Gray N White

Can We Print the Future of Healthcare?

Introduction

Three-dimensional (3D) bioprinting is bringing about a paradigm shift in personalised medicine in the 21st century.  According to a report by Mordor Intelligence (1), the global 3D bioprinting market was valued at USD 724.17 million in 2020 and is expected to reach USD 2398.27 million by 2026, growing at a CAGR of 21.91% over the forecast period (2021-2026). It has been predicted that the Asia-Pacific region has the highest scope for growth due to present demands (2).

There’s presently an overwhelming demand for donated organs. However, it takes a long time to get an organ transplant through the donor list due to a shortage of adequate, compatible organ donors. There is also the matter of organ rejection and an extended course of immunosuppressants post transplantation (3). India has one of the lowest rates of organ donation in the world at 0.86 per million (4)

Traditional methods of tissue engineering haven’t had much success in this aspect, both from a feasibility and economic point of view (5), bringing about a need for alternatives. Additionally, there are certain conditions, like spinal cord injuries, that currently have no known cure.

There have also been increasing objections against the use of animals for drug testing, clinical trials and cosmetics over the past few years. 3D bioprinting has been hailed as a method that can potentially overcome all these problems. This article aims to evaluate the current trends, applications and challenges of 3D bioprinting.  

How does 3D Bioprinting work?

The aim of 3D bioprinting is to mimic the cell in an anatomically accurate way, while maintaining its structure and function. It works similarly to 3D printing, except that a living cell suspension is utilised instead of a thermoplastic or a resin.

According to Gu et al., the process of 3D bioprinting can be divided into 4 steps (6) – 

  1. Data acquisition – 3D models are obtained by X-ray, CT, MRI etc, and then divided into 2D horizontal slices by specific software. This data is further processed into particles or filaments according to different bioprinting approaches
  2. Bioink Preparation – Materials that include cells, growth factors, hydrogels, etc., collectively called ‘bioink’, are selected according to the requirement of printed structures and approaches
  3. Bioprinting – The bioink is deposited layer by layer
  4. Functionalization – After printing, the dispersed cells form connections and generate some functions of natural tissue/organ through physical and chemical stimulation

While there are various types of 3D bioprinting, the Extrusion-based bioprinting is currently the most widely used method (6).

The Scope of 3D Bioprinting 

While the long-term goal is to be able to use 3D bioprinting for organ regeneration and transplantation, it is quite arduous and currently not feasible. Instead, the current short-term goal is to use it to successfully replicate tissue for pharmaceutical drug trials, toxicology and research.

Innovating Healthcare

3D bioprinting provides the opportunity to test drugs at a lower cost, in a shorter duration and in a more biologically relevant way compared to animal testing. Pharmaceutical companies like Aspect Biosystems have been developing bioprinted lung tissue for this purpose since 2015 (3). It has expanded to address the management of type 1 diabetes, through printing human beta-like cells (2, 7)

Organovo Inc. developed a bioprinting process in which human primary hepatocytes, hepatic stellate cells, and endothelial cells were used to bioprint liver-like tissue constructs and then utilised to monitor the hepatic tissue response to methotrexate and thioacetamide exposure (8)

In another study, Kupffer cells were added to examine their impact on the injury/ fibrogenic response following cytokine and drug stimuli (9). Heinrich et al. demonstrated the construction of mini brains consisting of glioblastoma cells and macrophages as tools for testing therapeutics that target the interaction between these two cell types (10).

Several breakthroughs in 3D tissue bioprinting were demonstrated recently to create organ-level structures including bone, cornea, cartilage, heart, and skin. Zhou et al. constructed a patient-specific ear-shaped cartilage using expanded microtia chondrocytes and a biodegradable scaffold (8).

In situ bioprinting, or the placement of de novo tissue directly onto the desirable part of the body, has also been explored. Albana et al., demonstrated precise delivery of autologous/allogeneic dermal fibroblasts and epidermal keratinocytes directly into an injured area in animals, replicating the layered skin structure (11)

Recent advances have been made in creating a living neural tissue scaffold. This has important implications in the management of spinal cord injuries, widely known for being untreatable (12).

