Date of Award

2018

Degree Type

Dissertation

Degree Name

Doctor of Philosophy in Chemical Engineering

Department

Chemical Engineering

First Advisor

Stephen M. Kennedy

Abstract

Sequential delivery of biomolecules is very important as many biologics underlying injury and disease follow an orderly and sequenced series of events. Here we developed and introduced for the first time a dual compartment biomaterial system with an outer compartment made of gelatin and inner compartment that is a ferrogel which can be magnetically stimulated in order to provide on-demand, sequential delivery of multiple bio-instructive payload. We studied the potential application of this dual-compartment biomaterial system in different therapeutic contexts that may benefit from on-demand sequential deliveries, such as in cancer immunotherapy and in chronic wound healing.

Chronic wounds can be a result of arrest in the inflammation phase of healing. Although inflammation critically initiates repair and helps clear infections, a prolonged inflammatory reaction can cause considerable harm to the injury site. After an appropriate duration of inflammation, this inflammatory response can be shifted to a more pro-healing response through the delivery of cytokines like interleukin 4 (IL-4) and interleukin 10 (IL-10). These anti-inflammatory cytokines alter the phenotype of macrophages from pro-inflammatory (M1) to anti-inflammatory (M2), suggesting a potentially powerful drug delivery strategy if these cytokines can be delivered in a delayed manner. We hypothesize that the transition of macrophage phenotype from pro-inflammatory (M1) to anti-inflammatory (M2) can be controlled through sequenced delivery of interferon gamma (IFN-γ), followed by IL-4 and/or IL-10. The goal of this research was to develop a wound-healing hydrogel system that initially delivers pro-inflammatory IFN-γ, followed by magnetically triggered delivery of pro-healing (anti-inflammatory) IL-4 and/or IL-10. Our biomaterial system was composed of two- compartments: (1) a porous gelatin outer compartment designed to recruit macrophages and establish an initial pro-inflammatory (M1) phenotype, and (2) a magnetically responsive alginate inner compartment which was designed to deliver IL-4 and/or IL-10 when magnetically triggered to shift the response to anti-inflammatory by promoting (M2) phenotype. We showed that we can have fast release of IFNg (Promotes M1 phenotype) and MCP-1 (recruits macrophages) initially from the outer compartment while holding on to IL4 and IL10 that is loaded in the ferrogel and have them burst release when applying the magnetic field.

Biomaterial-based cancer immunotherapy strategies require materials capable of recruiting dendritic cells (DCs) and reprogramming them with cancer antigen and danger signal. This strategy requires the implantation of a biomaterial that is loaded with DC recruitment factors, danger signals, and cancer antigen. This co-delivery of danger signal and antigen results in DC activation and homing of cancer-antigen-presenting DCs to the lymph nodes, subsequently triggering an anti-tumor immune response from the host. However, danger signals and antigen diffuse out of the biomaterial while DCs are being actively recruited to the biomaterial. This may result in lower concentrations of these necessary reprogramming agents by the time DCs are recruited and consequently, lower quantities of activated DCs, and a reduced anti-tumor immune response. It is possible that sequential release of DC recruitment and reprogramming factors will enhance the number of reprogrammed DCs over simultaneous release, leading to improved anti-cancer immune responses. In order to test this, a material system with unique delivery capabilities must be developed. Therefore, we designed a biomaterial system capable of first recruiting DCs by initially releasing DC recruitment factors from outer compartment. This biomaterial can deliver reprogramming agents (i.e., cancer antigen) when magnetically stimulated only after a substantial population of DCs has been recruited. The results showed that we were able to deliver GM-CSF (DC recruitment factor) initially from the outer compartment followed by delivering HSP27 (model cancer antigen) when stimulated in the magnetic field.

Available for download on Saturday, November 30, 2019

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