A Porcine Orthotopic Forelimb Vascularized Composite Allotransplantation Model: Technical Considerations and Translational Implications

Fries, C. Anton; Villamaria, Carole Y.; Spencer, Jerry R.; Rickard, Rory F.; Gorantla, Vijay S.; Davis, Michael R.

doi:10.1097/prs.0000000000002451

Cited by 11 publications

(11 citation statements)

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“…Base deficit is a common feature of VCA perfusion and is intrinsically linked to acidosis 10 . To combat this, bicarbonate is often supplemented as a bolus at the start of perfusion, with continuous infusions and additional boluses to control base deficit 11‐18 . Bicarbonate supplementation rapidly stabilizes base, but often into base excess, which in turn may be reduced via increasing CO 2 concentrations in the circuit oxygenator.…”

Section: Discussionmentioning

confidence: 99%

“…10 To combat this, bicarbonate is often supplemented as a bolus at the start of perfusion, with continuous infusions and additional boluses to control base deficit. [11][12][13][14][15][16][17][18] Bicarbonate supplementation rapidly stabilizes base, but often into base excess, which in turn may be reduced via increasing CO 2 concentrations in the circuit oxygenator. The relationship between CO 2 , bicarbonate, lactate, glucose and pH is highly complex, as acidosis drives electrolytes from the muscle leading to hyperkalemia.…”

Section: Discussionmentioning

confidence: 99%

“…This technology is being rapidly adopted into the clinical setting for solid organ transplantation, with several studies demonstrating superior outcomes compared to SCS 8,9 . However, the application of this technology in VCA has been purely experimental to date, with several groups developing perfusion protocols for VCA preservation 10‐17 . We have recently reported that normothermic perfusion results in superior graft preservation and less reperfusion injury compared with SCS in a large animal model 10 .…”

Section: Introductionmentioning

confidence: 99%

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Renal hemofiltration prevents metabolic acidosis and reduces inflammation during normothermic machine perfusion of the vascularized composite allograft: A preclinical study

et al. 2021

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Introduction:Recent experimental evidence suggests normothermic machine perfusion of the vascularized composite allograft results in improved preservation compared to static cold storage, with less reperfusion injury in the immediate post-operative period. However, metabolic acidosis is a common feature of vascularized composite allograft perfusion, primarily due to the inability to process metabolic by-products. We evaluated the impact of combined limb-kidney perfusion on markers of metabolic acidosis and inflammation in a porcine model. Methods:Ten paired pig forelimbs were used for this study, grouped as either limb-only (LO, n = 5) perfusion, or limb-kidney (LK, n = 5) perfusion. Infrared thermal imaging was used to determine homogeneity of perfusion. Lactate, bicarbonate, base, pH, and electrolytes, along with an inflammatory profile generated via the quantification of cytokines and cell-free DNA in the perfusate were recorded. Results:The addition of a kidney to a limb perfusion circuit resulted in the rapid stabilization of lactate, bicarbonate, base, and pH. Conversely, the LO This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Renal hemofiltration prevents metabolic acidosis and reduces inflammation during normothermic machine perfusion of the vascularized composite allograft: A preclinical study

et al. 2021

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“…This protocol utilized an orthotopic, fully weight-bearing porcine forelimb VCA model that was developed by our group and previously published [13]. Salient procedural details are summarized as follows:…”

Section: Methodsmentioning

confidence: 99%

“…They have also demonstrated the utility of this platform in other diseases associated with over expression of MMPs and other enzymes [11,12]. This proof of concept study was designed to determine the tolerability and efficacy of the TAC delivery platform in a stringent, pre-clinical large animal (porcine), mismatched, orthotopic forelimb VCA model [13]. Specifically, we evaluated the tolerability and efficacy of two different doses of TAC-loaded TGMS hydrogel in porcine VCA.…”

Section: Introductionmentioning

confidence: 99%

Graft-implanted, enzyme responsive, tacrolimus-eluting hydrogel enables long-term survival of orthotopic porcine limb vascularized composite allografts: A proof of concept study

