TY - JOUR T1 - Graft-implanted, enzyme responsive, tacrolimus-eluting hydrogel enables long-term survival of orthotopic porcine limb vascularized composite allografts: A proof of concept study. JF - PLoS One Y1 - 2019 A1 - Fries, C Anton A1 - Lawson, Shari D A1 - Wang, Lin C A1 - Slaughter, Kai V A1 - Vemula, Praveen K A1 - Dhayani, Ashish A1 - Joshi, Nitin A1 - Karp, Jeffrey M A1 - Rickard, Rory F A1 - Gorantla, Vijay S A1 - Davis, Michael R AB -

BACKGROUND: Currently, patients receiving vascularized composite allotransplantation (VCA) grafts must take long-term systemic immunosuppressive therapy to prevent immunologic rejection. The morbidity and mortality associated with these medications is the single greatest barrier to more patients being able to receive these life-enhancing transplants. In contrast to solid organs, VCA, exemplified by hand or face transplants, allow visual diagnosis of clinical acute rejection (AR), directed biopsy and targeted graft therapies. Local immunosuppression in VCA could reduce systemic drug exposure and limit adverse effects. This proof of concept study evaluated, in a large animal forelimb VCA model, the efficacy and tolerability of a novel graft-implanted enzyme-responsive, tacrolimus (TAC)-eluting hydrogel platform, in achieving long-term graft survival.

METHODS: Orthotopic forelimb VCA were performed in single haplotype mismatched mini-swine. Controls (n = 2) received no treatment. Two groups received TAC hydrogel: high dose (n = 4, 91 mg TAC) and low dose (n = 4, 49 mg TAC). The goal was to find a dose that was tolerable and resulted in long-term graft survival. Limbs were evaluated for clinical and histopathological signs of AR. TAC levels were measured in serial blood and skin tissue samples. Tolerability of the dose was evaluated by monitoring animal feeding behavior and weight.

RESULTS: Control limbs underwent Banff Grade IV AR by post-operative day six. Low dose TAC hydrogel treatment resulted in long-term graft survival time to onset of Grade IV AR ranging from 56 days to 93 days. High dose TAC hydrogel also resulted in long-term graft survival (24 to 42 days), but was not well tolerated.

CONCLUSION: Graft-implanted TAC-loaded hydrogel delays the onset of Grade IV AR of mismatched porcine forelimb VCA grafts, resulting in long term graft survival and demonstrates dose-dependent tolerability.

VL - 14 IS - 1 ER - TY - JOUR T1 - Towards an arthritis flare-responsive drug delivery system. JF - Nat Commun Y1 - 2018 A1 - Joshi, Nitin A1 - Yan, Jing A1 - Levy, Seth A1 - Bhagchandani, Sachin A1 - Slaughter, Kai V A1 - Sherman, Nicholas E A1 - Amirault, Julian A1 - Wang, Yufeng A1 - Riegel, Logan A1 - He, Xueyin A1 - Rui, Tan Shi A1 - Valic, Michael A1 - Vemula, Praveen K A1 - Miranda, Oscar R A1 - Levy, Oren A1 - Gravallese, Ellen M A1 - Aliprantis, Antonios O A1 - Ermann, Joerg A1 - Karp, Jeffrey M AB -

Local delivery of therapeutics for the treatment of inflammatory arthritis (IA) is limited by short intra-articular half-lives. Since IA severity often fluctuates over time, a local drug delivery method that titrates drug release to arthritis activity would represent an attractive paradigm in IA therapy. Here we report the development of a hydrogel platform that exhibits disassembly and drug release controlled by the concentration of enzymes expressed during arthritis flares. In vitro, hydrogel loaded with triamcinolone acetonide (TA) releases drug on-demand upon exposure to enzymes or synovial fluid from patients with rheumatoid arthritis. In arthritic mice, hydrogel loaded with a fluorescent dye demonstrates flare-dependent disassembly measured as loss of fluorescence. Moreover, a single dose of TA-loaded hydrogel but not the equivalent dose of locally injected free TA reduces arthritis activity in the injected paw. Together, our data suggest flare-responsive hydrogel as a promising next-generation drug delivery approach for the treatment of IA.

VL - 9 IS - 1 ER -