Patient, parent and professional expert perspectives on personalized regenerative implants: a qualitative focus group study.

Background: Perspectives of patients, parents and professional experts on personalized regenerative implants for regenerative medicine purposes are largely unknown.Method: To better understand these perspectives, we conducted four focus groups with professional experts of mixed European nationality (n = 8), Dutch patients with regular implants (n = 8), Dutch and Belgian (n = 5) and Spanish (n = 8) parents of children with cleft palate.Results: Two overarching themes were identified: 'patient-centered research and care' and 'ambivalent attitudes toward personalized regenerative implants'.Discussion: The results reveal that stakeholders should adopt a participatory rather than an impairment discourse and address the ambivalence among professional experts, patients and parents.Conclusion: Considering stakeholder perspectives facilitates ethical and responsible development and use of personalized regenerative implants.

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What is a cure through gene therapy? An analysis and evaluation of the use of "cure".

The development of gene therapy has always come with the expectation that it will offer a cure for various disorders, of which hemophilia is a paradigm example. However, although the term is used regularly, it is unclear what exactly is meant with "cure". Therefore, the aim of this paper is to analyse how the concept of cure is used in practice and evaluate which of the interpretations is most suitable in discussions surrounding gene therapy. We analysed how cure is used in four different medical fields where the concept raises discussion. We show that cure can be used in three different ways: cure as normalization of the body, cure as obtaining a normal life, or cure as a change in identity. We argue that since cure is a practical term, its interpretation should be context-specific and the various uses can exist simultaneously, as long as their use is suitable to the function the notion of cure plays in each of the settings. We end by highlighting three different settings in the domain of hemophilia gene therapy in which the term cure is used and explore the function(s) it serves in each setting. We conclude that in the clinical application of gene therapy, it could be better to abandon the term cure, whereas more modest and specified definitions of cure are required in the context of health resource allocation decisions and decisions on research funding.

A value hierarchy for inclusive design of heart valve implants in regenerative medicine.

Aim: This paper investigates the conditions for inclusive design of regenerative medicine interventions from a bioethical perspective, taking regenerative valve implants as a showcase.Methods: A value hierarchy is construed to translate the value of justice into norms and design requirements for inclusive design of regenerative valve implants.Results: Three norms are proposed and translated into design requirements: regenerative valve implants should be designed to promote equal opportunity to good health for all potential users; equal respect for all potential users should be shown; and the implants should be designed to be accessible to everyone in need.Conclusion: The norms and design requirements help to design regenerative valve implants that are appropriate, respectful and available for everyone in need.

Scientists in the field of regenerative medicine are developing a new type of heart valve implant. After implantation, the synthetic implant slowly breaks down and is replaced by a new living heart valve. These so-called regenerative implants promise a complete cure. However, they also raise ethical questions. For example, questions related to justice and inclusion. In this paper, we explore how regenerative implants can be designed to be inclusive, meaning suitable, respectful and available for everyone. We argue that the design of regenerative implants should be adapted to relevant differences between users. The implants should be affordable in the short and long term. The implants should be suitable for use worldwide. The implants should be designed by teams of diverse age, gender and ethnicity. Users should be engaged in the design. And the communication about the implants to researchers and users should be inclusive. Overall, this paper provides ethical guidance to researchers and clinicians developing regenerative implants.

Developer perspectives on the ethics of AI-driven neural implants: a qualitative study.

Convergence of neural implants with artificial intelligence (AI) presents opportunities for the development of novel neural implants and improvement of existing neurotechnologies. While such technological innovation carries great promise for the restoration of neurological functions, they also raise ethical challenges. Developers of AI-driven neural implants possess valuable knowledge on the possibilities, limitations and challenges raised by these innovations; yet their perspectives are underrepresented in academic literature. This study aims to explore perspectives of developers of neurotechnology to outline ethical implications of three AI-driven neural implants: a cochlear implant, a visual neural implant, and a motor intention decoding speech-brain-computer-interface. We conducted semi-structured focus groups with developers (n = 19) of AI-driven neural implants. Respondents shared ethically relevant considerations about AI-driven neural implants that we clustered into three themes: (1) design aspects; (2) challenges in clinical trials; (3) impact on users and society. Developers considered accuracy and reliability of AI-driven neural implants conditional for users' safety, authenticity, and mental privacy. These needs were magnified by the convergence with AI. Yet, the need for accuracy and reliability may also conflict with potential benefits of AI in terms of efficiency and complex data interpretation. We discuss strategies to mitigate these challenges.

