Sequential drug delivery to modulate macrophage behavior and enhance implant integration

Abstract

Macrophages are major upstream regulators of the inflammatory response to implanted biomaterials. Sequential functions of distinct macrophage phenotypes are essential to the normal tissue repair process, which ideally results in vascularization and integration of implants. Improper timing of M1 or M2 macrophage activation results in dysfunctional healing in the form of chronic inflammation or fibrous encapsulation of the implant. Thus, biphasic drug delivery systems that modulate macrophage behavior are an appealing approach to promoting implant integration. In this review, we describe the timing and roles of macrophage phenotypes in healing, then highlight current drug delivery systems designed to sequentially modulate macrophage behavior.

Keywords: Angiogenesis; Implant integration; Macrophage.

Figure 1:. Integration of implanted biomaterials.

(A) Unsuccessful integration results in the fusion of foreign body giant cells, which then secrete extracellular matrix to form a fibrous capsule. This fibrous capsule isolates the biomaterial from the body as part of the foreign body response. (B) Complete integration, largely directed by macrophages, allows for cellular and vascular infiltration to support tissue development. Infiltrating cells may include pericytes to support vascularization, fibroblasts for matrix deposition, and mesenchymal stem cells for longterm stability.

Figure 2:. Dysfunctional timing of macrophage phenotypes in failed implant integration.

(A) Premature M2 activation may prevent implant integration via production of fibrotic cytokines such as TGF-β, though M1 macrophages may also play a role in fibrosis. (B) Early M1 macrophages that fail to transition to an M2 phenotype at later timepoints continue to secrete pro-inflammatory cytokines, resulting in chronic inflammation and delayed healing.

Figure 3:. General model of sequential drug delivery system for macrophage modulation and implant integration.

During the initial inflammatory phase, MCP-1 may be incorporated to recruit circulating monocytes to the implant site. Release of IFNγ or TNFα can promote the Ml phenotype in infiltrating macrophages, inducing sprouting of immature blood vessels from the surrounding vasculature. Subsequent release of IL-4 and/or IL-13 would activate switching to the M2(a) phenotype, resulting in the resolution of inflammation and stabilization of newly formed blood vessels.