Controlled Release of Anti-Inflammatory and Proangiogenic Factors from Macroporous Scaffolds

Abstract

The simultaneous local delivery of anti-inflammatory and pro-angiogenic 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, PDMS microbeads were loaded with either anti-inflammatory dexamethasone (Dex) or pro-angiogenic 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 the durability of drug release for both agents. Incubation of scaffolds with LPS-stimulated M1 macrophages found that Dex suppressed the production of pro-inflammatory and pro-angiogenic factors, when compared to drug-free control scaffolds; however, the co-incubation of macrophages with Dex and E2 scaffolds restored their pro-angiogenic features. Following implantation, Dex-loaded microbead scaffolds (Dex-µBS) suppressed host cell infiltration and integration, when compared to controls. In contrast, the co-delivery 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.

Integrating Additive Manufacturing Techniques to Improve Cell‐Based Implants for the Treatment of Type 1 Diabetes

“…They can also be used to locally deliver supportive agents, such as pro-survival factors to improve engraftment and/or immunotherapeutics to control inflammation and prevent immunological destruction. [19][20][21][22][23] In addition, the polymeric encapsulation of cells within immunoisolatory hydrogels can mitigate direct immune cell attack and enhance graft protection. [24,25] These biomaterial strategies for housing and supporting islets within a wide range of transplant sites have shown great promise, establishing the basis for hopeful application in humans.…”

“…[54][55][56][57] In addition to improved nutrient transport, implant porosity globally impacts biocompatibility and engraftment long-term, with optimal pore sizes facilitating healthy cellular infiltration and remodeling. [19,20] The intimate control of pore size and connectivity using particulate leaching and gas foaming methods, however, is limited, resulting in heterogeneity of the final scaffold product. In addition, uneven geometry as a result of the irregular porogen surface can lead to rough macro-scale topographies, potentially increasing the risk of pro-inflammatory responses.…”

“…For 𝛽-cell therapy in T1DM, the competency and consistency of the vascular network are essential to not only support efficient nutrient delivery but to ensure effective insulin kinetics. In earlier platforms, the infiltration by endogenous cells and subsequent anastomoses with islets was directed by modifying bulk material properties to create pores and/or surface geometric features that encourage vessel formation [19,11,[78][79][80][81][82] These approaches were successful in generating robust vasculature; however, islet loss post-transplantation during the delay in the formation of competent vascularization remains a challenge. In response, work has shifted to "priming" the transplant site by pre-vascularizing biomaterials with endogenous cells or generating vessels in vitro for accelerated vessel development.…”

“…[21] In addition, the incorporation of pro-islet therapeutics, such as small molecules (e.g., curcumin, exenatide, and vitamin D) and hormonal therapeutics (e.g., 17𝛽-estradiol), can lead to decreased apoptosis and elevated and/or more durable insulin secretion. [19,[105][106][107][108] Finally, local immunomodulation broadly involves the local release or presentation of agents that dampen the innate or adaptive immune response to transplanted cells, which would support enhanced engraftment and long-term survival while reducing the need for systemic immune suppression. These therapeutics can take many forms, ranging from small-molecule steroids (dexamethasone, fingolimod), [19,107,109,110] to larger macrolides (rapamycin, tacrolimus) [111,112] and proteins (PD-L1).…”

“…[19,[105][106][107][108] Finally, local immunomodulation broadly involves the local release or presentation of agents that dampen the innate or adaptive immune response to transplanted cells, which would support enhanced engraftment and long-term survival while reducing the need for systemic immune suppression. These therapeutics can take many forms, ranging from small-molecule steroids (dexamethasone, fingolimod), [19,107,109,110] to larger macrolides (rapamycin, tacrolimus) [111,112] and proteins (PD-L1). [113] Overall, these therapeutics can provide significant improvements when delivered in the context of local release or presentation; however, their delivery is typically limited to homogenous distribution within the graft.…”