A single localized dose of enzyme-responsive hydrogel improves long-term survival of a vascularized composite allograft



TRANSPLANTATION

A single localized dose of enzyme-responsive hydrogel improves long-term survival of a vascularized composite allograft

1. Thusitha Gajanayake1,2,*, 
2. Radu Olariu1,2,*, 
3. Franck M. Leclère1,2, 
4. Ashish Dhayani3, 
5. Zijiang Yang4,
6. Anjan K. Bongoni2,5, 
7. Yara Banz6, 
8. Mihai A. Constantinescu1,2, 
9. Jeffrey M. Karp4,†,
10. Praveen Kumar Vemula3,†, 
11. Robert Rieben2,† and 
12. Esther Vögelin1,2

+Author Affiliations

1. ¹Department of Plastic, Reconstructive and Hand Surgery, Bern University Hospital, Inselspital, CH-3010 Bern, Switzerland.
2. ²Department of Clinical Research, University of Bern, CH-3010 Bern, Switzerland.
3. ³Institute for Stem Cell Biology and Regenerative Medicine, National Centre for Biological Sciences Campus, Bangalore 560 065, India.
4. ⁴Division 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.
5. ⁵Graduate School for Cellular and Biomedical Sciences, University of Bern, CH-3010 Bern, Switzerland.
6. ⁶Institute of Pathology, University of Bern, CH-3010 Bern, Switzerland.

+Author Notes

• ↵* These authors contributed equally to this work.

1. ↵†Corresponding author. E-mail: robert.rieben@dkf.unibe.ch (R.R.); praveenv@instem.res.in (P.K.V.);jmkarp@partners.org (J.M.K.)

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.

• Copyright © 2014, American Association for the Advancement of Science

Citation: T. Gajanayake, R. Olariu, F. M. Leclère, A. Dhayani, Z. Yang, A. K. Bongoni, Y. Banz, M. A. Constantinescu, J. M. Karp, P. K. Vemula, R. Rieben, E. Vögelin, A single localized dose of enzyme-responsive hydrogel improves long-term survival of a vascularized composite allograft. Sci. Transl. Med. 6, 249ra110 (2014).

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