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A Modified Heterotopic Swine Hind Limb Transplant Model for Translational Vascularized Composite Allotransplantation (VCA) Research

Vascularized Composite Allotransplantation (VCA) such as hand and face transplants represent a viable treatment option for complex musculoskeletal trauma ...

Johns Hopkins University School of Medicine

Which patients first? Planning the first clinical trial of xenotransplantation: a case for cardiac bridging.

The availability of pigs homozygous for alpha1,3-galactosyltransferase gene-knockout (GT-KO) has enabled study of the incidence and cytotoxicity of primate antibodies directed to antigens other than Galalpha1,3Gal (Gal), termed non-Gal antigens.

Allosensitized humans are at no greater risk of humoral rejection of GT-KO pig organs than other humans.

As pigs homozygous for alpha1,3-galactosyltransferase gene-knockout (GT-KO) are available, primate antibodies to pig non-Gal antigens can be studied.

Antibodies directed to pig non-Gal antigens in naÃ¯ve and sensitized baboons.

The shortage of donor organs is a major barrier to clinical organ transplantation. Although xenotransplantation is considered one of the alternatives to human organ transplantation, there are immunologic and physiologic incompatibilities between humans and pigs. With the exception of coagulation, the major potential physiologic incompatibilities relating to function of the kidney, heart, liver, lungs, pancreatic islets, and hormones are reviewed. Some of these physiologic differences can be overcome by producing genetically altered pigs to improve compatibility with humans. The possibility of producing such pigs for organ transplantation is considered.

Selected physiologic compatibilities and incompatibilities between human and porcine organ systems.

Some chromosomal alterations can be associated with vascular abnormalities. For instance, Turner syndrome can be complicated by agenesis or hypoplasia of the portal venous system causing presinusoidal portal hypertension. Liver transplantation to treat this condition overcomes portal hypertension and reconstitutes the diminished hepatic function due to severe atrophy of the portal venous inflow.

Cruveilhier-Baumgarten disease in a patient with Turner syndrome: case report of a rare indication for liver transplantation.

To report a case of a woman with poorly controlled hypertension who was found to have multiple paragangliomas and mutation in the B subunit of succinate dehydrogenase (mitochondrial complex II).

Familial paragangliomas: case report and literature review.

Survival benefit of cytoreductive surgery combined with hyperthermic intraperitoneal chemoperfusion was demonstrated by a prospective randomized trial for colorectal peritoneal carcinomatosis. Because of a recent substantial improvement in chemotherapy, the authors analyzed treatment options of colorectal carcinomatosis in the current era.

Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion versus systemic chemotherapy alone for colorectal peritoneal carcinomatosis.

The authors describe the development of an ultrafast three-dimensional (3D) optical coherence tomography (OCT) imaging system that provides real-time intraoperative video images of the surgical site to assist surgeons during microsurgical procedures. This system is based on a full-range complex conjugate free Fourier-domain OCT (FD-OCT). The system was built in a CPU-GPU heterogeneous computing architecture capable of video OCT image processing. The system displays at a maximum speed of 10 volume/s for an image volume size of 160 Ã— 80 Ã— 1024(X Ã— Y Ã— Z) pixels. We have used this system to visualize and guide two prototypical microsurgical maneuvers: microvascular anastomosis of the rat femoral artery and ultramicrovascular isolation of the retinal arterioles of the bovine retina. Our preliminary experiments using 3D-OCT-guided microvascular anastomosis showed optimal visualization of the rat femoral artery (diameter<0.8 mm), instruments, and suture material. Real-time intraoperative guidance helped facilitate precise suture placement due to optimized views of the vessel wall during anastomosis. Using the bovine retina as a model system, we have performed "ultra microvascular" feasibility studies by guiding handheld surgical micro-instruments to isolate retinal arterioles (diameter ~0.1 mm). Isolation of the microvessels was confirmed by successfully passing a suture beneath the vessel in the 3D imaging environment.

Real-time three-dimensional Fourier-domain optical coherence tomography video image guided microsurgeries.

