Directing immunomodulation using biomaterials for endogenous regeneration

Stem cell therapy and tissue engineering hold considerable potential for innovative and transformative strategies to repair damaged tissue form and function. Although many approaches are adopting ex vivo expanded cells for transplantation, an alternative is to manipulate the biomaterial-host interactions that recruit the patients' own stem cells endogenously for regeneration. There are several considerations in targeting the biomaterial-host interactions therapeutically, not the least of which is the biomimetic design of extracellular matrix (ECM)-mimicking materials and the administration of navigation cues and small molecules that target specific aspects of the native healing cascades to stimulate homing of endogenous stem cells and, thereafter, their expansion and differentiation. A sequence of coordinated interactions between the local niche cells and implanted biomaterials offers signals and sign posts that may instruct the cells traveling toward the injured tissues. Furthermore, stem cell function is critically influenced by extrinsic signals provided by the niche as well as by the implanted biomaterials. Novel strategies harnessing growth factors and immunological cues to design materials not only can modulate the behavior of stem cells but also can alter innate and adaptive immunity in a controlled manner. We envisage that successful and safe endogenous regeneration will involve at least three aspects, i.e., homing of sufficient stem cells, controlling cell fate determination, and blunting host immune responses to outside biomaterial devices. Improving our understanding of the biological and physicochemical signals of biomimetic biomaterials that govern immunomodulation for in situ tissue regeneration, particularly context-dependent macrophage (M phi) polarization, will lead to a concurrent improvement in clinical outcomes.