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Characterization of the host tissue response induced by a biosynthetic material composed of poly (4-hydroxybutyrate)

Pineda Molina, Catalina (2018) Characterization of the host tissue response induced by a biosynthetic material composed of poly (4-hydroxybutyrate). Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Biomaterial-associated infections and bacterial resistance to antibiotics represent two of the major causes of implant failure. Pre-clinical and clinical studies have associated the use of biosynthetic surgical mesh materials composed of poly (4-hydroxybutyrate) (P4HB) with decreased surgical site infection (SSI) and an improved long-term remodeling response. The mechanisms driving these beneficial effects of P4HB remain unknown. 4-hydroxybutyrate (4HB), the main degradation product of P4HB, is an endogenous short chain fatty acid (SCFA) that has been exhaustively studied for its role as a modulator of the neurotransmitter γ-aminobutyric acid (GABA) in the central nervous system (CNS) and as a modulator of reactive oxygen species (ROS) in endothelium. Other functions of 4HB within non-CNS tissues have been less studied; however, this SCFA is a hydroxylated form of butyrate, a known histone deacetylase (HDAC) inhibitor, which is secreted by commensal bacteria within the gastrointestinal tract. Butyrate exerts its immunomodulatory functions by suppressing pro-inflammatory macrophage activation and promoting antimicrobial peptide (AMP) secretion. However, the immunomodulatory effects of 4HB upon cells of the immune system and the ability of 4HB to induce the expression of AMP have not been studied.

The present dissertation evaluates the 4HB-mediated effects upon macrophage expression. The molecular mechanisms by which a specific AMP, cathelicidin LL-37, is expressed are described. A rat model of a partial thickness abdominal wall defect and a rat model of deliberate contamination in a subcutaneous tissue pocket are used to evaluate the host macrophage response and the expression of cathelicidin LL-37 in the presence of P4HB surgical mesh.

4HB promotes a pro-remodeling, regulatory phenotype and increases expression of AMP in subjected macrophages. The associated molecular mechanism involves transcriptional activation of cathelicidin LL-37 through MAP-kinase and NF-κB pathways. In vivo, P4HB mitigates the acute, pro-inflammatory host response and provides an increased resistance to bacterial contamination. The results of this work expand the understanding of the biologic activity of 4HB in cells of the immune system and show its potential to promote a constructive tissue remodeling effect for regenerative medicine applications.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Pineda Molina, CatalinaCAP131@pitt.eduCAP131
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairBadylak, Stephen
Committee MemberBrown,
Committee MemberMarra,
Committee MemberLee, Janet
Committee MemberPiganelli,
Thesis AdvisorBadylak, Stephen
Date: 7 November 2018
Date Type: Publication
Defense Date: 28 June 2018
Approval Date: 7 November 2018
Submission Date: 16 July 2018
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 149
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, Tissue Engineering, Host Response, Antimicrobial Peptides, Macrophages, 4-hydroxybutyrate
Date Deposited: 07 Nov 2019 06:00
Last Modified: 07 Nov 2020 06:16


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