The Ethical Implications of Tissue Engineering for Regenerative Purposes: A Systematic Review

Abstract

Tissue Engineering (TE) is a branch of Regenerative Medicine (RM) that combines stem cells and biomaterial scaffolds to create living tissue constructs to restore patients' organs after injury or disease. Over the last decade, emerging technologies such as 3D bioprinting, biofabrication, supramolecular materials, induced pluripotent stem cells, and organoids have entered the field. While this rapidly evolving field is expected to have great therapeutic potential, its development from bench to bedside presents several ethical and societal challenges. To make sure TE will reach its ultimate goal of improving patient welfare, these challenges should be mapped out and evaluated. Therefore, we performed a systematic review of the ethical implications of the development and application of TE for regenerative purposes, as mentioned in the academic literature. A search query in PubMed, Embase, Scopus, and PhilPapers yielded 2451 unique articles. After systematic screening, 237 relevant ethical and biomedical articles published between 2008 and 2021 were included in our review. We identified a broad range of ethical implications that could be categorized under 10 themes. Seven themes trace the development from bench to bedside: (1) animal experimentation, (2) handling human tissue, (3) informed consent, (4) therapeutic potential, (5) risk and safety, (6) clinical translation, and (7) societal impact. Three themes represent ethical safeguards relevant to all developmental phases: (8) scientific integrity, (9) regulation, and (10) patient and public involvement. This review reveals that since 2008 a significant body of literature has emerged on how to design clinical trials for TE in a responsible manner. However, several topics remain in need of more attention. These include the acceptability of alternative translational pathways outside clinical trials, soft impacts on society and questions of ownership over engineered tissues. Overall, this overview of the ethical and societal implications of the field will help promote responsible development of new interventions in TE and RM. It can also serve as a valuable resource and educational tool for scientists, engineers, and clinicians in the field by providing an overview of the ethical considerations relevant to their work.

Impact statement

To our knowledge, this is the first time that the ethical implications of Tissue Engineering (TE) have been reviewed systematically. By gathering existing scholarly work and identifying knowledge gaps, this review facilitates further research into the ethical and societal implications of TE and Regenerative Medicine (RM) and other emerging biomedical technologies. Moreover, it will serve as a valuable resource and educational tool for scientists, engineers, and clinicians in the field by providing an overview of the ethical considerations relevant to their work. As such, our review may promote successful and responsible development of new strategies in TE and RM.

Introduction

Tissue Engineering (TE) uses biomaterials, (stem) cells and bioactive molecules to construct functional, living three-dimensional (3D) tissues in a laboratory environment (in vitro) or directly in a patient's body (in situ). Examples include tissue engineered skin, 3D bioprinted bone, and liver organoids for transplantation. TE is one of three pillars of the broader field of Regenerative Medicine (RM), which aims to “replace or regenerate human cells, tissue, or organs to restore or establish normal function.”¹ Stem cell (SC) transplantation and gene transfer (GT) constitute the other two pillars.

As a rapidly evolving medical technology that has been argued to be potentially disruptive² and even paradigm-changing,³ TE holds great promise for novel cures, but also requires attention to the ethical implications of its development, clinical translation, and future impact on individuals and society. Addressing such ethical implications early on and embedding societal values into the design of TE products will help TE to reach its ultimate goal of improving patient welfare.⁴

The TE field has been maturing over the last two decades and ethical issues have received attention of ethicists, social scientists, and ethics-minded biomedical scientists and engineers. This body of literature has last been reviewed comprehensively in 2008, at which time the field was still in its infancy.⁵ Since then, the first applications have reached the stage of clinical application.^6,7 Emerging technologies such as 3D bioprinting, biofabrication, supramolecular materials, induced pluripotent stem cells (iPSCs), and organoids have entered the TE field, and a shift has taken place toward strategies that mobilize the inherent regenerative capacity of the human body–and its endogenous cell populations–to a greater extent than before (in situ TE).^2,8

Therefore, we have performed a systematic review (SR) of the ethical implications of the development and application of TE for regenerative purposes, as mentioned in the academic literature. While TE might have applications outside RM (e.g., as a drug screening platform or for in vitro meat production), we have focused on the clinical application of TE for tissue regeneration. To our knowledge, this is the first time that the ethical implications of this field have been reviewed in a systematic manner. An SR has the advantage of being comprehensive, methodologically rigorous and transparent, and of reducing (selection) bias.⁹

Method

We performed an SR to identify the ethical implications of the development and application of TE for regenerative purposes. The reviewing process was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for SRs¹⁰ and the adapted PRISMA ethics guidelines by Kahrass et al.⁹ Ethical implications were broadly understood to be expressions of an ethical or societal issue or consideration, which may but need not take the form of a fully argument-based reason.¹¹

Search strategy

Four databases (Embase, PubMed, Scopus, and PhilPapers) were searched for relevant English language articles using a search string combining search terms for (a) TE, RM, or bioprinting with (b) ethics or human rights, covering the period January 01, 2008 until October 05, 2021. An experienced librarian was consulted regarding the design of the search strings and choice of databases to ensure that relevant keywords were included, and that a comprehensive area of biomedical, bioengineering, and ethics literature was covered. The original search was performed on March 30, 2020 and updated on October 05, 2021. See Supplementary Data S1 for the complete search strategy of all databases.

Inclusion and exclusion criteria

Articles were screened for eligibility by A.J.K based on title, abstract, and keywords, and next, if applicable, based on the full text, using Rayyan software (Fig. 1). Inconclusive screening decisions were resolved through consultation with K.R.J. and A.L.B.

FIG. 1.

Overview of the number of articles identified and included throughout the several phases of the screening process, depicted according to the PRISMA guidelines.

Articles (e.g., original research, editorials, opinion articles, letters) published in English in a peer-reviewed academic journal in the period January 01, 2008 to October 05, 2021, which discussed an ethical implication of the development or application of TE for regenerative purposes, were eligible for inclusion. Also included were articles that discussed as their main topic ethical or societal implications of RM more generally, provided that these implications were applicable to TE as well.

Excluded were book chapters, conference articles, and news articles, in addition to articles on RM that discussed SC transplantation/research or GT instead of TE. Also excluded were ethical implications related to the source of (stem) cells and the use of embryonic tissues, which have been discussed in depth elsewhere.^12–14 Supplementary Data S1 for a more detailed description of the inclusion and exclusion criteria.

As a minimal standard for quality assessment, articles had to be published in a peer-reviewed journal.

