hickman-catheter-use-for-long-term-vascular-access-preclinical-swine

Hickman Catheter Use for Long-Term Vascular Access in a Preclinical Swine Model

Central venous catheters (CVCs) are invaluable devices in large animal research as they facilitate a wide range of medical applications, including blood ...

Johns Hopkins University School of Medicine

Over eighty million people in the United States have cardiovascular disease that can affect the heart causing myocardial infarction; the carotid arteries causing stroke; and the lower extremities leading to amputation. The treatment for end-stage cardiovascular disease is surgical-either endovascular therapy with balloons and stents-or open reconstruction to reestablish blood flow. All interventions damage or destroy the protective inner lining of the blood vessel-the endothelium. An intact endothelium is essential to provide a protective; antithrombotic lining of a blood vessel. Currently; there are no agents used in the clinical setting that promote reendothelialization. This process requires migration of endothelial cells to the denuded vessel; proliferation of endothelial cells on the denuded vessel surface; and the reconstitution of the tight adherence junctions responsible for the formation of an impermeable surface. These processes are all regulated in part and are dependent on small GTPases. As important as the small GTPases are for reendothelialization, dysregulation of these molecules can result in various vascular pathologies including aneurysm formation, atherosclerosis, diabetes, angiogenesis, and hypertension. A better understanding of the role of small GTPases in endothelial cell migration is essential to the development for novel agents to treat vascular disease.

Small GTPases and Their Role in Vascular Disease.

We herein investigate the safety and efficacy of single-agent anti-rejection regimens in a mouse vascularized composite allotransplantation (VCA) model. Orthotopic hind-limb transplantations (Balb/c → C57BL/6) were performed using 6- to 8-week-old mice. A thirty-day regimen of either rapamycin, tacrolimus (both 1, 3, 5 mg/kg/day) or cyclosporine (25, 35, 50 mg/kg/day) was used. Primary endpoints were animal and graft survival, and secondary chimerism and regulatory T-cell levels. For rapamycin and tacrolimus given at 1, 3, and 5 mg/kg/day, median graft survival time (MST) was 23 days (18-28 days), 30 days (23-30 days), and 30 d (30-30 days) and 14 days (13-18 days), 30 days (16-30 days), and 30 days (30-30 days), respectively. For cyclosporine dosed at 25 and 35 mg/kg/day, MST was 15 days (12-18 days) and 21 days (14-27 days). Toxicity from CsA 50 mg/kg led to 100% mortality. Mixed chimerism levels were higher in rapamycin-treated animals than in tacrolimus-treated recipients (P = 0.029). Tacrolimus was superior in preventing leukocyte recruitment to the allograft. In murine VCA, no standardized immunosuppressive regimen exists, limiting comparability of outcomes and survival. Our data demonstrate that rapamycin and tacrolimus maintenance treatment at 5 mg/kg/day both yielded allograft survival (<grade 3 rejection) in all animals. Rapamycin displayed less toxicity and maintained mixed chimerism but was not as potent in controlling leukocyte recruitment compared with tacrolimus.

Efficacy of single-agent immunosuppressive regimens in a murine model of vascularized composite allotransplantation.

To summarize the evolution of skin xenotransplantation and contextualize technological advances and the status of clinically applicable large animal research as well as prospects for translation of this work as a viable future treatment option.

Skin xenotransplantation: technological advances and future directions.

In vascularized composite allotransplantation (VCA), invasive tissue biopsies remain the gold standard in diagnosing rejection carrying significant morbidity. We aimed to show feasibility of tape-stripping for noninvasive immune monitoring in VCA. Tape-stripping was performed on allografts and native skin of upper extremity transplant recipients. Healthy nontransplanted individuals served as controls. The technique was also used in swine on naïve skin in nontransplanted animals, native skin of treated, transplanted swine, nonrejecting VCAs, and rejecting VCAs. Extracted protein was analyzed for differences in cytokine expression using Luminex technology. Significantly decreased levels of INFγ and IL-1Ra were seen between human allograft samples and native skin. In swine, rejecting grafts had increased IL-1Ra compared to naïve and native skin, decreased levels of GM-CSF compared to native skin, and decreased IL-10 compared to nonrejecting grafts. Unsupervised hierarchical clustering revealed rejecting grafts separated from the nonrejecting (P = 0.021). Variable importance in projection scores identified GM-CSF, IL-1Ra, and IL-2 as the most important profiles for group discrimination. Differences in cytokine expression are detectable in human VCA patient native skin and VCA graft skin using a noninvasive tape-stripping method. Swine studies suggest that differences in cytokines between rejecting and nonrejecting grafts are discernable.

Noninvasive evaluation of intragraft immune responses in upper extremity transplantation.

Given the multifunctional role of the penis in daily life, penile loss can be a physically and emotionally devastating injury. Options to restore penile loss have traditionally relied on autogenous free flap, local flaps, and skin grafts. These techniques provide satisfactory outcomes but carry high rates of urologic and prosthesis-related complications. Vascularized composite allotransplantation may offer a novel solution for these patients through reconstruction with true penile tissue. Still, penile transplants pose ethical, logistical, and psychosocial challenges. These obstacles are made more complex by the limited cases detailed in published literature. A review of the literature was conducted to assay current practices for penile reconstruction. Most modern complex penile reconstructions utilize autogenous pedicled or free tissue flaps, which may be harvested from a variety of donor sites. A total of five penile transplants have been described in the literature. Of these, four report satisfactory outcomes. The advent of genital allotransplantation has recently broadened the landscape of treatment for penile loss. Reconstruction using true penile tissue through vascularized penile allotransplantation has the possibility to engender increased penile function, sensation, and overall quality of life.

Article	Year
Small GTPases and Their Role in Vascular Disease. International journal of molecular sciences\| PubMed ID: 30791562	2019
Efficacy of single-agent immunosuppressive regimens in a murine model of vascularized composite allotransplantation. Transplant international : official journal of the European Society for Organ Transplantation\| PubMed ID: 32299127	2020
Skin xenotransplantation: technological advances and future directions. Current opinion in organ transplantation\| PubMed ID: 32773504	2020
Noninvasive evaluation of intragraft immune responses in upper extremity transplantation. Transplant international : official journal of the European Society for Organ Transplantation\| PubMed ID: 33626223	2021
Vascularized composite allotransplantation of the penis: current status and future perspectives. International journal of impotence research\| PubMed ID: 34711953	2022

Richa Kalsi

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