TABLE 2.
Overview of Interventions, Immunosuppressive Strategies and Outcomes of studies included.
| Author and year | Interventions | Immunosuppresion | Outcomes | Complications |
|---|---|---|---|---|
| Barone et al. [23] | Bone marrow transplantation | Low-dose total body irradiation (100cGy 2 days prior to surgery or 200cGy divided in 2 × 100 cGy doses on preoperative day 2 and 3), T-cell depletion wirh CD3-IT (0.05 mg/kg), CXA (target level 400–800 ng/mL), donor bone marrow cells (7.8 × 108 to 4 × 109 cells/kg of recipient body weight) | Bone marrow infusion led to better clinical outcomes; chimerism detected but insufficient for tolerance | Mixed chimerism after bone marrow transplantat; VCA appeared insufficient for tolerance induction |
| Berkane et al. [33] | Two study groups: supercooling intervention group and cold storage control group undergoing subsequent normothermic machine perfusion | No immunosuppressive therapy used | Supercooled VCAs restored vascular flow and had lower resistance during machine perfusion | N/A |
| Blades et al., 2024 [43] | Investigation of possible surgical complications | No immunosuppressive therapy used | All flaps survived initially, with adequate perfusion for 4 days. Flap rejection occurred between POD 5 and POD 9 in all animals | Minimal erythema observed post-transplant, no surgery-related deaths or infections |
| Elgendy et al. [26] | Treatment with Co-stimulation blockade and mTOR inhibitor, with or without preceding short-term calcineurin inhibitor therapy | mTOR inhibitor (rapamycin [0.02–0.2 mg/kg] or tacrolimus [0.1–0.125 mg/kg]) | TAC delayed AR (grade-I AR on POD 30, grade-IV on POD 74); rapid rejection with rapamycin (grade-I AR by POD 2 and 7, grade-IV AR by POD 17–20) | Rejection of allograft, erythema, severe necrotizing T cell mediated rejection with deep dermal arterial thrombosis |
| Fries et al. [35] | Tacrolimus eluting hydrogel implants with various concentrations (91 mg, high dose/49 mg, low dose) | Graft-implanted enzyme-responsive, TAC eluting hydrogel platform | Low-dose TAC prolonged survival; high-dose TAC caused poor tolerance (grade IV AR from POD 56–93) | High dose TAC group: one sample excluded due to flap failure on POD 1; four animals showed poor feeding and weight loss, requiring early euthanasia; four animals from high dose TAC group developed pancreatitis |
| Ibrahim et al. [36] | Development of novel tranlational VCA research model | Short-term tacrolimus monotherapy (target levels of 10–15 ng/mL) with or without bone marrow infusion | Long-term graft survival (>150 days) with viable vascularized bone marrow; successful immune monitoring | Venous thrombus in one case resolved by reanastomosis, no graft-versus-host disease |
| Kim et al. [25] | Treatment with tacrolimus for 30 days and ASC therapy (donor-derived ASCs [1.0 × 10^6 cells/kg]) | TAC, ASC-therapy | Adipose-derived stem cells demonstrated grade IV AR on POD 119 and rejection-free survival over POD 200 as well as upregulated T-regulatory cells | The control group reached Banff grade 4 acute rejection by an average of 7.5 days after transplantation. Allografts treated with ASCs demonstrated grade 4 rejection on day 119 |
| Kotsougiani et al. [28] | AV-bundle implantation in tibial allotransplant | TAC (target levels of 5–30 ng/mL), MMF (target levels of 1–3.5 ng/mL), MPDN (tapered to 0.1 mL) | Micro-CT showed bone formation and remodeling at the distal allograft junction; allograft survived without any healing problems or limited hindlimb perfusion during the 4-month follow-up | N/A |
| Kuo et al. [29] | Treatment with various dosages of mesenchymal stem cells, CXA, bone marrow transplantation and irradiation | Irradiation, bone marrow trnsplantation and CXA | Mesenchymal cells extended graft survival, combined CXA and stem cells showed significantly better survival, allografts with CXA exhibited delayed AR, examination of bromodeoxyuridine-labeled mesenchymal stem cells revealed donor mesenchymal stem cells engraftment into the recipient and donor skin | Graft-versus-host disease evident in CXA group |
| Kuo et al. [29] | Comparison of rejection in untreated, control and CXA-treatment groups | CXA in treatment group, untreated and control: N/A | 100% survival rate, CXA treatment delayed flap rejection significantly (POD 38-49), no significant difference in rejection signs in allo-cartilage | Swelling for 2 weeks (postoperative saliva gland hypersecretion), control group: progressive rejection by POD 7-28, lymphoid gland tissue and skin were susceptible to early rejection |
| Kuo et al. [30] | Various combinations of mesenchymal stem cells cyclosporine or irradiation | Mesenchymal stem cells, CXA, irradiation | Mesenchymal stem cells with irradiation and CXA: significantly increased allograft survival compared with other groups (>120 days; p < 0.01); histology showed lowest degree of AR in grafted skin and interstitial muscle layers in mesenchymal stem cell/irradiation/CXA group; significant increase in percentage of CD4+/CD25+ and CD4+/FoxP3+ T in the mesenchymal stem cell/irradiation/CXA group | Rejection episodes |