Data extraction and analysis

Full texts of the included articles were analyzed systematically using a data extraction sheet (Supplementary Data S1) (A.J.K.). For each article, information was extracted about publication type, publication year, and about the topic and aim, substantiated by relevant quotes. Moreover, one-sentence descriptions of the relevant ethical implications mentioned in each article were extracted (referred to as an implication mention), substantiated by one or more quotes. Quote lengths diverged from one sentence up to page-length. Additional quotes were extracted to preserve contextual information relevant to the ethical implications where necessary.

A thematic analysis was conducted to synthesize the data, using data synthesis sheets (Supplementary Data S1).¹⁵ Implication mentions were compared across articles, and combined into implication types based on close similarity (compare “reason mention” and “reason type” as described by Strech and Sofaer)¹⁶ (A.J.K.). Implication types were then thematized using a coding tree of four hierarchical levels (i.e., with primary, secondary, and tertiary sub themes under each main theme) (A.J.K.). Each implication type was assigned to one sub theme. If more than one sub theme was applicable, the most suitable one was selected. The formulation of the implication types and the coding tree was then evaluated by all authors and optimized through an iterative process of discussion and adaptation until agreement on a meaningful thematization was reached between all authors (A.J.K., K.R.J., M.C.V., and A.L.B.).

Results

The database search resulted in the identification of 2451 unique articles. Of these, 237 articles were considered eligible and were included in this review (Fig. 1).

Characteristics of included articles

The included articles encompassed reviews in natural sciences (n = 61/237) and humanities (n = 19/237), original research in natural sciences (n = 13/237) and humanities (n = 56/237, of which were 8 empirical and 48 theoretical studies), perspectives (n = 68/237), and other publication types (n = 20/237, of which were 10 workgroup and project reports, 5 interviews, 3 methods articles, 1 case report, and 1 book review) (see Supplementary Data S2). The articles discussed TE for regenerative purposes as a main topic (n = 115/237, including 21 on bioprinted implants and 4 on organoid transplantation) or subtopic (n = 65/237, including as a main topic: 9 on Advanced Therapy Medicinal Products (ATMP), 8 on SC transplantation, 6 on RM, and 6 on in vitro TE), or discussed RM, broadly yet in a manner relevant to TE, as their main topic (n = 51/237) or subtopic (n = 6/237) (Supplementary Data S2). The articles were published in 2008 (n = 10), 2009 (n = 17), 2010 (n = 13), 2011(n = 9), 2012 (n = 10), 2013 (n = 18), 2014 (n = 22), 2015 (n = 33), 2016 (n = 16), 2017 (n = 23), 2018 (n = 14), 2019 (n = 24), 2020 (n = 21), and 2021 (n = 18).

Synthesis of the ethical implications of TE for regenerative purposes

A range of ethical implications of TE for regenerative purposes was identified in the included literature. These were categorized into 10 main themes. The first seven themes cluster phases of TE development from bench to bedside:

• (1)animal welfare
• (2)handling human tissue
• (3)informed consent
• (4)therapeutic potential
• (5)risk and safety
• (6)clinical translation
• (7)societal impact.

The remaining three themes group overarching ethical domains for safeguarding responsible development:

• (8)scientific integrity
• (9)regulation
• (10)patient and public involvement.

The ethical implications (as “implication types”) identified in the literature are discussed below per main theme and sub theme, and are also summarized in Tables 1–10. Supplementary Data S3 for one-sentence descriptions of the “implication mentions” per article corresponding to each aggregated “implication type”.

Table 1.

Overview of the Ethical Implications of Tissue Engineering for Regenerative Purposes, as Identified in Relation to Animal Welfare

Animal welfare	For tissue engineering for regenerative purposes …
Sub theme	Ethical implications	References
Animal experimentation	… animal welfare should be balanced with scientific need and reliability of animal models	17–29
	… in vitro, ex vivo and in silico models should be applied to (partially) replace the use of animals	30–48
	… methods should be applied to reduce the number of animals per experiment	49–53
	… the use of non-human primates or companion animals should be avoided, or experiments should be refined to minimize suffering	18,27,50,54–58
Animal-derived TE components	… animal-free TE scaffold and culture components are preferred	22,38,59–69

The ethical implications are presented as aggregated “implication types”, categorized into sub themes. See Supplementary Data S3 for one-sentence descriptions of every ethical implication as mentioned in each relevant article (i.e., “implication mentions”).

Table 2.

Overview of the Ethical Implications of Tissue Engineering for Regenerative Purposes, as Identified in Relation to Handling Human Tissue

Handling human tissue	Tissue engineering for regenerative purposes …
Sub theme	Ethical implications	References
Tissue collection, storage, and use	… requires tissue collection methods that are not harmful to the donor	17,22
	… requires consent of (the family of) the donor for the collection, storage, and use of their tissues	17,19,20,22,23,58,70–76
	… requires that donors be fully informed on future use and possible financial interests, before collection, storage, and use of their tissues	7,77–86
	… requires protection of donor privacy when storing and using their tissues and data	7,17,19,22,23,58,73,75,77,78,80,82,86–90
	… raises the question under what conditions private, public, or hybrid model biobanks are acceptable	73,74,84,85,88,91–96
	… should be composed of non-human-derived scaffold components	72,97–100
Ownership and commodification	… raises the question who has ownership over tissue engineered products	7,17,22,23,75,79,88,101–104
	… raises the question if tissue engineered products should be patentable	17,73,74,82,101,105–109
	… reinforces commercialization of human tissues, which is at odds with altruistic donation and risks donor exploitation	71–74,80,84,88,93,110–115

The ethical implications are presented as aggregated “implication types”, categorized into sub themes. See Supplementary Data S3 for one-sentence descriptions of every ethical implication as mentioned in each relevant article (i.e., “implication mentions”).

Table 3.

Overview of the Ethical Implications of Tissue Engineering for Regenerative Purposes, as Identified in Relation to Informed Consent

Informed consent	For tissue engineering for regenerative purposes …
Sub theme	Ethical implications	References
Challenges to informed consent	… consent might be challenged by the participant's capacity to consent	75,116
	… informed consent might be challenged by therapeutic misconception	19,23,37,74,115,117–119
	… the voluntariness of consent might be challenged by pressure from family or researchers	22,120
	… informed consent for innovative therapies might be challenged by positive bias of the physician	119,121–123
	… informed consent is challenged by the inherent uncertainty involved in risk assessment	20,22,23,71,81,88,104,112,118,119,124,125
Conditions for informed consent	… well-considered informed consent requires that patients receive relevant information, e.g., on risk-benefit ratio, cell source, and alternative treatment options	37,74,119,126–128
	… well-considered informed consent requires that patients receive support and information in understandable language	17,119,129–131

The ethical implications are presented as aggregated “implication types”, categorized into sub themes. See Supplementary Data S3 for one-sentence descriptions of every ethical implication as mentioned in each relevant article (i.e., “implication mentions”).

