Why 3d Bioprinting Will Revolutionize Medicine... Eventually

We live in an era of expansive medical innovation. New technologies are being churned out so rapidly that it's difficult for us to ultimately determine which ones will either make a significant impact on our lives, or fall by the wayside. This is not only a challenge for investors, but also for clinicians seeking solutions for the patients they serve. While completing my Doctor of Medical Science (DMSc) degree in 2020 and as part of a research project, I argued that the promise and potential of 3d bioprinting should not be ignored. I believe that this technology will revolutionize medicine as significantly as antibiotics, vaccinations, insulin, chemotherapy, or x-ray imaging has. Yet, many of my colleagues remain in the dark about this fascinating subject. The following is a summary based on my own exhaustive literature review.

3d bioprinting AKA bioprinting, simply defined, is an emerging technology which combines 3d printing techniques (e.g. scaffolds) with living cells. It represents a giant leap forward for the field of regenerative medicine (which I previously described ). Since the inception of bioprinting in the early 2000's, it has become an increasingly popular topic. There was a 40-fold increase in bioprinting related publications observed over the last decade. Using basic inkjet methods, advanced laser, or extrusion-based techniques, these cell-laden structures can be used for either biomedical applications or regenerative therapies . Biomedical uses include the creation of ex-vivo organoids for drug studies, while regenerative applications include implants that could actually repair/replace human tissue. This technology is still in its infancy but advances could soon lead to a bioprinting boom. Bioengineers worldwide have already published their work with living prototypes of various tissues including heart valves, artificial bone, and skin grafts. Whole organ bioprinting is also being explored.

Biomedical Applications

Biomedical applications are leading the charge. Currently in the US, these are the only human trials that appear to be progressing in a meaningful way. One trial aims to create 3d printed organoids/tumors from the cells of myeloma patients ex-vivo to study their response to chemotherapeutic drugs. Another involves the use of preserved cardiovascular thrombi taken from patients to study cardiovascular morbidity and mortality factors. Biomedical approaches may advance personalized medicine and improve therapies, and also reduce the use of animals in research.

Regenerative Applications

In contrast to biomedical applications, regenerative applications (those involving implantation into a living patient), seem to elicit the most excitement in the media but remain further away on the horizon. Imagine a time when patients no longer have to wait on organ transplant lists. When a new pancreas could be generated to cure a patient's diabetes. When a patient's severe burn wound could be rapidly restored to normal hair bearing skin. The possibilities are indeed endless. When I sought to understand these potential applications, I found it helpful to divide them into the following categories; whole organs, cardiovascular, orthopedic, and cutaneous reconstruction.

Whole Organs

Without a doubt, the holy grail of bioprinting would be the ability to create whole, living, and functional organs. In a comprehensive report on this subject , researchers concluded that we have underestimated the complexity of biological tissue and may need to rethink our approach at regenerating them. They argue that until advances in cell biology, material science, engineering, and other important fields appropriately converge on this challenge - we will remain unable to effectively implant a functional whole organ in a patient.

Cardiovascular

Potential cardiovascular applications are many, and any procedures which aim to restore proper blood blow to vital tissues may be impacted. Heart valve defects , coronary artery blockages, and stenoses or aneurysms could all be addressed with this technology. The regeneration of a functional myocardium appears to be more difficult , but the hope is there. This would be life-changing for the many survivors of a myocardial infarction.

Furthermore, the survivability of any large bioprinted tissue is directly dependent on adequate vascularization and perfusion, but blood vessels can only generate so quickly. In a 2019 review on vascular bioprinting techniques , this problem was cited as a significant and rate-limiting hurdle for bioprinting. For this reason, advances in vascular bioprinting would have a significant ripple effect. These researchers described how various types of cells, including stem cells, can be used to create structures that mimic native blood vessels.

Orthopedic

In several ways, the orthopedic world is poised to see the earliest applications of regenerative bioprinting in humans. This is good news as degenerative skeletal diseases such as OA and traumatic critical bone defects are a rising problem with our aging population. Synthetic, xenogeneic, and allogeneic materials have already been in use for many years and have led to open attitudes towards natural constructs and the precision that bioprinting can provide . Vascularized bone tissue has already been created in the lab, and bioprinted constructs were used in animal studies well over a decade ago (the process was considered to be too cumbersome for use in the human surgical setting ). In a 2018 cartilage bioprinting review , the authors describe some promising advancements, including a hand-held multi-nozzle device called the Biopen which in animal models, has shown an ability to deposit stem cells inside protective biopolymer and hydrogel layers. These can then be placed directly onto chondral defects.?This device has also been used in plastic surgery and otorhinolaryngology research, and was considered to be one of the most likely techniques to be applied in humans soon.

Cutaneous Reconstruction

Finally, the reconstruction of cutaneous wounds through the bioprinting of skin and soft tissue is another area in which patients could benefit greatly. There is extensive ongoing research in skin tissue engineering, and products are available (including cellular ones) which aid in healing and significantly improve patient outcomes. However, no commercially available products have been shown to regenerate normal skin or make skin grafting obsolete. While skin grafts continue to be used, they are fraught with challenges including donor site availability/morbidity, the loss of skin appendages, long-term cosmetic issues, and contracture limiting range of motion. Several bioprinting methods are being explored, particularly for use in burn patients where there is a great need to achieve rapid wound closure, reduce infection, decrease LOS, and improve long-term cosmesis/function. In an animal study using athymic mice, researchers were able to form a stratified epidermis, dermis, and blood vessels in full-thickness wounds with bioprinting techniques. This is compelling but does not address one of the major challenges with skin bioprinting. There is a limit to how quickly cells can be cultured, and billions of cells are necessary to print transplant-ready skin. This number rises exponentially with increasing wound size. New cell-expansion technologies are desperately needed to overcome this problem.

Conclusion

In conclusion, bioprinting is likely to become one of the most influential medical advancements of our time, drastically altering multiple disease states and patient care pathways. It is still in the early stages of development and we are many years away from seeing this being used in our patients. It goes without saying, that for the effective adoption of this technology, products will need to show high clinical utility, acceptable ease-of-use, and deliver a strong healthcare economic argument. We will also need to address ethical concerns such as cell sourcing. I predict that the biomedical applications (such as the generation of 3d tumors for drug studies in oncology), will be the first to impact us. In the regenerative implant arena, orthopedic use will come first, followed by either cardiovascular applications or cutaneous reconstruction. Whole organ regeneration is further away still, but I definitely hope to see this in my lifetime.