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Local Injections of Tacrolimus-loaded Hydrogel Reduce Systemic Immunosuppression-related Toxicity in Vascularized Composite Allotransplantation

Dzhonova, Dzhuliya V., PhD1,2; Olariu, Radu, MD3; Leckenby, Jonathan, MD3; Banz, Yara, MD, PhD4; Prost, Jean-Christophe, PhD5; Dhayani, Ashish, MSc6,7; Vemula, Praveen K., PhD6; Voegelin, Esther, MD3; Taddeo, Adriano, PhD1,3; Rieben, Robert, PhD1

doi: 10.1097/TP.0000000000002283
Original Basic Science—General

Background Routine application of vascularized composite allotransplantation is hampered by immunosuppression-related health comorbidities. To mitigate these, we developed an inflammation-responsive hydrogel for local immunosuppression. Here, we report on its long-term effect on graft survival, immunological, and toxicological impact.

Methods Brown Norway-to-Lewis rat hindlimb transplantations were treated either systemically with daily injections of 1 mg/kg tacrolimus (TAC) or with subcutaneous intragraft injections of hydrogel containing 7 mg TAC, every 70 days. Animals were monitored for rejection or other pathology for 280 days. Systemic and graft TAC levels, regulatory T cells, and donor cell chimerism were measured periodically. At endpoint, markers for kidney, liver, and metabolic state were compared to naive age-matched rats.

Results Both daily systemic TAC and subcutaneous intragraft TAC hydrogel at 70-day intervals were able to sustain graft survival longer than 280 days in 5 of 6 recipients. In the hydrogel group, 1 graft progressed to grade 3 rejection at postoperative day 149. In systemic TAC group, 1 animal was euthanized due to lymphoma on postoperative day 275. Hydrogel treatment provided stable graft and reduced systemic TAC levels, and a 4 times smaller total TAC dose compared with systemic immunosuppression. Hydrogel-treated animals showed preserved kidney function, absence of malignancies or opportunistic infections and increased hematopoietic chimerism compared with systemic immunosuppression.

Conclusions Our findings demonstrate that localized immunosuppression with TAC hydrogel is a long-term safe and reliable treatment. It may reduce the burden of systemic immunosuppression in vascularized composite allotransplantation, potentially boosting the clinical application of this surgical intervention.

Dzhonova et al document the ability of locally delivered tacrolimus within hydrogels, every 70 days, to sustain allogeneic hind limb survival in a Brown Norway-to-Lewis rat model. Local delivery reduced systemic tacrolimus levels and drug toxicity compared to daily injections.

1 Department for BioMedical Research, University of Bern, Bern, Switzerland.

2 Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.

3 Clinic of Plastic and Hand Surgery, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland.

4 Institute of Pathology, University of Bern, Bern, Switzerland.

5 Center of Laboratory Medicine, University Institute of Clinical Chemistry, University Hospital, Bern, Switzerland.

6 Institute for Stem Cell Biology and Regenerative Medicine, Bangalore, India.

7 The School of Chemical and Biotechnology, SASTRA University, Tamil Nadu, India.

Received 28 January 2018. Revision received 12 March 2018.

Accepted 7 April 2018.

This work was supported by Indo-Swiss Joint Research Program of the Swiss National Science Foundation (SNF, grant 156773) and the Department of Science and Technology, Govt. of India (grant INT/SWISS/SNSFP-51/2015) to R.R., E.V. and P.K.V., respectively. A.D. thanks the University Grant Commission for the senior research fellowship.

The authors declare no conflicts of interest.

D.V.D. performed and analyzed the in vivo experiments, flow cytometry, TGMS-TAC hydrogel preparation, DSA analyses. R.O. and J.L. designed and performed the hindlimb transplantations. Y.B. performed and analyzed the histopathological evaluations. J.-C.P. performed the tissue TAC analyses. A.D. and P.K.V. designed and developed the TGMS-TAC hydrogel. D.V.D., A.T., and R.R. wrote the article. E.V., P.K.V., A.T. and R.R. designed and supervised the studies, and reviewed the article.

Correspondence: Adriano Taddeo, PhD, Department for BioMedical Research, University of Bern, Murtenstrasse, 50 3008, Bern Switzerland. (; Robert Rieben, PhD, Department for BioMedical Research, University of Bern, Murtenstrasse, 50 3008, Bern, Switzerland. (

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