3D bioprinting, an additive manufacturing technique, allows the building of living tissues and organs layer by precise layer, much like a conventional 3D printer creates objects1. Here, the ‘ink’ contains living cells and biocompatible materials. This technique has the capability to precisely mimic the intricate natural extracellular matrix and cellular arrangement found in biological tissues, thus making it possible to create functional, living biological constructs. 3D bioprinting is poised to revolutionize healthcare as we know it, especially the fields of regenerative medicine and tissue engineering, by offering unprecedented control over the placement of cells and biomaterials that traditional methods often lack1, 2.
The “why” behind 3D bioprinting
The impetus behind 3D bioprinting stems from the severe shortage of organs for transplantation globally, which has led to immense suffering and loss of life3. 3D bioprinting offers a potential solution by providing the ability to create personalized tissues using a patient’s own cells, thereby eliminating the critical risk of immune rejection.
3D bioprinting also helps to achieve precise cellular arrangements, such as the creation of complex vascular networks within thick tissues, in addition to scaling up production for complex structures, areas where traditional tissue engineering struggles4.
The art and science of 3D bioprinting
The magic of 3D bioprinting lies in its two primary components: the bio-inks and the specialized printing technologies.
Bio-Inks
Bio-inks are essentially composed of living cells suspended within polymers. The polymers can be natural polymers like alginate, gelatin, collagen, hyaluronic acid, and fibrin, as well as synthetic polymers like PEG and PLGA1. The choice of cells within the bio-ink can range from patient-specific induced pluripotent stem cells and mesenchymal stem cells to differentiated cells like cardiomyocytes (heart muscle cells), hepatocytes (liver cells), or neurons5.
An ideal bio-ink must possess several critical properties.
- Biocompatible: The bioink must be non-toxic and not trigger an immune response from the body, ensuring the printed cells and tissues can survive and function6.
- Biodegradable: The material should be able to break down naturally in the body at a rate that allows the newly formed tissue to take over and provide structural support6.
- Mechanically stable: It needs to be strong enough to hold its shape after printing without collapsing6. This way it can support the cells and the growing tissue until it matures fully.
- Printable: The bioink must have specific fluid properties, such as the right viscosity and flow, to be extruded accurately through a nozzle6. This will ensure that the desired shape is printed with high resolution.
- Cell viability support: The material must provide a nourishing environment for the embedded cells, to ensure that they remain alive and healthy both during and after the printing process6.
- Mimics extracellular matrix (ECM): The bioink’s composition should closely resemble the native ECM of the target tissue6. This will help to provide the necessary signals and cues to encourage the cells to grow, differentiate, and organize properly.
Bioprinting technologies
Different bioprinting technologies offer varying degrees of precision, speed, and suitability for different tissue types:
Extrusion-based bioprinting
In this method, continuous strands of viscous bio-ink are dispensed through a nozzle to achieve high cell densities and good mechanical strength. This makes it suitable for printing larger, more robust structures like cartilage and bone scaffolds7. However, the technique suffers from lower resolution and potential for some shear stress on cells.
Inkjet-based bioprinting
In this technique, tiny picoliter-volume droplets of bio-ink are deposited onto a substrate with high resolution and speed8. This makes it ideal for precise cell patterning and creating thin tissue layers, which are often used in drug screening platforms. However, it can only handle lower cell densities and produce more fragile structures.
Laser-assisted bioprinting (LAB)
This method utilizes a pulsed laser to vaporize and deposit high-resolution droplets of bio-ink, offering exceptional precision in cell placement and minimal cell damage. Such capabilities make LAB invaluable for printing intricate structures like vascular networks and neuronal circuits9, 10. However, it is a slower and more expensive method.
Light-based bioprinting
Light-based bioprinting uses UV or visible light to quickly crosslink photosensitive bio-inks layer by layer. This enables the printing of complex, high-resolution geometries, such as complex scaffolds and detailed tissue models, with good cell viability. A drawback is the requirement for photo-initiators, which can sometimes be cytotoxic, and the limited range of photosensitive bio-inks11.
Once printed, these delicate constructs are typically moved into bioreactors, with precise control over nutrients, oxygen, and mechanical stimulation, for mimicking the conditions inside the human body12. This crucial post-printing maturation phase allows the cells within the construct to differentiate, self-organize, and develop into functional tissue, including vital vascular networks, before they are ready for implantation or further study.
