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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”).

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).

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}

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).

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}
Conditions for informed consent	… well-considered informed consent requires that patients receive support and information in understandable language	^{17,119,129–131}

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).

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

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).

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}

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).

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 pathway	… 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}
Unproven commercial interventions	… researchers and physicians should protect patients against the risks of unproven interventions	^{7,18,120,183,187,188}

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).

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}
Impact on health care and markets	… 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}
Human experience and identity	… blurs the boundaries between the natural and the artificial	^{17,88,140,223–225}

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).

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}

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).

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}

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

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}

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.

Footnotes

Acknowledgments

We thank Paulien Wiersma of the Utrecht University Library for revising the database search strategy. We would like to thank our colleagues from the Medical Humanities Department for their valuable comments on earlier versions of this work.

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

References

Mason

, Dunnill

. A brief definition of regenerative medicine. Regen Med, 2008; 3(1):1–5; doi: 10.2217/17460751.3.1.1

Wissing

, Bonito

, Bouten

CVC

, et al. Biomaterial-driven in situ cardiovascular tissue engineering—a multi-disciplinary perspective. NPJ Regen Med, 2017; 2(1):1–20; doi: 10.1038/s41536-017-0023-2

Trommelmans

, Selling

, Dierickx

. Is tissue engineering a new paradigm in medicine? Consequences for the ethical evaluation of tissue engineering research. Med Health Care Philos, 2009; 12(4):459–467; doi: 10.1007/s11019-009-9192-0

Jongsma

, Bredenoord

. Ethics parallel research: An approach for (early) ethical guidance of biomedical innovation. BMC Med Ethics, 2020; 21(81):1–9; doi: 10.1186/s12910-020-00524-z

De Vries

RBM

, Oerlemans

AJM

, Trommelmans

, et al. Ethical aspects of tissue engineering: A review. Tissue Eng Part B Rev, 2008; 14(4):367–375; doi: 10.1089/ten.teb.2008.0199

Kim

, Smoak

, Melchiorri

, et al. An Overview of the Tissue Engineering Market in the United States from 2011 to 2018. Tissue Eng Part A, 2019; 25(1–2):1–8; doi: 10.1089/ten.tea.2018.0138

O'Donnell

, Ives

, Mohiuddin

, et al. Beyond the present constraints that prevent a wide spread of tissue engineering and regenerative medicine approaches. Front Bioeng Biotechnol, 2019; 7:1–12; doi: 10.3389/fbioe.2019.00095

Slingerland

, Smits

AIPM

, Bouten

CVC

. Then and now: Hypes and hopes of regenerative medicine. Trends Biotechnol, 2013; 31(3):121–123; doi: 10.1016/j.tibtech.2012.12.001

Kahrass

, Borry

, Gastmans

, et al. PRISMA-Ethics – Reporting Guideline for Systematic Reviews on Ethics Literature: Development, explanations and examples. OSF Prepr 2021; doi: 10.31219/osf.io/g5kfb

10.

Moher

, Liberati

, Tetzlaff

, et al. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. Ann Intern Med, 2009; 151(4):264–269; doi: 10.7326/0003-4819-151-4-200908180-00135

11.

Mertz

, Kahrass

, Strech

. Current state of ethics literature synthesis: A systematic review of reviews. BMC Med, 2016; 14(1):1–12; doi: 10.1186/s12916-016-0688-1

12.

Hug

, Hermerén

. Do we still need human embryonic stem cells for stem cell-based therapies? Epistemic and Ethical Aspects. Stem Cell Rev Reports, 2011; 7(4):761–774; doi: 10.1007/s12015-011-9257-3

13.

Zarzeczny

, Caulfield

. Emerging ethical, legal and social issues associated with stem cell research & and the current role of the moral status of the embryo. Stem Cell Rev Reports, 2009; 5(2):96–101; doi: 10.1007/s12015-009-9062-4

14.

Power

, Rasko

JEJ

. Will cell reprogramming resolve the embryonic stem cell controversy? a narrative review. Ann Intern Med, 2011; 155(2):114–121; doi: 10.7326/0003-4819-155-2-201107190-00007

15.

Barnett-Page

, Thomas

. Methods for the synthesis of qualitative research: A critical review. BMC Med Res Methodol, 2009; 9(1):59; doi: 10.1186/1471-2288-9-59

16.

Strech

, Sofaer

. How to write a systematic review of reasons. J Med Ethics, 2012; 38(2):121–126; doi: 10.1136/medethics-2011-100096

17.

Vijayavenkataraman

, Lu

, Fuh

JYH

. 3D bioprinting – An Ethical, Legal and Social Aspects (ELSA) framework. Bioprinting, 2016; 1:11–21; doi: 10.1016/j.bprint.2016.08.001

18.

Rozlin

, Muhammad Aa'zamuddin

, Norhamiza

, et al. Tissue engineering of articular cartilage: From bench to bed-side. Tissue Eng Regen Med, 2014; 12(1):1–11; doi: 10.1007/s13770-014-9044-8

19.

Lowenthal

, Sugarman

. Ethics and policy issues for stem cell research and pulmonary medicine. Chest, 2015; 147(3):824–834; doi: 10.1378/chest.14-1696

20.

Nicholson

Reflections on the ethics of biomaterials science. New Bioeth, 2013; 19(1):54–63; doi: 10.1179/2050287713z.00000000021

21.

Sculean

, Nikolidakis

, Nikou

, et al. Biomaterials for promoting periodontal regeneration in human intrabony defects: A systematic review. Periodontol 2000, 2015; 68(1):182–216; doi: 10.1111/prd.12086

22.

Oerlemans

AJM

, Rodrigues

CHCML

, Verkerk

, et al. Ethical aspects of soft tissue engineering for congenital birth defects in children-what do experts in the field say?. Tissue Eng Part B Rev, 2010; 16(4):397–403; doi: 10.1089/ten.teb.2009.0666

23.

Otto

, Breugem

, Malda

, et al. Ethical considerations in the translation of regenerative biofabrication technologies into clinic and society. Biofabrication, 2016; 8(4):042001; doi: 10.1088/1758-5090/8/4/042001

24.

Liguori

, Jeronimus

, De Aquinas Liguori

, et al. Ethical Issues in the Use of Animal Models for Tissue Engineering: Reflections on Legal Aspects, Moral Theory, Three Rs Strategies, and Harm'Benefit Analysis. Tissue Eng Part C Methods, 2017; 23(12):850–862; doi: 10.1089/ten.tec.2017.0189

25.

Kashi

, Saha

. Ethics in biomaterials research. J Long Term Eff Med Implants, 2009; 19(1):19–30; doi: 10.1615/jlongtermeffmedimplants.v19.i1.30

26.

Levin

Bench to bedside: Approaches for engineered intestine, esophagus, and colon. Gastroenterol Clin North Am, 2019; 48(4):607–623; doi: 10.1016/j.gtc.2019.08.012

27.

Moran

, Ramesh

, Brama

PAJ

, et al. The benefits and limitations of animal models for translational research in cartilage repair. J Exp Orthop, 2016; 3(1):1–12; doi: 10.1186/s40634-015-0037-x

28.

Falcon

, Karchner

, Henning

, et al. Ethics of using animal models as predictors of human response in tissue engineering. Ethics Biol Eng Med, 2019; 10(1):37–49; doi: 10.1615/EthicsBiologyEngMed.2020033718

29.

Abbas

, Elawad

, Pullattayil

, et al. Quality of reporting in preclinical urethral tissue engineering studies: A systematic review to assess adherence to the arrive guidelines. Animals, 2021; 11(8):2456; doi: 10.3390/ani11082456

30.