Table 4.

Overview of the Ethical Implications of Tissue Engineering for Regenerative Purposes, as Identified in Relation to Therapeutic Potential

Therapeutic potential	Tissue engineering for regenerative purposes …
Sub theme	Ethical implications	References
Therapeutic promise	… has the potential to provide a cure for diseases where currently non is available or where side effects are high	75,82,106,116,132–135
	… may provide an alternative to donor organ transplantation, removing the need for immunosuppression and solving organ shortages	17,23,60,74,75,78,79,81,88,89,101–103,112,117,125,128,133,136–152
	… is excisable, which is a benefit compared to other RM strategies	81,125
Objectives for wellbeing	… should aim to improve the quality of life of patients	20,153

The ethical implications are presented as aggregated “implication types”, categorized into sub themes. See Supplementary Data S3 for one-sentence descriptions of every ethical implication as mentioned in each relevant article (i.e., “implication mentions”).

Table 5.

Overview of the Ethical Implications of Tissue Engineering for Regenerative Purposes, as Identified in Relation to Risk and Safety

Risk and safety	Tissue engineering for regenerative purposes …
Sub theme	Ethical implications	References
Safety risks	… bears risks related to the presence of living cells, such as immunogenicity, mutagenesis, and tumorigenicity	22,23,70,75,79,81,86,88,89,101,124,125,141,154–156
	… bears risks related to the scaffold components, such as contamination, immunogenicity, and cytotoxicity	22,23,72,79,81,116,124,125,155–158
	… bears safety risks related to the complexity of TE constructs in terms of variability, dynamic interaction, and irreversibility	3,25,70,75,78–81,102,115,119,122,124,132
	… involves inherent uncertainties related to the complexity of TE and to the limited predictive value of animal models	3,23,71,80,88,104,153,159–161
Safety measures	… requires that risks are minimized and are proportional to benefits to the individual and society	3,23,37,73,126,131,132,158,161,162
	… requires appropriate preclinical testing before first-in-human trials	26,29,37,120,124,126,129,131,154,161,163
	… requires long-term follow-up of trial participants	37,58,120,124,154,164–166
	… requires that TE implants are detectable in case of emergency situations	102
	… requires that safety measures are not unnecessarily burdensome	131,132,165,167

The ethical implications are presented as aggregated “implication types”, categorized into sub themes. See Supplementary Data S3 for one-sentence descriptions of every ethical implication as mentioned in each relevant article (i.e., “implication mentions”).

Table 6.

Overview of the Ethical Implications of Tissue Engineering for Regenerative Purposes, as Identified in Relation to Clinical Translation

Clinical translation	For tissue engineering for regenerative purposes …
Sub theme	Ethical implications	References
Clinical trial design	… randomized controlled trials might be challenging if no standard of care is available and if sham surgery would be required as a control	131,161,167–173
	… first-in-human clinical trials should include patients with mid- or end-stage disease	3,19,23,37,70,73,74,81,124,161,168,174,175
	… first-in-human clinical trials should include efficacy endpoints and capture both objective and subjective outcomes	21,37,70,73,75,81,125,126,131,155,156,160,164,167,168,176
	… registries are needed to collect long-term safety and efficacy data	3,17,37,74,86,101,117,120,126,131,167,177
	… clinical trials should be designed carefully, and results should be published transparently, to avoid bias and promote reproducibility	71,74,125,127,163,164,178,179
Innovative therapy pathway	… innovative therapy as alternative to clinical trials may promote patient access to experimental treatments	23,37,74,122,180
	… innovative therapy as alternative to clinical trials is at tension with the need to protect patients from risks and with the need for evidence collection	7,19,121,123,131,166,178,181–183
Unproven commercial interventions	… unproven interventions expose patients to the risk of physical harm and financial exploitation	19,74,120,122,123,156,178,180,184–186
	… researchers and physicians should protect patients against the risks of unproven interventions	7,18,120,183,187,188

The ethical implications are presented as aggregated “implication types”, categorized into sub themes. See Supplementary Data S3 for one-sentence descriptions of every ethical implication as mentioned in each relevant article (i.e., “implication mentions”).

Table 7.

Overview of the Ethical Implications of Tissue Engineering for Regenerative Purposes, as Identified in Relation to Societal Impact

Societal impact	Tissue engineering for regenerative purposes …
Sub theme	Ethical implications	References
Distributive justice	… could exacerbate local and global socioeconomic health disparities	17,19,22,23,70,75,79,88,102,104,107,140,158,180,189–195
	… should be developed to be cost effective to improve accessibility	25,37,74,89,90,112,124,155,166,170,196–198
	… poses a value trade-off between the future fruits of innovation and current patient demands	71,74,88,104,137,146,158,169,199–202
	… should be reimbursed based on clinical effectiveness, costs, and patient preferences	19,102,123,154,167,178,182
Impact on health care and markets	… might provide an alternative to ethically contentious health care practices like organ donation, xenotransplantation, and gestational motherhood	133,140,149,203–205
	… could help ending illegal organ trade	79,90,140,141,206
Biosecurity	… bears risks of bioterrorism related to unregulated home-use	17,81,107,125,190,207
Longevity and enhancement	… raises the question whether we should pursue longevity or accept ageing as a normal part of life	88,103,110,192,193,208–211
	… might change social acceptability of life organ donation and unhealthy lifestyles	17,88,101,108,192,212
	… raises opportunities and concerns related to the possibility of enhancement	20,23,70,75,88,108,110,112,158,180,190,213,214
Human experience and identity	… raises presents the body as malleable and challenges our conception of what it means to be human	17,88,101,104,110,115,180,189,210,215–223
	… blurs the boundaries between the natural and the artificial	17,88,140,223–225

The ethical implications are presented as aggregated “implication types”, categorized into sub themes. See Supplementary Data S3 for one-sentence descriptions of every ethical implication as mentioned in each relevant article (i.e., “implication mentions”).

Table 8.

