. 2022 Sep;39(9):2179-2190.

doi: 10.1007/s11095-022-03345-4. Epub 2022 Aug 2.

Tacrolimus-Eluting Disk within the Allograft Enables Vascularized Composite Allograft Survival with Site-Specific Immunosuppression without Systemic Toxicity

Firuz G Feturi¹, Jignesh V Unadkat², Wensheng Zhang², Mohamed El Hag³, Yong Wang², Chiaki Komatsu², Damian Grybowski², Zhaoxiang Zhang², Vasil Erbas⁴, Huseyin Sahin⁵, Sean Mcclaine², Sinan Oksuz⁶, Jan Plock⁷, Vijay S Gorantla⁸, Kia M Washington^{2

9}, Mario G Solari², Raman Venkataramanan^#^{10

11}, Alexander M Spiess^#¹²

Affiliations

¹ Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, 7220 Salk Hall, 3501 Terrace Street, Pittsburgh, PA, 15261, USA.
² Department of Plastic and Reconstructive Surgery, School of Medicine, University of Pittsburgh, Scaife Hall, Suite 6B, 3550 Terrace Street, Scaife Hall, Suite 6B, Pittsburgh, PA, 15261, USA.
³ Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
⁴ Department of Plastic, Reconstructive and Aesthetic Surgery, Medical Park Gaziantep Hospital, Gaziantep, Turkey.
⁵ Private Cagsu Hospital, Duzce, Turkey.
⁶ Department of Plastic, Reconstructive and Aesthetic Surgery, School of Medicine, Gulhane Military Medical Academy, Ankara, Turkey.
⁷ Division of Plastic and Hand Surgery, University Hospital Zurich, Zurich, Switzerland.
⁸ Departments of Surgery, Ophthalmology and Bioengineering, Wake Forest School of Medicine, Wake Forest Institute of Regenerative Medicine, Winston Salem, NC, USA.
⁹ Division of Plastic and Reconstructive Surgery, University of Colorado Hospital, Aurora, CO, 80045, USA.
¹⁰ Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, 7220 Salk Hall, 3501 Terrace Street, Pittsburgh, PA, 15261, USA. rv@pitt.edu.
¹¹ Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. rv@pitt.edu.
¹² Department of Plastic and Reconstructive Surgery, School of Medicine, University of Pittsburgh, Scaife Hall, Suite 6B, 3550 Terrace Street, Scaife Hall, Suite 6B, Pittsburgh, PA, 15261, USA. spiessam@upmc.edu.

^# Contributed equally.

PMID: 35915321
DOI: 10.1007/s11095-022-03345-4

Tacrolimus-Eluting Disk within the Allograft Enables Vascularized Composite Allograft Survival with Site-Specific Immunosuppression without Systemic Toxicity

Firuz G Feturi et al. Pharm Res. 2022 Sep.

. 2022 Sep;39(9):2179-2190.

doi: 10.1007/s11095-022-03345-4. Epub 2022 Aug 2.

Authors

Affiliations

¹ Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, 7220 Salk Hall, 3501 Terrace Street, Pittsburgh, PA, 15261, USA.
² Department of Plastic and Reconstructive Surgery, School of Medicine, University of Pittsburgh, Scaife Hall, Suite 6B, 3550 Terrace Street, Scaife Hall, Suite 6B, Pittsburgh, PA, 15261, USA.
³ Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
⁴ Department of Plastic, Reconstructive and Aesthetic Surgery, Medical Park Gaziantep Hospital, Gaziantep, Turkey.
⁵ Private Cagsu Hospital, Duzce, Turkey.
⁶ Department of Plastic, Reconstructive and Aesthetic Surgery, School of Medicine, Gulhane Military Medical Academy, Ankara, Turkey.
⁷ Division of Plastic and Hand Surgery, University Hospital Zurich, Zurich, Switzerland.
⁸ Departments of Surgery, Ophthalmology and Bioengineering, Wake Forest School of Medicine, Wake Forest Institute of Regenerative Medicine, Winston Salem, NC, USA.
⁹ Division of Plastic and Reconstructive Surgery, University of Colorado Hospital, Aurora, CO, 80045, USA.
¹⁰ Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, 7220 Salk Hall, 3501 Terrace Street, Pittsburgh, PA, 15261, USA. rv@pitt.edu.
¹¹ Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA. rv@pitt.edu.
¹² Department of Plastic and Reconstructive Surgery, School of Medicine, University of Pittsburgh, Scaife Hall, Suite 6B, 3550 Terrace Street, Scaife Hall, Suite 6B, Pittsburgh, PA, 15261, USA. spiessam@upmc.edu.

^# Contributed equally.

PMID: 35915321
DOI: 10.1007/s11095-022-03345-4

Abstract

Aim: Widespread clinical application of vascularized composite allotransplantation (VCA) has been limited by the need for lifelong systemic immunosuppression to prevent rejection. Our goal was to develop a site-specific immunosuppressive strategy that promotes VCA allograft survival and minimizes the risk of systemic side effects.

Methods: Tacrolimus loaded polycaprolactone (TAC-PCL) disks were prepared and tested for their efficacy in sustaining VCA allograft survival via site-specific immunosuppression. Brown Norway-to-Lewis rat hind limb transplantations were performed; animals received one TAC disk either in the transplanted (DTx) or in the contralateral non-transplanted (DnonTx) limbs. In another group, animals received DTx and lymphadenectomy on Tx side. Blood and allograft levels of TAC were measured using LC-MS/MS. Systemic toxicity was evaluated.

Results: Animals that received DTx achieved long-term allograft survival (> 200 days) without signs of metabolic and infectious complications. In these animals, TAC blood levels were low but stable between 2 to 5 ng/mL for nearly 100 days. High concentrations of TAC were achieved in the allografts and the draining lymph nodes (DLN). Animals that underwent lymphadenectomy rejected their allograft by 175 days. Animals that received DnonTx rejected their allografts by day 70.

Conclusion: Controlled delivery of TAC directly within the allograft (with a single TAC disk) effectively inhibits rejection and prolongs VCA allograft survival, while mitigating the complications of systemic immunosuppression. There was a survival benefit of delivering TAC within the allograft as compared to a remote site. We believe this approach of local drug delivery has significant implications for drug administration in transplantation.

Keywords: drug-eluting biomaterials; rejection; site specific immunosuppression; tacrolimus; vascularized composite allografts.

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Tacrolimus-Eluting Disk within the Allograft Enables Vascularized Composite Allograft Survival with Site-Specific Immunosuppression without Systemic Toxicity

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Tacrolimus-Eluting Disk within the Allograft Enables Vascularized Composite Allograft Survival with Site-Specific Immunosuppression without Systemic Toxicity

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