Tissue transglutaminase: A new method of facilitating hydrogel formation for cartilage regeneration and cartilage surface modificationPublic Deposited
Articular cartilage is a type of connective tissue that protects the underlying bone from the compressive forces of daily activities. When cartilage is damaged via a traumatic event, chondral defects are formed and require medical intervention. However, current treatments are of inconsistent efficacy and only benefit a subset of patients. Chondrocyte-containing hydrogels have been suggested as potential treatments of chondral defects but often lack the ability to adhere to and integrate with the native cartilage tissue. Tissue transglutaminase provides a potential mechanism of crosslinking hydrogels to native cartilage tissue. Tissue transglutaminase (tTG) is an ubiquitous enzyme that crosslinks lysine and glutamine residues in peptides and proteins. tTG can potentially be used in a multifaceted manner, crosslinking molecules to tissue and crosslinking polymers modified with peptide substrates to form hydrogels. Two tTG crosslinked hydrogel systems were evaluated for in vitro culture of chondrocytes, which proliferated and produced a limited quantity of GAG. To examine the ability of tTG to couple peptide-polymer conjugates to cartilage, and hence the hydrogel that contains them, small synthetic peptide substrates of tTG and their PEG conjugates were coupled to the cut surface of cartilage. Serendipidiously, it was determined that tTG was able to couple the peptides to the cut surface and also the articular surface, thus demonstrating that tTG could be utilized to modify the articular surface with drugs and biologically important molecules. This is of potential utility for the treatment of osteoarthritis, a degenerative joint disease, since some drugs are delivered intra-articularly to treat the disease but drug retention is problematic. Surface modifications to cartilage would make treatment more effective and minimize systemic side effects. To investigate the use of tTG to modify the articular surface of cartilage, a lysine peptide was used to make a peptide prodrug of hydrocortisone for localization to the articular surface of cartilage as a technique of local drug delivery to the joint. These results suggest that tTG may be most useful for coupling biologically important molecules to tissue surfaces. Further modifications and optimization are necessary to improve the utility of tTG in the formation of hydrogels.