et al. 2019

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BackgroundCurrently, patients receiving vascularized composite allotransplantation (VCA) grafts must take long-term systemic immunosuppressive therapy to prevent immunologic rejection. The morbidity and mortality associated with these medications is the single greatest barrier to more patients being able to receive these life-enhancing transplants. In contrast to solid organs, VCA, exemplified by hand or face transplants, allow visual diagnosis of clinical acute rejection (AR), directed biopsy and targeted graft therapies. Local immunosuppression in VCA could reduce systemic drug exposure and limit adverse effects. This proof of concept study evaluated, in a large animal forelimb VCA model, the efficacy and tolerability of a novel graft-implanted enzyme-responsive, tacrolimus (TAC)—eluting hydrogel platform, in achieving long-term graft survival.MethodsOrthotopic forelimb VCA were performed in single haplotype mismatched mini-swine. Controls (n = 2) received no treatment. Two groups received TAC hydrogel: high dose (n = 4, 91 mg TAC) and low dose (n = 4, 49 mg TAC). The goal was to find a dose that was tolerable and resulted in long-term graft survival. Limbs were evaluated for clinical and histopathological signs of AR. TAC levels were measured in serial blood and skin tissue samples. Tolerability of the dose was evaluated by monitoring animal feeding behavior and weight.ResultsControl limbs underwent Banff Grade IV AR by post-operative day six. Low dose TAC hydrogel treatment resulted in long-term graft survival time to onset of Grade IV AR ranging from 56 days to 93 days. High dose TAC hydrogel also resulted in long-term graft survival (24 to 42 days), but was not well tolerated.ConclusionGraft-implanted TAC-loaded hydrogel delays the onset of Grade IV AR of mismatched porcine forelimb VCA grafts, resulting in long term graft survival and demonstrates dose-dependent tolerability.

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Orthotopic forelimb transplantation in a Yucatan minipig model: Anatomic and in vivo study

Figueroa,

Ordenana,

Rezaei

et al. 2024

Microsurgery

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IntroductionAbove elbow transplants represent 19% of the upper extremity transplants. Previous large‐animal models have been too distal or heterotopic, did not use immunosuppression and had short survival. We hypothesize that an orthotopic forelimb transplant model, under standard immunosuppression, is feasible and can be used to address questions on peri‐transplant ischemia reperfusion injury, and post‐transplantation vascular, immunologic, infectious, and functional outcomes.Materials and methodsFour forelimbs were used for anatomical studies. Four mock transplants were performed to establish technique/level of muscle/tendon repairs. Four donor and four recipient female Yucatan minipigs were utilized for in‐vivo transplants (endpoint 90‐days). Forelimbs were amputated at the midarm and preserved through ex vivo normothermic perfusion (EVNP) utilizing an RBC‐based perfusate. Hourly perfusate fluid‐dynamics, gases, electrolytes were recorded. Contractility during EVNLP was graded hourly using the Medical Research Council scale. EVNP termination criteria included systolic arterial pressure ≥115 mmHg, compartment pressure ≥30 mmHg (at EVNP endpoint), oxygen saturation reduction of 20%, and weight change ≥2%. Indocyanine green (ICG) angiography was performed after revascularization. Limb rejection was evaluated clinically (rash, edema, temperature), and histologically (BANFF classification) collecting per cause and protocol biopsies (POD 1, 7, 30, 60 and endpoint). Systemic infections were assessed by blood culture and tissue histology. CT scan was used to confirm bone bridging at endpoint.ResultsAnimals 2, 4 reached endpoint with grade 0‐I rejection. Limbs 1, 3 presented grade III rejection on days 6, 61. CsA troughs averaged 461 ± 189 ng/mL. EVNLP averaged 4.3 ± 0.52 h. Perfusate lactate, PO2, and pH were 5.6 ± 0.9 mmol/L, 557 ± 72 mmHg and 7.5 ± 0.1, respectively. Muscle contractions were 4 [1] during EVNLP. Transplants 2, 3, 4 showed bone bridging on CT.ConclusionWe present preliminary evidence supporting the feasibility of an orthotopic, mid‐humeral forelimb allotransplantation model under standard immunosuppression regimen. Further research should validate the immunological, infectious, and functional outcomes of this model.

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A Porcine Orthotopic Forelimb Vascularized Composite Allotransplantation Model: Technical Considerations and Translational Implications

Cited by 11 publications

References 35 publications

Renal hemofiltration prevents metabolic acidosis and reduces inflammation during normothermic machine perfusion of the vascularized composite allograft: A preclinical study

Renal hemofiltration prevents metabolic acidosis and reduces inflammation during normothermic machine perfusion of the vascularized composite allograft: A preclinical study

Graft-implanted, enzyme responsive, tacrolimus-eluting hydrogel enables long-term survival of orthotopic porcine limb vascularized composite allografts: A proof of concept study

Orthotopic forelimb transplantation in a Yucatan minipig model: Anatomic and in vivo study

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