Feasibility of the annulus fibrosus repair with in situ gelating hydrogels – A biomechanical study

Abstract

The surgical standard of care for lumbar discectomy leaves the annulus fibrosus (AF) defect unrepaired, despite considerable risk for a recurrent herniation. Identification of a viable defect repair strategy has until now been elusive. The scope of this ex vivo biomechanical study was to evaluate crosslinking hydrogels as potentially promising AF defect sealants, and provide a baseline for their use in combination with collagen scaffolds that restore disc volume. This study directly compared genipin crosslinked fibrin hydrogel (FibGen) as a promising preclinical candidate against a clinically available adhesive composed of glutaraldehyde and albumin (BioGlue). Forty-two bovine coccygeal functional spine units (FSU) were randomly allocated into four groups, namely untreated (control, n = 12), repaired with either one of the tested hydrogels (BioGlue, n = 12; FibGen, n = 12), or FibGen used in combination with a collagen hydrogel scaffold (FibGen+Scaffold, n = 6). All specimens underwent a moderate mechanical testing protocol in intact, injured and repaired states. After completion of the moderate testing protocol, the samples underwent a ramp-to-failure test. Lumbar discectomy destabilized the FSU as quantified by increased torsional range of motion (28.0° (19.1, 45.1) vs. 41.39° (27.3, 84.9), p<0.001), torsional neutral zone (3.1° (1.2, 7.7) vs. 4.8° (2.1, 12.1), Z = -3.49, p < 0.001), hysteresis(24.4 J (12.8, 76.0) vs. 27.6 J (16.4, 54.4), Z = -2.61, p = 0.009), with loss of both disc height (7.0 mm (5.0, 10.5) vs 6.1 mm (4.0, 9.3), Z = -5.16, p < 0.001) and torsional stiffness (0.76 Nmdeg-1 (0.38, 1.07) vs. 0.66 Nmdeg-1 (0.38, 0.97), Z = -3.98, p < 0.001). Most FibGen repaired AF endured the entire testing procedure whereas only a minority of BioGlue repaired AF and all FibGen+Scaffold repaired AF failed (6/10 vs. 3/12 vs. 0/6 respectively, p = 0.041). Both BioGlue and FibGen+Scaffold repaired AF partially restored disc height (0.47 mm (0.07, 2.41), p = 0.048 and 1.52 mm (0.41, 2.57), p = 0.021 respectively) compared to sham treatment (0.08 mm (-0.63, 0.88)) whereas FibGen-only repaired AF had no such effect (0.04 mm (-0.73, 1.13), U = 48.0, p = 1). The AF injury model demonstrated considerable change of FSU mechanics that could be partially restored by use of an AF sealant. While inclusion of a volumetric collagen scaffold led to repair failure, use of FibGen alone demonstrated clinically relevant promise for prevention of mechanical reherniation, outperforming an FDA approved sealant in this ex vivo test series.

Composite biomaterial repair strategy to restore biomechanical function and reduce herniation risk in an ex vivo large animal model of intervertebral disc herniation with varying injury severity

“…Few studies investigate a combination repair and we hypothesized that a combination biomaterial repair strategy following simulated herniation and discectomy injury was necessary to restore NP hydrostatic pressure and AF tension and return biomechanical properties to the Intact condition. CMC-MC was selected as the NP replacement hydrogel due to its swelling potential [22] and FibGen was selected as the AF sealant for its ability to resist reherniation under physiological loads [26–29]. Both hydrogels were also previously determined to be biocompatible, injectable and capable of in situ gelation suggesting they show promise for application to augment current discectomy procedures [25,26,33,39].…”

“…CMC-MC has high swelling potential and has demonstrated its ability to restore disc height and biomechanical restoration following a discectomy injury in bovine IVDs ex vivo [22,23]. FibGen has been tuned to match AF shear mechanical properties and has been shown to seal AF defects and resist reherniation under cyclic loading at physiological levels [24–29]. Both CMC-MC and FibGen are capable of rapid in situ gelation which is important for clinical translation when considering ease of application without extending surgical procedure times.…”

Recent advances of hydrogel‐based biomaterials for intervertebral disc tissue treatment: A literature review

“…The genipin‐crosslinked fibrin (FibGen) hydrogel is injectable with significantly improved compressive, tensile and shear modulus (N. Gupta, Cruz, Nasser, Rosenberg, & Iatridis, 2019), and thus is considered as an AF defect sealant. Some in vitro and ex vivo experiments have found that FibGen is capable of restoring IVD height, compressive properties, and partial range of motion without herniation compared to intact IVD (Likhitpanichkul et al., 2014; Long, Zderic, et al., 2018; Scheibler et al., 2018). Injection of FibGen alone shows satisfying sealing ability to prevent herniation in ovine IVD model up to 1 month, while composite repair strategy combined with poly‐trimethylene carbonate does not meet the need (Long et al., 2020; Figure 4).…”

Regeneration of skeletal system with genipin crosslinked biomaterials

“…The genipin concentration used for AF regeneration tends to be higher than that used for cartilage regeneration. 74 – 76 Cruz et al 77 investigated the mechanical properties of genipin-crosslinked fibrin gel formed using genipin concentrations from 1% to 36%. The results showed that the compressive strength increased from 25 to 150 kPa and the shear modulus increased from 10 to 110 kPa, which are much higher than the values of natural AF tissue.…”

“…Scheibler et al 74 Fibrin gel 8% Genipin-crosslinked fibrin gel adhesive reinforced the strength of polyurethane membrane to prevent herniation risk in repairing AF defect.…”