3D printing and bioprinting: ethical and legal issues

Safety

A major ethical issue occurring in any novel application of advanced technologies is that of safety. ⁶

6 Patuzzo S, Goracci G, Ciliberti R, Gasperini L. 3D bioprinting technology: scientific aspects and ethical issues. Sci Eng Ethics 2017;10; Gilbert F, Viana JNM, O'Connell CD, Dodds S. Enthusiastic portrayal of 3D bioprinting in the media: ethical side effects. Bioethics 2017;6–7.

To make sure that 3D bioprinting applications do not create risks for the individual health of patients (and possibly for public health and the environment as well), we need to determine acceptable standards of safety for the use of replicated biological material. This is not entirely a technical matter, in the sense that the term “acceptable” presupposes an evaluation of available technical data, which encompasses also a certain selection between risks; safety standards eventually mean prevention of major detectable risks, even if we are aware of the possible occurrence of risks considered as insignificant or other unforeseen risks. To make that distinction, by suggesting a safety threshold, this inevitably presupposes ethical judgments about the risk “quality,” which cannot be deduced simply by measuring biomarkers or other relevant scientific data.

Indeed the achievement of “absolute” safety is never the case for any biomedical novelty, as unforeseen natural effects may always emerge. In conventional clinical trials, for instance, aiming for the development of new pharmaceuticals, strict safety standards need to be confirmed in every step, during the research, until the successful completion of the trial and the grant of licensing for marketing the new product. Still, this is a short-term evaluation of safety issues, directly related to the reaction of the volunteers' organism during the trial phases. This does not cover potential risks that may occur in the long term, after the product's disposal in the market and its normal administration to patients, according to the approved prescription guidance. For addressing that problem, a standard procedure of pharmacovigilance for detecting such risks usually ensures a higher degree of safety. ⁷

7 WHO/The Uppsala Monitoring Center, The importance of Pharmacovigilance. Safety monitoring of medicinal products, WHO ed. 2002, Chapt. 4.

This example is characteristic of the inevitable relative judgments on safety in biomedical applications, that is, the relative accuracy of risk assessment in relevance.

Following the above approach, in principle, safety management of bioprinted products should be addressed under the same ethical terms as for other known biomedical products (drugs, transplants, implants, etc.) meant for interventional medical acts. We know that, for such products, certainty of risks is crucial for determining standards of safety. The opposite approach, known as “precautionary principle,” characterizes currently the application of novel technologies in the environment, particularly those involving genetic engineering, nanotechnology, etc. ⁸

8 See, in general, Andorno R. The precautionary principle: a new legal standard for a technological age. J Int Biotech L 2004;1:11. Also, in the field of “soft-law,” see The Rio Declaration on Environment and Development (Rio de Janeiro, 1992), Principle 15.

These technologies are associated with high degree of risk uncertainty, due to the relatively limited level of our knowledge regarding fundamental biological data, such as genes' and genomes' interactions and phenotyping, details on the function of food chain, etc. To prevent unforeseen risks that might create serious and extensive harm to the environment, which could be irreversible, the “precautionary principle” requires measures to be taken even in conditions of risk uncertainty (including a complete ban of the concrete application), which is something more strict than an effort to positively detect such risks. The justification of that stricter approach of safety lies on the extent of possible environmental degradation, when a novel application is deliberated in the Nature. This is not the case of medical interventions in individual organisms, where the risks may occur to a rather limited extent, even if theoretically we cannot exclude wider implications affecting public health. Therefore, for guaranteeing safety in biomedical applications of all kinds, it is sufficient to detect risks in a positive sense, and take appropriate measures for addressing them, with no need to apply a “precautionary” approach.

Risks in 3D bioprinting are categorized in two main groups. First, it is necessary to ensure safety of the replicated biological material itself, if used in the form of transplants, that is, to avoid the possibility of contamination and emergence of pathogens that could compromise not only the individual health of the receiver of the transplants, but public health as well. Second, safety is involved in the functioning of the new transplants in the receivers' organism, that is, their suitability with the new biological environment. The first issue is already known from the field of xenotransplantations, where major problems related to pathogenic transplants (due to deep differences in the animal/human biology) risking generating serious infectious diseases obstruct such applications. ⁹

9 For other moral dilemmas in relevance, see Caplan AL. Is xenografting morally wrong? (Transplantation Proceedings 1992). In: Kuhse H, Singer P, editor. Bioethics. An anthology. Oxford: Blackwell; 1999, p. 404.

The second issue is already addressed in conventional tissue and organ transplantations. The difference with 3 D bioprinting is that there is no evidence that transplants produced are indeed functional, as they have never have been part of a donor's organism previously; their potential is to be tested for the first time in the receivers' organism, which might prove much more dangerous, even if the quality of the graft as such has been tested successfully.

Consent

The development and use of 3D printed and bioprinted products need to refer to the standard governing all medical acts, that is, the informed consent of patients. Informed consent ensures respect of the patient's autonomy, in other words it establishes personal control over the biological condition of our organism. The autonomy maxim represents a fundamental shift in understanding the patient/physician relationships, as opposed to the approach of medical paternalism, dominant for centuries in Western medicine, according to which the physician needs to hold full control and responsibility over the condition of health of a rather “passive” patient. Extensive changes occurred not only due to notorious historical deviations from the basic medical duty ¹⁰

10 See, for the Nazi's Germany and Japan's experience, McNeill PM. Experimentation on human beings. In: Kuhse H, Singer P, editors. A companion to bioethics. Oxford: Blackwell; 2001, p. 369. Also, in the U.S., Curran WJ. The Tuskagee syphilis study. N Eng J Med 1973;730.

but also due to the complexity in practicing medicine (given the increased degree of physicians' specialization, the rapid introduction of technology, and the availability of massive information difficult to be “digested” in everyday medical performance), led eventually to the recognition of an active role for patients (or, in general, for healthcare receivers) in their relationships with the attending physicians.