| Kuo et al. [31] | Various dosages of ASCs, tacrolimus or irradiation | TAC, irradiation | Multiple injections of adipose-derived stem cells, irradiation and TAC increased allograft survival significantly | Lymphocyte infiltration in the alloskin and interstitial muscle layers of treatment group |
| Leonard et al. [24] | Stem cell transfusion | 100 cGy irradiation, T cell depletion with CD3-IT (50 μg/kg), hematopoietic cell transplantation (15 × 109 cells/kg) | Following withdrawal of immunosuppression both VCAs transplanted into stable chimeras Recipients of hematopoietic cell transplantation displayed no clinical signs of AR up to POD 504 |
Two animals developed skin graft versus host disease |
| Mathes et al. [32] | Treatment with CXA and bone marrow transplantation (2 × 109 cells/kg) | CXA (target levels of 400–800 ng/mL) | Donor cell engraftment and multilineage macro chimerism after in utero transplantation of adult bone marrow cells, and chimeric animals were unresponsive to donor antigens in vitro; both control VCAs rejected by POD 21; chimeric animals accepted VCAs (no DSAs or alloreactivity) | All grafts demonstrated some mild lymphocytic infiltration at the day 7 biopsy. All of the animals developed a severe dermal perivascular lymphocytic infiltration with scattered eosinophils and went on to reject their donor skin grafts |
| Park et al. [44] | Vascular anastomosis of the carotid artery and jugular vein, fixation of the maxillo-mandibular complex with titanium plates | No immunosuppressive therapy used | Successful transplant without early arterial or venous insufficiency, acute rejection from POD 7-8 onwards | Acute rejection POD 7-8, pink discoloration, edema, erythematous papule with flap necrosis on POD 14–18 |
| Shanmugarajah et al. [38] | Hematopoietic stem cell transplantant, irradiation | T cell depletion with CD3-IT (50 μg/kg), 100 cGy TBI and 45 days of CXA (target levels of 400–800 ng/mL) | HC class II–mismatched chimeras were tolerant of VCAs; HC class I–mismatched animals rejected VCA skin, (infiltration of CD8+ lymphocytes) |
One HC class II mismatched model displayed clinical features of chronic graft versus host disease (euthanized on POD 190) |
| Tratnig-Frankl et al. [39] | Treatment with either saline (control), sodium iodide (NaI), or hydrogen sulfide (H2S) injections | No postoperative immunosuppression | No effect of H2S or NaI treatment in comparison to NaCl in delaying AR, flap survival and histology revealed no significant differences between the groups | One technical failure occurred in the saline MISMATCH subgroup |
| Wachtman et al. [27] | Bone marrow infusion and irradiation | Total body (100 cGy) and thymic (700 cGy) irradiation, bone marrow infusion, tacrolimus (0.1 mg/kg/day), CTLA4-Ig (20 mg/kg) | Experimental groups rejected allografts (skin and muscle) on POD 5 to 30; skin and muscle histology in all long-term survivors were normal | Rejection episodes |
| Waldner et al. [40] | Investigation of VRAM flap applicability in VCA research | TAC, rapamycin, CTLA4-Ig | POD 5: all grafts demonstrated pale-pink skin color without edema; follow-up showed improved correlation between clinical appearance and progression of graft rejection in histology |
Intraoperative cardiac arrest in one sample (death due to anesthesia); one recipient experienced flap loss due to venous compromise; Banff grade I AR with erythemous and edematous grafts |
| Wang et al. [45] | Treatment with sub-normothermic ex-vivo perfusion using hyper-oxygenated University of Wisconsin (UW) solution | No immunosuppressive therapy used | Experimental group showed significantly later onset of grade 1 AR at 13.7 days (SD = 0.52, p < 0.05); by POD 15 75% of the flaps showed no evidence of grade 4 AR | Rejection episodes |
| Wu et al. [42] | Treatment with various dosages (28 mg/4cc and 49 mg/4cc) of tacrolimus-eluting hydrogel injected into the donor flap | TAC-eluting hydrogel (28 mg/4cc and 49 mg/4cc) | TAC-eluting hydrogel prolonged graft survival in both groups (grade 4 AR on average by POD 20 and 28) | Rejection episodes |
| Zhang et al. [34] | Treatment with various combinations of TGMS and TAC | Locally administered TAC-loaded on-demand drug delivery system | Repeated intra-graft TGMS-TAC administrations prolong graft survival | Grade III-IV rejection |
MGH, Massachusetts General Hospital; SLA, Swine leukocyte antigen; HC, histocompatibility complex; MHC, major histocompatibility complex; VCA, vascularized composite allotransplant; SH, single haplotype; PAA, pig allelic antigen; CS, Cold Storage; TAC, tacrolimus; MMF, Mycophenolate Mofetil; MPDN, Methylprednisolone; CXA, cyclosporine A; CD3-IT, CD3-Immunotoxin; (CTLA4-Ig), cytotoxic T-lymphocyte antigen 4 immunoglobulin; POD, postoperative day; AR, acute rejection; DSAs, donor specific antibodies; N/A, not applicable; TGMS, triglycerol monostearate; VRAM, vertical rectus abdominus myocutaneous flap; ASC, adipose-derived stem cell; AV, arteriovenous.