A Perspective on Bioprinting Ethics

bs_bs_banner C 2016 International Center for Artificial Organs and Transplantation and Wiley Periodicals, Inc. Copyright V Invited Editorial A Perspective on Bioprinting Ethics INTRODUCTION Bioprinting is defined as the use of three-dimensional (3D) printing technology with materials that incorporate viable living cells, for example, to produce tissue for reconstructive surgery (1). Biopolymers or cell-laden hydrogels are arranged spatially in a 3D pattern and built layer by layer into a tissue or organ. The three main bioprinting techniques are laser-assisted bioprinting, inkjet bioprinting, and extrusion bioprinting (2) (Fig. 1). The scope of bioprinting in regenerative medicine is wide. It includes engineered tissues of bone, cartilage, skin, vascular tissues, heart valves, and liver tissues; also the scope includes cancer applications and precision medicine (2–6). Given the high potential of this technology, more and more research labs are getting involved in bioprinting. The number of papers referencing bioprinting has increased fourfold from 2012 to 2015, doi:10.1111/aor.12873 new journals are introduced, and incipient books are being published (7). Hardware is becoming more available and affordable, with burgeoning bioprinting companies introducing new bioprinters in the market; research on biomaterials that can be bioprinted is advancing faster and use of stem cells in bioprinting is being explored. Even with all these developments, the feasibility of having a functional tissue or organ fabricated by bioprinting has a long way to go. The two main challenges to be addressed are vascularization and innervation of the bioprinted tissues. There are many other challenges including the printing resolution, limitations on the viscosity of bioinks, long-term viability of the printed cells, maturation of the printed construct into a tissue, and limited understanding of the cell metabolism throughout the bioprinting process. It might take at least a couple of decades to realize the greater goal of printing a functional organ. In spite of all these limitations, the pace at which the challenges are being addressed by the research community is commendable. While there is appreciable technical progress in the field, the ethical challenges associated with this technology are not contemplated yet. It is high time to foresee the possible ethical and policy issues that might become en route snags to clinical translation of this technology. This paper reviews and foresees some of the unique ethical challenges facing bioprinting compared to tissue engineering in general and discusses the pros and cons of different proposed solutions to overcome these challenges.  BIOPRINTING VIS-A-VIS TISSUE ENGINEERING Bioprinting is a subset technology of the broader field of tissue engineering. It is a sophisticated tool that has the potential to fabricate biomimetic 3D tissues replicating native tissues in vivo and hence, in a way, unique. Before we move on to discuss the ethical challenges unique to bioprinting, it is important to understand how bioprinting stands Artificial Organs 2016, 40(11):1033–1038 1034 INVITED EDITORIAL FIG. 1. Three main bioprinting technologies: (a) Laser-assisted bioprinting focuses laser pulses on to the donor slide, thus creating high pressure to propel droplets of cell-laden hydrogel on to the collector slide. (b) Inkjet printing ejects droplets of biopolymer or cell-laden hydrogels through a nozzle by either thermal energy application (electrically heating to produce vapor bubbles that forces droplets to come out through the nozzle) or piezoelectric actuator (actuation of piezoelectric crystals by applying electrical energy at high frequencies). (c) Extrusion or robotic dispensing bioprinters extrude biopolymers or cell-laden hydrogels through the nozzle by applying air pressure (pneumatic) or mechanical systems (piston or screw) (adapted from [2]). [Color figure can be viewed at wileyonlinelibrary.com] out from general tissue engineering (8). It is appropriate to issue certain caveats here. Bioprinting still has a long way to go to realize the highly desired goal of functional tissue/organ printing. There are myriad challenges to be overcome to achieve this feat. Hence, the uniqueness of bioprinting discussed in this section should be considered as at the matured stage of the technology and as an ideal case (with the assumption that bioprinting matures to the level of organ printing). First and foremost is the ability of this technology to make 3D biomimetic functional tissues that could possibly move toward organ printing in the future. The very idea that fully functional organs can be printed in labs came up only with the advent of bioprinting technology. Though realization of this idea may take a bit of time, it is not impossible and scientists around the globe are diligently striving to achieve this goal. Second, the technology is becoming more accessible with affordable commercial bioprinters being introduced in the market. In the future, not only the bioprinters but also the bioinks of different compositions (according to the intended application) might be available commercially, just like cartridges sold along with printers. With everything available in market, it seems anyone who has money and basic learning skills can bioprint the tissues or organs they wish, unlike the other tissue engineering methods which require specialized training and skill sets. Though it is a highly ideal situation and the technology is far from it, it is important to acknowledge the possibility of such a Artif Organs, Vol. 40, No. 11, 2016 situation when the technology matures. Third