Nature-versus-nurture considered harmful: Actionability as an alternative tool for understanding the exposome from an ethical perspective.

Exposome research is put forward as a major tool for solving the nature-versus-nurture debate because the exposome is said to represent "the nature of nurture." Against this influential idea, we argue that the adoption of the nature-versus-nurture debate into the exposome research program is a mistake that needs to be undone to allow for a proper bioethical assessment of exposome research. We first argue that this adoption is originally based on an equivocation between the traditional nature-versus-nurture debate and a debate about disease prediction/etiology. Second, due to this mistake, exposome research is pushed to adopt a limited conception of agential control that is harmful to one's thinking about the good that exposome research can do for human health and wellbeing. To fully excise the nature-versus-nurture debate from exposome research, we argue that exposome researchers and bioethicists need to think about the exposome afresh from the perspective of actionability. We define the concept of actionability and related concepts and show how these can be used to analyze the ethical aspects of the exposome. In particular, we focus on refuting the popular "gun analogy" in exposome research, returning results to study participants and risk-taking in the context of a well-lived life.

Embodiment and regenerative implants: a proposal for entanglement.

Regenerative Medicine promises to develop treatments to regrow healthy tissues and cure the physical body. One of the emerging developments within this field is regenerative implants, such as jawbone or heart valve implants, that can be broken down by the body and are gradually replaced with living tissue. Yet challenges for embodiment are to be expected, given that the implants are designed to integrate deeply into the tissue of the living body, so that implant and body become one. In this paper, we explore how regenerative implants may affect the embodied experience of implant recipients. To this end, we take a phenomenological approach. First, we explore what insights the existing phenomenological and empirical literature on embodiment offers regarding the experience of illness and of living with regular (non-regenerative) implants and organ transplants. Second, we apply these insights to better understand how future implant recipients might experience living with regenerative implants. Third, we conclude that concepts and considerations from the existing phenomenological literature do not sufficiently address what it might be like to live with an implantable technology that, over time, becomes one with the living body. We argue that the interwovenness and intimate relationship of people living with regenerative implants should be understood in terms of 'entanglement'. Entanglement allows us to explore the complexities of human-technology relations, acknowledging the inseparability of humans and implantable technologies. Our theoretical foundations regarding the role of embodiment may be tested empirically once more people will be living with regenerative implants.

Hope, but never expect? Comparing parents' pre- and post-disclosure attitudes toward return of results from diagnostic exome sequencing for their child.

BACKGROUND: Counseling for whole-exome sequencing (WES) could benefit from aligning parents' pre- and post-disclosure attitudes. A few studies have qualitatively compared parents' pre- and post-disclosure attitudes toward receiving WES results for their child in a diagnostic setting. This study explored these attitudes in the context of children with a developmental delay. METHODS: Semi-structured interviews were conducted with parents (n = 27) of 16 children undergoing diagnostic WES in trio-analysis, both before and after receiving results. RESULTS: Three key insights emerged. First, the distinction between hoping and expecting was relevant for shaping parents' experiences with receiving results related to the primary indication. Second, parents of young children whose development of autonomous capacities was uncertain sometimes found themselves in a situation resembling a Catch-22 when confronted with decisions about unsolicited findings (UFs): an important reason for consenting to WES was to gain a better picture of how the child might develop, but in order to make responsible choices about UFs, some ideas of their child's development is needed. Third, default opt-ins and opt-outs helped parents fathom new kinds of considerations for accepting or declining UFs in different categories, thereby aiding decision-making. CONCLUSION: Results from this study are relevant for counseling and policy development.

