Researchers from Harvard’s Wyss Institute for Biologically Inspired Engineering and the John A. Paulson School of Engineering and Applied Sciences (MA, USA) have developed a novel technique yielding viable, organ-specific tissues with high cell density and function, overcoming several hurdles in the 3D printing of organs. The research, published in Science Advances, represents a major breakthrough in 3D printed organ technology and viability.
The team reports that in the United States, 20 people lose their lives waiting for an organ transplant every day. While 30,000 transplant procedures are performed annually, 113,000 people remain on the waiting list.
Since the dawn of regenerative medicine strategies and bioprinting technologies, artificial organs have been regarded as a potential solution for the organ shortage crisis. Recent advances in 3D printing have led to a boom in using the technology within the research and development space, however, 3D printed organs have consistently lacked the cellular density and organ level functions required for them to be considered for organ repair and replacement procedures.
A novel technique, known as 'Sacrificial Writing into Functional Tissue' (SWIFT), embeds vascular channels into stem cell-derived organ building blocks (OBBs) using 3D printing. This represents a major hurdle being overcome as the process yields viable, organ-specific tissue with high cell density and function.
"This is an entirely new paradigm for tissue fabrication," commented co-author, Mark Skylar-Scott (Wyss Institute). "Rather than trying to 3D print an entire organ's worth of cells, SWIFT focuses on only printing the vessels necessary to support a living tissue construct that contains large quantities of OBBs, which may ultimately be used therapeutically to repair and replace human organs with lab-grown versions containing patients' own cells."
SWIFT utilizes a two-step process. It begins with hundreds of thousands of stem cell-derived aggregates being formatted into a dense, living matrix of OBBs that contain approximately 200 million cells per millimeter. A vascular network is then embedded into the matrix by writing and removing sacrificial ink. This is what enables oxygen and other nutrients to be delivered to the cells.
"Forming a dense matrix from these OBBs kills two birds with one stone: not only does it achieve a high cellular density akin to that of human organs, but the matrix's viscosity also enables printing of a pervasive network of perfusable channels within it to mimic the blood vessels that support human organs," explained co-author Sébastien Uzel (Wyss Institute).
The cellular aggregates used in the SWIFT matrix are derived from adult pluripotent stem cells and then mixed with a tailored extracellular matrix solution (ECM). Subsequent centrifugation compacts the cells into the desired dense matrix.
At cold temperatures, 0–4oC, the matrix is able to be manipulated without damaging the cells, making it the ideal candidate for sacrificial 3D printing. A thin nozzle moves through the matrix and deposits a strand of gelatin ‘ink’ that pushes the cells out of the way without damaging the matrix. It is then heated to 37oC where the matrix stiffens and becomes more solid. The gelatin is melted and washed away, leaving a seamlessly connected network of channels embedded within the tissue that can be perfused with oxygenated media to nourish the cells. The size of the channels can vary from 400μm–1 mm.
Organ specific tissues that were printed and perfused with channels embedded using SWIFT remained viable while those that were not experienced cell death at their core after 12 hours.
To test the organ specific functions, they printed, evacuated and perfused a vascular network into heart-derived cells and flowed media through for a week. The cardiac OBBs fused together to form a more solid cardiac tissue structure. Additionally, contractions became more synchronous and increased in strength by 20 times, mimicking key features of the heart.
Further research is currently underway with other universities to transplant these tissues into animal models in order to investigate their integration into host systems. This research provides promising evidence which may hopefully, on day provide some relief from the organ shortage problem.
Sources: Skylar-Scott M, Uzel S, Nam L et al. Biomanufacturing of organ-specific tissues with high cellular density and embedded vascular channels. Sci Adv, 2019; 5 (9): eaaw2459 (2019); https://wyss.harvard.edu/a-swifter-way-towards-3d-printed-organs/
Is 3D printing organs possible?
This is a little bit of a complicated question and one which cannot really be answered definitively...
It is now possible to print - or 'bioprint' - tissues and organoids (small, 3D tissue cell cultures devised from stem cells) which suit a variety of demands within the clinical research and development space, for example, in the early stages of clinical drugs trials. However, some research teams have reported success in 3D printing or bioprinting tissues as small parts of organs, which may, one day, form the basis for printing entire organs or large tissue structures.
The short answer, therefore, is that yes - 3D printing or bioprinting organs is technically possible on a very basic and primitive level, but we are unlikely to be able to observe the benefits of printed organ (or even tissue) transplants for a long time to come.
Find out more about the latest research projects in bioprinting:
- Volumetric bioprinting technique allows quick production of complex vascularized tissue
- Collagen scaffolds: a FRESH take on bioprinting organs
- Breathtaking bioprinting: ‘breathing’ lung model 3D printed
- Vascularized heart 3D printed utilizing patient’s own cells and biological materials
- Applications in neuro R&D
How does 3D printing organs and tissues work?
Essentially, the main principle of 3D printing or bioprinting organs is not dissimilar to standard 3D printing as additive 'layers' are laid in sequence. The fundamental difference is the choice of filament: bioink, typically consisting of a cell-infused hydrogel or alternative media is used for bioprinting tissues, which obviously requires modified, specific 3D printing hardware to ensure the maintenance of the bioink's viability.
It is fairly common for teams to 3D print porous structures called 'scaffolds' that can accommodate induced stem cells which will, ultimately, be responsible for guiding the development of the desired tissue. This is not true in all cases, however, as some teams have been successful in developing techniques for the raw printing of cells, often into specific media, without the need for the printed scaffolds.
A variety of techniques now exist for refining bioprinting techniques - such as the SWIFT technique described in this story - which may employ additional technologies including ultrasound and even magnetism.
Find out more about 3D bioprinting techniques:
- Novel study produces 3D printed tissues without a scaffold
- 3D printed scaffolds for regenerative bone healing strategy
- Collagen scaffolds: a FRESH take on bioprinting organs
What are pluripotent stem cells and why are they appropriate for 3D printing organs?
'Pluripotent' is defined by The Glossary for Cell & Gene Therapy and Regenerative Medicine 2018 as:
"capable of developing into any of the three primary germ cell layers and therefore all cells of the adult body, but not extra-embryonic tissues (e.g., placenta)"
By inducing these cells to develop into the tissue desired or required, researchers are able to develop specific tissues, especially when using a scaffold (or alternative technique as described above).
In the future, this may mean that stem cells harvested from individual patients could be used to 3D print organs or tissue structures specific to that patient, reducing the risk of rejection. However, it is my opinion that is far more likely that bioprinted tissues from stem cells harvested from patients will sooner be adopted in complex cases for patient-specific drugs trials, where scientists may be able to test drugs on tissues to ensure their efficacy prior to administration.
Find out more about stem cell research and regenerative medicine on our sister site, RegMedNet.
>> You can also find out more about the glossary and the journal, Regenerative Medicine, here.
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