The World Health Organization estimates that some form of liver disease affects over 650 million people worldwide. Of those, over 21 million people are estimated to live with chronic liver disease, and about 800,000 expire annually. Despite the relatively slow progression of the disease, liver transplantation remains the only definitive treatment for end-stage chronic liver failure, and it is also the only treatment for severe acute liver failure and some forms of inborn errors of metabolism. Because organ donation has not kept up with demand in the past 15 years, the number of patients on the liver transplant waiting list has increased significantly. To overcome the shortage of livers for transplantation, several approaches have been developed such as artificial/bioartificial liver assist devices, new surgical methods (split liver method, living donation) and cellular therapies. Despite increasing the pool of available organs for transplantation, or extending the life of the patients on the liver waiting list for a short period of time, these approaches invariably fail to provide a long-term solution to organ shortage. Hence, new promising technologies like regenerative medicine, and more specifically organ bioengineering, will hopefully help to bridge the gap between the pool of available livers for transplantation and patients waiting for one. The candidate and others have recently developed methods for organ decellularization using detergent perfusion through the vasculature of solid organs. However, to successfully transplant a bioengineered liver it is critical that the newly bioengineered liver’s vascular network is fully functional and re-vascularized, able to maintain vascular patency and hemostasis once anastomosed with the host´s circulatory system. It is precisely here, that the current knowledge and technology is still quite limited making transplants of bioengineered organs unviable past a few hours, or at best a few days, because of blood clotting due to poor re-vascularization. Hence, it is imperative that more efficient revascularization methods can be investigated to improve bioengineered organ´s vascular patency and the probability of successful transplantation. In order to accomplish this, effective cell seeding is vital, followed by a gradual maturation phase of the newly developed and re-vascularized vascular structures, similarly to what has been proposed and implemented in tissue-engineered blood vessels.
We found that “near-physiological” higher fluid flow pressures in the portal vein (10-20mmHg) after cell seeding resulted in increased tissue growth and cell proliferation, while higher fluid flow pressures >50mmHg lead to cell death. Finally, we also found that within this range (10-20mmHg), there was a significant increase in the number of reendothelialized vascular structures, which was fluid flow pressure dependent, suggesting that precise mechanical stimulation is essential for efficient re-vascularization of acellular liver scaffolds ex vivo (Baptista et al. Tissue Engineering C - Methods, 2016). These results are in agreement with observations of small-for-size liver transplantations, where many have found that extreme hyperperfusion, indicative of high shear stress, leads to cell death and numerous other complications. Yet, mild elevations in flow rate are indispensible for liver regeneration following small-for-size transplantation, which we believe are correlated with fluid flow pressures within the 10-20mmHg range.
With this ultimate goal, we believe that this project will have a broad socio-economic impact, since it will help to generate some of the necessary technologies to create lab grown organs (with its own potential implications in intellectual property), adding more livers into the transplantation pool.
