Plastic Surgery Research Council

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Single Locally Implanted Tacrolimus Disc prolongs Vascularized Composite Allograft Survival via Loco-regional Immunosuppression and without Systemic Side Effects
Firuz G. Feturi, PhD, Jignesh V. Unadkat, MD, Damian Grybowsky, MD, Yong Wong, MD, Bing Li, MD, Vasil Erbas, MD, Lewei Dong, MD, Zhaoxiang Zhang, MD, Huseyin Sahin, MD, Wensheng Zhang, MD, Vijay Gorantla, MD, Kia Washington, MD, Mario Solari, MD, Raman Venkataramanan, PhD, Alexander M. Spiess, MD.
University of Pittsburgh, Pittsburgh, PA, USA.

Purpose
More than 185,000 amputations occur in United States each year. The most common is a partial hand amputation (61,000), with the next most common, a loss of one arm (25,000). The majority (77%) of cases are due to traumatic accidents. Vascularized composite allotransplantation (VCA), in the form of hand or arm allotransplantation, provides another option for hand reconstruction. The skin component of VCA is highly antigenic and mandates high doses of systemic immunosuppressive drugs. Oral dosing of tacrolimus (TAC) leads to fluctuating blood levels of the medication, risking toxicity or lack of efficacy. We propose a drug delivery platform that consists of an encapsulated sustained-release version of oral TAC that provides sustained drug release into the graft tissues and regional lymph nodes, while minimizing systemic blood levels. This results in lower overall systemic drug exposure, while the sustained loco regional delivery facilitates VCA survival.
Methods
TAC loaded polycaprolactone discs were prepared by solvent casting. Drug release kinetics were evaluated in-vitro in PBS and in-vivo by subcutaneous implantation of the disc in the hind limb of rats. Following orthotopic hind limb allotransplantation, animals (n=6/group) received no treatment (Group 1), one disc in the transplanted limb (Group 2), one disc in the contralateral un-transplanted limb (Group 3), or TAC 1mg/kg/day intraperitoneally (Group 4). TAC levels in blood and tissues were measured using LC-MS/MS. In addition to allograft survival, systemic toxicity was evaluated using metrics such as % change in body weight (BW), blood glucose, and creatinine clearance (CrCl).
Results
Implantation of a single TAC disc (5mg, 5 % w/w) resulted in blood levels between 5 to 10 ng/ml during the first 20 days, followed by blood levels between 2 to 5 ng/ml for nearly 100 days. High levels of TAC were achieved locally when the disc was implanted into the transplanted limb, when compared to TAC levels in the blood and/or contralateral limb (P<0.05). These levels were able to inhibit immune activation while preserving T regulatory cells, and prevent rejection, and thereby sustained the allograft for >150 days (Group 2), while animals in Group 1 and 3 had median survival 8 4 days and 71 7 days (P<0.001). No significant change in BW, glucose levels, and CrCL rates was observed in the animals received TAC disc (Group 2 and 3), as compared with animals in Group 4 (P<0.05).
Conclusion
A single TAC disc implanted into the TX limb was effective in sustaining allograft survival via loco-regional immunosuppression, without systemic side effects. Our study offers an alternative to the current
treatment paradigms which use systemic immunosuppression, to loco regional immunosuppression using a locally implantable drug delivery system. With this research, we hope to establish the basis for the development of more advanced technologies for targeted immunosuppressive drug therapy.


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