The simultaneous local delivery of anti-inflammatory and proangiogenic agents via biomaterial scaffolds presents a promising method for improving the engraftment of tissue-engineered implants while avoiding potentially detrimental systemic delivery. In this study, polydimethylsiloxane (PDMS) microbeads were loaded with either anti-inflammatory dexamethasone (Dex) or proangiogenic 17β-estradiol (E2) and subsequently integrated into a single macroporous scaffold to create a controlled, dual-drug delivery platform. Compared to a standard monolithic drug dispersion scaffold, macroporous scaffolds containing drug-loaded microbeads exhibited reduced initial burst release and increased durability of drug release for both agents. The incubation of scaffolds with lipopolysaccharide (LPS)-stimulated M1 macrophages found that Dex suppressed the production of proinflammatory and proangiogenic factors when compared to drug-free control scaffolds; however, the coincubation of macrophages with Dex and E2 scaffolds restored their proangiogenic features. Following implantation, Dex-loaded microbead scaffolds (Dex-μBS) suppressed host cell infiltration and integration, when compared to controls. In contrast, the codelivery of dexamethasone with estrogen from the microbead scaffold (Dex+E2-μBS) dampened overall host cell infiltration, but restored graft vascularization. These results demonstrate the utility of a microbead scaffold approach for the controlled, tailored, and local release of multiple drugs from an open framework implant. It further highlights the complementary impacts of local Dex and E2 delivery to direct the healthy integration of implants, which has broad applications to the field of tissue engineering and regenerative medicine. Impact statement Inflammatory responses and vascularization are two significant challenges associated with the engraftment of tissue-engineered implants. To overcome these challenges, we developed a microbead scaffold platform for the local delivery of anti-inflammatory and proangiogenic agents. This drug delivery system showed the potential to simultaneously control the release of multiple agents, leading to a healthy integration of implants with host tissues. This multifunctional platform could be useful to numerous cellular transplants and engineered tissues.
Keywords: 17β-estradiol; controlled release; depots; dexamethasone; dual-drug delivery; macrophage phenotype; microbeads; vascularization.