Tartarini

, Mele

. Adult stem cell therapies for wound healing: Biomaterials and computational models. Front Bioeng Biotechnol, 2016; 3:1–7; doi: 10.3389/fbioe.2015.00206

31.

Dikici

, Aldemir Dikici

, Bhaloo

, et al. Assessment of the Angiogenic Potential of 2-Deoxy-D-Ribose Using a Novel in vitro 3D dynamic model in comparison with established in vitro assays. Front Bioeng Biotechnol, 2020; 7:1–20; doi: 10.3389/fbioe.2019.00451

32.

Sauer

UG.

Animal and non-animal experiments in nanotechnology - The results of a critical literature survey. ALTEX, 2009; 26(2):109–127; doi: 10.14573/altex.2009.2.109

33.

Lammers

, Tjabringa

, Schalkwijk

, et al. A molecularly defined array based on native fibrillar collagen for the assessment of skin tissue engineering biomaterials. Biomaterials, 2009; 30(31):6213–6220; doi: 10.1016/j.biomaterials.2009.07.050

34.

Ahmed

, Ahmed

, Masoud

, et al. Stem cells based in vitro models: Trends and prospects in biomaterials cytotoxicity studies. Biomed Mater, 2021; 16(4); doi: 10.1088/1748-605X/abe6d8

35.

Ghareeb

, Lako

, Steel

. Coculture techniques for modeling retinal development and disease, and enabling regenerative medicine. Stem Cells Transl Med, 2020; 9(12):1531–1548; doi: 10.1002/sctm.20-0201

36.

McCrary

, Bousalis

, Mobini

, et al. Decellularized tissues as platforms for in vitro modeling of healthy and diseased tissues. Acta Biomater, 2020; 111:1–19; doi: 10.1016/j.actbio.2020.05.031

37.

Baker

, McQuilling

, King

NMP

. Ethical considerations in tissue engineering research: Case studies in translation. Methods, 2016; 99:135–144; doi: 10.1016/j.ymeth.2015.08.010

38.

Edwards

, Thomas

, Guilliatt

. Regenerative medicine: From the laboratory looking out. Palgrave Commun, 2017; 3(1):27; doi: 10.1057/s41599-017-0036-x

39.

Smith

, Kanczler

, Oreffo

ROC

. A new take on an old story: Chick limb organ culture for skeletal niche development and regenerative medicine evaluation. Eur Cells Mater, 2013; 26:91–106; doi: 10.22203/eCM.v026a07

40.

Smith

, Kanczler

, Gothard

, et al. Evaluation of skeletal tissue repair, Part 1: Assessment of novel growth-factor-releasing hydrogels in an ex vivo chick femur defect model. Acta Biomater, 2014; 10(10):4186–4196; doi: 10.1016/j.actbio.2014.06.011

41.

Weightman

, Pickard

, Yang

, et al. An in vitro spinal cord injury model to screen neuroregenerative materials. Biomaterials, 2014; 35(12):3756–3765; doi: 10.1016/j.biomaterials.2014.01.022

42.

Peeters

, Van Rijn

, Vergroesen

PPA

, et al. Bioluminescence-mediated longitudinal monitoring of adipose-derived stem cells in a large mammal ex vivo organ culture. Sci Rep, 2015; 5:1–12; doi: 10.1038/srep13960

43.

Richardson

, Hoyland

, Mobasheri

, et al. Mesenchymal stem cells in regenerative medicine: Opportunities and challenges for articular cartilage and intervertebral disc tissue engineering. J Cell Physiol, 2010; 222(1):23–32; doi: 10.1002/jcp.21915

44.

Sloan

, Lynch

. Dental tissue repair: Novel models for tissue regeneration strategies. Open Dent J, 2013; 6(1):214–219; doi: 10.2174/1874210601206010214

45.

Moreno-Jiménez

, Kanczler

, Hulsart-Billstrom

, et al. The chorioallantoic membrane assay for biomaterial testing in tissue engineering: A short-term in vivo preclinical model. Tissue Eng Part C Methods, 2017; 23(12):938–952; doi: 10.1089/ten.tec.2017.0186

46.

Abubakar

, Noordin

, Azmi

, et al. The use of rats and mice as animal models in ex vivo bone growth and development studies. Bone Jt Res, 2016; 5(12):610–618; doi: 10.1302/2046-3758.512.BJR-2016-0102.R2

47.

Baiguera

, Macchiarini

, Ribatti

. Chorioallantoic membrane for in vivo investigation of tissue-engineered construct biocompatibility. J Biomed Mater Res Part B Appl Biomater, 2012; 100 B(5):1425–1434; doi: 10.1002/jbm.b.32653

48.

Rashidi

, Sottile

. The chick embryo: Hatching a model for contemporary biomedical research. BioEssays, 2009; 31(4):459–465; doi: 10.1002/bies.200800168

49.

Yeo

, Wiraja

, Mantalaris

, et al. Nanosensors for regenerative medicine. J Biomed Nanotechnol, 2014; 10(10):2722–2746; doi: 10.1166/jbn.2014.1992

50.

Hahn

, Witte

, Arens

, et al. Double-plating of ovine critical sized defects of the tibia: A low morbidity model enabling continuous in vivo monitoring of bone healing. BMC Musculoskelet Disord, 2011; 12:2–7; doi: 10.1186/1471-2474-12-214

51.

Trachtenberg

, Vo

, Mikos

. Pre-clinical characterization of tissue engineering constructs for bone and cartilage regeneration. Ann Biomed Eng, 2015; 43(3):681–696; doi: 10.1007/s10439-014-1151-0

52.

Oliveira

, Ribeiro

, Miguel

, et al. In vivo high-content evaluation of three-dimensional scaffolds biocompatibility. Tissue Eng Part C Methods, 2014; 20(11):851–864; doi: 10.1089/ten.tec.2013.0738

53.

De Vries

RBM

, Buma

, Leenaars

, et al. Reducing the number of laboratory animals used in tissue engineering research by restricting the variety of animal models. Articular cartilage tissue engineering as a case study. Tissue Eng Part B Rev, 2012; 18(6):427–435; doi: 10.1089/ten.teb.2012.0059

54.

Alvites

, Branquinho

, Sousa

, et al. Small ruminants and its use in regenerative medicine: Recent works and future perspectives. Biology (Basel), 2021; 10(3):1–21; doi: 10.3390/biology10030249

55.

Mangione

, Salmon

, EzEldeen

, et al. Characteristics of large animal models for current cell-based oral tissue regeneration. Tissue Eng Part B Rev, 2022; 28(3):489–505; doi: 10.1089/ten.teb.2020.0384

56.

Quinn

RW.

Animal models for bench to bedside translation of regenerative cardiac constructs. Prog Pediatr Cardiol, 2013; 35(2):91–94; doi: 10.1016/j.ppedcard.2013.08.001

57.

Baklaushev

, Durov

, Kim

, et al. Development of a motor and somatosensory evoked potentials-guided spinal cord Injury model in non-human primates. J Neurosci Methods, 2019; 311:200–214; doi: 10.1016/j.jneumeth.2018.10.030

58.

Afshar

, Aghayan

, Sadighi

, et al. Ethics of research on stem cells and regenerative medicine: Ethical guidelines in the Islamic Republic of Iran. Stem Cell Res Ther, 2020; 11(396):1–5; doi: 10.1186/s13287-020-01916-z

59.

Wellings

Novel 3D scaffolds for tissue culture, regenerative medicine and wound care. Sp2, 2014; 20–22

60.

Kanwar

, Vijayavenkataraman

. Design of 3D printed scaffolds for bone tissue engineering: A review. Bioprinting, 2021; 24:e00167; doi: 10.1016/j.bprint.2021.e00167

61.

