Although the sci-fi dream of regenerative medicine where diseased organs can be immediately replaced by those that are bioprinted is still many years in the future, 3D bioprinters today are already beginning to revolutionize the sector. Process optimization that is afforded by this technology will improve rates of lead candidate success, which will drastically decrease development costs.
Additive manufacturing (AM), commonly referred to as ‘3D printing,’ is a revolutionary technology that seems to bleed across disciplines. However, compared to other AM technologies, ”the term ‘bioprinting’ is more conceptual and is not restricted to a specific technology.”1 The term ‘printing’ is perhaps misleading. A more accurate description would be ‘cell patterning,’ since 3D bioprinters do not ‘print’ anything, but instead — with growing precision — align and layer cells in a way that best fosters a relationship between adjacent cells, while creating a structural artifice that enables the formation of a complex system.
How 3D Bioprinters Work
Prior to 3D bioprinting a tissue or organ, a researcher must begin by cultivating the necessary cell types. Before the discovery of inducible pluripotent stem (iPS) cells, if a researcher wanted to propagate a specific cell type, a physician would have had to extract the desired cell type from a precise location within the organ or tissue. As organs and tissues are composed of multiple cell types, a biopsy would be necessary to extract and preserve each cell type for propagation. Thankfully, this is no longer the case. iPS cells, taken from the skin of a patient, can be differentiated into the cell types needed to create most tissues.
Once cells are differentiated and propagated in bioreactors — or by other means of cell culturing — the different cell types are added to separate ‘ink cartridges’ in the bioprinter. Using a derivative of CAD software, cells are patterned and layered in a three-dimensional space with a sacrificial hydrogel that acts as a temporary scaffold to hold the spatial arrangement of cells in place, as well as a stand-in for the extracellular area that will be fabricated by the cells during a post-printing process.
After the alignment of cells in two- and three-dimensional space, the biological manifold is added to a bioreactor where the cells will begin to develop their ‘story.’ Both the slow disintegration of the hydrogel — which allows for the gradual introduction of neighboring cells — and the infusion of chemical signals and growth factors into the bioreactor chamber facilitate tissue maturation. During this process, the cells make intercellular connections by reaching out to each other, much like the root system of a tree searching for nutrients. This is also the point in which vascularization will begin to occur naturally.
The term ‘printing’ is perhaps misleading. A more accurate description would be ‘cell patterning,’ since 3D bioprinters do not ‘print’ anything.
What we are capable of today, which is very exciting, more closely resembles cellular blobs that to some degree are able to mimic organ tissue functions. Although these ‘organoids’ have some mechanical functionality, they still lack the machine-like mechanisms of organs such as the heart and lungs.
The Revolution Today
Regardless of the shortcomings in organ development, 3D bioprinting is already revolutionizing the drug discovery domain. For decades, researchers have struggled with how animal models fail to translate in disease and drug research. Supplementing this with human cell models has helped curb such woes, but even in concert (as they have been used for decades), only one out of 5,000 compounds from the drug pipeline succeeds to market level.2
Current 3D bioprinter technology (despite shortcomings in organ fabrication) still has the potential to revolutionize drug discovery by improving rates of lead candidate success, which will drastically decrease drug development costs.
These 3D bioprinters add a level of complexity to current human cell models. Instead of relying on testing of compounds on a specific cell type, 3D bioprinting allows for the creation of interconnected heterotypic cell types, which create both layers and junctions. Using 3D-printed tissues, researchers can see how small molecules and therapeutics penetrate structural elements intrinsic to tissues and organs, rather than only cells. For example, one cell layer may be hydrophobic while the next is hydrophilic.3
The implications for testing precise medicine that affects one cell type but does not affect adjoining cells has a profound implication for the efficacy of screening compounds. Although these models exist — some even in three dimensions through such processes as microfluidic 3D cellular scaffolds (i.e., ‘organs on chips’ or ‘tissues on chips’) — the real revolution, the revolution that is occurring today with 3D bioprinters, is moving these assay designs from the small scale to the high-throughput and ultra-high-throughput compound screening range. The challenge is to create 3D models where there is not just communication between the cells, but cross talk between tissues and organs.
References
- Vanderburgh, Joseph, Julie A. Sterling, Scott A. Guelcher. “3D Printing of Tissue Engineered Constructs for In Vitro Modeling of Disease Progression and Drug Screening.” Annals of Biomedical Engineering 45.1 (2017): 164-179. Web.
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McCabe, Caitlin. “Can 3-D Printing of Living Tissue Speed Up Drug Development?” The Wall Street Journal. 16 Feb. 2015. Web.
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Shepherd, Benjamin. Organovo Stem Cell Meeting on the Mesa. Organovo Holdings. 27 Oct. 2014. Webinar.
