Daniel Jordi, Hachim Diaz
(2018)
DEVELOPMENT OF CYTOKINE ELUTING COATINGS TO MODULATE MACROPHAGE BEHAVIOUR AND MITIGATE THE FOREIGN BODY REACTION AGAINST IMPLANTABLE BIOMATERIALS.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Recent studies have implicated that an inadequate host biomaterial response, driven predominately by pro-inflammatory (M1) macrophages and downstream formation of fibrotic capsule, is a major cause of the severe surgical mesh-related complications in pelvic prolapsed woman. We have hypothesized that shifting this macrophage response towards an anti-inflammatory (M2) phenotype will lead to a better implant integration into the host tissue. A coating for local and transient delivery of interleukin-4 (IL-4, an M2 cytokine) was developed, using layer-by-layer (LbL) deposition of chitosan and dermatan sulfate. Implantation studies revealed that the released IL-4 promoted a predominant M2-like macrophage response, associated to decreased fibrotic capsule deposition and changes in collagen composition, suggesting improved mesh integration into the host tissue and potential for reduction in downstream complications.
Immunosenescence, dysregulated macrophage function, and delayed resolution of the immune response against pathogens have been demonstrated in aged individuals. We have sought to elucidate the impacts of aging upon the host response to polypropylene mesh in aged versus young mice. The host response in aged mice resulted in delayed cell recruitment, significant differences in macrophage marker expression and a highly shifted pro-inflammatory (M1) response at early stages, associated with an unresolved host response in the long-term, compared to young mice.
A sequential delivery of MCP-1 (macrophage chemoattractant protein-1) and IL-4 has been developed to restore the delayed cell recruitment and reverse the inflammatory macrophage response in old mice, respectively. The host response to single and sequential delivery regimens was well distinct in old versus young implanted mice. While single delivery of IL-4 was not enough to counteract the high inflammatory response in old mice, the sequential delivery of MCP-1 and IL-4 was capable of restoring recruitment and M2-like macrophage response, associated to decreased capsule deposition in the long term. Contrarily, the sequential delivery regimen in young mice was not as effective as IL-4 alone promoting an M2-like response, but still capable of reducing inflammatory macrophages and capsule deposition. These results demonstrate that a proper understanding of biological context has the potential to improve the performance of biomaterials-based approaches in aged individuals.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
| Creators | Email | Pitt Username | ORCID  |
|---|
| Daniel Jordi, Hachim Diaz | djh88@pitt.edu | djh88 | |
|
| ETD Committee: |
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| Date: |
17 April 2018 |
| Date Type: |
Publication |
| Defense Date: |
2 November 2017 |
| Approval Date: |
17 April 2018 |
| Submission Date: |
17 November 2017 |
| Access Restriction: |
1 year -- Restrict access to University of Pittsburgh for a period of 1 year. |
| Number of Pages: |
148 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
Swanson School of Engineering > Bioengineering |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
biomaterials, host response, macrophages, delivery, cytokines, coating, layer by layer, surgical mesh |
| Date Deposited: |
17 Apr 2019 05:00 |
| Last Modified: |
17 Apr 2019 05:15 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/33383 |
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