title: A single localized dose of enzyme-responsive hydrogel improves long-term survival of a vascularized composite allograft.
abstract: Currently, systemic immunosuppression is used in vascularized composite allotransplantation (VCA). This treatment has considerable side effects and reduces the quality of life of VCA recipients. We loaded the immunosuppressive drug tacrolimus into a self-assembled hydrogel, which releases the drug in response to proteolytic enzymes that are overexpressed during inflammation. A one-time local injection of the tacrolimus-laden hydrogel significantly prolonged graft survival in a Brown Norway-to-Lewis rat hindlimb transplantation model, leading to a median graft survival of >100 days compared to 33.5 days in tacrolimus only-treated recipients. Control groups with no treatment or hydrogel only showed a graft survival of 11 days. Histopathological evaluation, including anti-graft antibodies and complement C3, revealed significantly reduced immune responses in the tacrolimus-hydrogel group compared with tacrolimus only. In conclusion, a single-dose local injection of an enzyme-responsive tacrolimus-hydrogel is capable of preventing VCA rejection for >100 days in a rat model and may offer a new approach for immunosuppression in VCA.
authors.affiliation: Department of Plastic, Reconstructive and Hand Surgery, Bern University Hospital, Inselspital, CH-3010 Bern, Switzerland. Department of Clinical Research, University of Bern, CH-3010 Bern, Switzerland.
authors.forename: Thusitha
authors.initials: T
authors.lastname: Gajanayake
authors.affiliation: Department of Plastic, Reconstructive and Hand Surgery, Bern University Hospital, Inselspital, CH-3010 Bern, Switzerland. Department of Clinical Research, University of Bern, CH-3010 Bern, Switzerland.
authors.forename: Radu
authors.initials: R
authors.lastname: Olariu
authors.affiliation: Department of Plastic, Reconstructive and Hand Surgery, Bern University Hospital, Inselspital, CH-3010 Bern, Switzerland. Department of Clinical Research, University of Bern, CH-3010 Bern, Switzerland.
authors.forename: Franck M
authors.initials: FM
authors.lastname: Leclère
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, National Centre for Biological Sciences Campus, Bangalore 560 065, India.
authors.forename: Ashish
authors.initials: A
authors.lastname: Dhayani
authors.affiliation: Division of Biomedical Engineering and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard-MIT Division of Heath Sciences and Technology, and Harvard Stem Cell Institute, Boston, MA 02139, USA.
authors.forename: Zijiang
authors.initials: Z
authors.lastname: Yang
authors.affiliation: Department of Clinical Research, University of Bern, CH-3010 Bern, Switzerland. Graduate School for Cellular and Biomedical Sciences, University of Bern, CH-3010 Bern, Switzerland.
authors.forename: Anjan K
authors.initials: AK
authors.lastname: Bongoni
authors.affiliation: Institute of Pathology, University of Bern, CH-3010 Bern, Switzerland.
authors.forename: Yara
authors.initials: Y
authors.lastname: Banz
authors.affiliation: Department of Plastic, Reconstructive and Hand Surgery, Bern University Hospital, Inselspital, CH-3010 Bern, Switzerland. Department of Clinical Research, University of Bern, CH-3010 Bern, Switzerland.
authors.forename: Mihai A
authors.initials: MA
authors.lastname: Constantinescu
authors.affiliation: Division of Biomedical Engineering and Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Harvard-MIT Division of Heath Sciences and Technology, and Harvard Stem Cell Institute, Boston, MA 02139, USA. robert.rieben@dkf.unibe.ch praveenv@instem.res.in jmkarp@partners.org.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Karp
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, National Centre for Biological Sciences Campus, Bangalore 560 065, India. robert.rieben@dkf.unibe.ch praveenv@instem.res.in jmkarp@partners.org.
authors.forename: Praveen Kumar
authors.initials: PK
authors.lastname: Vemula
authors.affiliation: Department of Clinical Research, University of Bern, CH-3010 Bern, Switzerland. robert.rieben@dkf.unibe.ch praveenv@instem.res.in jmkarp@partners.org.
authors.forename: Robert
authors.initials: R
authors.lastname: Rieben
authors.affiliation: Department of Plastic, Reconstructive and Hand Surgery, Bern University Hospital, Inselspital, CH-3010 Bern, Switzerland. Department of Clinical Research, University of Bern, CH-3010 Bern, Switzerland.
authors.forename: Esther
authors.initials: E
authors.lastname: Vögelin
mesh_terms: D000818:Animals; D000918:Antibody Specificity / Q000187:drug effects / Q000276:immunology; D015415:Biomarkers / Q000097:blood; D002460:Cell Line; D003167:Complement Activation / Q000187:drug effects; D003165:Complement System Proteins / Q000378:metabolism; D064595:Composite Tissue Allografts / Q000187:drug effects*; D016207:Cytokines / Q000378:metabolism; D004798:Enzymes / Q000494:pharmacology*; D006085:Graft Survival / Q000187:drug effects*; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000737:chemistry / Q000494:pharmacology*; D056724:Immunity, Humoral / Q000187:drug effects; D007249:Inflammation / Q000473:pathology; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D051381:Rats; D012867:Skin / Q000187:drug effects / Q000378:metabolism; D016559:Tacrolimus / Q000097:blood / Q000494:pharmacology; D013997:Time Factors; D014280:Triglycerides / Q000737:chemistry
chemical_list: D015415:Biomarkers; D016207:Cytokines; D004798:Enzymes; D014280:Triglycerides; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; D003165:Complement System Proteins; D016559:Tacrolimus