Overview of the Ethical Implications of Tissue Engineering for Regenerative Purposes, as Identified in Relation to Scientific Integrity

Scientific integrity	For tissue engineering for regenerative purposes …
Sub theme	Ethical implications	References
Responsible conduct	… researchers and media should refrain from overstated promises to prevent hype	23,85,88,112,137,140,146,156,169,178,180,191,194,226
	… a benign research environment and better oversight mechanisms are needed to prevent fraud	129,169,227,228
	… scientists should (be trained to) be aware of the societal and ethical implications of their work	3,25,37,74,102,107,168,192,229–231
Transdisciplinary collaboration	… successful development co-depends on transdisciplinary and international collaborations between scientists, clinicians, regulators, and industry	37,92,102,106,121,125,131,137,177,182,232–236
	… commercial pressure might lead to premature testing and commercialization, so that government sponsored trials are preferable	17,20,67,80,89,106,115,118,131,162,168,174,177,178,180,194,237
	… responsible development is fostered by involvement of ethics and social science scholars in the innovation process	17,38,106,140,181,238,239

The ethical implications are presented as aggregated “implication types”, categorized into sub themes. See Supplementary Data S3 for one-sentence descriptions of every ethical implication as mentioned in each relevant article (i.e., “implication mentions”).

Table 9.

Overview of the Ethical Implications of Tissue Engineering for Regenerative Purposes, as Identified in Relation to Regulation

Regulation	For tissue engineering for regenerative purposes …
Sub theme	Ethical implications	References
Guidelines and oversight	… adequate regulatory frameworks should be established and be harmonized internationally	70,103,120,154,157,178,180,181,234,240
	… uniform guidelines and oversight for the use of human tissues should be established	84,85,93,128,136,162,165,241
	… uniform safety, quality and efficacy standards, and controls for TE products and processes should be established	23,25,75,106,108,120,124,126,127,132,171,174,179,195,242–245
	… regulation of innovative therapies offered outside clinical trials is needed	19,122,153
	… regulation should foster a balance between safety requirements and speed of innovation, to promote patient access	3,20,22,74,80,102,111,135,144,246
	… clarification or revision of the current regulatory classification of TE products is needed	17,78,79,81,89,101,126,217,224
Liability	… it should be determined who is responsible for quality control and maintenance and who should be held liable if complications arise	20,75,83,101,102,112,121,126,217

The ethical implications are presented as aggregated “implication types”, categorized into sub themes. See Supplementary Data S3 for one-sentence descriptions of every ethical implication as mentioned in each relevant article (i.e., “implication mentions”).

Table 10.

Overview of the Ethical Implications of Tissue Engineering for Regenerative Purposes, as Identified in Relation to Patient and Public Involvement

Patient and public involvement	For tissue engineering for regenerative purposes …
Sub theme	Ethical implications	References
Public engagement	… the public should be educated on the opportunities, hurdles, and ethical aspects	23,82,88,108,131,147,158,180,181,185,245,247
	… patients and the public should be consulted to include their values and needs	20,71,74,82,88,107,175,181,195,230,233,237,248,249
	… (bio)art may pose critical questions and provide new spaces for public dialog	38,215,222,250,251

The ethical implications are presented as aggregated “implication types”, categorized into sub themes. See Supplementary Data S3 for one-sentence descriptions of every ethical implication as mentioned in each relevant article (i.e., “implication mentions”).

Animal welfare

The literature discusses ethical implications related to animal welfare that can be subdivided between conditions for preclinical testing on animals and concerns related to animal-derived TE components (Table 1 and Supplementary Data S3).

Animal experimentation

Animal welfare should be balanced with the scientific need and expected human benefit of animal models.^17,18 The design should therefore take the predictive value of a particular animal model for humans into account^19–24 and the experiments should be performed in accordance with the 3R principles (replace, reduce, and refine).^25–29

To replace animals for biomaterial testing or to study regenerative processes, the use of computational modeling³⁰ or in vitro models^31–33 are advocated. These include SCs,³⁴ organoids,³⁵ decellularized tissue,³⁶ and organs-on-a-chip.^37,38 Ex vivo tissue culture systems^39–44 and the chorioallantoic membrane assay^45–48 are proposed as means of partial replacement. To reduce the number of animals per experiment, continuous monitoring of each animal,^49–51 testing of multiple biomaterials per animal,⁵² and skipping small animal models in favor of one large animal model⁵³ are suggested. Last, a preference is expressed not to use companion animals,^{18,27,50,54,55} such as dogs, or primates⁵⁶ as large animal models, and, if primates have to be used, to refine the experiments by minimizing the suffering caused.^57,58

Animal-derived TE components

Animal-derived decellularized scaffolds and culture medium components might raise religious and moral objections related to xenotransplantation and animal welfare, especially among religious or vegan patients.^22,59–62 Autologous,⁶³ allogeneic,^64–66 or plant-based components^67–69 are proposed as alternatives.

Handling human tissue

The literature identifies ethical considerations regarding how to handle human tissues. These can be grouped in two sub themes: first, the collection, storage, and use of cells and tissues from human donors for research and clinical applications, and second, ownership over and commodification of donated and engineered tissues (Table 2 and Supplementary Data S3).

Tissue collection, storage, and use

Tissues should be collected through non-invasive methods that do not cause harm or pain to the donor.^17,22 Consent of the donor or their family is required for collection and storage of tissues,^{22,23,58,70–72} which should be explicit^19,73 and voluntary.^74,75 Some suggest that consent should be specific to the intended use¹⁷ while others argue that broad consent suffices.^20,76 As a prerequisite for consent, donors should be provided relevant information, including information on present and foreseeable use of the collected tissues,^7,77–81 on the need to forego financial rights over the tissue,⁸² and on policies outlining the return of findings^83,84 and the possibility to withdraw.^85,86

To safeguard the confidentiality and privacy of the donor of collected and stored samples,^{19,22,58,80,82,86,87} some suggest that sample anonymization is desirable,^7,17,77 while others point out that this would limit clinical value⁷³ and the possibility of return of findings²³ and of dynamic (ongoing) consent.⁸⁸ Particularly, safeguarding privacy and confidentiality of the (medical) data and digital models required to create personalized 3D bioprinted tissues is warranted.^75,78,89,90

A dispute exists whether private (commercial) biobanking is acceptable⁹¹ or that public banking should be preferred⁷⁴ for tissue storage. Specifically, private banking is said to be based on a (false) promise of yet-to-be-developed RM treatments,^88,92 which could erode public trust.^85,93 Yet public banks would fail in providing a supply that is inclusive to all.⁸⁴ A hybrid model of public-private biobanking is therefore advocated that allows privately stored tissues to become publicly available, increasing the publicly available supplies^94–96 and accelerating research.⁷³

Finally, moral and religious objections could be raised to the use of (decellularized) human tissues, especially cadaveric tissues, as scaffold components. Synthetic scaffolds,⁹⁷ animal-derived scaffolds,^72,98 or (decellularized) tissues from living donors^99,100 would therefore be preferred.