Applications and impact of 3D bioprinting
The potential applications of 3D bioprinting are vast and transformative.
Regenerative medicine and organ fabrication
3D bioprinting is revolutionizing regenerative medicine by enabling the precise fabrication of living tissues and organs.
- In the field of dermatology, bioprinting can produce functional skin grafts for patients with severe burns and wounds, which can significantly improve healing and reduce the risk of infection13.
- For orthopedic applications, the technology allows for the creation of load-bearing cartilage and bone implants, which are custom-designed for a patient’s specific needs14.
- For cardiovascular diseases, 3D bioprinting enables the printing of vascular grafts and heart tissue patches, that could one day be used to repair damaged heart muscle15.
- For neurological applications, researchers are working to utilize 3D bioprinting to print nerve tissue to repair spinal cord injuries and damaged peripheral nerves16.
- The ultimate vision for this field is the bioprinting of entire, transplantable human organs, such as livers and kidneys, to alleviate the critical shortage of donor organs worldwide17.
Drug discovery and development
3D bioprinting is profoundly changing drug discovery and development by providing more accurate and relevant models for research18. It is now possible to create sophisticated 3D disease models, including realistic tumor models, bioprinted organoids, and “organ-on-a-chip” systems, to better understand disease progression and test the efficacy of new drugs19, 20.
Now, it is also possible to use a patient’s own cells for creating custom models21. This allows researchers to screen for the most effective treatments for that individual.
By providing human-specific tissue models for preclinical testing, 3D bioprinting can potentially reduce the reliance on animal testing, leading to more reliable and ethically sound research outcomes.
Advanced research and disease modeling
Beyond medical applications, 3D bioprinting is a powerful tool for fundamental biological research and disease modeling22.
It is now possible to study complex cell-to-cell interactions and observe how tissues develop in a controlled, 3D environment that closely mimics the human body23. This helps to acquire a deeper understanding of biological processes that are difficult to study using traditional two-dimensional cell cultures.
Additionally, 3D bioprinting allows for the integration of living cells into robotic components, leading to the development of novel “bio-actuators” and “bio-robotics” with unique functionalities24, 25.
Challenges and Future Directions
Despite its incredible promise, 3D bioprinting faces significant hurdles.
- Attaining vascularization while creating large tissue constructs remains the most formidable challenge26. This is crucial, as developing an intricate network of blood vessels throughout the entire printed tissue is essential to ensure that cells receive adequate oxygen and nutrients, and to remove waste.
- Scaling up to print truly functional, large, and complex organs (like a full heart, kidney, or liver) with all their intricacies is challenging, but research is ongoing to make that possible in the future27.
- Ensuring that printed tissues fully mature to adult functionality and seamlessly integrate with the host body is highly critical21.
- Developing bio-inks that are ideal for long-term cell survival and viability and tissue development is an active area of research28.
- Clear and consistent regulatory frameworks need to be established for these novel biological products29.
- Reducing the high cost of current bioprinting technologies, through the development and availability of low-cost bioprinter models, is essential for widespread clinical adoption30.
The future of 3D bioprinting is exceptionally bright.
- Multi-material and multi-cell bioprinting are expected to see rapid advancements31. This will enable the creation of even more complex and heterogeneous tissues with higher precision.
- In vivo bioprinting also holds immense potential32. In this technique, tissues are directly printed within the body for repair, for example, printing a skin graft directly onto a wound.
- Organ-on-a-chip systems will see greater integration with 3D bioprinting going forward20. This will be like combining living tissues with microfluidics for more advanced and realistic drug testing and disease modeling.
- More sophisticated bioreactors will likely be developed, which will enhance and accelerate the maturation and functional development of bioprinted tissues and organs33.
- Artificial intelligence, nanotechnology, and robotics will find increased integration with 3D bioprinting, which will lead to accelerated discovery and automation34-36.
Conclusion
3D bioprinting stands as a transformative technology at the intersection of engineering, biology, and medicine, with the potential to fundamentally change healthcare. As research progresses from laboratories to rigorous clinical trials, we might enter an era where replacement parts for the human body are not merely harvested or mechanically replaced, but grown intelligently, cell by living cell.