The Dose Response Relationship between Intervertebral Disc Flexion-Extension Neutral Zone Metrics and Injected Genipin Concentration

Abstract

This study establishes the efficacy of using injection delivery to affect disc joint mechanics and quantifies the dose response between injected genipin and the flexion-extension stability of the disc.

Understanding the etiopathogenesis of lumbar intervertebral disc herniation: From clinical evidence to basic scientific research

“…It should be noted that researchers have also attempted to understand the link between diabetes and the increased risk of herniation through mechanical testing; however, these studies consistently reported an improved disc joint‐ and tissue‐level stability and strength with advanced glycation end‐products (AGE) accumulation under monotonic loading conditions, 157 , 158 , 159 , 160 , 161 , 162 , 163 , 164 contradicting clinical observations. 42 , 43 , 44 The discrepancies may be partially attributed to the lack of fatigue testing for damage accumulation, as a high‐AGE environment has been shown to compromise tissue energy dissipation capabilities in tendons.…”

Early Clinical Results of Intervertebral Joint Stabilization by Injectable Load-Sharing Polymers

“…It has previously been demonstrated 24 that there are sufficient collagen bonding sites in the annulus to effectively double the number of load-supporting genipin polymers, proportionally increasing the joint stabilization effects. 19 The current study has not authorized a second set of injections, but patient demographic data (primarily patient weight and body mass index [BMI]) were obtained in part to correlate with patient-reported outcomes and inform future clinical study designs.…”

Consecutive Applications of Protein Crosslinking Reagents to Intervertebral Disc Annulus Fibrosus Results in a Cumulative Increase in Crosslinking

“…The specimens from each disc were treated via injections with varying concentrations of GP (20,40,80, and 400 mM). Genipin was formulated in 50 mM 4-(2-Hydroxyethyl)-1-piperazinepropanesulfonic acid (EPPS), 50 mM sodium phosphate, pH 9 buffer for the 20-and 40-mM doses, whereas the 80-mM dose was formulated in the same buffer supplemented with 20% (vol/vol) DMSO to facilitate GP solubilization.…”

“…For example, significant differences in one in vitro joint stability metric, neutral zone stiffness have been found in spinal motion segments injected with 40 or 80 mM GP, but another joint stability metric, neutral zone length, was significantly reduced by the 80-mM GP injection but not by the 40 mM. 20 Because we have previously shown the GP reaction to be concentration dependent, 19 it could be argued that the effector of such mechanical differences was a differential reaction rate. However, because GP reaction is rapid and given sufficient incubation time it would be expected that crosslinking would reach a complete end point, it is more likely that the differential effects were due to number of crosslinks formed within the tissue rather than a difference of the reaction rate.…”

“…Comparing the crosslinking in samples injected once with higher or multiple times with a lower GP concentration could be achieved using a number of analytical methods including measuring increased resistance to proteolysis, 19 calorimetry, 21 and mechanical testing. 12,20 However, a simpler and more direct approach would be to monitor the crosslinking reaction directly by measuring the loss of free-amine residues on the tissue.…”