Ownership and commodification

The question is raised which parties may claim ownership over donated^7,22,23 and engineered^{17,75,79,88,90,101–104} tissues: the tissue donor, the patient receiving the implant, or the parties involved in producing the organ? Moreover, it is debated whether and under what conditions intellectual property rights over TE, for example, by patenting the technology or the product, is desirable. While patenting could foster innovation,¹⁰⁵ ensure quality control, and prevent misuse,^17,101 it might also hinder open science and research^82,106 and equal access to the fruits of the technology.^74,107,108 According to some, notwithstanding property interests of other parties, patients should retain a right to control certain uses and access to the organ.^73,109 Finally, TE creates a paradoxical and potentially undesirable situation in which altruistically donated tissues are turned into profitable materials for which donors have no right to financial gain.^{71–74,80,84,93,110} This appears at odds with human dignity¹¹¹ and the ban on the commodification of human body parts,¹¹² and might lead to donor exploitation or coercion.^88,113–115

Informed consent

The literature mentions informed consent as a necessary precondition for several phases of TE development: for tissue donation (as discussed under ‘Tissue collection, storage, and use’), participation in clinical trials, and clinical application, whether as innovative therapy, compassionate use, or routine treatment. A distinction can be made between challenges and conditions for obtaining valid, informed consent (Table 3 and Supplementary Data S3).

Challenges to consent

Consent might be challenged if the patient's capacity to consent is impaired, for example, in emergency situations¹¹⁶ or when treated for brain conditions.⁷⁵ Second, patients' hope or desperation for a cure might lead them to misunderstand the risky and experimental nature of a TE trial (therapeutic misconception) and affect the validity of their consent.^{19,23,37,74,115,117–119} Third, patients might feel pressured to participate by family members or researchers.^22,120 Fourth, possible positive bias and conflicting financial or professional interest of the physician-researcher involved in an experimental TE treatment might affect the neutrality of the information provided.^{119,121–123} And last, uncertainty about possible complications due to the novel,⁸¹ complex,^22,119,124 invasive,^20,118 and irreversible¹²⁵ nature of TE makes it difficult to provide accurate information about the risk-benefit ratio of the intervention.^{23,71,88,104,112}

Conditions for consent

Due to these challenges, medical professionals should provide, and carefully explain, all relevant information, including information on the characteristics of the TE intervention itself, the source of cells and other components, foreseeable risks and benefits, safety measures, alternative treatment options, and a disclosure of interests.^{37,119,126–128} Yet, even if high quality information is provided, consent should always be accompanied by oversight mechanisms to prevent patients from unacceptable risks.⁷⁴ Moreover, information should be provided in understandable language,^17,129 and may be supported by the use of educational materials¹¹⁹ and consultation of an independent medical professional.^130,131

Therapeutic potential

One of the main ethical opportunities and key drivers of TE is its therapeutic potential. The literature elaborately discusses its therapeutic promise, and briefly its objectives related to broader wellbeing (Table 4 and Supplementary Data S3).

Therapeutic promise

TE is proposed to address an unmet clinical need, having the potential to treat diseases for which currently no curative therapy is available^{75,106,116,132–134} or for which current therapies have risky side effects,¹³⁵ and to improve the quality of life of elderly patients.⁸² Most often, TE is presented as an alternative to donor organ transplantation. As such it would remove the need for immunosuppression,^133,136 improve length and quality of life^{60,74,79,88,103,128,137} and psychosocial outcomes (for face TE),^138,139 provide patient-tailored^{75,81,89,125,140} and/or off-the-shelf available^78,141,142 treatment options, and reduce the cost of care.^23,143 In the long run it might solve organ shortages,^{102,117,144–148} thus saving lives and avoiding complexities related to organ donation, including the surgical risks for donors,^149,150 the need for (prior or proxy) consent,^112,151,152 and the acceptability of directed donation.^17,101 Moreover, compared to other RM strategies such as SC injections or GT, cell scaffolding provides TE the benefit of excision if needed, thus allowing partial reversibility.^81,125

Objectives for wellbeing

Finally, TE should not merely be aimed at treating disease, but also at improving overall quality of life²⁰ and promoting human flourishing.¹⁵³

Risk and safety

Notwithstanding the therapeutic potential of TE, the literature discusses several risks of harm for the patients or trial participants, along with safety measures (Table 5 and Supplementary Data S3).

Risks to participant

Risks are associated with different aspects of TE constructs: The presence of living cells poses risks of immunogenicity,^70,88,154 mutagenesis (especially for bioprinting),^{89,101,124,155} undirected differentiation,^81,125,156 and teratoma and tumor formation,^{22,23,75,79,86,141} which are compounded by bioprinting forces. TE components such as scaffolds and bioactive factors pose risks of contamination and introduction of pathogens,^{22,23,79,124,155,157} potential immunogenicity,^72,158 and cytotoxicity (especially of degradation products).^{81,116,125,156}

The complexity of the TE constructs themselves pose risks that are foreseeable but hard to quantify, that is, risks associated with inherent variability of the constructs,^78,79,119 unpredictable dynamic interactions with the bodily environment,^{25,80,124,132} and the irreversibility of the surgical implantation and regeneration process.^{3,102,115,122} The latter particularly impedes patient's opportunity to withdraw from the trial.^70,75,81 In addition to the known risks, TE involves inherent uncertainties, because of the complexity and manufacturing variability of the construct,^23,71,159 and because the predictive value of preclinical animal studies is limited.^3,153 As a result it is challenging to provide a realistic risk-benefit analysis,^88,104,160 and to decide when evidence suffices to start first-in-human trials.^80,161

Safety measures

Trials might be justified if adequate safety measures are taken to minimize risks^131,132,162 and if the benefits to the individual (compared to available therapies)^3,126,161 and society (in terms of scientific value)^23,37,73,158 are maximized. The following safety measures are described: To understand the biological mechanisms underlying TE^126,154 and to evaluate safety and efficacy of the technology, thorough in vitro¹⁶³ and in vivo^{26,129,131,161} preclinical research is required and must be optimized to minimize translational distance.^{29,37,120,124} To monitor adverse events and the success of regeneration, there is a need for long-term follow-up of trial participants,^{37,58,154,164–166} and pediatric patients in particular.^120,124 Artificial organs should be identifiable in case emergency situations arise.¹⁰² However, safety measures should not be unnecessarily burdensome^131,132 or hamper patient access.^165,167

Clinical translation

The pathway of TE treatments from experimental design toward clinical application can roughly take three routes: through clinical trials (i.e., traditional pathway, aimed at evidence collection for research), as innovative therapy (i.e., non-research pathways aimed at improving patient access, including off-label use, compassionate use, and hospital exemption), or interventions can simply reach the market before evidence of efficacy and safety is complete (i.e., unproven commercial interventions). The literature discusses ethical implications related to each of these pathways (Table 6 and Supplementary Data S3).