comes the perception of this technology by the general public, given their religious and socio-cultural environments. The tissue grafts may be seen by people as a novel treatment method; will they hold the same view when you “make” artificial organs? Fourth is the moral degradation that might creep into the society with the maturation of bioprinting. Though the field of tissue engineering has come a long way, none could have imagined replacing their livers, kidneys, or hearts with custom-made artificial ones without the emergence of bioprinting. Will people care less about their body because they can replace their damaged organs with new ones from an organ shop? Other challenges include classification of the bioprinted product for approval, patenting issues, and policy concerns. ETHICAL CHALLENGES FACING BIOPRINTING The uniqueness of bioprinting has its own share of challenges accompanying it. Though it shares the common ethical concerns that the general field of tissue engineering faces, like the source and donation of cells, especially stem cells (9), the complicated review and approval process for a tissueengineered product (10), there are other challenges that are either unique to bioprinting or much amplified in complexity. They are discussed under different headings namely (i) Ethics concerning “cells”; (ii) Ownership of the bioprinted organ; (iii) Restricted use vs. open source; (iv) Religious and socio- INVITED EDITORIAL cultural acceptance; (v) Research funding, grant usage, and reporting of research results; (vi) Moral degradation; and (vii) Other legal and policy issues. Ethics concerning “cells” The most important constituent of bioprinting is the “cell.” The type of cells used and the cell metabolism play a vital role in determining the characteristics of the final bioprinted tissue. Though it is highly desirable to use the patient’s own cells in the bioprinting process, it is not always feasible. For instance, it is very difficult to harvest enough healthy cells from a patient with large-area third- or fourth-degree burn wounds to use in the bioprinting of skin (2). In situations as these, cells have to be obtained from other willing donors. Four major ethical concerns related with the donation of cells are: (1) privacy of the donor, (2) informed consent of the donor, (3) the possible invasiveness of the cell/ tissue obtaining procedure, and (4) ownership of the donated cell/tissue (9,11). It is sagacious enough to consider the ethical issues of using stem cells in bioprinting even when the technology is at an incipient stage because at some point in time the technology would require the use of stem cells. The main ethical question when it comes to stem cells is the “source.” Use of human fetal cells and human embryonic germ cells face heavy criticism. The primary source of these cells is the embryo or fetus, obtained via induced abortion, thereby legitimizing the practice of abortion. It is even thought to the extent of women conceiving specifically just to get the fetal cells via abortion (12,13). Mesenchymal stem cells (MSCs) are an alternative to fetal cells and embryonic germ cells but suitability of these cells in bioprinting has to be evaluated. Another option is to use xenogeneic cells. However, caution has to be exercised to take into account the social and religious aspects to the use of animal cells. Patients with strong religious beliefs might not accept the use of cells from particular animal species, for example, the reservations of Jews and Muslims for the use of porcine cells (14). Hence, it is important to assess the ethical concerns related to the use of donor cells and stem cells in bioprinting. Another important issue to be considered is the possible change in cell metabolism during the bioprinting process or as a worst case, cell mutagenesis. Though hydrogel-laden cells are successfully printed using various bioprinting processes and the viability of cells are ensured after the printing process, not much data are available as yet on the metabolism of cells before, during, and after the process. If the cells become mutagenic after the 1035 bioprinting process, it might possibly lead to cancer and various other heritable diseases. Further research is needed to prove that the cells retain their normal characteristics even after the process. It is also important to think who will be held liable if such a situation arises. Ownership of the bioprinted organ Organ transplants are possible now because of altruistic donation. While there are controversies surrounding whether the real motive behind every organ donation is altruism or any other factor, organs donors are the only source for those requiring an organ transplant. Bioprinting can play a big role in solving the waiting time crisis associated with organ transplants. An important ethical problem associated with altruistic donation is whether it should be directed (donor chooses the recipient) or kept anonymous (13). Directed donation discards the concept of a waiting list while denial of directed donation might discourage the donors from donating their organs. Bioprinting puts an end to this dilemma as organs can be custom-made for individual patients, ideally from their own cells. The real problem comes when the patients’ own cells cannot be used to bioprint the organ due to various medical reasons. The question of ownership then arises. Does the organ that is printed using the donor’s cells belong to the donor? Or does it belong to the clinician or bioprinting company or the hospital? Or is it a shared ownership? The problem of ownership has been raised (9) even with tissue-engineered products but it is amplified when it comes