Almarzouqi

, Rennekampff

, Almarzouki

, et al. Porcine-derived biomaterials in tissue engineering and reconstructive surgery: Considerations and alternatives in Muslim patients. J Tissue Eng Regen Med, 2019; 13(2):253–260; doi: 10.1002/term.2788

62.

Munirah

, Zainul Ibrahim

, Rozlin

, et al. Exploring the Islamic perspective on tissue engineering principles and practice. Glob J Al-Thaqafah, 2014; 4(2):29–40; doi: 10.7187/gjat642014.04.02

63.

Offner

, de Grado

, Meisels

, et al. Bone grafts, bone substitutes and regenerative medicine acceptance for the management of bone defects among french population: Issues about ethics, religion or fear?. Cell Med, 2019; 11:215517901985766; doi: 10.1177/2155179019857661

64.

Hou

, Li

, Luo

, et al. A composite demineralized bone matrix - Self assembling peptide scaffold for enhancing cell and growth factor activity in bone marrow. Biomaterials, 2014; 35(22):5689–5699; doi: 10.1016/j.biomaterials.2014.03.079

65.

Seo

J pil

, Tsuzuki

, Haneda

, et al. Comparison of allogeneic platelet lysate and fetal bovine serum for in vitro expansion of equine bone marrow-derived mesenchymal stem cells. Res Vet Sci, 2013; 95(2):693–698; doi: 10.1016/j.rvsc.2013.04.024

66.

Tekkatte

, Gunasingh

, Cherian

, et al. “Humanized” stem cell culture techniques: The animal serum controversy. Stem Cells Int, 2011; 2011:504723; doi: 10.4061/2011/504723

67.

Langridge

, Griffin

, Butler

. Regenerative medicine for skeletal muscle loss: A review of current tissue engineering approaches. J Mater Sci Mater Med, 2021; 32(1):15; doi: 10.1007/s10856-020-06476-5

68.

Zhu

, Zhang

, Wang

, et al. Current advances in the development of decellularized plant extracellular matrix. Front Bioeng Biotechnol, 2021; 9:712262; doi: 10.3389/fbioe.2021.712262

69.

Contessi Negrini

, Toffoletto

, Farè

, et al. Plant tissues as 3D natural scaffolds for adipose, bone and tendon tissue regeneration. Front Bioeng Biotechnol, 2020; 8:1–15; doi: 10.3389/fbioe.2020.00723

70.

Ruiz-alonso

, Villate-beitia

, Gallego

, et al. Current insights into 3D bioprinting: An advanced approach for eye tissue regeneration. Pharmaceutics, 2021; 13(3):1–28; doi: 10.3390/pharmaceutics13030308

71.

Hermerén

The ethics of regenerative medicine. Biol Futur, 2021; 72(2):113–118; doi: 10.1007/s42977-021-00075-3

72.

Lee

, Milan

, Urbani

, et al. Decellularized material as scaffolds for tissue engineering studies in long gap esophageal atresia. Expert Opin Biol Ther, 2017; 17(5):573–584; doi: 10.1080/14712598.2017.1308482

73.

Boers

, Van Delden

JJM

, Clevers

, et al. Organoid biobanking: Identifying the ethics. EMBO Rep, 2016; 17(7):938–941; doi: 10.15252/embr.201642613

74.

Cossu

, Birchall

, Brownc

, et al. Lancet commission: Stem cells and regenerative medicine. Lancet, 2018; 391(10123):883–910; doi: 10.1016/S0140-6736(17)31366-1

75.

Kirillova

, Bushev

, Abubakirov

, et al. Bioethical and legal issues in 3D bioprinting. Int J Bioprinting, 2020; 6(3):1–10; doi: 10.18063/IJB.V6I3.272

76.

Hempel

, Lomax

, Peckman

. Broad consent in biobanking. Nat Biotechnol, 2012; 30(9):826; doi: 10.1038/nbt.2349

77.

Oerlemans

AJM

, Van Den Berg

, Van Leeuwen

, et al. Ethical issues regarding the donation and source of cells for tissue engineering: A European focus group study. Tissue Eng Part B Rev, 2011; 17(4):229–234; doi: 10.1089/ten.teb.2010.0683

78.

, Faulkner

. 3D Bioprinting Regulations: A UK/EU Perspective. Eur J Risk Regul, 2017; 8(2):441–447; doi: 10.1017/err.2017.19

79.

Sekar

, Budharaju

, Zennifer

, et al. Current standards and ethical landscape of engineered tissues—3D bioprinting perspective. J Tissue Eng, 2021; 12: 20417314211027677; doi: 10.1177/20417314211027677

80.

, Arbit

, Herrick

, et al. Tissue engineered constructs: Perspectives on clinical translation. Ann Biomed Eng, 2015; 43(3):796–804; doi: 10.1007/s10439-015-1280-0

81.

Gilbert

, O'Connell

, Mladenovska

, et al. Print Me an Organ? ethical and regulatory issues emerging from 3D bioprinting in medicine. Sci Eng Ethics, 2018; 24(1):73–91; doi: 10.1007/s11948-017-9874-6

82.

Horch

, Popescu

, Vacanti

, et al. Ethical issues in cellular and molecular medicine and tissue engineering. J Cell Mol Med, 2008; 12(5B):1785–1793; doi: 10.1111/j.1582-4934.2008.00460.x

83.

Lowdell

, Thomas

. The expanding role of the clinical haematologist in the new world of advanced therapy medicinal products. Br J Haematol, 2017; 176(1):9–15; doi: 10.1111/bjh.14384

84.

Trommelmans

, Selling

, Dierickx

. The importance of the values attached to cells for a good informed consent procedure in cell donation for tissue engineering purposes. Cell Tissue Bank, 2009; 10(4):293–299; doi: 10.1007/s10561-009-9123-6

85.

Master

, Crowley

, Smith

, et al. Stem cell preservation for regenerative therapies: Ethical and governance considerations for the health care sector. NPJ Regen Med, 2020; 5(1):23; doi: 10.1038/s41536-020-00108-w

86.

Gómez-Barrena

, Rosset

, Müller

, et al. Bone regeneration: Stem cell therapies and clinical studies in orthopaedics and traumatology. J Cell Mol Med, 2011; 15(6):1266–1286; doi: 10.1111/j.1582-4934.2011.01265.x

87.

Reinke

, Dienelt

, Blankenstein

, et al. Qualifying stem cell sources: How to overcome potential pitfalls in regenerative medicine?. J Tissue Eng Regen Med, 2016; 10(1):3–10; doi: 10.1002/term.1923

88.

Oerlemans

AJM

, van Hoek

MEC

, van Leeuwen

, et al. Towards a richer debate on tissue engineering: A Consideration on the Basis of NEST-Ethics. Sci Eng Ethics, 2013; 19(3):963–981; doi: 10.1007/s11948-012-9419-y

89.

Ravnic

, Leberfinger

, Koduru

, et al. Transplantation of bioprinted tissues and organs: Technical and clinical challenges and future perspectives. Ann Surg, 2017; 266(1):48–58; doi: 10.1097/SLA.0000000000002141

90.

Singh

, Choudhury

, Yu

, et al. In situ bioprinting – Bioprinting from benchside to bedside?. Acta Biomater, 2020; 101:14–25; doi: 10.1016/j.actbio.2019.08.045

91.

Roberts

DE.

Umbilical cord blood banking: Public good or private benefit?. Med J Aust, 2008; 189(10):599; doi: 10.5694/j.1326-5377.2008.tb02197.x

92.

Martin

, Brown

, Turner

. Capitalizing hope: The commercial development of umbilical cord blood stem cell banking. New Genet Soc, 2008; 27(2):127–143; doi: 10.1080/14636770802077074

93.

