November 26, 2019
As one of the newest divisions of biomolecular engineering, tissue engineering has only been around for a couple of decades. Since then, it has developed primarily in response to the shortage of tissue and organs for transplants. While it faces a variety of challenges, from immune responses to financial costs, researchers like Laura Niklason are avidly working to develop a method of bioengineering to bring to the public market. A biomedical engineering professor at Yale, Niklason has successfully bioengineered blood vessels and created a company to sell them “off the shelf.” She is currently working to develop a functional bioengineered lung, paving the way for the future of organ transplants.
Niklason decided to develop bioengineered blood vessels after recognizing the inefficiency of current vessel implants. Often, these implants require extracting veins from other parts of the patient’s body and hoping that it is compatible. Specifically, arterial bypass graft implantations and hemodialysis treatments for end-stage renal disease are very common, and thus, the development of synthetic grafts could help create a more successful and cost-effective procedure. The Human Acellular Vessels (HAVs) have a shelf-life of 6 months and are nonspecific, allowing them to be given to any patients.
The process of producing these HAVs took years and is continually being improved upon. The basic process includes growing the vessels from human smooth muscle cells on a biodegradable scaffold, which acts like a 3D mold for the tissue. The cells are taken from the previously-unused human aortae in heart transplants. Decellularization of the HAVs depersonalizes them to prevent patient immune responses. Decellularization requires various detergents and buffers to get rid of DNA. The cells, when cultured in a bioreactor with various chemical and biological components, generate a collagen matrix along the scaffold. Finally, the mechanical and structural function of the HAVs are tested. Pressure testing compared the HAV integrity with normal veins. The burst pressure was found to be 1567 mmHg, which approaches normal veins which have 1680 mmHg (Quint 2013). Fluorescence is used to check that DNA was removed, and transmission electron microscopy is used to reveal the existence of structural proteins like elastin and collagen. All of these tests confirm that the HAVs are suitable for implantation.
They first tested the HAVs in rats for in vivo testing. They inserted an abdominal graft into 6 female rats, and, over the course of 6 weeks, analyzed function through ultrasound testing and micro-CT imaging. After six weeks, the grafts were explanted and analyzed for thickness and composition using various methods of staining. It was found that the vessels maintained their structural integrity. The first HAV implant in a human was in 2012. Since then, 60 more patients have received HAVs (Quint 2013). As of now, there does not seem to be additional health risks or degradation of the vessel. Currently the company is finishing stage III in its process to launch the product in the market. With a decreased rate of failure, cost-efficiency, and immediate availability, the design of HAVs has filled a gap in medicine and created a promising business model. Current challenges to the company include finding ways to further reduce costs, but once the product launches, it will be easier to cut costs while also maintaining profit.
As if creating the business was not enough, Niklason also has been dedicating time towards bioengineering a functional lung. There are about 400,000 deaths per year in the US due to lung disease. Damaged lungs struggle to regenerate tissue, creating a need for traditional lung transplants. These expensive procedures only have a 10-20% success rate in the long-term (Petersen 2010). A bioengineered lung could revolutionize the standard methods of treating lung disease. The procedure for developing a bioengineered lung is very similar to the bioengineered blood vessels.
After removing cellular components (DNA) of the neonatal rat lung tissue through detergents and buffers, the tissue is cultured in a bioreactor on a scaffold to retain structure. The bioreactor stimulates a fetal body environment using pumps and tubes to control pressure and volume. This helps promote tissue differentiation for different areas in the lung. Both liquid and air ventilation testing was performed. The engineered lungs had to then be tested to see if they perform similarly to real lungs. According to Niklason, “To be functional in vivo, an engineered lung should contain lung specific cells, display the branching geometry of the airways and contain a perfusing microvasculature, provide barrier function to separate blood from air, and have mechanical properties that allow ventilation at physiological pressures” (Petersen 2010). Compliance testing was completed by injecting air into the lung and analyzing the resulting pressure-volume curve. Overall, the rats survived for a short period with an implanted left lung, proving that the engineered lungs could function in terms of gas exchange.
Following this experiment, Niklason and her lab have been attempting to test this procedure with human tissues. Although the procedure itself works to create a bioengineered human lung, it is not ready for testing in human patients because there have been problems with blood leakage and clotting (Petersen 2010). On top of that, Niklason faces commercial challenges of attaining investments, reducing costs, and securing long-term profit; nonetheless, Niklason is overcoming these challenges, establishing herself as a leader in tissue engineering research. It is likely that the future of bioengineered organs will likely be founded in her methods and accomplishments.
Petersen, T. H., Calle, E. A., Zhao, L., Lee, E. J., Gui, L., Raredon, M. B., … Niklason, L. E. 2010
June 30. Tissue-engineered lungs for in vivo implantation. Science [Internet]. 329(5991),
538–541. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3640463/
Quint, C., Arief, M., Muto, A., Dardik, A., Niklason, L.E. 2013 March 1. Allogeneic human
tissue-engineering blood vessel.Journal of vascular surgery [Internet],, 55(3), 790–798.
Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3505682/