗方法，作为未来用于椎间盘退变和腰痛患者临床应用的先导。