Pirnay

, Baudoux

, Cornu

, et al. Access to human tissues for research and product development: From EU regulation to alarming legal developments in Belgium. EMBO Rep, 2015; 16(5):557–562; doi: 10.15252/embr.201540070

94.

Stewart

, Aparicio

, Kerridge

. Ethical and legal issues raised by cord blood banking - The challenges of the new bioeconomy. Med J Aust, 2013; 199(4):290–292; doi: 10.5694/mja12.11668

95.

McGuckin

, Forraz

Umbilical cord blood stem cells - An ethical source for regenerative medicine. Med Law, 2008; 27(1):147–165.

96.

Ballen

, Verter

, Kurtzberg

. Umbilical cord blood donation: Public or private?. Bone Marrow Transplant, 2015; 50(10):1271–1278; doi: 10.1038/bmt.2015.124

97.

Hikita

, Chung U

, Hoshi

, et al. Bone regenerative medicine in oral and maxillofacial region using a three-dimensional printer. Tissue Eng Part A, 2017; 23(11–12):515–521; doi: 10.1089/ten.tea.2016.0543

98.

Crowe

, Chiou

, McGoldrick

, et al. In vitro characteristics of porcine tendon hydrogel for tendon regeneration. Ann Plast Surg, 2016; 77(1):47–53; doi: 10.1097/SAP.0000000000000361

99.

Muhammad Aa'zamuddin

, Sha'ban

, Azharuddin

NSM

, et al. A Survey on Relevant Malaysian Fatwā about cadaver concerning tissue engineering research. Pertanika J Soc Sci Humanit, 2020; 28(2):1451–1466

100.

Muhammad Aa'zamuddin

, Nur Syamimi

, Abdurezak

, et al. Relevant Local Fatwā on the issues of using human tissues in articular cartilage tissue engineering experimentation. IIUM Med J Malaysia, 2021; 20(1):127–135; doi: 10.31436/IMJM.V20I1.1763

101.

Vijayavenkataraman

A perspective on bioprinting ethics. Artif Organs, 2016; 40(11):1033–1038; doi: 10.1111/aor.12873

102.

Hutchison

, Sparrow

. What pacemakers can teach us about the ethics of maintaining artificial organs. Hastings Cent Rep, 2016; 46(6):14–24; doi: 10.1002/hast.644

103.

Jeyaraj

, Natasha

, Kirby

, et al. Vascularisation in regenerative therapeutics and surgery. Mater Sci Eng C, 2015; 54:225–238; doi: 10.1016/j.msec.2015.05.045

104.

Trommelmans

The challenge of regenerative medicine. Hastings Cent Rep, 2010; 40(6):24–26; doi: 10.1002/j.1552-146X.2010.tb00074.x

105.

Furman

The dynamic state of patents in regenerative medicine. Tissue Eng Regen Med, 2013; 10(5):230–233; doi: 10.1007/s13770-013-1082-0

106.

Lavoie

The role of social scientists in accelerating innovation in regenerative medicine. Rev Policy Res, 2011; 28(6):613–630; doi: 10.1111/j.1541-1338.2011.00525.x

107.

Sample

, Boulicault

, Allen

, et al. Multi-cellular engineered living systems: Building a community around responsible research on emergence. Biofabrication, 2019; 11(4):043001; doi: 10.1088/1758-5090/ab268c

108.

Jamieson

, Keenan

, Kirkwood

, et al. A review of recent advances in 3D bioprinting with an eye on future regenerative therapies in veterinary medicine. Front Vet Sci, 2021; 7:1–13; doi: 10.3389/fvets.2020.584193

109.

Harbaugh

JT.

Do you own your 3D bioprinted body? Analyzing property issues at the intersection of digital information and biology. Am J Law Med, 2015; 41(1):167–189; doi: 10.1177/0098858815591512

110.

Lafontaine

Regenerative medicine's immortal body: From the fight against ageing to the extension of longevity. Body Soc, 2009; 15(4):53–71; doi: 10.1177/1357034X09347223

111.

Pirnay

, Vanderkelen

, De Vos

, et al. Business oriented EU human cell and tissue product legislation will adversely impact member states' health care systems. Cell Tissue Bank, 2013; 14(4):525–560; doi: 10.1007/s10561-013-9397-6

112.

Patuzzo

, Goracci

, Gasperini

, et al. 3D bioprinting technology: Scientific aspects and ethical issues. Sci Eng Ethics, 2018; 24(2):335–348; doi: 10.1007/s11948-017-9918-y

113.

Haddad

Services in the self: Embodied labor and the global bioeconomy. Life Sci Soc Policy, 2015; 11(9); doi: 10.1186/s40504-015-0027-x

114.

Tyagi

, Dhindsa

Tissue engineering and its applications in dentistry. Indian J Dent Res, 2009; 20(2):222–226.

115.

Leabu

A framework for assessment and management of ethical risks related to stem cell use in tissue engineering. Ethics Biol Eng Med, 2011; 2(4):333–345; doi: 10.1615/ethicsbiologyengmed.2012006025

116.

Das

, Carnicer-Lombarte

, Fawcett

, et al. Bio-inspired nano tools for neuroscience. Prog Neurobiol, 2016; 142:1–22; doi: 10.1016/j.pneurobio.2016.04.008

117.

Lim

, Jungebluth

, Ajalloueian

, et al. Whole organ and tissue reconstruction in thoracic regenerative surgery. Mayo Clin Proc, 2013; 88(10):1151–1166; doi: 10.1016/j.mayocp.2013.03.011

118.

Madonna

, Van Laake

, Davidson

, et al. Position Paper of the European Society of Cardiology Working Group Cellular Biology of the Heart: Cell-based therapies for myocardial repair and regeneration in ischemic heart disease and heart failure. Eur Heart J, 2016; 37(23):1789–1798; doi: 10.1093/eurheartj/ehw113

119.

Trommelmans

, Selling

, Dierickx

. Informing participants in clinical trials with ex vivo human tissue-engineered products: What to tell and how to tell it?. J Tissue Eng Regen Med, 2008; 2(4):236–241; doi: 10.1002/term.82

120.

Best

, Caplan

, Coleman

, et al. Not missing the future: A call to action for investigating the role of regenerative medicine therapies in pediatric/adolescent sports injuries. Curr Sports Med Rep, 2017; 16(3):202–210; doi: 10.1249/JSR.0000000000000357

121.

Keren-Paz

, El Haj

. Liability versus innovation: The legal case for regenerative medicine. Tissue Eng Part A, 2014; 20(19–20):2555–2560; doi: 10.1089/ten.tea.2013.0324

122.

Hyun

Allowing innovative stem cell-based therapies outside of clinical trials: Ethical and policy challenges. J Law Med Ethics, 2010; 38(2):277–285; doi: 10.1111/j.1748-720X.2010.00488.x

123.

Lysaght

Accelerating regenerative medicine: The Japanese experiment in ethics and regulation. Regen Med, 2017; 12(6):657–668; doi: 10.2217/rme-2017-0038

124.

Oerlemans

AJM

, Feitz

WFJ

, Van Leeuwen

, et al. Regenerative urology clinical trials: An ethical assessment of road blocks and solutions. Tissue Eng Part B Rev, 2013; 19(1):41–47; doi: 10.1089/ten.teb.2012.0136

125.

Jovic

, Combellack

, Jessop

, et al. 3D Bioprinting and the Future of Surgery. Front Surg, 2020; 7:1–10; doi: 10.3389/fsurg.2020.609836

126.

