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Neurological diseases and disorders affect a significant percentage of people and this number will continue to increase as the population ages. For many diseases, like Alzheimer’s and Parkinson’s, no true long-term cure exists as current treatments only mitigate the symptoms of these devastating diseases. One of the major obstacles to developing effective treatments is that our current tools for screening potential drugs lack the ability to accurately predict whether a new drug will be both effective as well as non-toxic. Currently, the tools used for predicting the effects of potential drug targets include animal models and cadaveric human tissues. Animal models can be inaccurate with regards to predicting the toxicity and efficacy of drugs while human tissue samples tend to be limited in availability. Our group takes a different strategy where we use 3D bioprinting to generate neural tissue from pluripotent stem cells. Pluripotent stem cells possess two unique and defining properties. The first property is pluripotency which means they can become any cell type found in the body. These cells can also replicate to generate more stem cells, which is their second defining property. One way to produce pluripotent stem cells requires the reprogramming of adult cells back into stem cell-like state. These cells are called induced pluripotent stem cells (iPSCs) and they can be derived from patients suffering from neurodegenerative disorders. These iPSC lines can then be differentiated into tissues similar to those found the nervous system while replicating the features of these diseases, such as Alzheimer’s disease .
This combination of 3D printing with patient-derived iPSCs has the potential to generate models of neurological diseases in a dish for more accurate screening of potential drug targets. In my research group, we use Aspect Biosystem’s novel RX1 printer to generate our neural tissues as it is both quick and reproducible while being gentle on stem cells during the printing process . It also enables us to print complex structures by positioning both cells and drug releasing microspheres in the appropriate places within our tissues. Our group has published a set of two papers showing that we can print neural tissues derived from human iPSCs while maintaining high levels of cell viability [3, 4]. These tissues can be cultured for extended periods of time (> 40 days) and they express mature neuronal markers. Similar proof of concept work has been done by Dr. Michael McAlpine’s group at the University of Minnesota where they used bioprinting to generate complex co-culture structures from stem cells that resemble the tissue found in the spinal cord .
In addition to generating personalized neural tissues for drug screening applications, pluripotent stem cells can also be directed to form structures that mimic the blood-brain barrier, which protects the central nervous system by limiting what materials can be transported into these tissues. Often getting drugs across the blood-brain barrier serves as a limiting step for potential therapeutics for treating neurodegenerative diseases and disorders. As such, it is imperative to be able to model this structure in a dish when testing potential treatments. The Lippman group at Vanderbilt University recently reviewed the current progress related to generating such in vitro models . Also, the Wellington group at the University of British Columbia validated a complex tissue-engineered model of the blood-brain barrier that could potentially be translated for bioprinting to increase throughput for drug screening applications . Overall, the field of 3D bioprinting in combination with iPSC technology offers huge potential for developing personalized medicine approaches to identifying promising drug targets for treating neurological diseases and disorders.
1. Willerth, S.M. Bioprinting neural tissues using stem cells as a tool for screening drug targets for Alzheimer’s disease. Journal of 3D Printing in Medicine. 2018. 2(4). p. 163-165.
3. Abelseth, E., Abelseth, L., de la Vega, L., Beyer, S., Wadsworth, S., and Willerth, S.M. 3D printing of neural tissues derived from human induced pluripotent stem cells using a fibrin-based bioink. ACS Biomaterials Science and Engineering. 2019. (5) p. 234-243.
4. de la Vega, L., Rosas Gomez, D., Abelseth, E., Abelseth, L., Alisson da Silva, V. and Willerth, S.M. 3D bioprinting human induced pluripotent stem cell-derived neural tissues using a novel Lab-on-a-Printer technology. Applied Science. 2018. 8(2414). p. 1-13.
5. Joung, D., Truong, V., Neitzke, C.C., Guo, S., Walsh, P.J., Monat, J.R., Meng. M.F. Park, S.H., Dutton, J.R., Parr, A.M. and McAlpine, M.C. 3D Printed Stem‐Cell Derived Neural Progenitors Generate Spinal Cord Scaffolds. Advanced Functional Materials. 2018. 28 (1801850). p. 1-10.
6. Bosworth, A.M., Faley, S.L., Bellan, L.M., and Lippmann, E.S. Modeling Neurovascular Disorders and Therapeutic Outcomes with Human-Induced Pluripotent Stem Cells. Frontiers in Biotechnology and Bioengineering. 2018. 5(87). p. 1-11.
7. Robert, J., Button, E.B., Yuen, B., Gilmour, M., Kang, K., Bahrabadi, A., Stukas, S., Zhao, W., Kulic, I., and Wellington, C.L. Clearance of beta-amyloid is facilitated by apolipoprotein E and circulating high-density lipoproteins in bioengineered human vessels. eLife. 2017. 10 (6). pii: e29595
About the author:
Dr. Willerth holds a Canada Research Chair in Biomedical Engineering at the University of Victoria where she has dual appointments in the Department of Mechanical Engineering and the Division of Medical Sciences as an Associate Professor. She serves as the Acting Director for the Centre for Biomedical Research at the University of Victoria and on the steering committee of the B.C. Regenerative Medicine Initiative. She also served as the President of the Canadian Biomaterials Society from 2017-2018. Her honors include being named the 2018 REACH award winner for Excellence in Undergraduate Research-inspired Teaching, a Woman of Innovation in 2017, one of the 2015 Young Innovators in Cellular and Biological Engineering and a “Star in Global Health” by Grand Challenges Canada in 2014. She spent Fall of 2016 on sabbatical at the Wisconsin Institute for Discovery supported by the International Collaboration on Repair Discoveries International Travel Award where she wrote her book “Engineering neural tissue using stem cells” published by Academic Press. She completed her postdoctoral work at the University of California-Berkeley after receiving her Ph.D. in Biomedical Engineering from Washington University. Her undergraduate degrees were in Biology and Chemical Engineering from the Massachusetts Institute of Technology.
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