Peripheral nerve repair across long gaps remains clinically challenging despite progress made with autograft transplantation. While scaffolds that present trophic factors and extracellular matrix molecules have been designed, matching the performance of autograft-induced repair has been challenging. In this study, we explored the effect of cytokine mediated ‘biasing’ of macrophage phenotypes on Schwann cell (SC) migration and axonal regeneration in vitro and in vivo. Macrophage phenotype was successfully modulated by local delivery of either Interferon-gamma (IFN-γ) or Interleukin-4 (IL-4) within polymeric nerve guidance channels, polarizing them toward pro-inflammatory (M1) or pro-healing (M2a and M2c) phenotypes, respectively. The initial polarization of macrophages to M2a and M2c phenotype results in enhanced SC infiltration and substantially faster axonal growth in a critically-sized rat sciatic nerve gap model (15 mm). The ratio of pro-healing to pro-inflammatory population of macrophages (CD206+/CCR7+), defined as regenerative bias, demonstrates a linear relationship with the number of axons at the distal end of the nerve scaffolds. The present results clearly suggest that rather than the extent of macrophage presence, their specific phenotype at the site of injury regulates the regenerative outcomes.

The use of solvent‐free microfluidics to fine‐tune the physical and chemical properties of chitosan nanoparticles for drug delivery is demonstrated. Nanoparticle self‐assembly is driven by pH changes in a water environment, which increases biocompatibility by avoiding organic solvent contamination common with traditional techniques. Controlling the time of mixing (2.5–75 ms) during nanoparticle self‐assembly enables us to adjust nanoparticle size and surface potential in order to maximize cellular uptake, which in turn dramatically increases drug effectiveness. The compact nanostructure of these nanoparticles preserves drug potency better than previous nanoparticles, and is more stable during long‐term circulation at physiological pH. However, when the nanoparticles encounter a tumor cell and the associated drop in pH, the drug contents are released. Moreover, the loading efficiency of hydrophobic drugs into the nanoparticles increases significantly from previous work to over 95%. The microfluidic techniques used here have applications not just for drug‐carrying nanoparticle fabrication, but also for the better control of virtually any self‐assembly process.

An immune response involves the action of all types of macrophages, classically activated subtype (M1) in the early inflammatory phase and regulatory and wound-healing subtypes (M2) in the resolution phase. The remarkable plasticity of macrophages makes them an interesting target in the context of immunomodulation. Here, we reviewed the current state of understanding regarding the role that different phenotypes of macrophages and monocytes play following injury and during the course of remodeling in different tissue types. Moreover, we explored recent designs of macrophage modulatory biomaterials for tissue engineering and regenerative medicine applications.