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Designing a Novel Immunomodulatory Surface Modification To Promote Biomaterial-tissue Integration
Start Date: 5/23/2019Start Time: 2:00 PM
End Date: 5/23/2019End Time: 4:00 PM

Event Description
BIOMED PhD Thesis Defense

Designing a Novel Immunomodulatory Surface Modification To Promote
Biomaterial-tissue Integration

Emily Beth Lurier, PhD 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

The foreign body response (FBR) to implanted biomaterials provides a major challenge for successful biomaterial-tissue integration in the body. During the FBR, biomaterials are encapsulated in a collagenous, scar-like capsule that prevents the material from interacting with the surrounding tissue. Ultimately, the biomaterial will fail due to degradation and encapsulation, resulting in the removal and replacement of the implant. The primary culprit of the FBR is macrophages, the primary cell type of the inflammatory response. Macrophages exist on a spectrum of behaviors, typically transitioning from an “M1” pro-inflammatory to “M2” pro-healing phenotype in healthy wound healing. The M2 phenotype can be further broken down into interleukin-4 (IL4) stimulated “M2a” and IL10 stimulated “M2c” macrophages, although the differences between these phenotypes in biomaterial-tissue integration have not been fully elucidated. During the FBR, this phenotypic transition is halted, and macrophages exhibit chronic M1 behavior leading to fibrous capsule formation. While many biomaterial strategies to inhibit chronic M1 behavior and promote the natural M1-to-M2 phenotype switch have been investigated, there is currently no method to inhibit the FBR. Furthermore, methods to temporally control macrophage behavior to prevent chronic responses in either direction have not been successfully implemented. Therefore, the overarching goals of this work were to (1) design an affinity-based cytokine release system to modulate macrophage phenotype over time and (2) test the ability of the drug delivery system using biotin-avidin to temporally modulate macrophage phenotype both in vitro and in vivo.

First, an investigation into the M2c phenotype revealed that this phenotype may act at early stages of wound healing, primarily contributing to matrix remodeling. M2c macrophages were found to secrete high quantities of matrix degrading enzymes suggesting that this phenotype may not be beneficial in biomaterial-tissue integration. Comparatively, M2a macrophages have been previously shown to inhibit fibrous capsule formation and promote angiogenesis in the context of biomaterial-tissue integration. Therefore, the M2a polarizing cytokine IL4 was bound to Gelfoam scaffolds, used as a model biomaterial throughout, via the biotin-avidin affinity conjugation system.

The biotin avidin system has been previously shown to release proteins over time and has the potential for creating a loadable protein drug delivery system in vitro. However, the ability to modulate macrophage activation by controlling the parameters of the system over time have not been thoroughly investigated. The effects of modulating both the fold molar excess of biotin on the scaffold surface and altering the avidin variants were investigated.  Increasing the fold molar excess (FME) of biotin on the scaffold conjugated with CaptAvidin, and not Streptavidin, was shown to decrease IL4 release over time. Additionally, in a similar manner, increasing the FME of biotin on the scaffold with CaptAvidin and IL4 decreased M2a activation in vitro. Scaffolds with low levels of biotinylation in vivo were shown to have the highest reduction in fibrous capsule formation compared to groups with no IL4, adsorbed IL4 or a high degree of biotinylation. However, differences in gene expression signatures of explants were minimal. A more thorough investigation is required to determine the in vivo effects of modified scaffolds on fibrosis and angiogenesis.
Overall, modifying scaffolds with biotin-avidin shows great potential in designing immunomodulatory drug delivery systems to control macrophage activation over time. Future studies should focus on utilizing the biotin-avidin system as a loadable cytokine release system to control the M1-to-M2 phenotypic transition which would have significant impact on treating pathologies where this transition is halted, like fibrosis and chronic wounds.
Contact Information:
Name: Ken Barbee
Phone: 215-895-1335
Email: barbee@drexel.edu
Emily Lurier
Bossone Research Center, Room 709, located at 32nd and Market Streets.
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