Biodegradable hydrogels for bone regeneration through growth factor release

For successful tissue regeneration, growth factors should be released over a long period of time at the site of action, but their in vivo half-life time is very short. The sustained release of growth factors could be achieved by taking advantage of biodegradable hydrogels prepared from acidic gelatin with an isoelectric point (IEP) of 5.0. When mixed with this negatively charged gelatin, positively charged growth factors ionically interacted at the neutral pH to form a polyion complex. Gelatin hydrogels were enzymatically degraded in the body with time and the time profile of growth factor release was in good accordance with that of in vivo hydrogel degradation. This indicates that the growth factor complexed with the acidic gelatin constituting hydrogels was released as a result of their biodegradation. This article briefly overviews the in vivo release of basic fibroblast growth factor (bFGF) and transforming growth factor p 1 (TGF-P 1) from gelatin hydrogels. INTRODUCTION Cell growth factors are known to greatly contribute to tissue regeneration at different stages of cell proliferation and differentiation (ref. 1). However, tissue regeneration by use of growth factors has not been always successful because of several reasons. One of them is too short half-life periods of growth factors in the body. A possible means to circumvent this problem is to incorporate a growth factor into an appropriate polymer matrix for achieving its sustained release at the site of action. It is very likely that the growth factor in the matrix is protected from proteolysis and antibody neutralization, resulting in prolonged retention of the biological activity in vivo. Many researchers have attempted to release growth factors from various polymer matrices over a long time period (ref. 2-20). The largest problem associated with this release technology is the loss of biological activity of growth factors during the growth factor-polymer formulation process due to denaturation and deactivation of growth factors. Protein is generally denatured and loses its biological activity when exposed to harsh environments, such as heating, sonication, and organic solutions (ref. 2 1-23). Therefore, it is required to exploit a new formulation method using polymer carriers for proteins under mild conditions to minimize protein denaturation. From this point of view, polymer hydrogels seem to be preferable as release matrix candidate of growth factors because of their biosafety and high inertness toward protein drugs (ref. 24). However, sustained release of growth factors over a long time period could not be expected from hydrogels, since the release is generally diffusion controlled through aqueous channels in the hydrogels. Thus, to achieve the sustained release of growth factors, it will be a key strategy to immobilize growth factors to polymer carrier molecules constituting the hydrogel through molecular interactions. As one trial for sustained release of growth factors from polymer hydrogels, we have been attempting to take advantage of polyion complexation which takes place between the growth factor and polymer molecules in hydrogels. Figure 1 schematically shows the concept of growth factor release from a biodegradable polymer carrier on the basis of polyion complexation. A positively charged growth factor will be electrostatically complexed with negatively charged polymer chains constituting the carrier matrix. It seems unlikely that all of the ionic interactions between two polyelectrolytes are dissociated at the same time, in contrast to lowmolecular-weight electrolytes. However, the complexed growth factor will be released from the growth factor-carrier complex, if a significant environmental change, such as increased ionic strength, takes place. Even if such an environmental change does not occur, degradation of the polymer carrier in the body will also lead to growth factor release. The latter is more likely to happen in vivo than the former for the polyion complex. Thus, the release carrier is preferred to be prepared from biodegradable polymers. In this case, the release of growth factors is regulated by controlling the carrier biodegradation.