Long Rose G, Ferguson Stephen J, Benneker Lorin M, Sakai Daisuke, Li Zhen, Pandit Abhay, Grijpma Dirk W, Eglin David, Zeiter Stephan, Schmid Tanja, Eberli Ursula, Nehrbass Dirk, Di Pauli von Treuheim Theodor, Alini Mauro, Iatridis James C, Grad Sibylle
Department of Genetics Harvard Medical School Boston Massachusetts.
ETH Zurich, Institute for Biomechanics Zurich Switzerland.
JOR Spine. 2019 Dec 21;3(1):e1074. doi: 10.1002/jsp2.1074. eCollection 2020 Mar.
Tissue engineering repair of annulus fibrosus (AF) defects has the potential to prevent disability and pain from intervertebral disc (IVD) herniation and its progression to degeneration. Clinical translation of AF repair methods requires assessment in long-term large animal models. An ovine AF injury model was developed using cervical spinal levels and a biopsy-type AF defect to assess composite tissue engineering repair in 1-month and 12-month studies. The repair used a fibrin hydrogel crosslinked with genipin (FibGen) to seal defects, poly(trimethylene carbonate) (PTMC) scaffolds to replace lost AF tissue, and polyurethane membranes to prevent herniation. In the 1-month study, PTMC scaffolds sealed with FibGen herniated with polyurethane membranes. When applied alone, FibGen integrated with the surrounding AF tissue without herniation, showing promise for long-term studies. The 12-month long-term study used only FibGen which showed fibrous healing, biomaterial resorption and no obvious hydrogel-related complications. However, the 2 mm biopsy punch injury condition also exhibited fibrotic healing at 12 months. Both untreated and FibGen treated groups showed equivalency with no detectable differences in histological grades of proteoglycans, cellular morphology, IVD structure and blood vessel formation, biomechanical properties including torque range and axial range of motion, Pfirrmann grade, IVD height, and quantitative scores of vertebral body changes from clinical computed tomography. The biopsy-type injury caused endplate defects with a high prevalence of osteophytes in all groups and no nucleus herniation, indicating that the biopsy-type injury requires further refinement, such as reduction to a slit-type defect that could penetrate the full depth of the AF without damaging the endplate. Results demonstrate translational feasibility of FibGen for AF repair to seal AF defects, although future study with a more refined injury model is required to validate the efficacy of FibGen before translation.
纤维环（AF）缺损的组织工程修复有潜力预防椎间盘（IVD）突出及其进展为退变所导致的残疾和疼痛。AF修复方法的临床转化需要在长期大型动物模型中进行评估。利用颈椎节段建立了一种绵羊AF损伤模型，并采用活检型AF缺损，以在1个月和12个月的研究中评估复合组织工程修复。该修复使用与京尼平交联的纤维蛋白水凝胶（FibGen）来封闭缺损，聚碳酸三亚甲基酯（PTMC）支架来替代缺失的AF组织，以及聚氨酯膜来防止突出。在1个月的研究中，用FibGen封闭的PTMC支架与聚氨酯膜一起突出。单独应用时，FibGen与周围AF组织整合且无突出，显示出在长期研究中的前景。12个月的长期研究仅使用了FibGen，结果显示有纤维愈合、生物材料吸收且无明显的水凝胶相关并发症。然而，2毫米活检穿刺损伤情况在12个月时也表现出纤维化愈合。未治疗组和FibGen治疗组在蛋白聚糖的组织学分级、细胞形态、IVD结构和血管形成、包括扭矩范围和轴向运动范围的生物力学性能、Pfirrmann分级、IVD高度以及临床计算机断层扫描椎体变化的定量评分方面均显示出等效性，无可检测到的差异。活检型损伤导致所有组中终板缺损且骨赘发生率高，无髓核突出，这表明活检型损伤需要进一步优化，例如减少为能够穿透AF全层而不损伤终板的裂隙型缺损。结果证明了FibGen用于AF修复以封闭AF缺损的转化可行性，尽管在转化之前需要用更优化的损伤模型进行进一步研究以验证FibGen的疗效。
