Abstract:
Stem cell mobilization, which involves the upregulation of circulating host stem cells, has emerged as a promising strategy to treat various chronic diseases and acute injuries. Treatment typically involves repeated administrations of various cytokines including granulocyte-colony stimulating factor (G-CSF) to stimulate the mobilization of stem cells into circulating blood. To circumvent complications resulting from the repeated drug administration, drug-encapsulating biodegradable materials in a form of hydrogel and microparticles were often used to derive sustained release of G-CSF into the circulation system. The successful use of a biomaterial in stem cell mobilization therapy greatly relies on its material properties. One key requirement is the ability to independently control stiffness and degradation rate of the material, so the hydrogel/microparticles prevent the premature release of G-CSF due to mechanical forces and release it in a sustained manner corresponding to the therapeutic window. However, the conventional material design is often plagued by the limited drug release rate with increasing material stiffness. Therefore, this study presents a new hydrogel system which is initially as stiff as poly(styrene) but allows us to regulate the degradation rate and subsequent drug release rate in a desired manner. The hydrogel was formed from Michael reaction between the acrylate groups of poly(ethylene glycol) diacrylates (PEGDA) and amine groups of poly(ethylene imine). Interestingly, increasing concentration of PEI of the hydrogel significantly increased both degradation rate and initial stiffness of the hydrogel. In contrast, increasing concentration of PEGDA increased the initial stiffness but decreased the degradation rate. The drug release rate was examined both in vitro and in vivo, and was found to be solely dependent on the hydrogel degradation rate. Furthermore, the stiff but rapidly degrading hydrogel system led to the sustained mobilization of stem cells into the circulation over five days even without repeated G-CSF administration. Overall, this study demonstrates that the hydrogel created in this study will be useful for delivering a broad array of growth factors and cytokines in a controlled and predictable manner. Figure 1 shows the in vivo release of fluorescent-labeled BSA from hydrogel (A) immediately after injection into the back from a mouse and (B) 7 hours after injection. This demonstrates the integrity of the hydrogel and its ability to retain the fluorescent BSA locally despite the constant motion of the mouse.