According to their new role, patients need to consent prior to undergoing any medical act proposed by the physician (regarding treatment, prevention, or diagnosis), with the necessary condition of appropriate information provided by the latter. ¹¹

11 Beauchamp TL, Childress JF. Principles of biomedical ethics, fifth ed. Oxford U.P.; 2001. p. 77.

That information may include more options, which means that the patient needs to choose among these, orienting the physician's therapeutic plan. On the other hand, patients do not dictate that plan, as they do not have the option to ask for specific medical acts. Being the expert, the physician is always the one who has the responsibility to propose ¹²

12 See, in that line, Patuzzo S, et al. p. 10.

and the nonexpert patient needs only to accept, choose or not, according to his/her preferences.

In that complex relationship, the physician may also disagree with the patient's stance, either for scientific or for conscious reasons, and abstain from the patient's care. ¹³

13 Beauchamp TL, Childress JF. p. 38.

Such a disagreement usually emerges before starting the informed consent process, in cases where the patient requires a medical intervention unacceptable on scientific grounds or contrary to the physician's moral beliefs. On the other hand, after setting up the therapeutic relationship, the patient always has the option to refuse treatment, within the informed consent framework, if does not consent to the physician's proposals. ¹⁴

14 Cantor NL. A patient's decision to decline life-saving medical treatment: bodily integrity versus the preservation of life. Rut L Rev 1973;26:228–64.

Nevertheless, in emergency situations, where time is a crucial factor for the medical act's effectiveness, the informed consent process needs to be followed only in compliance with that condition. Thus, if there is no time to inform the patient or his/her proxies, to obtain genuine consent, the attending physician has a moral duty to proceed immediately to the necessary medical act, based upon his/her scientific knowledge and experience, with the sole purpose to perform effectively. ¹⁵

15 See Moskop JC, Iserson KV. Triage in medicine, part II: underlying values and principles. Ann Emerg Med 2007;49:282–7, Oviedo Convention, article 8.

Still, even in cases of emergency, the physician needs to consider previous wishes of the patient (advance directives), if existing, as those are evidence of personal autonomy and deserve respect. ¹⁶

16 Capron AM. Advance directives. In: Kuhse H, Singer P, editors. A companion to bioethics. Oxford: Blackwell; 2001. p. 261.

Genuine consent and the role of patient education

A major difficulty that we need to address regarding consent is to confirm its genuine nature. ¹⁷

17 See, in general, Beauchamp TL, Childress JF. pp. 88–93.

Genuine consent means that the interested person expresses free decision after having received appropriate information by the expert physician. Information should be complete and nonbiased to ensure freedom in decision making by the nonexpert patient. Even in conventional medical practice, that process presents problems, since no objective evidence exists to confirm physicians' good performance in information. Indeed, written documentation is not enough to check this; patients need specific information, ¹⁸

18 Beauchamp TL, Childress JF. p. 83.

in oral form mostly, enabling them to pose questions and have concrete answers by their attending physician. Therefore, the quality of information depends on factors like the physician's selection of its important elements, according to his/her subjective assumptions, or the subjective level of knowledge and ability of each patient to understand and process these elements. Such factors are not measurable and are always suspect to facilitate manipulation of the patients' will, even nonintentional. ¹⁹

19 Beauchamp TL, Childress JF. p. 95.

Biased consent is often due to the information that nonexpert persons receive from other than the attending physician sources, mostly from the media. That is the case of novel biomedical applications, products of advanced technologies in biomedicine, including 3D printing or 3D bioprinting. The world of media represents the most eager promoter of impressive novelties, promising breakthroughs in Medicine, even if no reliable scientific evidence in relevance exists. The announcement of such promising applications, mostly by popular media, shapes the information that the general public absorbs, and forms a basic positive stance to most people, patients or not. ²⁰

20 Gilbert F, et al. p. 1.

That portion of unconfirmed or even false original knowledge becomes problematic in patient–doctor relationships, when specific information on available treating options is required by the attending physician. A patient may object to conventional proposed options, if already convinced by a novel application, just because a popular anchorman or website has said so. This is problematic for the informed consent process, since the patient's prejudice in favor of the novelty obstructs communication with the attending physician. An extra effort by the latter is, thus, required to “clean” the patient's understanding from the false information upon which he/she relies, enabling appropriate transmission of reliable knowledge. ²¹

21 For the responsibility of experts regarding the presentation of scientific announcements to the public, see Gilbert F, et al. p. 9.

That form of transmitting reliable knowledge by the attending physician, based upon a face-to-face approach, is essential, since a patient is more open to accept information by the expert he/she trusts mostly in the concrete therapeutic relationship. Yet regarding novel technological applications, such as 3D printing or bioprinting, there is no guarantee that the attending physician is always able to accomplish this role, particularly when educated patients have already strong beliefs about certain applications. Such strong beliefs are usually formed after personal elaboration of relevant information that patients have received from various sources (media, Internet, popular nonscientific articles, etc.). As the physician is not always familiar with that volume and details of information accessible by the general public, a need for developing strategies of patient education, with the aim to “filter” popular information, ensuring transmission of basic knowledge, seems obvious. Education will enable patients to prepare their general attitude regarding the use of novel applications with valid information, facilitating the role of attending physicians during the informed consent process. The patient organizations are major players in developing programs of education, along with medical associations, and official scientific media open to patient access.