Tumour Models and Cancer Research

Progress has also been made in cancer research. Tumours are characterised by a high degree of heterogeneity and complexity. The fabrication of suitable in vitro models of the microenvironment is difficult as two-dimensional (2D) models do not completely recapitulate the biochemical and biophysical signals of the tumour environment. Thus, three-dimensional (3D) tumour models, particularly 3D bioprinted models, are emerging as a vital tool since it has a competitive advantage due to the ability to precisely control and define the desired structure and position of multiple types of cells in a high-throughput manner (13)

In 2019 Langer et al., made 3D bioprinted scaffold-free tumours using patient-derived cells to examine if the growth and development of pancreatic cells could be recapitulated in vitro. This model was able to mimic many features of pancreatic adenocarcinoma tumour cells, including response to extrinsic signals and in vivo morphology (14). Similar in-vitro 3D bioprinted tumour models have been developed for glioblastoma, breast cancer and ovarian cancer as well (15)

Challenges of 3D Bioprinting

The challenges of 3D bioprinting can be broadly categorised under 3 headings –

Technical Concerns

A major drawback is that suitable printing materials are not currently available which can withstand high temperatures, organic solvents and crosslinking agents in the printer (16).

The cell source may either be animal derived, autologous or allogeneic. Animal sources, while enabling greater mass production, pose the risk of xenosis. Autologous and allogeneic sources offer greater biocompatibility but involve tighter regulation, lengthier production times and higher costs. Teratoma formation, recurrence or potentiation of malignancy from stem cells is also a concern. There is also the risk of immunogenicity, inflammation and infection due to the foreign nature of some components of the bioink derived from non-human sources (17)

Further research is needed to investigate the risk of toxicity as by-products are released into the bloodstream and undergo renal or hepatic clearance (18)

Regulatory Concerns

Current legislation does not regulate the circulation of biological materials taken from donors for the purpose of conducting scientific research, does not provide guarantees of protection rights of donors, and does not stipulate the mandatory procedure for the preliminary approval of research by ethical committees (19, 20). There is also the added possibility of illegal trafficking of such tissues and organs.

Ethical Concerns

In the case of xenogeneic cells, it is necessary to take into consideration the social and religious aspects of animal cell utilisation. Patients with xenotransplantation might experience psychosocial problems associated with their personal identity (21). A study by Vermeulen et al. (22) showed that only 40% of the public were willing to accept an animal organ, and had reactions of disgust or ‘yuck’ for mixing of human and animal sources. Moreover, patients with religious beliefs may disagree with the use of cells of certain animal species. Another issue is that patients cannot withdraw their consent post-implantation.

Conclusion

3D bioprinting has been evolving at a rapid rate with newer inventions and technology turning over every other day. It provides a unique opportunity in the field of personalised medicine to  potentially solve the overwhelming demand for organ transplantation, as well as transform traditional methods of pharmaceutical drug testing, research and toxicology.  As promising as it is, it poses several legal and ethical concerns which haven’t been addressed, largely due to the mere pace of development and innovation, many of which have surpassed our current understanding of their implications.  Before being made clinically accessible and produced on a mass scale, these concerns need to be addressed. Additionally, newer technology such as 4D bioprinting, in which the concept of time has been integrated into 3D bioprinting, is emerging as the next-generation form of innovation.  

