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Biomaterial-mediated Control over Macrophage Behavior for Tissue Regeneration
Start Date: 6/5/2019Start Time: 1:00 PM
End Date: 6/5/2019End Time: 3:00 PM
Event Description
BIOMED PhD Thesis Defense

Title:
Biomaterial-mediated Control over Macrophage Behavior for Tissue Regeneration

Speaker:
Claire Witherel, PhD Candidate
School of Biomedical Engineering, Science and Health Systems
Drexel University

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

Details:
Macrophages, the primary cell of the immune response, and fibroblasts, the major producers of extracellular matrix (ECM), have significant roles in wound healing and the foreign body response to implanted biomaterials. Macrophages are known to exhibit a spectrum of  unique phenotypes in response to their environment; M1 macrophages, are associated with increased inflammation and initiating angiogenesis, while M2a macrophages have been associated with anti-inflammatory behavior and extracellular matrix deposition. Temporal control of macrophage phenotype from M1 to M2a has been shown to be critical in normal wound healing. On the other hand, dysregulated macrophage behavior has been associated with detrimental pathologies including chronic wounds and fibrosis. Therefore, the development of immunomodulatory biomaterials that can harness the natural immune response for repair and healing, hold significant promise for future of regenerative medicine. While it’s appreciated that macrophages play a significant role in aberrant healing outcomes, it is not well understood how they direct pro-healing outcomes, especially within the context of a biomaterial implant.

Therefore, the overall goals of this work were to 1. thoroughly characterize macrophage-biomaterial interactions and macrophage-fibroblast interactions to further our understanding of how these cells may influence functional tissue regeneration, and 2. Utilize a model drug-eluting biomaterial to directly assess the role of M2a macrophages in tissue regeneration.

To accomplish these goals, I investigated how macrophages change their behavior in response to commercially-available wound matrices in vitro. Collectively, these studies showed that four biomaterial-based wound matrices promoted pro-inflammatory macrophage behavior (more M1-like) and that macrophage-biomaterial contact was required for a bioactive (i.e. containing cells and proteins) wound matrix to inhibit  inflammation in pro-inflammatory macrophages. Next, I investigated the effects of macrophage-secreted signals on fibroblast behavior and extracellular matrix formation in vitro. Additionally, I employed model drug-eluting biomaterials to develop an M2a-promoting hydrogel to directly assess the role of M2a macrophages in the foreign body response in vivo. Together, these studies illustrated that M2a macrophages significantly influence fibroblast matrix deposition in vitro (generating thinner extracellular matrix fibers with an increased elastic moduli) relative to other macrophage phenotypes. The M2a-promoting biomaterial resulted in a significant reduction in innate immune cell recruitment after 21 days, suggesting that the slight increase in fibrous capsule formation around the M2a-promoting biomaterial (compared to control) may be due to increased presence of other key extracellular matrix-producing cells, such as fibroblasts or mesenchymal stem cells.

This work is critical for understanding how transient control of macrophage behavior is directly linked to tissue repair and regeneration outcomes. Due to the importance of macrophage behavior in all tissues, this project has the potential to translate into a myriad of other fields, especially those in which abnormal inflammation prevent tissue repair or regeneration.
Contact Information:
Name: Ken Barbee
Phone: 215-895-1335
Email: barbee@drexel.edu
Claire Witherel
Location:
Pearlstein Business Learning Center, Room 101, located at 3230 Market Street.
Audience:
  • Undergraduate Students
  • Graduate Students
  • Faculty
  • Staff

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