Progressive Perfusion Tech

How game-changing perfusion techniques are expanding the donated organ pool Organ transplant has been one of the modern marvels of medicine. Replenishing a deceased organ with a donated healthy organ has fulfilled the great promise of modern medicine. Today, about 1.5 million solid organ transplants are performed every year globally. Besides, strategic investment in developing newer technologies have amplified the transplant provider’s effort to serve the patient community better by innovative organ preservation technologies and improved organ survival. [caption id="attachment_11526" align="aligncenter" width="305"] Dr Darius Mirza Professor of Hepatobiliary & Transplant Surgery, QE Hospital & Birmingham Children’s Hospital, UK[/caption] The Foundation Solid-organ transplantation came of age in the 1950s and 1960s once clinicians understood the steps needed to prevent rejection. As the field developed, surgical aspects of organ selection, removal, preservation and implantation were understood. One of the keys to better transplanted survival was organ preservation. This requires slowing down the metabolism and this has conventionally been done by cooling to reduce the impact of lack circulation once the transplant organ has been retrieved. The conventional method of preservation is termed static cold storage (SCS), with the organs preserved at a temperature between 0 - 4 degrees centigrade, and the metabolism slowed by a factor of 10-12 fold. However, new techniques have now been introduced that do not require cold temperatures. Challenges Galore There are a number of challenges with organ preservation and transport. The ultimate goal of transplant is to have a functional organ but the transport and preservation often are difficult because of injury to the donated organ. SCS is less costly and efficient but results in additional organ injury due to ischaemia, toxin build-up or lack of nutrients. Dynamic perfusion can be done at body temperature or cold (0-4 deg C) or at temperatures somewhere in between, but requires machines to pump oxygenated fluid or human blood or a blood substitute to the organ. This new thought has changed the face of transplant medicine. Earlier, organs that were non-optimal were discarded but now using new technology these organs can be saved and transplanted. Studies have shown that the new perfusion techniques have lesser a degree of organ injury during preservation, allowing better function in these organs once implanted into a patient. [caption id="attachment_11525" align="aligncenter" width="428"] Photo Courtesy: Ex-Vivo Organ Support System - University of Alberta[/caption] Importance of Novel Perfusion Tech Transplant medicine has been plagued by one major limitation; the actual organ availability. There is a huge need for donated organs, but out of the donated organs, there are few that are not used and are rejected. This gap between available organs and actually used organs is a major concern for transplant surgeons around the globe. One way out is to preserve these vulnerable organs in a way that these can be used. One of the areas of interest in transplant medicine is to develop new strategies for the preservation of marginal grafts that are prone to injury when treated with standard techniques, such as static cold storage (SCS). In fact, a number of innovative preservation methods in kidney, liver and lung transplant are currently under investigation in animal models, pre-clinical and clinical trials, comparing different strategies, ranging from hypothermic (4–10 °C) to subnormothermic (20–25 °C) – including controlled oxygenated rewarming – and normothermic (35–37 °C) conditions.New techniques of organ perfusion and preservation are a vital developing area of organ donation and transplantation.   OrganOx Metra device In 2013, Professor Constantin Coussios and Professor Peter Friend, who were with Oxford University's Department of Engineering Science and Nuffield Department of Surgical Sciences and Director of the Oxford Transplant Centre respectively succeeded in keeping a human livers outside the body, alive and functioning on an innovative machine which was later, successfully transplant them into a patient. Prof Coussio, Friend and colleagues had been researching the technology since 1994. This device was the first completely automated liver perfusion device of its kind. It kept the organ perfused with oxygenated red blood cells at normal body temperature, just like inside the body, and could be observed making bile, which made it an extraordinary feat of engineering. This device was further developed by a company called OrganOx and the device is called Metra. Till 2020, the device had been used for about 800 liver transplants. Including 220 livers that formed the Consortium for Organ Preservation in Europe (COPE) randomised controlled trial published in Nature in April 2018. Recently, the VITTAL trial (Transplantation of discarded livers following viability testing with normothermic machine perfusion) was published in Nature Communications in June, 2020. It reported on the perfusion of 31 livers which were previously determined to be unsuitable for transplantation by all liver transplant centres in the UK. Dr Mirza, Consultant Transplant Surgeon at University Hospitals Birmingham NHS Foundation Trust and Honorary Professor at the University of Birmingham, was the VITTAL project lead. This challenging study was designed to assess the function of discarded livers in real-life situation. The major challenge in this pioneering clinical trial was to assure patients safety while pushing the envelope of sub-optimal liver utilisation. The study reported that 22 of the 31 livers (71 per cent) met criteria and were transplanted. Early outcomes were excellent with 100 per cent 90-day graft and patient