Multicompartment Drug Release System for Dynamic Modulation of Tissue Responses

Abstract

Pharmacological modulation of responses to injury is complicated by the need to deliver multiple drugs with spatiotemporal resolution. Here, a novel controlled delivery system containing three separate compartments with each releasing its contents over different timescales is fabricated. Core-shell electrospun fibers create two of the compartments in the system, while electrosprayed spheres create the third. Utility is demonstrated by targeting the foreign body response to implants because it is a dynamic process resulting in implant failure. Sequential delivery of a drug targeting nuclear factor-κB (NF-κB) and an antifibrotic is characterized in in vitro experiments. Specifically, macrophage fusion and p65 nuclear translocation in the presence of releasate or with macrophages cultured on the surfaces of the constructs are evaluated. In addition, releasate from pirfenidone scaffolds is shown to reduce transforming growth factor-β (TGF-β)-induced pSMAD3 nuclear localization in fibroblasts. In vivo, drug eluting constructs successfully mitigate macrophage fusion at one week and fibrotic encapsulation in a dose-dependent manner at four weeks, demonstrating effective release of both drugs over different timescales. Future studies can employ this system to improve and prolong implant lifetimes, or load it with other drugs to modulate other dynamic processes.

Engineered immunological niches to monitor disease activity and treatment efficacy in relapsing multiple sclerosis

“…Mice were housed in a 12 h light-dark cycle in a pathogen-free environment. Mice were anesthetized with isofluorane, before subcutaneous implantation with scaffolds 42,43 . Mice received subcutaneous injections of carprofen (5 mg/kg) immediately before surgery and 24 h after surgery.…”

Macrophage and Fibroblast Interactions in Biomaterial‐Mediated Fibrosis

“…Electrospinning provides a tunable platform to alter cellular function based on both surface topography and controlled release of biochemical cues. One strategy first employed a core–shell electrospun fiber, yielding two different components that each contained different drugs; core–shell fibers were electrospun into a mat and then electrosprayed, creating a third component . Capitalizing on previous work that NF‐κB signaling was required for macrophages to fuse into FBGCs, Morris et al designed their multicomponent system to release Bay 11‐7082, a NF‐κB inhibitor from the shell, along with an antibiotic ampicillin from the core and an antifibrotic pirfenidone from electrosprayed coating .…”

“…One strategy first employed a core–shell electrospun fiber, yielding two different components that each contained different drugs; core–shell fibers were electrospun into a mat and then electrosprayed, creating a third component . Capitalizing on previous work that NF‐κB signaling was required for macrophages to fuse into FBGCs, Morris et al designed their multicomponent system to release Bay 11‐7082, a NF‐κB inhibitor from the shell, along with an antibiotic ampicillin from the core and an antifibrotic pirfenidone from electrosprayed coating . The strategy behind this design was to inhibit FBGC formation, reduce encapsulation of the implant, and prevent bacterial infection .…”

“…Capitalizing on previous work that NF‐κB signaling was required for macrophages to fuse into FBGCs, Morris et al designed their multicomponent system to release Bay 11‐7082, a NF‐κB inhibitor from the shell, along with an antibiotic ampicillin from the core and an antifibrotic pirfenidone from electrosprayed coating . The strategy behind this design was to inhibit FBGC formation, reduce encapsulation of the implant, and prevent bacterial infection . In vitro benchtop release studies illustrated drug release on different time scales, which was also reflected in vivo, where macrophage fusion was successfully mitigated after 1 week, TGF‐β1 secretion was suppressed, and fibrotic encapsulation was decreased in a dose‐dependent manner over 4 weeks …”

“…The strategy behind this design was to inhibit FBGC formation, reduce encapsulation of the implant, and prevent bacterial infection . In vitro benchtop release studies illustrated drug release on different time scales, which was also reflected in vivo, where macrophage fusion was successfully mitigated after 1 week, TGF‐β1 secretion was suppressed, and fibrotic encapsulation was decreased in a dose‐dependent manner over 4 weeks …”