Rheolution Article | June 2021
How close are we to have a 3D printed organ?
by Dr. Dimitria Bonizol Camasao
Senior Application Specialist, Rheolution Inc.
From creating customized pieces to fix something at home to replacing defective parts of machines and even developing prototypes of new products, the commercialization of 3D printers has created new possibilities for users worldwide. A next step is to use this technology to produce parts or entire healthy organs to improve or even establish new treatments for diseases. The possibility of producing customized shapes using different materials has been attracting researchers and companies in the biomedical field to start developing personalized 3D printed organs.
The idea behind printing organs involves the use of hydrogels as the “ink” because they are the material that closely matches the properties of the tissue matrix. Human cells are also incorporated into the hydrogel to give life and functionality to these constructs. The bioink (hydrogels with cells) is then loaded into the printer and processed in the desired form following a model created with a computer-aided design (CAD) software. This process involves a number of challenges before, during and after the printing process, especially concerning the viscoelastic properties of the bioink and the final construct. But this is not negative: having identified the shortcomings of the process means a clearer path to mastering it! Some of the main issues that researchers are currently working on to bring extrusion-based 3D printer into the medical care are described below:
A. Poor shape fidelity of hydrogels
The inherent low viscosity (before printing) and slow gelation (during and after printing) of hydrogels do not allow them to stand on their own and keep their shape once printed. One strategy to improve this issue is to blend hydrogels with different synthetic biopolymers. Another option is to modify the hydrogel by adding chemical groups to their chains which under specific stimulus will bind and accelerate the gelation. These stimuli include changes to the pH, temperature, addition of other chemicals, light at specific wavelengths, among others.
B. Cell viability:
The printing process can be harmful for cells. First, the printer needs to fit in a biological hood to maintain the sterility of the printed construct. In addition, the parts of the printer that will be in contact with cells should be sterile and should not release toxic compounds into the bioink. Processing conditions such as temperature and solvent need to be carefully selected. For example, high temperature and concentrated solvents can immediately kill the cells. The level of shear stress generated within the printer’s nozzle due to the pressure applied for extrusion can also significantly affect cell behavior and viability or even disrupt the cell membrane.
C. Matching the properties of tissues:
The final 3D printed organ or construct needs to be a favorable environment for the resident cells so they can grow, multiply and enrich it by producing the proteins normally found in tissues. The biomaterial used in the bioink is expected to provide an initial support for the cells and it will be progressively degraded and replaced by the forming tissue in vitro or in vivo. Therefore, the initial mechanical properties of the printed construct must be as close as possible to those of the native tissues (more information about this topic can be found in our previous publication). The viscoelastic properties of hydrogels have been tuned by varying the working concentration or by chemically modifying it at different levels. The viscoelastic properties of the construct as a whole have been tuned by varying its microstructure (porosity, pore size, nozzle/fiber dimensions) and composition (pure or blended hydrogels).
Overall, hydrogels are being modified and developed to meet the processing requirements of the different 3D printing technologies AND the requirements for cell survival and function. This is not an easy task but great advances have already been made in the field. For example, the Wake Forest School of Medicine in collaboration with the Armed Forces Institute of Regenerative Medicine have developed a printer to print skin cells on burn wounds and have reported to be close to clinical trials. Their main goal is to bring the technology to battlefields to immediately treat soldiers suffering extensive burns suffered in severe traumas. This could overcome the lack of efficient alternatives since unburned skin to harvest is not always available and skin products are limited in size and take a long time to produce. A later release to the civilian population is also intended.
We are getting closer to using 3D printing in medical care. The great effort devoted to make the use of this technology a reality in the field is reflected in the high number of publications in the last decades and in the emergence of clinical trials. The technology has the potential to help in the treatment of several diseases and it is a unique solution to organ shortage. Organ transplants may not be as challenging in the future!
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Ever fantasized about sci-fi healing tanks? The principle of neutral buoyancy behind them has sparked a unique solution for 3D printing with soft, liquid-like inks. The Freeform Reversible Embedding of Suspended Hydrogels (FRESH) bioprinting technique has been developed to support the printing of these tricky materials, ideal for tissue engineering applications. The secret lies in a cleverly engineered support bath, able to hold the soft structures while permitting extruder needle movement. With versatility, high cell viability, and potential for large construct printing, FRESH opens up a world of possibilities, bringing us a step closer to 3D bioprinting patient-specific tissues based on anatomical data.
Exploring the frontier of 3D printing, Cornell University researchers have enhanced the Freeform Reversible Embedding of Suspended Hydrogels (FRESH) method. They introduced a computational approach for non-planar printing, enabling complex curved structures, improving printing accuracy and augmenting the mechanical properties of bioprints.
4D bioprinting introduces "time" as the fourth dimension, enabling printed objects to change over time. Physical stimuli like light, temperature, or magnetism can induce transformations. The bioprinting process can also allow targeted drug release through changes in temperature or pH. Nano-hydrogels can serve as drug carriers, directed by magnetic fields, and can be quickly degraded by enzymes. Furthermore, hydrogels can react to biological signals, aiding in tumor treatment by releasing drugs then biodegrading over time.
4D-bioprinting introduces "time" into the printing process, allowing printed structures to evolve. Researchers from the University of Illinois Chicago used oxidized and methacrylated alginate (OMA) to develop a bioink for 4D bioprinting. They made OMA into precursor beads, then transformed them into a "microgel" that could be easily printed into stable 3D constructs. Mixed with cells, the microgel became a bioink, which was printed into complex structures. The printed constructs could be further crosslinked to create 3D scaffolds that could change shape due to differential swelling, adding the 4th dimension, "time," to the printing process.
3D-bioprinting involves printing a biomaterial or 'bioink' that contains cells, forming structures similar to living tissues. The process requires careful optimization to ensure the material holds its shape and function, and that the cells survive the printing process. Current bioprinting techniques, such as extrusion, inkjet and laser-assisted bioprinting, come with their own advantages and limitations. The ultimate goal is to bring in vitro bioprinting into the operating room, overcoming challenges like sterility, regulation, and ethical considerations.
Recent advancements in 3D-bioprinting have opened the possibility of creating engineered tissues mimicking human native tissues. However, reproducing the extracellular matrix (ECM) composition and microscopic architecture within the biomaterial ink remains challenging. To tackle this, a research group from the AO Research Institute Davos developed a bioink containing both collagen type 1 and tyramine derivative hyaluronan for tissue engineering. They used optimal concentrations of these two components, along with human bone marrow-derived mesenchymal stromal cells. Two crosslinking pathways were used to induce gelation and create a 3D scaffold that was then printed using the bioink's shear-thinning properties. They successfully printed an anisotropic hydrogel, achieving control over the microscopic organization of the matrix. This breakthrough could pave the way for better mimicry of native human tissues, especially anisotropic ones, in tissue engineering applications.