Trommelmans

, Selling

, Dierickx

. Ethical reflections on clinical trials with human tissue engineered products. J Med Ethics, 2008; 34(9):e1; doi: 10.1136/jme.2007.022913

127.

Trommelmans

, Selling

, Dierickx

. An exploratory survey on the views of european tissue engineers concerning the ethical issues of tissue engineering research. Tissue Eng Part B Rev, 2009; 15(3):241–247; doi: 10.1089/ten.teb.2008.0647

128.

Parent

, Gelb

, Latham

, et al. The ethics of testing and research of manufactured organs on brain-dead/recently deceased subjects. J Med Ethics, 2020; 46(3):199–204; doi: 10.1136/medethics-2019-105674

129.

Arnason

Regulating clinical innovation: Trachea transplants and tissue engineering. Am J Bioeth, 2019; 19(6):32–34; doi: 10.1080/15265161.2019.1602179

130.

O'Keefe

, Tuan

, Lane

, et al. American Society for bone and mineral research-orthopaedic research society joint task force report on cell-based therapies. J Bone Miner Res, 2020; 35(1):3–17; doi: 10.1002/jbmr.3839

131.

Taylor

, Caplan

, Macchiarini

. Ethics of bioengineering organs and tissues. Expert Opin Biol Ther, 2014; 14(7):879–882; doi: 10.1517/14712598.2014.915308

132.

The Committee for Advanced Therapies (CAT). Challenges with advanced therapy medicinal products and how to meet them. Nat Rev Drug Discov, 2010; 9(3):195–201; doi: 10.1038/nrd3052

133.

Huh

, Kim

, Ku

. Perspective of bioartificial uterus as gynecological regenerative medicine. Tissue Eng Regen Med, 2012; 9(5):233–239; doi: 10.1007/s13770-012-0360-6

134.

Muhammad Aa'zamuddin

, Hashi

, Sha'ban

. An overview of the application of Maqasid Al-Shariah into cartilage tissue engineering. Int Med J Malaysia, 2016; 17(Specialissue1):151–156; doi: 10.31436/imjm.v17i1.1013

135.

Gaissmaier

, Koh

, Weise

, et al. Future perspectives of articular cartilage repair. Injury, 2008; 39(1 Suppl):114–120; doi: 10.1016/j.injury.2008.01.033

136.

Haag

, Jungebluth

, MacChiarini

. Tracheal replacement for primary tracheal cancer. Curr Opin Otolaryngol Head Neck Surg, 2013; 21(2):171–177; doi: 10.1097/MOO.0b013e32835e212b

137.

Oerlemans

AJM

, Van Hoek

MEC

, Van Leeuwen

, et al. Hype and expectations in tissue engineering. Regen Med, 2014; 9(1):113–122; doi: 10.2217/rme.13.89

138.

Simonacci

, Toni

, Raposio

Facial transplantation. An update of results and perspectives from tissue engineering. Ann Ital Chir, 2017; 88:352–359.

139.

Zou

, Tian

, Luo

, et al. Agarose composite hydrogel and PVA sacrificial materials for bioprinting large-scale, personalized face-like with nutrient networks. Carbohydr Polym, 2021; 269:118222; doi: 10.1016/j.carbpol.2021.118222

140.

Vermeulen

, Haddow

, Seymour

, et al. 3D bioprint me: A socioethical view of bioprinting human organs and tissues. J Med Ethics, 2017; 43(9):618–624; doi: 10.1136/medethics-2015-103347

141.

Daar

AS.

The future of replacement and restorative therapies: From organ transplantation to regenerative medicine. Transplant Proc, 2013; 45(10):3450–3452; doi: 10.1016/j.transproceed.2013.09.011

142.

Jank

, Xiong

, Moser

, et al. Engineered composite tissue as a bioartificial limb graft. Biomaterials, 2015; 61:246–256; doi: 10.1016/j.biomaterials.2015.04.051

143.

Siemionow

Vascularized composite allotransplantation: A new concept in musculoskeletal regeneration. J Mater Sci Mater Med, 2015; 26(12):266; doi: 10.1007/s10856-015-5601-5

144.

Feil

, Daum

, Amend

, et al. From tissue engineering to regenerative medicine in urology - The potential and the pitfalls. Adv Drug Deliv Rev, 2011; 63(4):375–378; doi: 10.1016/j.addr.2010.12.003

145.

Rajab

, Tchantchaleishvili

. Can tissue engineering produce bioartificial organs for transplantation?. Artif Organs, 2019; 43(6):536–541; doi: 10.1111/aor.13443

146.

Xinaris

Organoids for replacement therapy: Expectations, limitations and reality. Curr Opin Organ Transplant, 2019; 24(5):555–561; doi: 10.1097/MOT.0000000000000680

147.

Brockbank

KGM

, Swaja

, Wueste

, et al. Resolving the shortage of organs for transplantation: Ethics, science, and technology. J S C Med Assoc, 2010; 106(6):209–212.

148.

Vijayavenkataraman

, Yan

, Lu

, et al. 3D bioprinting of tissues and organs for regenerative medicine. Adv Drug Deliv Rev, 2018; 132:296–332; doi: 10.1016/j.addr.2018.07.004

149.

Hellström

, Bandstein

, Brännström

. Uterine tissue engineering and the future of uterus transplantation. Ann Biomed Eng, 2017; 45(7):1718–1730; doi: 10.1007/s10439-016-1776-2

150.

Hammond-Browning

UK criteria for uterus transplantation: A review. BJOG An Int J Obstet Gynaecol, 2019; 126(11):1320–1326; doi: 10.1111/1471-0528.15844

151.

Zaami

, Di Luca

, Marinelli

. Advancements in uterus transplant: New scenarios and future implications. Eur Rev Med Pharmacol Sci, 2019; 23(2):892–902; doi: 10.26355/eurrev_201901_16904

152.

Swierstra

, van de Bovenkamp

, Trappenburg

. Forging a fit between technology and morality: The Dutch debate on organ transplants. Technol Soc, 2010; 32(1):55–64; doi: 10.1016/j.techsoc.2010.01.001

153.

Ventura-Juncá

Science and ethics: Bridge to the future for regenerative medicine. Int J Stem Cells, 2011; 4(2):79–84; doi: 10.15283/ijsc.2011.4.2.79

154.

Jacques

, Suuronen

. The progression of regenerative medicine and its impact on therapy translation. Clin Transl Sci, 2020; 13(3):440–450; doi: 10.1111/cts.12736

155.

Gupta

, Agarwal

. Three-Dimensional Bioprinting: Role in craniomaxillary surgery ethics and future. J Craniofac Surg, 2020; 31(4):1114–1116; doi: 10.1097/SCS.0000000000006553

156.

Gilbert

, Viaña

JNM

, O'Connell

, et al. Enthusiastic portrayal of 3D bioprinting in the media: Ethical side effects. Bioethics, 2018; 32(2):94–102; doi: 10.1111/bioe.12414

157.

Chung

Stem-cell-based therapy in the field of urology: A review of stem cell basic science, clinical applications and future directions in the treatment of various sexual and urinary conditions. Expert Opin Biol Ther, 2015; 15(11):1623–1632; doi: 10.1517/14712598.2015.1075504

158.

Allon

, Ben-Yehudah

, Dekel

, et al. Ethical issues in nanomedicine: Tempest in a teapot?. Med Health Care Philos, 2017; 20(1):3–11; doi: 10.1007/s11019-016-9720-7

159.

Niemansburg

, Habets

MGJL

, Van Delden

JJM

, et al. Disclosure of risks and uncertainties are especially vital in light of regenerative medicine. Am J Bioeth, 2014; 14(4):14–16; doi: 10.1080/15265161.2014.889244

160.