to bioprinted organs. The perception of people changes when we talk of organs rather than tissues. People might associate more with a functional organ that is printed out of their cells like a heart or kidney than a tissue graft. Second, there might be differences between different organ domains. For example, the mental association of a donor with a heart or brain made out of their cells may be far higher than a bone graft or orthopedic constructs. These complexities have to be understood before framing a guideline for the ownership of bioprinted organs. Other related problems like informed consent of the donor, preventing the use of donated cells or tissues for purposes other than the intended ones (as informed to the donors), etc. are common to the field of tissue engineering and hence beyond the scope of this paper. Restricted use vs. open source The increased accessibility of this technology, as outlined before (in section “Bioprinting vis-a-vis Tissue Engineering”), means the chances of technology Artif Organs, Vol. 40, No. 11, 2016 1036 INVITED EDITORIAL misuse cannot be undermined. If the technology matures to a very ideal state and anybody can print the organ they wish to have by purchasing a bioprinter and suitable bioink, should we allow that to happen? Will it not end up in the wrong hands? Here comes the question of restricted use vs. open source. Open source is a great idea and lifesaving technologies like bioprinting can benefit a lot from it. It will foster new innovations in healthcare, thereby saving more lives. But, there are many challenges in having open source concept for bioprinting. Ensuring the quality and reliability of the product will be better if it is licensed to a company than having it as an open source technology. On the other hand, restricting the use of technology by licensing or patenting will curb the innovation in the field. There are trade-offs which had to be considered before adopting a policy framework for bioprinting. While discussing the patenting issues with bioprinting, Tran (15) differentiates between bioprinting process and bioprinted products and recommends that patents be granted to bioprinting processes but not to bioprinted products. This is one way of looking at the problem. Dividing the field of bioprinting into various tenets (process, materials, products, etc.) and deciding which approach is best for each (licensing or open source, grant patent or deny) might be an effective approach. Religious and socio-cultural acceptance The success of a technology lies with the acceptance of people. The religious and socio-cultural views of people vary greatly and depend on many factors. Different religions hold different views about a particular technology. Take for example, the use of human embryonic stem cells (hESCs) in tissue engineering, therapeutic, and reproductive cell cloning (16). Some religions prohibit the use of hESCs, therapeutic, and reproductive cell cloning (Catholics and Orthodox), some accept research on hESCs and therapeutic cloning but prohibit reproductive cloning (Christians and Muslims), some prohibit research on hESCs and therapeutic cloning but accept reproductive cloning (Buddhists), while some accept all three (Jewish). How will the bioprinted organ be viewed by various religious groups? Will they accept as it can save lives? Or will they deny as they might think “humans can’t play God”? These views have to be taken into consideration. It is also worth mentioning that different countries will have different perceptions on the technology (16,17). For instance, some countries like the UK, Denmark, Japan, the Netherlands, and Korea have authorized therapeutic cloning, while it is prohibited Artif Organs, Vol. 40, No. 11, 2016 in France, Germany, Spain, Italy, Austria, Ireland, Sweden, Belgium, India, Canada, and Australia. Will bioprinting face the same fate as well? Social acceptance of a person with a bioprinted organ is another factor to be discussed. Just like the first in vitro fertilization (IVF) baby or cloned animal is seen differently, people with a bioprinted organ might be seen with indifference at first. These soft issues concerning the treated patients have to be considered also. Though bioprinting is not as disrupting as IVF or cloning, it is better to evaluate the technology in totality to prevent the technology from being doomed. Research funding, grant usage, and reporting of research results There is much hype surrounding the bioprinting technology both in academia and in industry, garnering more attention from the investors and funding agencies. Lysaght and Hazlehurst (18) studied in detail the disappointing product launches in the field of tissue engineering and list a number of tissue-engineered products or technologies that were launched with much fanfare but later abandoned or discontinued. Investment on bioprinting research should not end up joining this long list of “promising” technologies that were claimed to be close to clinical translation but failed miserably as those claims were too early to be translated from bench to bedside. Care should be taken to ensure that the money for bioprinting research is properly allocated, in the best interests of the patients and tax payers. Researchers, on the other hand, should not report false claims and successes to attract more funds. This ethical dilemma between the funding agencies and the researchers should be handled with much care. A common global registry for the pre-clinical and clinical trials of bioprinted products will help in better transparency. It is important to ensure that the results as observed or obtained are reported without any amendments or embellishments. This