Zurab Machaidze

Soft robotic sleeve supports heart function

A soft robotic sleeve modeled on the structure of the human heart assists cardiovascular function in an ex vivo and in vivo porcine model of heart failure. Robots have a change of heart Ventricular assist devices help failing hearts function by pumping blood but require monitoring and anticoagulant therapy to prevent blood clot formation. Roche et al. created a soft robotic device with material properties similar to those of native heart tissue that sits snugly around the heart and provides ventricular assistance without ever contacting blood. The robotic sleeve uses compressed air to power artificial silicone muscles that compress and twist, mimicking the movements of the normal human heart. The authors show that the artificial muscles could be selectively activated to twist, compress, or simultaneously perform both actions on one side or both sides of the heart. The device increased cardiac ejection volume in vitro and when implanted in adult pigs during drug-induced cardiac arrest. There is much interest in form-fitting, low-modulus, implantable devices or soft robots that can mimic or assist in complex biological functions such as the contraction of heart muscle. We present a soft robotic sleeve that is implanted around the heart and actively compresses and twists to act as a cardiac ventricular assist device. The sleeve does not contact blood, obviating the need for anticoagulation therapy or blood thinners, and reduces complications with current ventricular assist devices, such as clotting and infection. Our approach used a biologically inspired design to orient individual contracting elements or actuators in a layered helical and circumferential fashion, mimicking the orientation of the outer two muscle layers of the mammalian heart. The resulting implantable soft robot mimicked the form and function of the native heart, with a stiffness value of the same order of magnitude as that of the heart tissue. We demonstrated feasibility of this soft sleeve device for supporting heart function in a porcine model of acute heart failure. The soft robotic sleeve can be customized to patient-specific needs and may have the potential to act as a bridge to transplant for patients with heart failure.

Pediatric intestinal retransplantation: techniques, management, and outcomes.

Background. Intestinal retransplantation (Re-ITx) has historically been associated with high morbidity and mortality. Methods. The outcomes of all children receiving Re-ITx between 1990 and 2007 at our center were reviewed. Results. One hundred seventy-two children received primary intestinal grafts. Fourteen children (8.1%) were retransplanted with 15 grafts. Causes of graft failure were acute cellular rejection (ACR, n=4), liver failure (n=2), chronic rejection (n=3), posttransplant lymphoproliferative disorder (n=1), graft dysmotility or dysfunction (n=3), ACR with severe infection (n=1), and arterial graft aneurysm (n=1). Initial transplants were isolated bowel in nine, liver-bowel in five, and one multivisceral. The mean time of initial graft survival was 34.2 months. Re-ITx was with isolated bowel in two, liver-bowel in four, and multivisceral in nine (four with kidney). Initial immunosuppression was Tac-Pred based in nine and rabbit antithymocyte globulin-Tac based in six cases. Re-ITx was carried out under Tac-Pred in six, rabbit antithymocyte globulin-Tac in eight, and alemtuzumab monoclonal anti-CD52 antibody in one. Ten (71.4%) patients are alive with functioning grafts at a mean current follow-up time of 55.9 months. Four patients died from posttransplant lymphoproliferative disorder, severe ACR, fungal sepsis, and bleeding from pseudoaneurysm, respectively, at a mean time of 5.7 months post-Re-ITx. All surviving patients weaned-off total parenteral nutrition at a median time of 32 days and 90% are off intravenous fluids. Conclusions. Improved long-term survival and outcome in pediatric Re-ITx may be attributed to improvements in initial immunosuppression protocols, technical modifications, proper timing, and improved infectious disease monitoring. Careful patient selection and posttransplant management are essential for successful long-term outcome.

Increased transfusion-free survival following auxiliary pig liver xenotransplantation.

Pig to baboon liver xenotransplantation typically results in severe thrombocytopenia and coagulation disturbances, culminating in death from hemorrhage within 9 days, in spite of continuous transfusions. We studied the contribution of anticoagulant production and clotting pathway deficiencies to fatal bleeding in baboon recipients of porcine livers.

Mechanisms of Xenogeneic Baboon Platelet Aggregation and Phagocytosis by Porcine Liver Sinusoidal Endothelial Cells

Background Baboons receiving xenogeneic livers from wild type and transgenic pigs survive less than 10 days. One of the major issues is the early development of profound thrombocytopenia that results in fatal hemorrhage. Histological examination of xenotransplanted livers has shown baboon platelet activation, phagocytosis and sequestration within the sinusoids. In order to study the mechanisms of platelet consumption in liver xenotransplantation, we have developed an in vitro system to examine the interaction between pig endothelial cells with baboon platelets and to thereby identify molecular mechanisms and therapies. Methods Fresh pig hepatocytes, liver sinusoidal and aortic endothelial cells were isolated by collagenase digestion of livers and processing of aortae from GTKO and Gal+ MGH-miniature swine. These primary cell cultures were then tested for the differential ability to induce baboon or pig platelet aggregation. Phagocytosis was evaluated by direct observation of CFSE labeled-platelets, which are incubated with endothelial cells under confocal light microscopy. Aurintricarboxylic acid (GpIb antagonist blocking interactions with von Willebrand factor/vWF), eptifibatide (Gp IIb/IIIa antagonist), and anti-Mac-1 Ab (anti-αMβ2 integrin Ab) were tested for the ability to inhibit phagocytosis. Results None of the pig cells induced aggregation or phagocytosis of porcine platelets. However, pig hepatocytes, liver sinusoidal and aortic endothelial cells (GTKO and Gal+) all induced moderate aggregation of baboon platelets. Importantly, pig liver sinusoidal endothelial cells efficiently phagocytosed baboon platelets, while pig aortic endothelial cells and hepatocytes had minimal effects on platelet numbers. Anti-MAC-1 Ab, aurintricarboxylic acid or eptifibatide, significantly decreased baboon platelet phagocytosis by pig liver endothelial cells (P<0.01). Conclusions Although pig hepatocytes and aortic endothelial cells directly caused aggregation of baboon platelets, only pig liver endothelial cells efficiently phagocytosed baboon platelets. Blocking vWF and integrin adhesion pathways prevented both aggregation and phagocytosis.

