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The Effects of Exogenous Crosslinking on Hydration and Fluid Flow in the Intervertebral Disc Subjected to Compressive Creep Loading and Unloading

Chuang, Shih-Youeng, MD, PhD*; Popovich, John M. Jr., DPT; Lin, Leou-Chyr, MD*; Hedman, Thomas P., PhD‡§

doi: 10.1097/BRS.0b013e3181e68695

Study Design. In vitro study of genipin crosslinking effect on disc water content changes under compressive loading and unloading.

Objective. To investigate the influence of collagen crosslinking on hydration and fluid flow in different regions of intact discs, and to evaluate the nutritional implications.

Summary of Background Data. Age-related reductions of nutrient supply and waste product removal are critically important factors in disc pathogenesis. Diffusion and fluid flow are blocked by subchondral bone thickening, cartilaginous endplate calcification, loss of hydrophilic proteoglycans, and clogging of anular pores by degraded matrix molecules. Previous studies demonstrated increased hydraulic permeability and macromolecular transport through crosslinked collagenous matrices. Genipin has also demonstrated the capability to increase retention of proteoglycans.

Methods. A total of 57 bovine lumbar motion segments were divided randomly into phosphate buffered saline and 0.33% genipin-soaked treatment groups. Water content changes were measured using a mass-loss technique in 3 intervertebral disc regions following successive stages of compressive loading and unloading (post-treatment, after 1 hour 750 N compression, and after a subsequent 24-hour period of nominal loading). Net flow of fluid into or out of a region was determined from the percentage change in mean water content from successive groups.

Results. Fluid flow to and from the nucleus doubled with genipin crosslinking. Relative to the buffer-only controls, overall net fluid flow increased 103% in the nucleus pulposus, 36% in the inner anulus, and was 31% less in the outer anulus of genipin treated discs.

Conclusion. The effects of genipin crosslinking on matrix permeability and proteoglycan retention can alter hydration levels and fluid flow in the intervertebral disc. Resulting increases in fluid flow, including a doubling of flow to and from the nucleus, could lead to enhanced nutritional inflow and waste product outflow for the disc, and may have implications for emerging cell-based therapies.

Genipin crosslinking is capable of increasing permeability and proteoglycan retention in collagen matrices. This in vitro study of intact discs showed an increase in fluid flow including a doubling of inflow and outflow for the nucleus with genipin treatment. These results may have implications for nutritional flow in intervertebral discs.

From the *Department of Orthopaedic Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China; †Musculoskeletal Biomechanics Research Laboratory, Division of Biokinesiology and Physical Therapy, University of Southern California, Los Angeles, CA; and ‡Department of Biomedical Engineering, Texas A&M University, College Station, TX; and §Department of Surgery, Texas A&M Health Science Center, Georgetown, TX.

Acknowledgment date: October 23, 2009. Revision date: January 22, 2010. Acceptance date: May 4, 2010.

The manuscript submitted does not contain information about medical device(s)/drug(s).

No funds were received in support of this work. One or more of the authors(s) has/have received or will receive benefits for personal or professional use from a commercial party related directly or indirectly to the subject of this manuscript: e.g., honoraria, gifts, consultancies, royalties, stocks, stock options, decision making position.

Address correspondence and reprint requests to Thomas P. Hedman, PhD, Biomedical Engineering Department, Texas A&M University, 337 Zachry Engineering Center, 3120 TAMU, College Station, TX 77843; E-mail:

© 2010 Lippincott Williams & Wilkins, Inc.