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Site Specific Immunosuppression for Promoting Vascularized Composite Allograft Survival and Reducing Systemic Immunosuppression Related Morbidity

Feturi, Firuz (2020) Site Specific Immunosuppression for Promoting Vascularized Composite Allograft Survival and Reducing Systemic Immunosuppression Related Morbidity. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Widespread clinical applicability of vascularized composite allotransplantation (VCA) has been limited by the high incidence of rejection and the requirement for systemic, lifelong, multi-drug maintenance immunosuppression for allograft survival that can lead to infectious and metabolic complications. Our goal was to evaluate a site-specific immunosuppressive strategy that promotes VCA graft survival and reduces the need for systemic immunosuppression.
Hand and face allografts provide the opportunity for site-specific delivery of immunosuppressive drugs given the accessibility, feasibility of visual monitoring. Conceivably, site-specific graft immunosuppression could provide therapeutic drug levels in the allograft, reduce systemic drug exposure and toxicity, and improve patient compliance and outcomes. This work attempts to develop effective drug delivery strategies for site-specific immunosuppression, while minimizing the need for systemic immunosuppression. We have described two strategies for site-specific immunosuppression in a rodent model of VCA. 1) Topical drug administration, and 2) locally implantable prolonged release formulation. These strategies were able to sustain the survival of VCA graft with minimal systemic immunosuppression.
We have developed a topical formulation of mycophenolic acid (MPA), and showed that MPA lipoderm (1%), and Tacrolimus (TAC) ointment (0.03%) provide high concentrations in the skin confirming the ability of targeting drugs to local tissues by topical administration, with low systemic concentrations. Combined treatment with topical TAC and MPA and low dose of systemic TAC is effective in reducing systemic morbidity while sustaining VCA graft survival (>100 days). However, daily topical drug administration requires high patient compliance. We prepared a locally implantable formulation that consisted of TAC and polycaprolactone that can be placed in the allograft to provide sustained drug release over a prolonged period without any need for additional systemic immunosuppressive drugs. This approach prolonged VCA graft survival while minimizing the risk of systemic toxicity.
The results described in this dissertation show that replacement of systemic administration with site-specific immunosuppression is feasible and leads to better outcomes in a small animal model of VCA. Site-specific immunosuppression requires further investigation and development through pre-clinical and clinical research to achieve the optimal immunosuppression with minimal side effects. This will not only improve patient compliance and quality of life, but also increase the clinical applicability of VCA.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Feturi, Firuzfgf3@pitt.edufgf30000-0002-9711-4201
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorRaman, Venkataramananrv@pitt.edurv
Committee MemberBeumer, Janbeumerjh@upmc.edujhb11
Committee MemberLi, Songsol4@pitt.edusol4
Committee MemberPoloyac, Samuelpoloyac@pitt.edupoloyac
Committee MemberSolari, Mariosolarimg@upmc.edumgs48
Date: 20 April 2020
Date Type: Publication
Defense Date: 25 July 2019
Approval Date: 20 April 2020
Submission Date: 21 March 2020
Access Restriction: 2 year -- Restrict access to University of Pittsburgh for a period of 2 years.
Number of Pages: 240
Institution: University of Pittsburgh
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Pharmaceutical Formulation and Delivery, Drug-eluting Biomaterials, Site Specific Immunosuppression, Rejection, Vascularized Composite Allotransplantation
Date Deposited: 20 Apr 2020 13:55
Last Modified: 20 Apr 2020 13:55
URI: http://d-scholarship.pitt.edu/id/eprint/38361

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