Testing of microencapsulated porcine hepatocytes in a new model of fulminant liver failure in baboons

There is no standard therapy for acute liver failure. Hepatocyte transplantation has been proposed for temporary liver function support, while the injured liver regenerates or while waiting for transplantation. We have previously shown such efficacy for microencapsulated porcine hepatocytes in mice with fulminant liver failure. We aimed to establish a large animal model for fulminant liver failure to assess the efficacy of microencapsulated porcine hepatocytes in temporary liver function support.

Pilot Study Evaluating Regulatory T Cell-Promoting Immunosuppression and Nonimmunogenic Donor Antigen Delivery in a Nonhuman Primate Islet Allotransplantation Model

The full potential of islet transplantation will only be realized through the development of tolerogenic regimens that obviate the need for maintenance immunosuppression. Here, we report an immunotherapy regimen that combines 1‐ethyl‐3‐(3′‐dimethylaminopropyl)‐carbodiimide (ECDI)‐treated donor lymphoid cell infusion (ECDI‐DLI) with thymoglobulin, anti‐interleukin‐6 receptor antibody and rapamycin to achieve prolonged allogeneic islet graft survival in a nonhuman primate (NHP) model. Prolonged graft survival is associated with Treg expansion, donor‐specific T cell hyporesponsiveness and a transient absence of donor‐specific alloantibody production during the period of graft survival. This regimen shows promise for clinical translation.

Cardioscopic Tool-Delivery Instrument for Beating-Heart Surgery

This paper describes an instrument that provides solutions to two open challenges in beating-heart intracardiac surgery-providing high-fidelity imaging of tool-tissue contact and controlling tool penetration into tissue over the cardiac cycle. Tool delivery is illustrated in the context of tissue removal for which these challenges equate to the visualization of the tissue as it is being removed and to control of cutting depth. Cardioscopic imaging is provided by a camera and illumination system encased in an optical window. When the optical window is pressed against tissue, it displaces the blood between the camera and tissue allowing clear visualization. Control of cutting depth is achieved via precise extension of the cutting tool from a port in the optical window. Successful tool use is demonstrated in ex vivo and in vivo experiments.

Auxiliary liver transplantation: Location, location, location...

In the November issue of Pediatric Transplantation, Haberal et al. report long-term survival after heterotopic segmental auxiliary liver transplantation (HSALT) in a 17-yr-old female with cryptogenic cirrhosis. After encountering significant adhesions and fibrosis in the portal hilum during an initial deceased donor split transplant attempt, the decision was made to proceed with HSALT. Follow-up imaging studies have shown a progressive decrease in the size of the native liver and spleen, and regeneration of the HSALT graft. The patient is clinically well at nine-yr follow-up.

Cardioscopically Guided Beating Heart Surgery: Paravalvular Leak Repair

PURPOSE There remains a paucity of direct visualization techniques for beating-heart intracardiac procedures. To address this need, we evaluated a novel cardioscope in the context of aortic paravalvular leaks (PVLs) localization and closure. DESCRIPTION A porcine aortic PVL model was created using a custom-made bioprosthetic valve, and PVL presence was verified by epicardial echocardiography. Transapical delivery of occlusion devices guided solely by cardioscopy was attempted 13 times in a total of three pigs. Device retrieval after release was attempted six times. Echocardiography, morphologic evaluation, and delivery time were used to assess results. EVALUATION Cardioscopic imaging enabled localization of PVLs via visualization of regurgitant jet flow in a paravalvular channel at the base of the prosthetic aortic valve. Occluders were successfully placed in 11 of 13 attempts (84.6%), taking on average 3:03 ± 1:34 min. Devices were cardioscopically removed successfully in three of six attempts (50%), taking 3:41 ± 1:46 min. No damage to the ventricle or annulus was observed at necropsy. CONCLUSIONS Cardioscopy can facilitate intracardiac interventions by providing direct visualization of anatomic structures inside the blood-filled, beating-heart model.

In vivo tissue regeneration with robotic implants

A robotic implant for inducing tissue growth in tubular organs is demonstrated through esophageal lengthening in swine. Robots that reside inside the body to restore or enhance biological function have long been a staple of science fiction. Creating such robotic implants poses challenges both in signaling between the implant and the biological host, as well as in implant design. To investigate these challenges, we created a robotic implant to perform in vivo tissue regeneration via mechanostimulation. The robot is designed to induce lengthening of tubular organs, such as the esophagus and intestines, by computer-controlled application of traction forces. Esophageal testing in swine demonstrates that the applied forces can induce cell proliferation and lengthening of the organ without a reduction in diameter, while the animal is awake, mobile, and able to eat normally. Such robots can serve as research tools for studying mechanotransduction-based signaling and can also be used clinically for conditions such as long-gap esophageal atresia and short bowel syndrome.