Increasingly biomaterials are being used and developed for various applications where the device must interface with central nervous system tissue for extended periods of time including such applications as drug delivery, fluid drainage, bridging devices, sensing, transplantation vehicles, and neural stimulation. Although a number of devices are being used clinically, available evidence suggests that biocompatibility can be improved in all applications. A consistent feature of the foreign body response to all implanted devices is persistent inflammation at the biotic-abiotic interface signaled by biomarkers of macrophage / microglial activation. We have shown that conventional biomaterials exposed to serum support the attachment and activation of microglia, which serve as a source of proinflammatory and cytotoxic cytokines IL-1B, IL-6, and TNF-alpha, as well as anti-inflammatory factors like IL-10 and TGF-beta. Since macrophage secreted factors are thought to play a role in shaping the foreign body reaction, we hypothesize that surfaces that reduce their degree of activation may be useful in reducing device-associated inflammation. Previous studies have reported that insoluble cues presented by astrocyte monolayers are capable of inducing a resting phenotype in activated microglia and various tissue macrophages. We cultured microglia cells isolated from postnatal rats in DMEM with 10% FBS on confluent monolayers of live and fixed astrocytes, we found a significant number of cells showed a ramified and less activated phenotype as determined by morphological observations and reaction with antisera against CD11b (OX42; mouse IgG2a), and the complement receptor CR3b. To mimic the pattern of ligands on the surface of astrocyte monolayers, we developed a method to precisely control the spatial distribution of proteins and glycosoaminoglycans that allows a pixel-by-pixel mapping at a resolution of approximately 500-nanometer pixel size. Our studies have shown that it is feasible to mimic the complex patterns of aggrecan, fibronectin and laminin expressed by astrocyte monolayers using a combination of microcontact printing and microfluidic technology that are resistant to displacement in serum containing culture conditions. Studies underway are investigating the efficacy of such an approach for modulating the activation state of brain-derived macrophages.

Support contributed by: NIH RO1 NS467700