Date Published: May 28, 2019
Publisher: Public Library of Science
Author(s): Warren W. Hom, Melanie Tschopp, Huizi A. Lin, Philip Nasser, Damien M. Laudier, Andrew C. Hecht, Steven B. Nicoll, James C. Iatridis, Lachlan J. Smith.
Back pain commonly arises from intervertebral disc (IVD) damage including annulus fibrosus (AF) defects and nucleus pulposus (NP) loss. Poor IVD healing motivates developing tissue engineering repair strategies. This study evaluated a composite injectable IVD biomaterial repair strategy using carboxymethylcellulose-methylcellulose (CMC-MC) and genipin-crosslinked fibrin (FibGen) that mimic NP and AF properties, respectively. Bovine ex vivo caudal IVDs were evaluated in cyclic compression-tension, torsion, and compression-to-failure tests to determine IVD biomechanical properties, height loss, and herniation risk following experimentally-induced severe herniation injury and discectomy (4 mm biopsy defect with 20% NP removed). FibGen with and without CMC-MC had failure strength similar to discectomy injury suggesting no increased risk compared to surgical procedures, yet no biomaterials improved axial or torsional biomechanical properties suggesting they were incapable of adequately restoring AF tension. FibGen had the largest failure strength and was further evaluated in additional discectomy injury models with varying AF defect types (2 mm biopsy, 4 mm cruciate, 4 mm biopsy) and NP removal volume (0%, 20%). All simulated discectomy defects significantly compromised failure strength and biomechanical properties. The 0% NP removal group had mean values of axial biomechanical properties closer to intact levels than defects with 20% NP removed but they were not statistically different and 0% NP removal also decreased failure strength. FibGen with and without CMC-MC failed at super-physiological stress levels above simulated discectomy suggesting repair with these tissue engineered biomaterials may perform better than discectomy alone, although restored biomechanical function may require additional healing with the potential application of these biomaterials as sealants and cell/drug delivery carriers.
Intervertebral disc (IVD) injuries can result in herniation when the central nucleus pulposus (NP) tissue protrudes or extrudes through defects in the surrounding annulus fibrosus (AF). Herniated IVD tissue can impinge upon surrounding nerves to cause radiculopathy with pain and disability in the back, neck, arms, and/or legs depending on the IVD level of the injury . Conservative methods to address these symptoms include physical therapy and pain medication, but if these treatments fail then the next step is to remove the herniated tissue through discectomy surgery. There are approximately 300,000 annual discectomy procedures performed in the United States and this procedure is very successful for improving acute pain and disability due to neuropathy [2,3]. Current discectomy procedures do not replace the removed NP tissue or repair AF defects. Furthermore, the IVD is avascular and has a low cell-density, which contributes to its poor healing potential [4,5]. As such, there is a need to develop improved IVD repair strategies to prevent disc height loss, altered biomechanics, and accelerated degeneration from IVD injury and complications from discectomy procedures, including reherniation and recurrent pain at the same level [6–10].
Discectomy procedures alleviate many symptoms associated with IVD herniation but do not address the damage and loss of NP and AF tissues which can result in reherniation and recurrent pain [6–10]. This 2 part biomechanical study developed and characterized injectable IVD biomaterial repair strategies capable of being applied during discectomy procedures to repair herniated IVDs. CMC-MC as an NP hydrogel replacement and FibGen as an AF sealant were applied. Part 1 evaluated effects of biomaterial repair strategy using hydrogel alone and in combination with large AF defects and NP tissue removal that simulate herniation and an ‘aggressive’ discectomy procedure. The combined hydrogel repair did not significantly improve IVD biomechanical properties suggesting no repair strategy was capable of restoring NP swelling and AF tension. However, failure strength of all repair strategies were greater than physiological loading levels (discussed below) and mean failure strength was largest for the FibGen group, although it was not significantly different from other groups and had the greatest variability. Part 2 evaluated effects of AF defect type and NP removal volume to determine their influence on biomechanical behaviors and FibGen repair capacity. Axial and torsional biomechanical properties were not significantly different between the three AF defects tested suggesting that amount of NP volume removed was more important than the AF defect type in determining the extent of biomechanical changes. Failure strength was greater for the 2-mm Defect and Cruciate Defect, highlighting that AF defect size and type was an important determinant of herniation potential. FibGen repair resulted in greater failure strength for larger defects indicating the importance of an AF sealant for a large defect.
This study investigated the combination of CMC-MC, an NP replacement, and FibGen, an AF sealant to restore IVD biomechanics after discectomy by restoring NP pressurization and AF tension. Although the biomechanical properties were not restored back to Intact levels, FibGen and the combined hydrogel remained adherent in the large 4-mm AF defect during axial and torsional cyclic loading and had failure strength above moderate levels of physiological loading. CMC-MC and FibGen have both previously demonstrated the ability to support the encapsulation of cells [28,33] and future work will continue to develop both hydrogels for sustained delivery of cells and soluble therapeutic factors with in vivo assessments. Results also demonstrated that NP removal volume had a greater impact on biomechanical dysfunction and that AF defect type had a larger impact on failure risk with implications for discectomy procedures with cruciate cuts exhibiting higher failure strength than similarly sized biopsy defects. IVD repair with FibGen showed the greatest increase in failure strength for nearly all conditions suggesting it is particularly important for large AF defects, although small defects had high failure strength and did not show an increase with repair. Variability observed in the results also highlights the need to optimize delivery methods as well as the biomaterial being delivered. No biomaterials were capable of recovering AF tension and NP swelling to restore biomechanical function, suggesting healing may be required to achieve this objective. The current study and literature lead us to conclude that FibGen and CMC-MC remain biomaterial candidates with potential benefit as sealants with low reherniation risk and reduced disc height loss. Therefore, their use as a carrier to deliver cells and bioactive factors that promote healing may be the most promising method to promote healing and allow for restored IVD biomechanical function.