survival (primary endpoint of the study). One-year patient survival was also 100 per cent. Organ Care System In 2014, St Vincent's Hospital Heart Lung Transplant Unit in Darlinghurst, New South Wales, Australia used a novel portable machine to house and transport donor organs, during heart transplant. The Organ Care System (OCS) developed by Massachusetts-based TransMedics is the only device available for ex vivo perfusion of human donor hearts in a warm beating state. Currently, the OCS Heart, OCS Lung, and OCS Liver systems are CE Marked and are in use at leading transplant centres in Europe, Australia and Canada. Todate there has been more than 950 successful human transplants using the OCS System world-wide. In April 2018, OCS Lung INSPIRE Trial was published in the peer-reviewed journal The Lancet Respiratory Medicine. The INSPIRE Trial was the first and largest controlled clinical organ preservation trial ever done in lung transplantation and was conducted at 21 leading international academic transplant centres. The primary objective of the INSPIRE Trial was to compare the safety and effectiveness of the OCS Lung System to the current cold storage standard of care for the preservation of standard criteria donor lungs. The trial results  demonstrated assurance of the safety and effectiveness of the OCS Lung System in standard criteria doublelung transplantation. "This publication is an important milestone for the field of lung transplantation. For the first time, we have published prospective clinical evidence that there is a new modality to reduce the most severe and common clinical complication after lung transplantation – PGD3," said Dr Gregor Warnecke, Vice Chairman of Cardiothoracic and Transplant Surgery Department in Hannover Medical School, Germany, and the Principal Investigator of the INSPIRE Trial. EVOSS System In early 2020, a team of researchers at the University of Alberta, Canada announced the development of the Ex-Vivo Organ Support System (EVOSS). Developed by the University of Alberta surgeons Darren Freed, and Jayan Nagendran, the platform uses negative-pressure ventilation to replicate the way our chest cavity expands and contracts with each breath. By mimicking the natural process of breathing, it ventilates donated lungs in an ex-vivo organ perfusion device, which constantly supplies the lungs with blood and oxygen and keeps them warm, similar to the conditions inside the body, the university said. Currently, organs are stored on ice while being transported, which often results in organ damage. The only thing physicians can do to minimise the risk of damage is to reduce the time between when the organ is harvested and when it is transplanted. Lungs can be kept from six to eight hours on the ice, but up to 48 hours on the EVOSS device. This additional time also allows for organs to be assessed and repaired, which increases the number of viable organs available. Freed and Nagendran have founded Tevosol, University of Alberta spinoff company to commercialise their product. The ex vivo research trial was published in Nature Communications in November, 2020. The study with 12 transplants demonstrate the safety and feasibility of NPV-ESLP.   Liver4Life project The Wyss Zurich institute, along with highly specialised technical expertise and biomedical experts from the University Hospital Zurich (USZ), ETH Zurich and the University of Zurich (UZH) are working on a new organ perfusion technology called Liver4Life project. The Wyss Zurich project (Liver4Life) started in 2015 and aimed to develop a novel therapeutic strategy for liver regeneration consisting of: i) surgical resection of a small healhy piece of the liver from the patient; ii) growth of this piece outside of the body in a perfusion machine until a sufficient size is reached; iii) retransplantation of the regenerated liver to the original patient while removing the remaining diseased part. Current perfusion systems are not able to keep a liver alive outside of the body for a sufficient time to allow growth and regeneration to occur. The challenging aim of the project was to extend the viability of liver tissue outside of the body for a few days and allow its growth. They developed a perfusion machine that provides necessary nutrients and oxygen supply, and is equipped to monitor growth, as well as assess the functional capacity of the liver. Until now, livers could be stored safely outside the body for only a few hours. With the novel perfusion technology, livers - and even injured livers – can now be kept alive outside of the body for an entire week. This breakthrough may increase the number of available organs for transplantation saving many lives of patients with severe liver diseases or cancer. The pilot study published on January 13, 2021 in Nature Biotechnology shows that six of ten perfused poor quality human livers, declined for transplantation by all centres in Europe, recovered to full function within one week of perfusion on the machine. The next step will be to use these organs for transplantation. The proposed technology opens a large avenue for many applications offering a new life for many patients with end-stage liver disease or cancer. Looking Ahead This is a new field as far as clinical application is concerned and most of the recent progress has been translational – moving this technology into the realm of everyday transplantation in selected situations. The effort should be to make this common for all transplants. This can happen be making machines cheaper and more portable, use of perfusion fluids that can carry oxygen at higher temperatures, ability to improve function by repairing some of the damage these organs acquire during the process of death of the donor. These are the key areas of improvements in perfusion technology and should be looked at in future.