Hogle

, Das

. The social production of evidence: Regenerative medicine and the 21st Century Cures Act. Regen Med, 2017; 12(6):581–586; doi: 10.2217/rme-2017-0058

161.

Niemansburg

, Van Delden

JJM

, Dhert

WJA

, et al. Regenerative medicine interventions for orthopedic disorders: Ethical issues in the translation into patients. Regen Med, 2013; 8(1):65–73; doi: 10.2217/rme.12.112

162.

Mathur

, Fernández-Avilés

, Dimmeler

, et al. The consensus of the Task Force of the European Society of Cardiology concerning the clinical investigation of the use of autologous adult stem cells for the treatment of acute myocardial infarction and heart failure: Update 2016. Eur Heart J, 2017; 38(39):2930–2935; doi: 10.1093/eurheartj/ehw640

163.

Attico

, Sceberras

, Pellegrini

. Approaches for effective clinical application of stem cell transplantation. Curr Transplant Reports, 2018; 5(3):244–250; doi: 10.1007/s40472-018-0202-0

164.

Taylor

, Sampaio

, Gobin

. Building new hearts: A review of trends in cardiac tissue engineering. Am J Transplant, 2014; 14(11):2448–2459; doi: 10.1111/ajt.12939

165.

Schneider

CK.

Advanced therapies: Critical points and perspectives. Pharm Policy Law, 2010; 12(1–2):25–28; doi: 10.3233/PPL-2010-0260

166.

Marenah

, Li

, Kumar

, et al. Quality assurance and adverse event management in regenerative medicine for knee osteoarthritis: Current concepts. J Clin Orthop Trauma, 2019; 10(1):53–58; doi: 10.1016/j.jcot.2018.09.005

167.

Jönsson

, Hampson

, Michaels

, et al. Advanced therapy medicinal products and health technology assessment principles and practices for value-based and sustainable healthcare. Eur J Health Econ, 2019; 20(3):427–438; doi: 10.1007/s10198-018-1007-x

168.

Niemansburg

, Van Delden

JJM

, Öner

, et al. Ethical Implications of Regenerative Medicine in Orthopedics: An Empirical Study with Surgeons and Scientists in the Field. Spine J, 2014; 14(6):1029–1035; doi: 10.1016/j.spinee.2013.10.016

169.

Brooks

Stem cell research: Time for a dose of realism. BMJ, 2017; 356:1–3; doi: 10.1136/bmj.j443

170.

Trommelmans

, Dierickx

. Standard of care in clinical research with human tissue engineered products (HTEPs). Am J Bioeth, 2009; 9(3):44–49; doi: 10.1080/15265160802668962

171.

Hughes

Christian K. Schneider. Nat Rev Drug Discov, 2009; 8:270; doi: 10.1038/nrd2864

172.

Goula

, Gkioka

, Michalopoulos

, et al. Advanced therapy medicinal products challenges and perspectives in regenerative medicine. J Clin Med Res, 2020; 12(12):780–786; doi: 10.14740/jocmr3964

173.

De Windt

, Niemansburg

, Vonk

, et al. Ethics in musculoskeletal regenerative medicine; guidance in choosing the appropriate comparator in clinical trials. Osteoarthr Cartil, 2019; 27(1):34–40; doi: 10.1016/j.joca.2018.08.022

174.

Arjmand

, Abedi

, Arabi

, et al. Regenerative medicine for the treatment of ischemic heart disease; status and future perspectives. Front Cell Dev Biol, 2021; 9:1–19; doi: 10.3389/fcell.2021.704903

175.

Niemansburg

, Habets

MGJL

, Dhert

WJA

, et al. Participant selection for preventive Regenerative Medicine trials: Ethical challenges of selecting individuals at risk. J Med Ethics, 2015; 41(11):914–916; doi: 10.1136/medethics-2014-102625

176.

Duarte-Silva

, Guerra-Pinto

, Camelo-Barbosa

, et al. Integration and vascular ingrowth of a collagen meniscal implant: A case report. Malaysian Orthop J, 2019; 13(2):38–41; doi: 10.5704/MOJ.1907.007

177.

Hildebrandt

Horses for courses: An approach to the qualification of clinical trial sites and investigators in ATMPs. Drug Discov Today, 2020; 25(2):265–268; doi: 10.1016/j.drudis.2019.10.003

178.

Kleiderman

, Boily

, Hasilo

, et al. Overcoming barriers to facilitate the regulation of multi-centre regenerative medicine clinical trials. Stem Cell Res Ther, 2018; 9(1):1–9; doi: 10.1186/s13287-018-1055-2

179.

Dohan Ehrenfest

, Piattelli

, Sammartino

, et al. New Biomaterials and Regenerative Medicine Strategies in Periodontology, Oral Surgery, Esthetic and Implant Dentistry 2018. Biomed Res Int, 2019; 2019:10–13; doi: 10.1155/2019/1363581

180.

Chan

Research translation and emerging health technologies: Synthetic biology and beyond. Health Care Anal, 2018; 26(4):310–325; doi: 10.1007/s10728-016-0334-2

181.

Illes

, Sipp

, Kleiderman

, et al. A blueprint for the next generation of ELSI research, training, and outreach in regenerative medicine. NPJ Regen Med, 2017; 2(1):21; doi: 10.1038/s41536-017-0026-z

182.

Fears

, Akutsu

, Alentajan-Aleta

, et al. Inclusivity and diversity: Integrating international perspectives on stem cell challenges and potential. Stem Cell Reports, 2021; 16(8):1847–1852; doi: 10.1016/j.stemcr.2021.07.003

183.

Marks

, Hahn

. Identifying the risks of unproven regenerative medicine therapies. JAMA, 2020; 324(3):241–242; doi: 10.1001/jama.2020.9375

184.

Sharma

Stem cells and tissue engineering in medical practice: Ethical and regulatory policies. Curr Drug Targets, 2018; 20(4):388–398; doi: 10.2174/1389450119666180831095830

185.

Smith

, Martin-Lillie

, Higano

, et al. Challenging misinformation and engaging patients: Characterizing a regenerative medicine consult service. Regen Med, 2020; 15:1427–1440; doi: 10.2217/rme-2020-0018

186.

Pirnay

, Vanderkelen

, Zizi

, et al. Human cells and tissues: The need for a global ethical framework. Bull World Health Organ, 2010; 88(11):870–872; doi: 10.2471/BLT.09.074542

187.

Ryan

, Ikonomou

, Atarod

, et al. Stem cells, cell therapies, and bioengineering in lung biology and diseases 2017. Am J Respir Cell Mol Biol, 2019; 61(4):429–439; doi: 10.1165/rcmb.2019-0286ST

188.

Bauchet

, Lonjon

, Perrin

, et al. Strategies for spinal cord repair after injury: A review of the literature and information. Ann Phys Rehabil Med, 2009; 52(4):330–351; doi: 10.1016/j.annrmp.2008.10.004

189.

Rimmer

Who owns your body? Patricia Piccinini and the future of bioethics. J Law Med, 2013; 21(2):370–378.

190.

Wolinsky

Printing organs cell-by-cell. EMBO Rep, 2014; 15(8):836–838; doi: 10.15252/embr.201439207

191.

Realising the potential of stem-cell research in Europe. Lancet, 2013; 382(9905):1609; doi: 10.1016/S0140-6736(13)62352-1

192.

Niemansburg

, Tempels

, Dhert

, et al. Societal impacts of regenerative medicine: Reflections on the views of orthopedic professionals. Regen Med, 2015; 10(1):17–24; doi: 10.2217/rme.14.69

193.

Abeer

Future medicine: Nanomedicine. J Int Med Sci Acad, 2012; 25(3):187–192.

