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

Transplantation. 2018 Oct;102(10):1684-1694. doi: 10.1097/TP.0000000000002283.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcineurin Inhibitors / administration & dosage*
  • Composite Tissue Allografts / drug effects
  • Composite Tissue Allografts / immunology
  • Composite Tissue Allografts / pathology
  • Composite Tissue Allografts / transplantation
  • Disease Models, Animal
  • Drug Carriers / chemistry*
  • Graft Rejection / immunology
  • Graft Rejection / pathology
  • Graft Rejection / prevention & control*
  • Graft Survival / drug effects
  • Graft Survival / immunology
  • Hindlimb / transplantation
  • Humans
  • Hydrogels / chemistry
  • Immunosuppression Therapy / adverse effects*
  • Immunosuppression Therapy / methods
  • Injections, Intralesional
  • Injections, Subcutaneous
  • Male
  • Rats
  • Rats, Inbred BN
  • Rats, Inbred Lew
  • Tacrolimus / administration & dosage*
  • Vascularized Composite Allotransplantation / adverse effects*


  • Calcineurin Inhibitors
  • Drug Carriers
  • Hydrogels
  • Tacrolimus