A Step Closer to a Bioengineered Liver Fit for Transplantation
Industry Insight Nov 13, 2019
Currently over 6,300 people in the UK are waiting for an organ transplant, and sadly everyday around three people die waiting. In efforts to reduce the reliance on organ donors and improve the outlook for patients, alternative sources of organs are being explored by several research groups.
In a study recently published in Nature Biomedical Engineering, bioengineered livers created by decellularization and recellularization were implanted into pigs, where they were able to sustain continuous perfusion for up to 15 days. We spoke to Miromatrix’s CEO, Dr Jeff Ross, to learn more about the study and how it advances the state of bioengineering organs.
Anna MacDonald (AM): What are some of the main challenges faced when creating bioengineered organs?
Dr Jeff Ross (JR): There are several challenges -- one that has plagued the tissue engineering field is creating a functional vasculature that can support organ function. For many years, engineered tissue was essentially thin sheets of tissue which lacked vasculature to support greater thickness. At Miromatrix, we developed a method to utilize what nature already created by starting with an existing porcine organ that was going to be discarded and simply removing the existing cells through a process called decellularization. We then reintroduce human cells on the decellularized organ through a process called recellularization to develop a functional organ with a defined vasculature. This approach is advantageous because the resulting bioengineered organ is the appropriate size and contains similar-sized vessels for transplantation. Another big paradigm is creating an organ that’s easy to transplant and has a higher chance of being accepted by the body. While strides have been made when it comes to 3D printed organs or transgenic organs, they still have a long way to go. Our process and patented technology have the potential to bioengineer fully functioning whole organs derived from the patient’s own stem cells, so patients could avoid some of the immunotherapies that are required today.
AM: Can you tell us about perfusion decellularization and the advantages this method offers in the process of creating bioengineered organs?
JR: Our patented perfusion decellularization process essentially washes out the cells from a discarded pig organ, leaving all of the blood vessels and microstructures that define that organ intact. Our ground-breaking technology then introduces human cells into the organ matrix, ultimately recellularizing it, thus bioengineering a new organ.
AM: In a recent study, this method was used to create a bioengineered liver. Can you give us an overview of the study and its results?
JR: We’re excited to show our progress in our mission to end the organ transplant waiting list by bioengineering transplantable organs. The data we collected in our recent research helps us take a major step towards that goal by solving one of the greatest hurdles in engineering transplantable organs, developing a functional vasculature capable of sustaining normal blood perfusion to support organ function. Miromatrix’s data published in Nature Biomedical Engineering demonstrates the ability to revascularize clinical scale liver constructs with human vascular cells that not only enables sustained perfusion for over 15 days following transplantation but also demonstrate the appropriate characteristics of liver-specific endothelial cells, clearing a major hurdle and enabling the advancement of a bioengineered liver to address the tremendous need today for thousands of patients. Our next step is to take our research to the clinic. Having solved the critical vascular issue, we are now able to include hepatocytes and bile duct cells within the liver grafts to bioengineer the whole liver. These grafts are being implanted into pigs, and the results are very encouraging. We’ve had preliminary talks with the U.S. Food and Drug Administration (FDA) and defined required steps before this research can be tested in humans.
AM: What further work needs to be done before bioengineered livers will be available to patients? How soon do you see them being a viable transplant option?
JR: We are preparing to publish the results we believe demonstrate that we can revascularize an organ, place it back into a large animal, achieve sustained perfusion and demonstrate initial function. This will be our next big tipping point and will lead to our planned recovery studies, which are a key step toward human trials. At Miromatrix, we’re aiming for our first human clinical studies to happen in the next three years. Thanks to a recent grant from the National Institutes of Health (NIH), we’re much closer to our goal. There is still a lot to be done, but we are making great progress, and the future is closer to becoming a reality.
AM: What about rejection? Would patients still need to take immunosuppressive drugs?
JR: To address the chronic need for transplantable organs, we have defined two products. Our first organs will be derived from primary cells isolated from organs unsuitable for transplant for various reasons but have healthy cells. We believe this approach will lead to quicker regulatory approval and enable helping patients sooner. The initial product will likely require immunosuppression similar to other donor organs today. Our second-generation product consists of organs derived from the patient’s own stem cells or from a super donor, enabling greatly reduced or no immunosuppression, which is really the ultimate solution for transplantation. The regulatory pathway for this product will likely be longer, which is why we are focusing on primary cells to start.
The other question we’re tackling: what about the porcine organ matrix; will this cause an immune response? Through our previous biologic products, MIROMESH® and MIRODERM®, we’ve been able to demonstrate the vast potential of decellularized organs. Like our bioengineered livers, MIROMESH and MIRODERM are derived from pig livers. Using the same process of perfusion decellularization, we removed all of the liver’s cells while still leaving the overall liver matrix intact, including the blood vessels. The decellularized livers are then made into MIROMESH and MIRODERM. So far, thousands of patients have been implanted with our material with no reported adverse reactions in patients related to immunological responses. The data helps de-risk our approach and provides the initial data to support starting with a pig matrix as a safe approach.
Jeff Ross was speaking to Anna MacDonald, Science Writer for Technology Networks.