Hydrogels are being extensively used as cell encapsulation or mobilization devices for both fundamental biology studies and cell transplantation therapies because of their structural similarity to natural extracellular matrices. Successful use of a hydrogel in these applications greatly relies on an ability to control stiffness and permeability of a cell-encapsulating hydrogel, both of which significantly influence cellular phenotypes. However, conventional hydrogel design is often plagued by the inverse dependency between stiffness and permeability, thus limiting a capability to control cellular function to recreate new tissues. This study presents a novel strategy to control stiffness and permeability of a cell-encapsulating hydrogel in an independent manner by integrating bio-inspired material chemistry and microfabrication technique. The resulting hydrogel is ultimately used to promote the recreation of vascular network and also regeneration of bone tissues at tissue defects.
First, we incorporated methacrylic alginate (MA) into a poly(ethylene glycol) diacrylate (PEGDA) hydrogel to mimic the critical function of glycosaminoglycan in a natural ECM. We have found that incorporation of MA into the PEGDA hydrogel system increased both elastic modulus and swelling ratio. Cells encapsulated into the stiffer composite PEGDA-MA hydrogel remained more viable and bioactive to express angiogenic factors as compared with cells encapsulated in the pure PEGDA hydrogel. Second, we introduced microchannels with diameter of 500 μm into a cell-encapsulating hydrogel using stereolithographic assembly (SLA) unit via in situ photo-cross-linking. The incorporation of microchannels into the PEGDA-MA hydrogel enhanced the water diffusivity without changing gel rigidity, as examined with MRI. These microchannels further improved the cellular secretion of VEGF. Remarkably, we have found that the cell-encapsulating PEGDA-MA hydrogel with microchannels significantly increased the density of blood vessels at implantation sites. In addition, the gel implanted at a rat calvarial defect enhanced the bone tissue formation with vascularization. Overall, the design principles established in this study will be broadly useful to regulating the emergent behavior of a wide array of cells for tissue regeneration.