Shifts in macrophage phenotype at the biomaterial interface via IL-4 eluting coatings are associated with improved implant integration

Abstract

The present study tests the hypothesis that transient, early-stage shifts in macrophage polarization at the tissue-implant interface from a pro-inflammatory (M1) to an anti-inflammatory/regulatory (M2) phenotype mitigates the host inflammatory reaction against a non-degradable polypropylene mesh material and improves implant integration downstream. To address this hypothesis, a nanometer-thickness coating capable of releasing IL-4 (an M2 polarizing cytokine) from an implant surface at early stages of the host response has been developed. Results of XPS, ATR-FTIR and Alcian blue staining confirmed the presence of a uniform, conformal coating consisting of chitosan and dermatan sulfate. Immunolabeling showed uniform loading of IL-4 throughout the surface of the implant. ELISA assays revealed that the amount and release time of IL-4 from coated implants were tunable based upon the number of coating bilayers and that release followed a power law dependence profile. In-vitro macrophage culture assays showed that implants coated with IL-4 promoted polarization to an M2 phenotype, demonstrating maintenance of IL-4 bioactivity following processing and sterilization. Finally, in-vivo studies showed that mice with IL-4 coated implants had increased percentages of M2 macrophages and decreased percentages of M1 macrophages at the tissue-implant interface during early stages of the host response. These changes were correlated with diminished formation of fibrotic capsule surrounding the implant and improved tissue integration downstream. The results of this study demonstrate a versatile cytokine delivery system for shifting early-stage macrophage polarization at the tissue-implant interface of a non-degradable material and suggest that modulation of the innate immune reaction at early stages of the host response may represent a preferred strategy for promoting biomaterial integration and success.

Effects of aging upon the host response to implants

“…The population which was present at the 7‐day time point was found to express significantly less Arg‐1 and significantly more iNOS in 18‐month‐old mice as compared to 8‐week‐old, suggesting a more M1‐like proinflammatory profile. Previous studies have shown the 7–14‐day postimplantation time frame to be significantly predictive of downstream outcomes, with higher numbers of M2 polarized cells and higher ratios of M2:M1 cells as indicators of improved integration and remodeling . Thus, this finding indicates the potential for poor downstream integration and remodeling in 18‐month‐old mice.…”

“…1985) were observed. A power analysis was performed to determine that 7 animals per group was required to maintain a statistical power of at least 80%, based on previous studies using the same model …”

“…An increasing number of studies in the field of biomaterials and regenerative medicine have now begun to apply the macrophage M1/M2 paradigm, and have shown that macrophage phenotype can be modulated by biomaterials with improved tissue remodeling, integration, and long‐term functional outcomes as a result . For example, a recent study demonstrated that transient, early‐stage (7 days postimplantation) shifts in macrophage polarization from an M1 to M2 phenotype at the host–implant interface mitigated the foreign body reaction to polypropylene mesh and improved implant integration downstream . Studies such as this demonstrate the critical nature of the earliest events in the host–implant interaction in determining downstream integration and suggest that methods which seek to modulate, rather than avoid, this response will meet with greater success.…”

Effects of age-related shifts in cellular function and local microenvironment upon the innate immune response to implants

“…permanent implants versus regenerative medicine-based approaches to tissue reconstruction) [13,30–36]. As a result, multiple strategies have now been devised to promote shifts in macrophage phenotype at the host-tissue interface.…”

A three dimensional in vitro glial scar model to investigate the local strain effects from micromotion around neural implants

“…Future work will investigate the interplay between additional cell types present in the culture such as neurons and microglia. Potential future studies may also examine drug interactions (anti-inflammatory drugs that modulate macrophage (40, 41) or astrocyte behavior (42)), BBB breach (by incorporating IgG or blood borne macrophages in the culture), and incorporation of live cell imaging techniques to further understand the drivers and dynamics of glial scar formation within this model.…”