References

  1. Mordor Intelligence. 3D Bioprinting Market – Growth, Trends, COVID-19 Impact, And Forecasts (2022-2027).  Available at: https://www.mordorintelligence.com/industry-reports/3d-bioprinting-giving-new-life-drivers-barriers-and-trends-industry  Accessed on: 17/02/2022.
  2. Market Data Forecast, APAC 3D Bioprinting Market Size & Growth (2021-2026), published April 2021.      Available at: https://www.marketdataforecast.com/market-reports/apac-3d-bioprinting-market Accessed on: 17/02/2022.
  3. Jovic TH, Combellack EJ, Jessop ZM, Whitaker IS. 3D Bioprinting and the Future of Surgery. Front Surg. 2020;7:609836. doi:10.3389/fsurg.2020.609836
  4. Organ India. Organ Donation Facts and Figures. Available at: https://www.organindia.org/make-a-pledge/ Accessed on: 17/02/2022.
  5.  Liu X, Hao M, Chen Z, et al. 3D bioprinted neural tissue constructs for spinal cord injury repair. Biomaterials. 2021;272:120771. doi:10.1016/j.biomaterials.2021.120771
  6. Gu Z, Fu J, Lin H, He Y. Development of 3D bioprinting: From printing methods to biomedical applications. Asian J Pharm Sci. 2020;15(5):529-557. 
  7. Farina M, Ballerini A, Fraga DW, Nicolov E, Hogan M, Demarchi D, et al. 3D printed vascularized device for subcutaneous transplantation of human islets. Biotechnol J. (2017) 12:1700169. doi: 10.1002/biot.201700169
  8. Ramadan Q, Zourob M. 3D Bioprinting at the Frontier of Regenerative Medicine, Pharmaceutical, and Food Industries. Front Med Technol. 2021;2:607648. doi:10.3389/fmedt.2020.607648
  9. Norona LM, Nguyen DG, Gerber DA, Presnell Merrie SC, Mosedale, et al. Bioprinted liver provides early insight into the role of Kupffer cells in TGF-β1 and methotrexate-induced fibrogenesis. PLoS ONE(2019) 14:e0208958. doi: 10.1371/journal.pone.0208958
  10. Heinrich MA Bansal R Lammers T Zhang YS Schiffelers RM Prakash J3D-bioprinted mini-brain: a glioblastoma model to study cellular interactions and therapeutics. Adv Mater. (2019) 31:1806590. doi: 10.1002/adma.201806590
  11. Albanna M, Binder KW, Murphy SV, Kim J, Qasem SA, Zhao W, et al. In situ bioprinting of autologous skin cells accelerates wound healing of extensive excisional full-thickness wounds. Sci Rep. (2019) 9:1856. doi: 10.1038/s41598-018-38366-w
  12. Liu X, Hao M, Chen Z, et al. 3D bioprinted neural tissue constructs for spinal cord injury repair. Biomaterials. 2021;272:120771. doi:10.1016/j.biomaterials.2021.120771
  13. Kang Y, Datta P, Shanmughapriya S, Ozbolat IT. 3D Bioprinting of Tumour Models for Cancer Research. ACS Appl. Bio Mater. 2020, 3, 9, 5552–5573
  14. Langer, E. M. et al. Modelling tumour phenotypes in vitro with three-dimensional bioprinting. Cell Rep. 26, 608–623.e6 (2019).
  15. Datta, P., Dey, M., Ataie, Z. et al. 3D bioprinting for reconstituting the cancer microenvironment. npj Precis. Onc. 4, 18 (2020).  
  16. Mao, Hongli & Yang, Li & Zhu, Haofang & Wu, Lihuang & Ji, Peihong & Yang, Jiquan & Gu, Zhongwei. (2020). Recent advances and challenges in materials for 3D bioprinting. Progress in Natural Science: Materials International. 30. 10.1016/j.pnsc.2020.09.015. 
  17. Jovic TH, Combellack EJ, Jessop ZM, Whitaker IS. 3D Bioprinting and the Future of Surgery. Front Surg. 2020;7:609836. doi:10.3389/fsurg.2020.609836
  18. Navarro J, Calderon GA, Miller JS, Fisher JP. Bioinks for three-dimensional printing in regenerative medicine. Princ Regen Med. (2019) 805–30. 10.1016/B978-0-12-809880-6.00046-1 
  19. Vasiliev SA, Osavelyuk AM, Burtcev AK, et al. Problems of Legal Regulation of Diagnostics and Human Genome Editing in the Russian Federation. Lex Russica. 2019;6:71–79. DOI:10.17803/1729-5920.2019.151.6.071-079. 
  20. Stambolsky DV, Bryzgalina EV, Efimenko AY, et al. Informed Consent to the Receipt and use of Human Cellular Material. Juristic and Ethical Regulation Russ J Cardiol. 2018;12:84–90. doi:10.15829/1560-4071-2018-12-84-91.
  21. Gulyaev VA, Khubutiya MS, Novruzbekov MS, et al. Xenotransplantation:History, Problems and Development Prospects. Transplantol Russ J Transplant. 2019;11:37–54.
  22. Vermeulen N, Haddow G, Seymour T, et al. 3D bioprint me: a socioethical view of bioprinting human organs and tissues. Journal of Medical Ethics 2017;43:618-624.

Leave a comment:

About Author
Categories