Translating 3D Bioprinting for Clinical Applications

blank blank Sep 06, 2021

The enormous potential to transform regenerative medicine and current bottlenecks to progress. One question I am often asked when interacting with the general public is, “how close are we to being able to 3D bioprint human organs”? This question has become increasingly relevant as 3D bioprinting technologies continue to advance to the point where technology previously only featured in science fiction shows is on the horizon. For example, the television show Westworld – based on the Michael Crichton novel, envisions a world where people, horses, and an assortment of other living things can be produced using only their fictional 3D printing technologies. Interestingly, we already have 3D bioprinters capable of generating tissue substitutes with the end goal of transplantation. Dr. Axel Guenther’s group at the University of Toronto has been hard at work developing a novel, handheld 3D bioprinting system for generating skin tissues that are not only directly implantable but also able to promote skin regeneration and scar reduction in trauma care (Figure 1). This printer has already been evaluated in animal models and is expected to be seen in a clinical setting within 5 years. You can read more about Dr. Guenther’s group here.

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Figure 1. Handheld 3-D skin printer developed by Dr. Guenther’s group. Image provided by Daria Perevezentsev via University of Toronto Engineering News

However, skin is a relatively simple organ to reproduce through 3D bioprinting in terms of its cellular composition and structure- not all structures are mechanically stable once printed. Therefore, other research groups are currently developing tools to generate more complex organs – such as heart replacements or artificial pancreases. Dr. Adam Feinberg’s group at Carnegie Mellon University and his start-up company – FluidForm – have done extensive work in developing tools for 3D printing more complex structures- using their novel technique freeform reversible embedding of suspended hydrogels (FRESH). Using FRESH (Figure 2), printed structures are supported until they are fully cured- allowing even hearts and heart valves to be printed. This technology was recently reviewed by their group as detailed here. Another team at the Vancouver based biotechnology company, Aspect Biosystems, is currently running several major pre-clinical programs working towards generating the necessary data for translating the efficacy of 3D bioprinted tissue models for clinical translation. More about their research efforts can be read here.

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Figure 2. A schematic depicting the FRESH printing process. Image provided by Andrew Hudson (FluidForm) via 3DHeals.

One major challenge in engineering implantable organs is figuring out how to generate the number of cells required to produce such engineered tissue, while also being able to print stable structures that will accurately mimic the function of the target tissue. Typical tissues found in the body have high cell densities and thus printing truly mimetic organs requires millions of cells to be cultured prior to starting the printing process. The degree of complexity found in the target tissue will also dictate the difficulty of the process needed to replicate that structure. As stated above, bioprinting skin replacements then present a lower bar to clinical translation compared to more complex organs such as the heart. Stem cells serve as an important tool for bioprinting as these cells can both self-replicate to produce more stem cells as well as differentiate into mature phenotypes. Thus, the use of bioreactors- systems designed to grow large quantities of cells- will play an important role in enabling the use of 3D bioprinting for the generation of replacement organs. These systems contain monitoring systems to ensure cell survival and function are maximized during the expansion process and are produced by companies like Pall and Sartorius.  

The tissues found in our body are nourished and maintained by a system of blood vessels known as vasculature. Being able to replicate this network in a bioprinted tissue can be challenging due to the requirements to maintain functional blood vessels while also ensuring proper integration into the tissues. Prellis Biologics has developed a novel laser-based 3D printer that generates high-resolution structures that resemble the different types of vasculature found in the tissues of the body- while also being cell and transplant compatible. While these structures are not yet of sufficient size to enable replication of larger organs – this technology represents an important first step towards generating vascularized tissues. 

Similar technologies have been developed by Dr. Jordan Miller (Rice University and Volumetric Bio) who has developed a 3D bioprinter that uses stereolithography to quickly and consistently generate functional blood vessels. This technology is also compatible with the use of other bioprinters when generating 3D bioprinted tissue models. 

A final challenge when 3D bioprinting tissues for human implantation, is the development and validation of bioinks that do not use animal-derived products, as these materials can trigger an immune response. My company- Axolotl Biosciences has developed a novel bioink that does not rely on such components while also being compatible with any patient’s cells- further minimizing the risks associated with transplantation (Figure 3). Our novel bioinks support superior levels of stem cell survival (>90%) and differentiation compared to other commercially available inks. Our recent Advanced NanoBiomed Research publication demonstrates how our microsphere-laden inks could generate responsive neural tissues from stem cells. You can learn more about Axolotl Biosciences on our website.

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Figure 3. Axolotl Biosciences has a novel bioink shown here. Our ink is compatible with multiple bioprinters, including the Cellink BioX platform. Image courtesy from Axolotl.

Overall, while there are several major challenges to be addressed, thanks to the innovative solutions of research groups all over the world- the future is quite promising for the development of 3D bioprinted tissues for transplantation.

About the Author:

Stephanie Willerth

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 a Full Professor. She runs an active research group that engineers tissues from stem cells and is currently starting a company to sell bioinks for engineering neural tissues. 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. 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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