Clinical trial design

Several suggestions are provided on how to optimize the design of clinical trials for TE. First, while randomized controlled trials (RCT's) should be used where possible,^168,169 this might be ethically challenging, especially if no standard of care is available.^{167,170–172} Sham surgery may be required as a comparator, but is justifiable only if surgery is minimally invasive and if anticipated social value outweighs harm to the control group.^131,161,173 Moreover, adequate and fair participant selection is challenging,^19,73 because fewer patients can be enrolled than are eligible,⁷⁴ little is known about comorbidities,¹⁷⁴ and end-stage patients are especially vulnerable to therapeutic misconception.^23,37

Still, consensus seems to exist that for high-risk TE, performing first-in-human phase I trials on healthy volunteers or stable patients is unacceptable.³ Patients with mid- or end-stage disease should be included instead,^{70,81,124,161,168,175} because they might benefit most and risk losing least. Regarding outcome measures, first-in-human trials may involve efficacy endpoints in addition to safety endpoints,^73,81 to maximize the scientific value. Efficacy endpoints should include objective outcomes, such as overall survival¹⁶⁷ and success of tissue regeneration,^126,164 evaluation of which should preferably not rely on invasive biopsies,^21,176 and subjective outcomes related to patient wellbeing.^{37,131,160,168} For personalized (3D bioprinted) implants, heterogeneous outcomes are to be expected and limit the possibility to extrapolate the results.^{70,75,125,155,156}

Finally, curated registries should be set up and used to collect long-term data from clinical trials and follow-up studies regarding safety and efficacy of TE interventions.^{3,17,37,74,86,101,120,126,167} This would allow to trace adverse events,¹⁷⁷ help build a solid evidence-base, and allow to evaluate when the intervention needs no longer be considered experimental.^117,131 Moreover, in combination with general non-biased and transparent publishing practices and the use of scientifically valid and rigorous research methods,^{71,74,125,127,163,164,178,179} this could promote reproducibility and foster translation of TE products to the clinic.

Innovative therapy pathway

Because the use of traditional clinical trials for TE is faced by several challenges, alternatives are needed. One option is to allow patients to access experimental RM and TE treatments as innovative therapy outside clinical trials. This would improve patients access^74,122,180 and circumvent the need for sham surgery.^23,37 However, such access might be at tension with the need to protect patients from considerable risk,^7,121,178 and the need to generate conclusive evidence regarding safety and efficacy of the product^123,181,182 and could therefore harm public trust. Publishing outcomes and adverse events in open registries might partially overcome these concerns.^{19,131,166,183}

Unproven commercial interventions

Commercial clinics also offer SC-based RM interventions (which could include TE interventions) without sufficient proof of efficacy and safety. Authors warn that such unproven interventions operate outside existing regulations and are based on false promises,^{123,180,184,185} thus exposing vulnerable patients to the risk of physical harm and financial exploitation,^{19,74,156,178,186} and harming public trust in the RM field.^120,122 Both researchers and physicians are responsible to inform patients and protect them against these risks.^{7,18,120,183,187,188}

Societal impact

The literature discusses several societal impacts of TE and RM development. These include so-called “soft” impacts related to human values, experiences, identity, relations, and perceptions. The literature covers challenges to distributive justice, the impact on health care and market, biosecurity, longevity and enhancement, and human experience and identity (Table 7 and Supplementary Data S3).

Distributive justice

Concern exists that the expected high costs of TE interventions will limit its accessibility. If only those who can afford to pay will benefit in terms of quality and length of life,^{17,75,140,189–191} this may exacerbate socioeconomic health disparities^{19,22,23,70,107,158,192,193} both locally¹⁰² and globally.^{79,88,104,180,194,195} However, if, in the long run, the costs of TE will decrease, treatments could become cost effective.^{89,112,166,196} Efforts should be made toward that end so as to improve accessibility.^{25,37,74,90,124,155,170,197,198} Additionally, to ensure equal access to TE treatments, reimbursement will be necessary^154,182 and reimbursement decisions should be based on evidence of clinical benefit,¹²³ patient preferences,¹⁶⁷ and initial and lifetime costs^102,167,178 compared to current treatments options.

Moreover, while there is an imperative to fund RM and TE research,^199,200 this might draw resources away from existing health care solutions, exposing a value trade-off between the future fruits of innovation and the demand of patients in need today.^71,74,88,104 Resources should therefore be allocated based on good science rather than hype^137,146,169 and arrangements for benefit-sharing (such as price limits or revenue sharing) should be put in place.^158,201,202

Impact on health care and markets

TE might provide an alternative to several ethically contentious health care practices: TE organs might circumvent personal identity issues related to organ donation,²⁰³ and naturalness objections against xenotransplantation.¹⁴⁰ Transplantable bioartificial uteri might provide an alternative to gestational surrogate motherhood^149,204,205 and could possibly contribute to the realization of human ectogenesis on the long run.¹³³ TE organs could also help ending illegal organ trade,^79,141,206 provided that regulations are adopted to prevent new black markets in TE organs.^90,140

Biosecurity

Concern is raised that TE technology, and particularly 3D bioprinting because of its relative accessibility and affordability, might lead to unregulated home-use, which could facilitate bioterrorism.^{17,81,107,125,190,207}

Longevity and enhancement

TE might help to prolong the average human life span or even “cure aging”, which raises the question whether longevity is socially desirable^193,208,209 or that ageing should be viewed as a normal part of life.^88,103,192 In particular, an expanded life span might impact the retirement system²¹⁰ and could decrease solidarity with older generations.^110,211 If TE tissues and organs would become widely available, this could also affect social norms: unhealthy and reckless lifestyles might be normalizsed^{17,88,101,108,192} and support for organ donation might decrease.²¹² Moreover, TE could be used for cosmetic purposes or potentially to enhance physical or cognitive abilities. While the pursuit of enhancement is deeply embedded in human culture^23,75,112 and could help to pursue the good life,⁸⁸ it raises concerns about potential harm,¹⁰⁸ increasing inequalities,^70,158 fair resource distribution,^20,110 and the legitimate goals of medicine.^{180,190,213,214}