Vascular and microvascular anastomoses are critical components of reconstructive microsurgery, vascular surgery, and transplant surgery. Intraoperative surgical guidance using a surgical imaging modality that provides an in-depth view and three-dimensional (3-D) imaging can potentially improve outcome following both conventional and innovative anastomosis techniques. Objective postoperative imaging of the anastomosed vessel can potentially improve the salvage rate when combined with other clinical assessment tools, such as capillary refill, temperature, blanching, and skin turgor. Compared to other contemporary postoperative monitoring modalities--computed tomography angiograms, magnetic resonance (MR) angiograms, and ultrasound Doppler--optical coherence tomography (OCT) is a noninvasive high-resolution (micron-level), high-speed, 3-D imaging modality that has been adopted widely in biomedical and clinical applications. For the first time, to the best of our knowledge, the feasibility of real-time 3-D phase-resolved Doppler OCT (PRDOCT) as an assisted intra- and postoperative imaging modality for microvascular anastomosis of rodent femoral vessels is demonstrated, which will provide new insights and a potential breakthrough to microvascular and supermicrovascular surgery.

Microvascular anastomosis guidance and evaluation using real-time three-dimensional Fourier-domain Doppler optical coherence tomography.

Wider application of vascularized composite allotransplantation (VCA) is limited by the need for chronic immunosuppression. Recent data suggest that the lymphatic system plays an important role in mediating rejection. This study used near-infrared (NIR) lymphography to describe lymphatic reconstitution in a rat VCA model. Syngeneic (Lewis-Lewis) and allogeneic (Brown Norway-Lewis) rat orthotopic hind limb transplants were performed without immunosuppression. Animals were imaged pre- and postoperatively using indocyanine green (ICG) lymphography. Images were collected using an NIR imaging system. Co-localization was achieved through use of an acrylic paint/hydrogen peroxide mixture. In all transplants, ICG first crossed graft suture lines on postoperative day (POD) 5. Clinical signs of rejection also appeared on POD 5 in allogeneic transplants, with most exhibiting Grade 3 rejection by POD 6. Injection of an acrylic paint/hydrogen peroxide mixture on POD 5 confirmed the existence of continuous lymphatic vessels crossing the suture line and draining into the inguinal lymph node. NIR lymphography is a minimally invasive imaging modality that can be used to study lymphatic vessels in a rat VCA model. In allogeneic transplants, lymphatic reconstitution correlated with clinical rejection. Lymphatic reconstitution may represent an early target for immunomodulation.

Article	Year
Which patients first? Planning the first clinical trial of xenotransplantation: a case for cardiac bridging. Xenotransplantation\| PubMed ID: 15807765	2005
Allosensitized humans are at no greater risk of humoral rejection of GT-KO pig organs than other humans. Xenotransplantation\| PubMed ID: 16768729	2006
Antibodies directed to pig non-Gal antigens in naÃ¯ve and sensitized baboons. Xenotransplantation\| PubMed ID: 16925663	2006
Selected physiologic compatibilities and incompatibilities between human and porcine organ systems. Xenotransplantation\| PubMed ID: 17059572	2006
Cruveilhier-Baumgarten disease in a patient with Turner syndrome: case report of a rare indication for liver transplantation. Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society\| PubMed ID: 18306332	2008
Familial paragangliomas: case report and literature review. Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists\| PubMed ID: 18753105	2008
Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion versus systemic chemotherapy alone for colorectal peritoneal carcinomatosis. Cancer\| PubMed ID: 20564081	2010
Real-time three-dimensional Fourier-domain optical coherence tomography video image guided microsurgeries. Journal of biomedical optics\| PubMed ID: 23224164	2012
Microvascular anastomosis guidance and evaluation using real-time three-dimensional Fourier-domain Doppler optical coherence tomography. Journal of biomedical optics\| PubMed ID: 23856833	2013
Near-infrared lymphography as a minimally invasive modality for imaging lymphatic reconstitution in a rat orthotopic hind limb transplantation model. Transplant international : official journal of the European Society for Organ Transplantation\| PubMed ID: 23879384	2013

Zuhaib Ibrahim

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