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Bioprinting iPSCs for Disease Modeling

Can you imagine a future in which doctors can study poisons using a custom-made liver or scientists can test drugs on home-grown brains? While such visions may appear fanciful, a study published a few months ago by Advanced Healthcare Materials may have brought us one step closer. Led by Dr. Jeremy Crook, of the University of Wollongong and University of Melbourne, this project introduces a method of bioprinting that successfully combines a 3D scaffolding construct (a supporting structure on which cells can grow) and batches of induced pluripotent stem cells (a.k.a. iPSCs, a type of pluripotent stem cell created by reprogramming more differentiated cells) that can then be differentiated and organized into tissue-like structures. For the authors, this new method of bioprinting cells will hopefully make a significant difference in how scientists study diseases—how they are caused, what damage they do, and how they can be treated.

courtesy google images

The sophistication of disease models has advanced slowly throughout the years. For decades, the only remotely reliable models available for drug testing were animals, ranging from small, less human-like mammals like mice and rats to large primates that share over 97% of human DNA. Even today, using animal models is currently standard procedure in disease research, and the U.S. Federal Drug Administration almost always requires that drugs be tested in vivo (or in a living organism) before they are allowed to enter the clinical trial process. However, the cost of many animal studies is enormous, the moral justifications are dubious, and the accuracy is limited. No matter how evolutionarily similar to humans an animal model may be, drugs that have consistently functioned safely in even pigs or chimpanzees may still cause unexpected and dangerous reactions in a human system. As a result, scientists have started seriously exploring the possibility of using human cells themselves as alternate disease models.

The goal of a good disease model is to accurately simulate the relevant pathological conditions found in the human body. For example, if a researcher wants to study pancreatic cancer, the ideal cell model would be a live three dimensional (3D) human pancreas, with all the complex cell-cell interactions that could play a role in the disease’s course. But until recently, the closest scientists could get to growing an organ was to culture and differentiate human stem cells in a single, flat layer of a two dimensional (2D) well plate. Since then, various efforts to create 3D stem cell structures, from suspending cell spheroids in liquid to encapsulating them in gels, have shown signs of promise. That said, Dr. Crook’s bioprinting method may prove to be among the most practical disease modeling protocols yet.

Bioprinting itself is useful because it uniformly spaces cells along the construct and guides them to form structures that closely resemble the architecture of the desired tissue. In addition, while 3D gel encapsulation of cells is usually done manually, the mechanization of cell seeding within constructs like these allows for the possibility of increased scale, which would be especially useful in clinical and industrial settings. There are a lot of factors to consider in the process of bioprinting: the bioink/scaffold components must be well-defined and animal-free (so the cells produced can be used in clinical trials); the porosity/viscosity of the 3D construct must be perfectly adjusted (so cells can get nutrients, yet be encouraged to adhere to the scaffold); and the printing procedure and gelation (gel-forming process) must be gentle enough for cells to survive. In addition to adjusting for all of these elements, Dr. Crook’s bioink uses novel components like carboxymethyl-chitosan (CMC) and alginate, which not only provide the structural stability for the gel to form, but in some cases actually promote cell adhesion and proliferation.

Realistically, there are limitations to modern bioprinting technology. From improving differentiation efficiency in 3D models to enhancing the resemblance between synthetic scaffolds and human tissue, researchers in the field will likely have their hands full for decades. Still, this study represents an important benchmark in the shift toward reliable, modifiable, and complex cellular disease modeling.

Since 2012, Antara Rao has worked with SSSCR to raise awareness about stem cell science and encourage students to get involved in research. She has served as president of SSSCR’s UC Berkeley chapter and is now the Communications and Sponsorship Coordinator for SSSCR-International’s Executive Committee. Antara’s past research has included 3D differentiation of human Embryonic Stem Cells (hESCs) for potential therapeutic application to Parkinson’s and Huntington’s Disease, and she plans to continue working on clinically relevant stem cell research as a PhD candidate at the University of California, San Francisco, studying Developmental and Stem Cell Biology. Outside of lab, she keeps herself sane with some of her other interests: baking, board games, Kathak dance, and historical literature.

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