Human experience and identity

TE presents the body as malleable^110,189,215 or machine-like.¹⁰⁴ This raises the question whether the human body or life itself is something that should be engineered,^{17,115,180,216} and might challenge our understanding of what it means to be human,^210,217,218 and our perception of the self^219,220 and of others.¹⁰¹ The engineering ideal driving TE might obscure the existential and embodied experiences of patients.^88,221–223 Last, TE organs blur the boundaries between the corporal and the technical,^88,224 life and non-life,^140,225 and natural and engineered. While its social acceptance might depend on whether it will be perceived as the one or the other,¹⁷ TE is best presented as engineered.²²³

Scientific integrity

The literature identifies issues of scientific integrity related to individual conduct and to transdisciplinary collaboration (Table 8 and Supplementary Data S3).

Responsible conduct

TE, SC and organoid research, and organ bioprinting are surrounded by hype and high public expectations.^88,180,194 To prevent disillusionment and promote public trust, researchers, scientific journals, and popular media should set realistic expectations,^{140,146,169,178,191,226} by making modest claims and refraining from overstated promises.^{23,85,112,137,156} The TE field has been faced with a serious case of scientific misconduct and research fraud by the thoracic surgeon Paolo Macchiarini. This indicates the need for a more benign research environment and better oversight mechanisms within TE, to promote integrity of conduct and to restore trust in the field.^{129,169,227,228} Responsible conduct requires that scientists express scientific virtues such as openness, honesty, and accountability^74,107 and that they anticipate how their choices affect the final TE product and its beneficiaries.^3,37,102 They should therefore be trained to become aware of and be able to engage in discourse on the societal and ethical implications of TE.^{25,168,192,229–231}

Transdisciplinary collaboration

Successful TE development co-depends on transdisciplinary collaboration between engineers, scientists, and clinicians^102,137,232 in a globally inclusive manner^182,233; adequate training of physician-researchers to gain necessary expertise knowledge and skills to implement TE safely in clinical trials^{37,121,131,234,235}; infrastructures of knowledge exchange¹⁰⁶; and mutual collaboration and relationships of trust between academia, industry, and regulators.^{92,125,177,236}

However, industry involvement and commercial pressure might steer the research agenda,¹⁰⁶ incentivize selection of trial sites in areas with permissive regulations,^177,180,237 and lead to premature clinical testing and commercialization of TE products.^{20,115,118,174,178,194} To deal with potential conflicts of interest and to maintain trust from physicians and the public, independent oversight mechanisms are needed,^80,89,168 full disclosure of interests should be provided by those involved in clinical trials^67,131 and trials sponsored by governments rather than industry might be preferred.^17,162

Finally, ethics, humanities, and social science scholars should be involved in the innovation process to take ethical, legal, and societal considerations into account, to manage potential conflicts of interest and to promote successful and responsible translation of TE to the clinic.^{17,38,106,140,181,238,239}

Regulation

The need for adequate regulatory frameworks for TE is widely discussed in the literature. The relevant ethical implications can be divided in the need for appropriate guidelines and oversight, and liability issues (Table 9 and Supplementary Data S3).

Need for guidelines and oversight

The regulatory frameworks guiding TE development should be revaluated.^103,120,181 Particularly, given regional disparities in TE regulations, many authors call for international harmonization^{70,154,157,178,240} or, at minimum, agreement on an international code of conduct.^180,234 In particular, guidelines and adequate oversight should be established for the collection, storage, and use of human tissues^{84,93,128,136,162,241} and for ownership rights over such tissues.^85,165 Moreover, there is a need to set uniform safety, quality, and efficacy standards for cell culture,^120,126 biomaterials,^{23,25,242,243} manufacturing processes,^75,108,124 and TE end products^{106,171,195,244,245} and to establish ethical oversight^127,132 or regulatory controls^174,179 to guide risk assessment. Finally, global regulations to guide the application of experimental TE and RM treatments as innovative therapy outside clinical trials are needed.^19,122,153

A particular challenge for TE regulation is fostering a balance between the product safety and speed of product development.^3,20 While regulations should prevent commercial pressure from impeding good patient care,¹⁰² regulations should not be unnecessarily risk-averse, so as not to slow down progress,^135,144,246 drive up costs, or impede patient access.^74,111 This relates to the question when clinical evidence suffices to introduce TE products into regular clinical practice.^22,80 Another regulatory challenge for TE and 3D-bioprinted products is that–because they combine features of drugs, devices, and biologicals and because of their personalized nature–they fall in between most currently existing classificatory categories.^78,217 These classifications should therefore be urgently revised to provide clarity.^{17,79,81,89,101,126,224}

Liability

Considering the multidisciplinary nature of TE development, it should be determined who (regulator, engineer, manufacturer, or clinician) is responsible for quality assurance¹¹² and long-time maintenance¹⁰² of TE implants and who should be held liable in case serious complications arise.^20,75,83,101 This is especially challenging in case a patient decides to withdraw from a trial.¹²⁶ While one author warns that currently patient protection lags behind because companies can avoid liability for TE product failure too easily,²¹⁷ another argues that physicians should be better protected from negligence claims if innovative therapies turn out harmful, in order not to stifle innovation.¹²¹

Patient and public involvement

The literature shows a general interest in involving patients and the public in a dialog on TE development, to promote public trust and to enable scientific citizenship (Table 10 and Supplementary Data S3). As a start, the public should be educated on the opportunities and hurdles, along with ethical and societal aspects of TE. This requires scientists to communicate clearly about their research, and provide accessible and reliable information sources,^{23,82,88,108,131,147,158,180,181,245,247} or even set up counseling services to counter misinformation.¹⁸⁵

Next, a wide range of stakeholders, including lay people and patients, should be consulted on their values, needs, expectations, and concerns regarding TE development.^{74,82,88,195,233,248} In particular, such consultation could probe the acceptability of risks,^20,237 approaches to deal with uncertainties,⁷¹ and fair distribution of health care resources.^175,230 Patient advocates are especially well-positioned to articulate patient needs.^181,249 One author group points out that to foster truly inclusive deliberation, scientists should be attentive to a wide variety of stakeholders and empower them to make informed and meaningful contributions.¹⁰⁷

Finally, (bio)artists are particularly well positioned to explain or visualize scientific work,³⁸ to critically question the TE field, its implications and assumptions^215,250 and to provide alternative places for discourse on the intersection of art and bioethics.^222,251

Discussion

In this SR of 237 academic peer-reviewed articles, we identified a range of ethical implications of TE for regenerative purposes. These stretch over 10 overarching themes, representing phases of TE development and implementation (animal welfare, handling human tissue, informed consent, therapeutic potential, risk and safety, clinical translation, and societal impact), and safeguards necessary for responsible development (scientific integrity, regulation, and public and patient involvement).

