InBrief
In the United States (US), there are approximately 104,000 people on the organ transplant list with a new person added to that list every 10 minutes. Each day, 17 people in the US die waiting for an organ transplant, and about a million people worldwide are in need of a kidney.[1,2] Thus the idea of being able to produce replacement organs is highly desirable.
The cost of initiating renal dialysis treatment in US patients is estimated to be around $80,000 for each Medicare patient and $238,000 for a privately insured patient.[3] Medicare costs for continuing renal dialysis treatment are about $40,000 per patient per year.[4] In 2020, according to research published by the American Society of Nephrology, the average cost of a kidney transplant was $442,500.[5] When 3D kidneys become available, costs of removing the kidney from a donor and transporting it to the recipient would be eliminated, but there would be other expenses such as maintaining cell banks that can grow cells for bioinks.[1] However, it is possible that implanting 3D printed organs will be less expensive than traditional transplants[5], and depending on life expectancy, less expensive than renal dialysis.
History
In 2006 Anthony Atala and his colleagues performed one of the first partial replacement of organs grown from a patient’s own tissue. Seven children with myelomeningocele* who had high-pressure or poorly compliant bladders were determined to be candidates for cystoplasty**. A biopsy was performed and bladder and muscle cells were taken from the patients and those cells were allowed to proliferate in the laboratory. They spread a layer of the cells on the outside of a bladder-shaped, biodegradable mold of synthetic polymer and collagen, with muscle on the outside and bladder urothelial cells on the inside. The organ part was bathed in nutrients for about seven weeks, at which time they were then successfully surgically attached to the patient's bladder. Subjects that had omentum wrapped around the implant had the most improvement in bladder function.[6,7]
(* A condition where the spine does not fuse properly and the infant is born with a sac containing part of the spinal cord.)
(** Surgery to enlarge the urinary bladder.)
More recently the idea of using 3D printers to produce organs has been explored. The term “3D printing” was first coined by Charles W. Hull in 1986. He named the method “stereolithography,” and used a thin layer of materials sequentially printed layer by layer with UV light to form a 3D structure [8]. This method was later modified using biomaterials to form 3D printed scaffolds of cells. Biomaterials are natural or synthetic substances containing living stem cells, which are also called bioinks and are the key components of bioprinting.[8]
The 3D Bioprinting Process
To begin the process of bioprinting an organ, doctors typically start with a patient’s own cells. The process involves taking a small needle biopsy of an organ or performing a minimally invasive surgical procedure that removes a small piece of tissue. This tissue is processed and put inside a sterile incubator or bioreactor, which is a pressurized stainless-steel vessel that duplicates the body’s oxygen and temperature levels and supplies the cells with individualized nutrients that vary by cell type. Those cells are then combined with a gel, to produce a bioink, which is a printable mixture of living cells, water-rich molecules called hydrogels, and the media and growth factors that help the cells continue to proliferate and differentiate. The hydrogels mimic the human body’s extracellular matrix, which contains substances including proteins, collagen and hyaluronic acid. Collagen and gelatin are two of the most common biomaterials used for bioprinting tissues or organs. Biomaterials typically are nontoxic, biodegradable and biocompatible to avoid a negative immune response. The bioink is then loaded into a printing chamber in a 3D printer. A printhead and nozzle are used to extrude the bioink and build the material up layer by layer. Similar to a color printer where you have several different cartridges, where each cartridge prints a different color, bioprinting uses different type cells instead of ink. The length of the printing process depends on the organ or tissue being printed, the fineness of the resolution and the number of printheads needed. Depending on the organ’s complexity, there is sometimes a need to mature the tissue further in a bioreactor. While organs or partial organs can be produced by 3D printing now, the issue of connecting it to the patient’s vascular and nervous system and have it actually function has not been solved, and it is estimated by some experts that it may take at least another decade to do so.[1]
In the 3D bioprinting process a computer-generated model first needs to be produced as a template for the 3D printer to follow. Computer-aided design in the future will allow patient individualization of a 3D printed organ by the printers being programmed with data from a patient’s imaging scans. 3D printing of organs is technically very difficult. Just a few of the issues involved in reproducing a lung are requirements to produce very small individual alveoli and their surrounding vascular structures, duplicating a dual vascular system, and creating ciliated cells in the mucosa.[8]
The Future of 3D Organ Printing
In 2014, a California-based company called Organovo was the first to successfully engineer commercially available 3D bioprinted human liver and kidney tissue. Although the tissue is actual liver and kidney tissue, it is not usable at the present time for transplants, but can be used for research purposes. One published example is using 3D printed liver tissue for drug testing, to determine if there are any toxic effects on liver cells from the drug being tested.[5,10]
There is now animal experimentation using rat omental tissue or progenitor cells from bone marrow to create cardiac tissue which is then grafted onto their hearts.[11,12] In one study, after implanting a patch of cardiac cells in rats who had induced myocardial infarctions, the implants improved cardiac function.[11] Researchers are also attempting to use spider web silk as the framework for cardiac bioprinting, as spider silk is felt to be an excellent source to produce hydrogels needed for 3D printing.[13,14] Ureters, the esophagus, bile ducts, urethras, intestines, skeletal muscle and bone are all areas of current interest in organ bioprinting, and it is possible in the future that almost any body part might be able to be reproduced.[8] With respect to the time frame of 3D printing being used clinically, it is felt that organs such as skin may be the first tissue to be successfully bioprinted. It is predicted the next stage will be production of hollow tubes such as blood vessels, followed by hollow organs such as urinary bladders and finally, much further in the future, solid organs.[15]
Conclusion
In the future, 3D bioprinting of tissue and organs may become the preferred way of treating patients who require organ or tissue transplants. The technology is in its infancy, and while tissue from organs can be produced now, and used for research purposes, the tissue is not functional due to the complexity and multiple functions of real human organs. It is estimated it might take at least a decade to be able to solve some of these problems and actually use 3D printed organs clinically.
