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

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.

%B PLoS One %V 14 %P e0210914 %8 2019 %G eng %N 1 %R 10.1371/journal.pone.0210914 %0 Book Section %B Metal Allergy: From Dermatitis to Implant and Device Failure %D 2018 %T Prevention of Metal Exposure: Chelating Agents and Barrier Creams %A Mahato, Manohar %A Sherman, Nicholas E. %A Kiran Kumar Mudnakudu, N. %A Joshi, Nitin %A Briand, Elisabeth %A Karp, Jeffrey M. %A Vemula, Praveen Kumar %E Chen, Jennifer K %E Thyssen, Jacob P. %X

Metals are a group of elements which are ubiquitous in modern life. They are used in the fields of cosmetics, water purification, medicine, paint, food products, pesticides, and almost innumerable others. As the use of metals has increased in recent decades, so has human exposure to these elements. Metals such as mercury, lead, arsenic, nickel, and others have been implicated in negatively affecting human homeostasis by causing chronic inflammatory diseases, among other serious conditions. Both acute and chronic metal toxicity in vital organs could arise from local or systemic exposure to numerous metals. Although some metals have health benefits, overaccumulation of metals in body tissues can result in deleterious, toxic effects. Most exposure to metals occurs via cutaneous, inhalation, or oral routes. At the highest risk of negative effects of exposure are pregnant women and children. To ameliorate or prevent the toxic effects of metals, chelating agents and barrier creams are used widely in medical practice today. In this chapter, we will discuss preventing metal toxicity from overexposure via chelation therapy and skin barrier creams.

%B Metal Allergy: From Dermatitis to Implant and Device Failure %I Springer International Publishing %C Cham %P 227–246 %@ 978-3-319-58503-1 %G eng %U https://doi.org/10.1007/978-3-319-58503-1_18 %R 10.1007/978-3-319-58503-1_18 %0 Journal Article %J Nat Commun %D 2018 %T Towards an arthritis flare-responsive drug delivery system. %A Joshi, Nitin %A Yan, Jing %A Levy, Seth %A Bhagchandani, Sachin %A Slaughter, Kai V %A Sherman, Nicholas E %A Amirault, Julian %A Wang, Yufeng %A Riegel, Logan %A He, Xueyin %A Rui, Tan Shi %A Valic, Michael %A Vemula, Praveen K %A Miranda, Oscar R %A Levy, Oren %A Gravallese, Ellen M %A Aliprantis, Antonios O %A Ermann, Joerg %A Karp, Jeffrey M %X

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.

%B Nat Commun %V 9 %P 1275 %8 2018 Apr 03 %G eng %N 1 %R 10.1038/s41467-018-03691-1