Thermoresponsive, redox-polymerized cellulosic hydrogels undergo in situ gelation and restore intervertebral disc biomechanics post discectomy

Abstract

Back and neck pain are commonly associated with intervertebral disc (IVD) degeneration. Structural augmentation of diseased nucleus pulposus (NP) tissue with biomaterials could restore degeneration-related IVD height loss and degraded biomechanical behaviors; however, effective NP replacement biomaterials are not commercially available. This study developed a novel, crosslinked, dual-polymer network (DPN) hydrogel comprised of methacrylated carboxymethylcellulose (CMC) and methylcellulose (MC), and used in vitro, in situ and in vivo testing to assess its efficacy as an injectable, in situ gelling, biocompatible material that matches native NP properties and restores IVD biomechanical behaviors. Thermogelling MC was required to enable consistent and timely gelation of CMC in situ within whole IVDs. The CMC-MC hydrogel was tuned to match compressive and swelling NP tissue properties. When injected into whole IVDs after discectomy injury, CMC-MC restored IVD height and compressive biomechanical behaviors, including range of motion and neutral zone stiffness, to intact levels. Subcutaneous implantation of the hydrogels in rats further demonstrated good biocompatibility of CMC-MC with a relatively thin fibrous capsule, similar to comparable biomaterials. In conclusion, CMC-MC is an injectable, tunable and biocompatible hydrogel with strong potential to be used as an NP replacement biomaterial since it can gel in situ, match NP properties, and restore IVD height and biomechanical function. Future investigations will evaluate herniation risk under severe loading conditions and assess long-term in vivo performance.

Hydrogels in the clinic

“…Another approach is to use in situ crosslinking to inject a hydrogel precursor which gels via a chemical reaction either within a mixing tip or within the physiological environment 38‐40 . Depending upon the application of interest, these chemical crosslinking reagents can be biodegradable or nonbiodegradable.…”

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

“…Prior studies, which used the same axial loading magnitudes and similar durations as this study, showed that repair of IVD defects with FibGen and CMC-MC significantly improved axial biomechanical properties, and that FibGen had a trend of improved torsional properties [23,26,27]. In this study, neither FibGen and CMC-MC nor the combination repair restored axial or torsional biomechanical properties.…”

“…[26] and less severe AF defects used by Varma et al . [23]). Results therefore highlight the importance of controlling for IVD injury severity in study design as well as a continuing need to develop repair strategies for more severe injuries.…”

“…CMC and MC polymers (Sigma-Aldrich, St. Louis, MO) were methacrylated as previously described [23,33] and mixed along with 20 mM each of the redox initiators ammonium persulfate (Sigma-Aldrich) and N,N,N’,N’-tetramethylethylenediamine (Fisher Scientific, Hampton, NH) using a 1:1 dual barrel syringe (Pac-Dent, Brea, CA). The filled syringe was then warmed in a 37°C water bath for 30 minutes before injection into an injured motion segment.…”

“…Two previously investigated hydrogels which demonstrated promising IVD biomechanical restoration and biocompatibility were redox-polymerized carboxymethylcellulose-methylcellulose (CMC-MC) for NP replacement and a genipin-crosslinked fibrin (FibGen) hydrogel for AF repair. 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].…”