Biomaterial Strategies for Immunomodulation

Strategies to enhance, suppress, or qualitatively shape the immune response are of importance for diverse biomedical applications, such as the development of new vaccines, treatments for autoimmune diseases and allergies, strategies for regenerative medicine, and immunotherapies for cancer. However, the intricate cellular and molecular signals regulating the immune system are major hurdles to predictably manipulating the immune response and developing safe and effective therapies. To meet this challenge, biomaterials are being developed that control how, where, and when immune cells are stimulated in vivo, and that can finely control their differentiation in vitro. We review recent advances in the field of biomaterials for immunomodulation, focusing particularly on designing biomaterials to provide controlled immunostimulation, targeting drugs and vaccines to lymphoid organs, and serving as scaffolds to organize immune cells and emulate lymphoid tissues. These ongoing efforts highlight the many ways in which biomaterials can be brought to bear to engineer the immune system.Bill & Melinda Gates FoundationUnited States. Army Research Office. Institute for Soldier Nanotechnologies (Contract W911NF-13-D-0001)Ragon Institute of MGH, MIT and HarvardCancer Research Institute (New York, N.Y.) (Irvington Postdoctoral Fellowship)National Institutes of Health (U.S.) (Awards AI104715, CA172164, CA174795, and AI095109

Reduced Acute Inflammatory Responses to Microgel Conformal Coatings

Implantation of synthetic materials into the body elicits inflammatory host responses that limit medical device integration and biological performance. This inflammatory cascade involves protein adsorption, leukocyte recruitment and activation, cytokine release, and fibrous encapsulation of the implant. We present a coating strategy based on thin films of poly(N-isopropylacrylamide) hydrogel microparticles (i.e. microgels) cross-linked with poly(ethylene glycol) diacrylate. These particles were grafted onto a clinically relevant polymeric material to generate conformal coatings that significantly reduced in vitro fibrinogen adsorption and primary human monocyte/macrophage adhesion and spreading. These microgel coatings also reduced leukocyte adhesion and expression of pro-inflammatory cytokines (TNF-alpha, IL-1 beta, MCP-1) in response to materials implanted acutely in the murine intraperitoneal space. These microgel coatings can be applied to biomedical implants as a protective coating to attenuate biofouling, leukocyte adhesion and activation, and adverse host responses for biomedical and biotechnological applications

Chronic Inflammatory Responses to Microgel-Based Implant Coatings

Inflammatory responses to implanted biomedical devices elicit a foreign body fibrotic reaction that limits device integration and performance in various biomedical applications. We examined chronic inflammatory responses to microgel conformal coatings consisting of thin films of poly(N-isopropylacrylamide) hydrogel microparticles cross-linked with poly(ethylene glycol) diacrylate deposited on poly(ethylene terephthalate) (PET). Unmodified and microgel-coated PET disks were implanted subcutaneously in rats for 4 weeks and explants were analyzed by histology and immunohistochemistry. Microgel coatings reduced chronic inflammation and resulted in a more mature/organized fibrous capsule. Microgel-coated samples exhibited 22% thinner fibrous capsules that contained 40% fewer cells compared to unmodified PET disks. Furthermore, microgel-coated samples contained significantly higher levels of macrophages (80%) than unmodified PET controls. These results demonstrate that microgel coatings reduce chronic inflammation to implanted biomaterials

IL-10-Functionalized Hydrogels Support Immunosuppressive Dendritic Cell Phenotype and Function

Biomaterial systems such as hydrogels enable localized delivery and postinjection modulation of cellular therapies in a wide array of contexts. Biomaterials as adjuvants have been an active area of investigation, but the study of functionalized biomaterials supporting immunosuppressive cell therapies for tolerogenic applications is still nascent. Here, we developed a 4-arm poly(ethylene-glycol)-maleimide (PEG-4MAL) hydrogel functionalized with interleukin-10 (IL-10) to improve the local delivery and efficacy of a cell therapy against autoimmune disease. The biophysical and biochemical properties of PEG-4MAL hydrogels were optimized to support dendritic cell (DC) viability and an immature phenotype. IL-10-functionalized PEG-4MAL (PEG-IL10) hydrogels exhibited controlled IL-10 release, extended the duration of DC support, and protected DCs from inflammatory assault. After incorporation in PEG-IL10 hydrogels, these DCs induced CD25+FoxP3+ regulatory T cells (Tregs) during in vitro coculture. These studies serve as a proof-of-concept for improving the efficacy of immunosuppressive cell therapies through biomaterial delivery. The flexible nature of this system enables its widespread application across a breadth of other tolerogenic applications for future investigation