194.

Ripamonti

, Duarte

, Ferretti

. Re-evaluating the induction of bone formation in primates. Biomaterials, 2014; 35(35):9407–9422; doi: 10.1016/j.biomaterials.2014.07.053

195.

Lucke

, Herbert

, Partridge

, et al. Anticipating the use of life extension technologies. EMBO Rep, 2010; 11(5):334–338; doi: 10.1038/embor.2010.48

196.

Hench

LL.

The future of bioactive ceramics. J Mater Sci Mater Med, 2015; 26(2):86; doi: 10.1007/s10856-015-5425-3

197.

Vemuganti

, Sangwan

. Interview: Affordability at the cutting edge: Stem cell therapy for ocular surface reconstruction. Regen Med, 2010; 5(3):337–340; doi: 10.2217/RME.10.29

198.

Madeddu

Cell therapy for the treatment of heart disease: Renovation work on the broken heart is still in progress. Free Radic Biol Med, 2021; 164:206–222; doi: 10.1016/j.freeradbiomed.2020.12.444

199.

Malloy

, Wubbenhorst

, Lee

. The perinatal revolution. Issues Law Med, 2019; 34(1):15–41.

200.

Mhashilkan

, Atala

. Effective Bio-economic approaches for stem cell therapy and regenerative medicine. Curr Stem Cell Res Ther, 2012; 7(1):1; doi: 10.2174/157488812798483430

201.

Chapman

AR.

Patenting in the Public Interest: The California Institute for Regenerative Medicine Model. Am J Bioeth, 2018; 18(12):61–63; doi: 10.1080/15265161.2018.1531165

202.

Gardner

Distributive justice and regenerative medicine. Regen Med, 2017; 12(7):865–874; doi: 10.2217/rme-2017-0036

203.

Tamari

Skin Matters: An Interview with Marc Lafrance. Theory Cult Soc, 2019; 36(7–8):273–291; doi: 10.1177/0263276419862853

204.

Miyazaki

, Maruyama

. Partial regeneration and reconstruction of the rat uterus through recellularization of a decellularized uterine matrix. Biomaterials, 2014; 35(31):8791–8800; doi: 10.1016/j.biomaterials.2014.06.052

205.

, Wang

, Ma

, et al. Reconstruction of functional uterine tissues through recellularizing the decellularized rat uterine scaffolds by MSCs in vivo and in vitro. Biomed Mater, 2021; 16(3):035023; doi: 10.1088/1748-605X/abd116

206.

Daadi

, Steinberg

. Manufacturing neurons from human embryonic stem cells: Biological and regulatory aspects to develop a safe cellular product for stroke cell therapy. Regen Med, 2009; 4(2):251–263; doi: 10.2217/17460751.4.2.251

207.

Rinaldi

, Colotti

. Use of organoids in medicinal chemistry: Challenges on ethics and biosecurity. Future Med Chem, 2019; 11(10):1087–1090; doi: 10.4155/fmc-2018-0341

208.

De Magalhães

JP.

The scientific quest for lasting youth: Prospects for curing aging. Rejuvenation Res, 2014; 17(5):458–467; doi: 10.1089/rej.2014.1580

209.

Zealley

, De Grey

ADNJ

. Strategies for engineered negligible senescence. Gerontology, 2013; 59(2):183–189; doi: 10.1159/000342197

210.

Satava

RM.

Advanced technologies and the future of medicine and surgery. Yonsei Med J, 2008; 49(6):873–878; doi: 10.3349/ymj.2008.49.6.873

211.

Lafontaine

The postmortal condition: From the biomedical deconstruction of death to the extension of longevity. Sci Cult (Lond), 2009; 18(3):297–312; doi: 10.1080/09505430903123008

212.

Rhodes

Bioethics: Looking forward and looking back. Am J Bioeth, 2013; 13(1):13–16; doi: 10.1080/15265161.2013.747318

213.

Poirot-Mazères

Legal aspects of the risks raised by nanotechnologies in the field of medicine. J Int Bioethique, 2011; 22(1):99–118; doi: 10.3917/jib.221.0099

214.

Djordjevic

ML.

Penile enhancement surgery. JDDG J der Dtsch Dermatologischen Gesellschaft, 2010; 8(9):645–647; doi: 10.1111/j.1610-0387.2010.07518.x

215.

Catts

, Zurr

. Growing for different ends. Int J Biochem Cell Biol, 2014; 56:20–29; doi: 10.1016/j.biocel.2014.09.025

216.

Maienschein

Controlling life: From jacques loeb to regenerative medicine. J Hist Biol, 2009; 42(2):215–230; doi: 10.1007/s10739-009-9180-5

217.

Parry

The social life of “Scaffolds”: Examining human rights in regenerative medicine. Sci Technol Hum Values, 2018; 43(1):95–120; doi: 10.1177/0162243917735179

218.

Sharp

LA.

Bioengineered bodies and the moral imagination. Lancet, 2009; 374(9694):970–971; doi: 10.1016/S0140-6736(09)61653-6

219.

Horton

Exhibition: Beauty, the body, and identity. Lancet, 2015; 385(9977):1499–1500; doi: 10.1016/S0140-6736(15)60741-3

220.

Moreno

, Gearhart

, Zoloth

, et al. Managing cell and human identity. Science, 2017; 356(6334):139–140; doi: 10.1126/science.aan2763

221.

Devisch

, Vanheule

. Singularity and medicine: Is there a place for heteronomy in medical ethics?. J Eval Clin Pract, 2014; 20(6):965–969; doi: 10.1111/jep.12110

222.

Couture

, Béisle-Pipon

, Cloutier

, et al. Merging arts and bioethics: An interdisciplinary experiment in cultural and scientific mediation. Bioethics, 2017; 31(8):616–630; doi: 10.1111/bioe.12391

223.

Derksen

MHG

, Horstman

. Engineering flesh: Towards an ethics of lived integrity. Med Health Care Philos, 2008; 11(3):269–283; doi: 10.1007/s11019-007-9115-x

224.

Fisch

Regenerating bodies. Sci Technol Hum Values, 2018; 43(1):121–128; doi: 10.1177/0162243917737364

225.

Shafer

“A spark of being”: Frankenstein and anesthesiology. Can J Anesth, 2019; 66(9):1022–1025; doi: 10.1007/s12630-019-01376-x

226.

Mason

, Manzotti

. Induced pluripotent stem cells: An emerging technology platform and the gartner hype cycle. Regen Med, 2009; 4(3):329–331; doi: 10.2217/rme.09.20

227.

Hallonsten

Corporate culture has no place in academia. Nature, 2016; 538(7623):7; doi: 10.1038/538007a

228.

Paolo Macchiarini is not guilty of scientific misconduct. Lancet, 2015; 386(9997):932; doi: 10.1016/S0140-6736(15)00118-X

229.

Merryman

WD.

Development of a tissue engineered heart valve for pediatrics: A case study in bioengineering ethics. Sci Eng Ethics, 2008; 14(1):93–101; doi: 10.1007/s11948-008-9053-x

230.

Shineha

, Inoue

, Ikka

, et al. A comparative analysis of attitudes on communication toward stem cell research and regenerative medicine between the public and the scientific community. Stem Cells Transl Med, 2018; 7(2):251–257; doi: 10.1002/sctm.17-0184

231.

Raman

, Bashir

. Biomimicry, Biofabrication, and biohybrid systems: The emergence and evolution of biological design. Adv Healthc Mater, 2017; 6(20):1–20; doi: 10.1002/adhm.201700496

232.

Dobrzański

, Dobrzańska-Danikiewicz

, Dobrzański

. Effect of biomedical materials in the implementation of a long and healthy life policy. Processes, 2021; 9(5):865; doi: 10.3390/pr9050865

233.