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References
[1] Rogers K. When we’ll be able to 3D-print organs and who will be able to afford them CNN Health. Updated March 10, 2023. Retrieved from: https://www.cnn.com/2022/06/10/health/3d-printed-organs-bioprinting-life-itself- wellness-scn/index.html [2] Organ Donation Statistics. Department of Health & Human Services Health Resources & Services Administration. Last Reviewed: March 2023. Retrieved from: https://www.organdonor.gov/learn/organ-donation- statistics#:~:text=Who%20is%20on%20the%20Transplant,the%20national%20transplant %20waiting%20list. [3] League RJ et al. Assessment of Spending for Patients Initiating Dialysis Care. JAMA Network Open. October 28, 2022. Retrieved from: https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2797907 [4] Pockros BM, Finch DJ, Weiner DE. Dialysis and Total Health Care Costs in the United States and Worldwide: The Financial Impact of a Single-Payer Dominant System in the US. J Am Soc Nephrol. 2021;32(9):2137-2139. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8729831/ [5] 3D-printed organs and their affordability. Global data. June 15, 2022. Retrieved from: https://www.medicaldevice-network.com/comment/3d-printed-organs-affordability/ [6] Atala A, Bauer SB, Soker S, Yoo JJ, Retik AB. Tissue-engineered autologous bladders for patients needing cystoplasty. Lancet. 2006;367(9518):1241-1246. Retrieved from: https://pubmed.ncbi.nlm.nih.gov/16631879/ [7] Pearson H. Scientists grow bladder replacement in lab. Nature. 4 April 2006. Retrieved from: https://www.nature.com/news/2006/060403/full/news060403-3.html#B1 [8] Panja N, Maji S, Choudhuri S, Ali KA, Hossain CM. 3D Bioprinting of Human Hollow Organs. AAPS PharmSciTech. 2022;23(5):139. Published 2022 May 10. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9088731/ [9] Ramadan Q and Zourob M (2021) 3D Bioprinting at the Frontier of Regenerative Medicine, Pharmaceutical, and Food Industries. Front. Med. Technol. 2:607648. Retrieved from: https://www.frontiersin.org/articles/10.3389/fmedt.2020.607648/full [10] Nguyen DG, Funk J, Robbins JB, et al. Bioprinted 3D Primary Liver Tissues Allow Assessment of Organ-Level Response to Clinical Drug Induced Toxicity In Vitro. PLoS One. 2016;11(7):e0158674. Published 2016 Jul 7. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4936711/
[11] Atluri P, Trubelja A, Fairman AS, et al. Normalization of postinfarct biomechanics using a novel tissue-engineered angiogenic construct. Circulation. 2013;128(11 Suppl 1):S95-S104. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4111241/ [12] Dvir T, Kedem A, Ruvinov E, et al. Prevascularization of cardiac patch on the omentum improves its therapeutic outcome. Proc Natl Acad Sci U S A. 2009;106(35):14990-14995. Retrieved from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2736451/ [13] Crawford M. 3D-printed spider silk can grow heart muscle cells. The Alliance of Advanced Biomedical Engineering. October 23, 2017. Retrieved from: https://aabme.asme.org/posts/3d-printed-spider-silk-can-grow-heart-muscle-cells [14] Petzold, J., Aigner, T. B., Touska, F., Zimmermann, K., Scheibel, T., Engel, F. B., Adv. Funct. Mater. 2017, 27, 1701427. Retrieved from: https://onlinelibrary.wiley.com/doi/10.1002/adfm.201701427 [15] Murphy, S., Atala, A. 3D bioprinting of tissues and organs. Nat Biotechnol 32, 773– 785 (2014). Retrieved from: https://www.nature.com/articles/nbt.2958