In vitro release of transforming growth factor-beta 1 from gelatin microparticles encapsulated in biodegradable, injectable oligo(poly(ethylene glycol) fumarate) hydrogels

This research investigates the in vitro release of transforming growth factor-beta1 (TGF-beta1) from novel, injectable hydrogels based on the polymer oligo(poly(ethylene glycol) fumarate) (OPF). These hydrogels can be used to encapsulate TGF-beta1-loaded-gelatin microparticles and can be crosslinked at physiological conditions within a clinically relevant time period. Experiments revealed that OPF formulation and crosslinking time may be adjusted to influence the equilibrium swelling ratio, elastic modulus, strain at fracture, and mesh size of these hydrogels. Studies with OPF-gelatin microparticle composites revealed that OPF formulation and crosslinking time, as well as microparticle loading and crosslinking extent, influence composite swelling. In vitro TGF-beta1 release studies demonstrated that burst release from OPF hydrogels with a mesh size of 136 A was approximately 53%, while burst release from hydrogels with a mesh size of 93 A was only 34%. For hydrogels with a large mesh size (136 A), encapsulation of loaded gelatin microparticles allowed burst release to be reduced to 29-32%, depending on microparticle loading. Likewise, final cumulative release after 28 days was reduced from 71% to 48-66% by encapsulation of loaded microparticles. However, inclusion of gelatin microparticles within OPF hydrogels of smaller mesh size (93 A) was seen to increase TGF-beta1 release rates. The equilibrium swelling ratio of the microparticle component of these composites was shown to be greater than the equilibrium swelling ratio of the OPF component. Therefore, increased release rates are the result of disruption of the polymer network during swelling. These combined results indicate that the kinetics of TGF-beta1 release can be controlled by adjusting OPF formulation and microparticle loading, factors affecting the swelling behavior these composites. By systematically altering these parameters, in vitro release rates from hydrogels and composites loaded with TGF-beta1 at concentrations of 200 ng/ml can be varied from 13 to 170 pg TGF-beta1/day for days 1-3 and from 7 to 47 pg TGF-beta1/day for days 6-21. Therefore, these studies demonstrate the potential of these novel hydrogels and composites in the sustained delivery of low dosages of TGF-beta1 to articular cartilage defects.