Acero

Framing regenerative medicine: Culturally specific stories of an emerging technoscience. BioSocieties; 2021; doi: 10.1057/s41292-021-00236-6

234.

Epelman

, Murray

, Garcia-Godoy

, et al. A practitioner survey of opinions toward regenerative endodontics. J Endod, 2009; 35(9):1204–1210; doi: 10.1016/j.joen.2009.04.059

235.

AY.

The ethical and regulatory-compliant training and practice of regenerative surgery in the United States and Abroad. Stem Cells Dev, 2013; 22(Suppl 1):54–58; doi: 10.1089/scd.2013.0303

236.

Gugatschka

, Ohno

, Saxena

, et al. Regenerative medicine of the larynx. where are we today? A review. J Voice, 2012; 26(5):670.e7–e670.e13; doi: 10.1016/j.jvoice.2012.03.009

237.

Sleeboom-Faulkner

Regulatory brokerage: Competitive advantage and regulation in the field of regenerative medicine. Soc Stud Sci, 2019; 49(3):355–380; doi: 10.1177/0306312719850628

238.

Garreta

, Kamm

, Chuva de Sousa Lopes

, et al. Rethinking organoid technology through bioengineering. Nat Mater, 2021; 20(2):145–155; doi: 10.1038/s41563-020-00804-4

239.

Garcia

, Monlezun

. Global convergence on the bioethics of surgical implants. Biomed Res Int, 2015; 2015:853125; doi: 10.1155/2015/853125

240.

Davis

, Cunnane

, Mulvihill

, et al. The role of stem cells for reconstructing the lower urinary tracts. Curr Stem Cell Res Ther, 2018; 13(6):458–465; doi: 10.2174/1574888x13666180426113907

241.

Muhammad Aa'zamuddin

, Zawawi

, Shaban

, et al. Legal aspects of articular cartilage tissue engineering experimentation: A review on malaysian acts, regulations and guidelines. Malaysian J Med Health Sci, 2020; 16(3):272–284.

242.

Moreno-Vega

, Gómez-Quintero

, Nuñez-Anita

, et al. Polymeric and ceramic nanoparticles in biomedical applications. J Nanotechnol, 2012; 2012: 936041; doi: 10.1155/2012/936041

243.

Romagnoli

Adipose mesenchymal stem cells in the field of bone tissue engineering. World J Stem Cells, 2014; 6(2):144; doi: 10.4252/wjsc.v6.i2.144

244.

Okolie

, Stachurek

, Kandasubramanian

, et al. 3d printing for hip implant applications: A review. Polymers (Basel), 2020; 12(11):1–29; doi: 10.3390/polym12112682

245.

Bauer

, Heller

, Fink

, et al. Social and legal frame conditions for 3D (and) bioprinting in medicine. Int J Comput Dent, 2016; 19(4):293–299.

246.

Keller

GS.

Biologic treatments are our future, but a more regulated one. Facial Plast Surg Clin North Am, 2018; 26(4):ix–xi; doi: 10.1016/j.fsc.2018.06.012

247.

Strech

, Hirschberg

, Meyer

, et al. Ethics Literacy and “Ethics University”: Two intertwined models for public involvement and empowerment in bioethics. Front Public Heal, 2016; 3:1–9; doi: 10.3389/fpubh.2015.00287

248.

Zoeller

Science and the lay perspective: Lay people's involvement in assessing tissue engineering. Tissue Eng Part A, 2014; 20(19–20):2561–2566; doi: 10.1089/ten.tea.2013.0292

249.

Fernandez

The making of an advocate. Regen Med, 2012; 7(6 Suppl):114–116; doi: 10.2217/rme.12.89

250.

Yetisen

, Davis

, Coskun

, et al. Bioart. Trends Biotechnol, 2015; 33(12):724–734; doi: 10.1016/j.tibtech.2015.09.011

251.

Holmberg

, Ideland

. Imagination laboratory: Making sense of bio-objects in contemporary genetic art. Soc Rev, 2016; 64(3):447–467; doi: 10.1111/1467-954X.12387

252.

Schork

NJ.

Time for one-person trials. Nature, 2015; 520(7549):609–611; doi: 10.1038/520609a

253.

Kane

, Bittlinger

, Kimmelman

. Individualized therapy trials: Navigating patient care, research goals and ethics. Nat Med, 2021; 27(10):1679–1686; doi: 10.1038/s41591-021-01519-y

254.

Chan

Current and emerging global themes in the bioethics of regenerative medicine: The tangled web of stem cell translation. Regen Med, 2017; 12(7):839–851; doi: 10.2217/rme-2017-0065

255.

Swierstra

Identifying the normative challenges posed by technology's “soft” impacts. Etikk Praksis, 2015; 9(1):5–20; doi: 10.5324/eip.v9i1.1838

256.

Assen

, Jongsma

, Isasi

, et al. Recognizing the ethical implications of stem cell research: A call for broadening the scope. Stem Cell Reports, 2021; 16(7):1656–1661; doi: 10.1016/j.stemcr.2021.05.021

257.

Sipp

Identity and ownership issues in the regulation of autologous cells. Regen Med, 2017; 12(7):827–838; doi: 10.2217/rme-2017-0063

258.

Kool

, Bos

AME

, van der Graaf

, et al. Ethics of oocyte banking for thirdparty assisted reproduction: A systematic review. Hum Reprod Update, 2018; 24(5):615–635; doi: 10.1093/humupd/dmy016

259.

Boers

, Van Delden

JJM

, Bredenoord

. Organoids as hybrids: Ethical implications for the exchange of human tissues. J Med Ethics, 2018; 45(2):131–139; doi: 10.1136/medethics-2018-104846

260.

The Glossary for Cell & Gene Therapy and Regenerative Medicine 2020. Regen Med, 2020; 15(12S):1–170; doi: 10.2217/rme-2020-1512s

261.

Mahtani

, Heneghan

, Aronson

. Single screening or double screening for study selection in systematic reviews?. BMJ Evid Based Med, 2020; 25(4):149–150; doi: 10.1136/bmjebm-2019-111269

262.

McDougall

Systematic reviews in bioethics: Types, challenges, and value. J Med Philos (United Kingdom), 2014; 39(1):89–97; doi: 10.1093/jmp/jht059

263.

Iglesias-López

, Agustí

, Obach

, et al. Regulatory framework for advanced therapy medicinal products in Europe and United States. Front Pharmacol, 2019; 10:1–14; doi: 10.3389/fphar.2019.00921

Supplementary Material

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

Abstract

Impact statement

Introduction

Method

Search strategy

Inclusion and exclusion criteria

Data extraction and analysis

Results

Characteristics of included articles

Synthesis of the ethical implications of TE for regenerative purposes

Animal welfare

Animal experimentation

Animal-derived TE components

Handling human tissue

Tissue collection, storage, and use

Ownership and commodification

Informed consent

Challenges to consent

Conditions for consent

Therapeutic potential

Therapeutic promise

Objectives for wellbeing

Risk and safety

Risks to participant

Safety measures

Clinical translation

Clinical trial design

Innovative therapy pathway

Unproven commercial interventions

Societal impact

Distributive justice

Impact on health care and markets

Biosecurity

Longevity and enhancement

Human experience and identity

Scientific integrity

Responsible conduct

Transdisciplinary collaboration

Regulation

Need for guidelines and oversight

Liability

Patient and public involvement

Discussion

Methodological choices, strengths, and limitations

Concluding Remarks

Footnotes

Acknowledgments

Authors' Contributions

Disclosure Statement

Funding Information

Supplementary Material

References

Supplementary Material