will help in assessing the true rate of success of this technology and the technology readiness level for clinical translation. Moral degradation Moral degradation can happen with the maturation of bioprinting and establishment of organ shops. Products that are widely accepted as injurious to health contain health warning labels. A pack of cigarettes bearing tobacco warning labels is an example. The warnings remind the consumers of the ill effects of the product or the habit itself. With bioprinting, when organ printing is realized and organ factories are established, will it degrade INVITED EDITORIAL the morale of people? Will they consume more tobacco now that they can get a new pair of lungs? Will they drink too much as they can get their liver replaced? Will the advertisements of the companies be on these lines? This is a serious ethical question to consider. Should the access to bioprinted organs be restricted to genuine patients rather than having it open to anybody who can afford to buy? If such restriction is put forth, will it be taken as deprivation of individual rights? Other legal and policy issues Other legal and policy issues concerning bioprinting are patenting and intellectual property (IP) rights, product classification and approval pathways, pre-clinical and clinical trials, and government regulations. It is estimated that 3D printing will result in a loss of at least 100 billion USD per year in intellectual property, by 2018 (19). Measures have to be taken to control the problem of IP theft. As discussed in section “Ownership of the Bioprinted Organ,” trade-offs between restricted use and open source have to be evaluated. Next comes the product classification and approval pathways for a bioprinted product. Is the existing FDA product classification of device, biologic, drug, and combination product (device/drug or device/biologic) enough for bioprinted products? Or does a new classification system and approval pathway have to be established? The question becomes prominent with the highly interdisciplinary nature of bioprinted products. A bioprinted product can function as an organ with provisions for sustained or targeted drug delivery or growth factors delivery. It is important to identify the classification under which such a multi-functional product will come and what are the tests required to approve it. Manufacturing process guidelines for fabricating a bioprinted product should also be established and approved. The feasibility of pre-clinical and clinical tests with bioprinted products have to be evaluated. Selection of patients, patient specificity, and fair evaluation of the success of clinical trials and accessibility of the clinical trial data by clinicians globally are related issues. Since bioprinting involves handling of patients’ clinical data (medical imaging data, lab reports), steps should be taken to ensure data privacy and confidentiality. Last but not least, the government policies and regulations on the use of technology, taking into account all the above considerations and challenges, play an important role in the success of this technology. Setting up a multidisciplinary panel at the national and international level to discuss and debate on 1037 the policy framework for bioprinting will aid in smooth clinical translation of this technology (8). CONCLUSION Life sciences and biomedical industries are greatly benefitting from the very useful bioprinting technology. Biomimetic functional engineered tissues and organs fabricated by bioprinting (at technological maturity) will not only serve the patients waiting for replacement tissues and organs but also pharmaceutical industries for drug discovery and testing. Though the technological progress is commendable, the ethical questions surrounding bioprinting are not addressed suitably. There are unique ethical challenges facing bioprinting compared to tissue engineering in general. The need for a separate “bioprinting ethics” framework should be appreciated and acknowledged. Guidelines have to be in place regarding the ownership of the bioprinted organ. Tradeoffs between licensing and open source policy have to be considered and a framework has to be established. Religious and socio-cultural views, along with the question of moral degradation have to be considered and addressed suitably. Legal and policy issues associated with this technology have to be addressed by the governments. Setting up a multidisciplinary panel at the national and international level to discuss and debate on the policy framework for bioprinting will aid in the smooth clinical translation of this technology, thereby proving better treatment options to ailing patients. Sanjairaj Vijayavenkataraman Department of Mechanical Engineering National University of Singapore Singapore E-mail: [email protected] Biosketch: Sanjairaj Vijayavenkataraman received his B.Eng (Mechanical Engineering) from College of Engineering, Guindy, Anna University, India. He is currently a President’s Graduate Fellow (doctoral candidate) in the department of Mechanical Engineering at National University of Singapore, Singapore. His research interests include 3D bioprinting, additive manufacturing, biomaterials and hydrogels. His research interests also lie in 2D materials such as graphene for biomedical and energy applications. REFERENCES 1. OED Online. Oxford University Press, June 2016. Web. 8 June 2016. Artif Organs, Vol. 40, No. 11, 2016 1038 INVITED EDITORIAL 2. Vijayavenkataraman S, Lu WF, Fuh JY. 3D bioprinting of skin: a state-of-the-art review on modelling, materials, and processes. Biofabrication 2016;8:032001. 3. 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