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Contribution of Scaffold Crosslinking & Pro-inflammatory Signals to Vascularization of Biomaterials

Thursday, March 21, 2019

10:00 AM-12:00 PM

BIOMED Master's Thesis Defense

Contribution of Scaffold Crosslinking and Pro-inflammatory Signals to Vascularization of Biomaterials In Vivo

Alicia Clark, Master's Candidate
School of Biomedical Engineering, Science and Health Systems
Drexel University

Kara L. Spiller, PhD
Associate Professor
School of Biomedical Engineering, Science and Health Systems
Drexel University

Current biomaterials used to support the repair and regeneration of damaged or diseased tissues often utilize crosslinked and non-crosslinked collagen, the most prominent protein in the human body. Crosslinked materials can be advantageous due to their increased mechanical strength, slower degradability, and structure that more closely mimics that in human tissues. One major challenge in collagen-based biomaterials is a lack of healthy vascularization after implantation and its integration in the body. Macrophages are one of the primary cells involved in angiogenesis and in response to implanted biomaterials, which suggests that biomaterials can modulate macrophage behavior and may have potential to facilitate enhanced angiogenesis. Previous research has suggested that pro-inflammatory M1 macrophages in crosslinked scaffolds initiate angiogenesis, however, the effect of crosslinking and macrophage behavior on vascularization is still poorly understood in vivo. Therefore, the goal of this study was to determine the effects of chemical crosslinking and the release of pro-inflammatory, M1-stimulating, interferon gamma (IFNg) on macrophage behavior and blood vessel infiltration into the scaffolds and within the scaffold cross-section edges in vivo.

Following pilot studies to optimize methods for blood vessel measurements, the work for this thesis come from 2 studies, one of which is a repeat of the other (n=6 mice total, 3 mice for each study). One scaffold from each group (non-crosslinked collagen control scaffold (Cg), non-crosslinked collagen scaffold with adsorbed IFNg (Cg+I), crosslinked collagen scaffold (Cg+X), and crosslinked collagen scaffold with IFNg (Cg+X+I) was implanted subcutaneously into the dorsal region of 8-week-old, C57BL/6J male mice. After 14 days, the mice were perfused with anti-mCD31 via a tail-vein injection to visualize blood vessels, and then sacrificed. Scaffolds were then explanted from the mice and processed for cryo-sectioning and staining. Blood vessels within the scaffolds and within the scaffold cross-section edges from each group were manually counted from z-stack images and averaged per mouse. Measurements of the furthest distances that the blood vessels traveled into each scaffold cross-section were also acquired. One cross-section from the Disc Center range and one cross-section from each of the Disc Edge ranges were randomly selected per group per mouse to analyze for both studies.

Results from both studies showed that EDC/NHS crosslinked collagen scaffolds (Cg+X) promoted a decrease in the infiltration of blood vessels within the scaffolds and edges of the scaffold cross-sections, compared to the non-crosslinked collagen scaffold controls (Cg). The addition of IFNg to EDC/NHS crosslinked scaffolds (Cg+X+I), however increased blood vessel infiltration within the scaffold and scaffold cross-section edges compared to the crosslinked scaffold alone (Cg+X). The results suggest that the addition of pro-inflammatory IFNg to EDC/NHS crosslinked scaffolds may increase vascularization within crosslinked scaffolds. These results therefore show the contribution of crosslinked biomaterials to vascularization and implicate a strategy to improve vascularization within crosslinked collagen scaffolds with use of pro-inflammatory macrophage mediators.

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