A prior literature review performed in 2008, De Vries et al noted that until then the literature on the ethics of TE and RM mainly focused on considerations relating to the source and collection of SCs in preclinical research and that the ethical evaluation of TE clinical trials lacked short.⁵ Our SR reveals that, since then, ethical reflection in academic discourse has followed the pace of TE development, shifting focus from preclinical to clinical translation, and providing several concrete recommendations on how this process should take place.

Our SR indicates several characteristics of TE that are specific to the ethical implications of the product. That is, (a) TE is highly innovative²³ and has a novel method and aim,^3,161 that is, tissue regeneration rather than “mere” restoration of function; (b) TE products are increasingly personalised,²³ for example, bioprinted from patient-derived cells after a patient-specific shape; (c) TE products deeply invade¹⁶¹ in and dynamically interact^3,126 with the human body and finally disappear⁸⁸; and (d) TE is multidisciplinary^38,119,140 in nature and relies on state-of-the-art technologies such as 3D (bio)printing, iPSCs, and organoid technology. Several ethical implications related to these characteristics are touched upon in this review but remain in need of further ethical reflection.

First, the novel aim and personalized character of TE challenge traditional clinical trial pathways and guidance is needed on how to proceed with clinical translation of TE. The possibility to perform traditional RCTs or to extrapolate the results from one patient to another is limited because suitable comparators are lacking, and TE interventions are patient specific. N-of-1 trials have been proposed as an alternative,^252,253 but guidelines are needed on how to reduce risks for individuals while maximizing the scientific value of the outcomes. Alternatively, patients could be provided access to unproven interventions as innovative therapies outside clinical trials when individual benefit can be reasonably expected.^23,74 This may be beneficial provided that a learning component, including registration and reporting, is maintained.^122,254

Second, TE constructs invade and integrate deeply into the human body, which may have implications for how the technology is perceived and experienced. For example, TE may impact embodiment and perceptions of (un)naturalness. While these so-called “soft” impacts on society are often indirect and intangible, their effect may be significant.^4,255 Therefore, we agree with others^88,192,256 that more efforts should be made to anticipate and evaluate the soft mid- and long-term impacts of TE and RM on society at large.

Third, the multidisciplinary nature and commercial incentives in the TE field raise questions to whom ownership rights and responsibilities regarding TE products should be ascribed. While this could be approached as a strictly legal question on the patentability of tissue products and processes,^105,109 a broader ethical analysis is needed that takes into account how individuals perceive ownership over TE implants. It has been shown that intuitions about ownership over tissues derived from one's own body tend to deviate from ownership rights as laid down in existing regulations.²⁵⁷ Both the value attached to cells and tissue contructs,^84,258,259 and the invasive character of TE implants that integrate deeply into the body could and should affect what degree of ownership and control is attributed and to whom. This will have implications for who will gain financially, and how much, and could therefore also impact the accessibility of TE interventions. Broadening the notion of ownership could help justify benefit sharing schemes^73,201,202 to improve access and to let patients and the public share in the benefits of TE and RM innovations.

Methodological choices, strengths, and limitations

Because the focus of the TE debate has moved toward settling conditions for responsible development and anticipating future implications, we opted for an SR of “ethical implications” rather than “reasons for/against” as is sometimes done for ethics literature.^11,16 We broadly interpreted “ethical implications” to include considerations of a philosophical, existential, artistic, legal, regulatory, and anticipatory nature and questions of governance, public and patient involvement, and (scientific) misconduct.

We restricted the scope of our SR to “TE for regenerative purposes” because of its clinical significance and because we expected that at least some of the ethical implications would be related to the particular characteristics and purpose of TE thus defined. However, demarcating “TE for regenerative purposes” as distinct from other forms of RM was challenging because in the literature different definitions of “TE” and “RM” are used,²⁶⁰ but often not explicated. Moreover, in practice, TE, SC interventions, and GT often overlap or are combined. A detailed list of inclusion and exclusion criteria that was used to guide this demarcation is provided in Supplementary Data S1.

Overall, we present a comprehensive review that covers over two hundred articles, indicating a broad set of ethical considerations related to all phases of TE development, including potential future societal impact. Three possible limitations should be mentioned. First, by excluding book chapters and conference articles we may have missed a small number of ethical implications. Second, both phases of literature screening (title/abstract screening and full text screening) were performed by one reviewer only, a method for which support exists²⁶¹ but that might be more fallible than traditional double-blind screening. However, as has been argued elsewhere,²⁶² we may have captured all (or most) relevant ethical implications, even if a small number of articles was missed. Third, while we touch upon several regulatory considerations, we did not discuss existing regulatory regimes in detail, as this is outside the scope of our review. However, others have recently compared ATMP and bioprinting regulations across jurisdictions.^79,263

Concluding Remarks

Overall, as TE and RM shift toward clinical translation, it raises ethical questions regarding fundamental and clinical research, translation to the patient, and its impact on society at large. To our knowledge, this is the first time that the ethical implications of this field have been reviewed systematically. By gathering existing scholarly work and identifying knowledge gaps, this SR facilitates further research into the ethical and societal implications of TE and RM. Moreover, it will serve as a valuable resource and educational tool for TE and RM scientists, engineers, and clinicians by providing an overview of the ethical considerations relevant to their work. As such, our review will help promote successful and responsible development of new interventions in TE and RM in a manner attentive of the current and future ethical and societal implications encountered along the way. Given its broad and comprehensive scope, it may also serve as a steppingstone for the ethical analysis of other emerging biomedical technologies.

Authors' Contributions

All authors contributed to conceptualization and writing of this article.

Disclosure Statement

Annelien Bredenoord is a member of the Dutch Senate. She also serves as a member of the Ethics Committee of the ISSCR and the Ethics Advisory Board of IQVIA. The other authors have no conflicts of interest to declare.

Funding Information

This research was financially supported by the Gravitation Program “Materials Driven Regeneration,” funded by the Netherlands Organization for Scientific Research (024.003.013).

Supplementary Material

Supplementary Data S1

Supplementary Data S2

Supplementary Data S3