Human fetal brain self-organizes into long-term expanding organoids.

Human brain development involves an orchestrated, massive neural progenitor expansion while a multi-cellular tissue architecture is established. Continuously expanding organoids can be grown directly from multiple somatic tissues, yet to date, brain organoids can solely be established from pluripotent stem cells. Here, we show that healthy human fetal brain in vitro self-organizes into organoids (FeBOs), phenocopying aspects of in vivo cellular heterogeneity and complex organization. FeBOs can be expanded over long time periods. FeBO growth requires maintenance of tissue integrity, which ensures production of a tissue-like extracellular matrix (ECM) niche, ultimately endowing FeBO expansion. FeBO lines derived from different areas of the central nervous system (CNS), including dorsal and ventral forebrain, preserve their regional identity and allow to probe aspects of positional identity. Using CRISPR-Cas9, we showcase the generation of syngeneic mutant FeBO lines for the study of brain cancer. Taken together, FeBOs constitute a complementary CNS organoid platform.

Potentiality switches and epistemic uncertainty: the Argument from Potential in times of human embryo-like structures.

Recent advancements in developmental biology enable the creation of embryo-like structures from human stem cells, which we refer to as human embryo-like structures (hELS). These structures provide promising tools to complement-and perhaps ultimately replace-the use of human embryos in clinical and fundamental research. But what if these hELS-when further improved-also have a claim to moral status? What would that imply for their research use? In this paper, we explore these questions in relation to the traditional answer as to why human embryos should be given greater protection than other (non-)human cells: the so-called Argument from Potential (AfP). According to the AfP, human embryos deserve special moral status because they have the unique potential to develop into persons. While some take the development of hELS to challenge the very foundations of the AfP, the ongoing debate suggests that its dismissal would be premature. Since the AfP is a spectrum of views with different moral implications, it does not need to imply that research with human embryos or hELS that (may) have 'active' potential should be completely off-limits. However, the problem with determining active potential in hELS is that this depends on development passing through 'potentiality switches' about the precise coordinates of which we are still in the dark. As long as this epistemic uncertainty persists, extending embryo research regulations to research with specific types of hELS would amount to a form of regulative precaution that as such would require further justification.

Ethical aspects of hemophilia gene therapy: a qualitative interview study with stakeholders.

Background: There are great expectations for the potential role of gene therapy in the treatment of hemophilia. At the same time, developments in the field of hemophilia gene therapy have always raised ethical issues. It remains unknown how these ethical issues are perceived by stakeholders, particularly regarding the most recent developments in the field. Objectives: To obtain insight into stakeholders' morally reasoned opinions on gene therapy for hemophilia. Methods: We conducted qualitative research with Dutch people with hemophilia (n = 13), parents of children with hemophilia (n = 5), physicians (n = 4), nurses (n = 3), a regulator (n = 1), and a representative from a pharmaceutical company (n = 1). We conducted semistructured interviews based on a topic list and reported the results according to the Consolidated Criteria for Reporting Qualitative Research guidelines. Results: We identified 3 main themes. The theme freedom and independence describes the hope people with hemophilia have of increasing their freedom through gene therapy, as well as concerns that gene therapy increases their dependence on their treatment center. The theme trust and altruism describes how people with hemophilia have a high level of trust in their physician and treatment center as well as in scientific research. As a result of this trust, they are willing to participate in research to help other people with hemophilia. The theme incremental benefits describes doubts respondents have about the added value of gene therapy compared to standard treatment. Conclusion: Stakeholders embrace the theoretical potential of gene therapy, while several people with hemophilia question the added value of the current gene transfer products for themselves.

Uncertain futures and unsolicited findings in pediatric genomic sequencing: guidelines for return of results in cases of developmental delay.

BACKGROUND: Massively parallel sequencing techniques, such as whole exome sequencing (WES) and whole genome sequencing (WGS), may reveal unsolicited findings (UFs) unrelated to the diagnostic aim. Such techniques are frequently used for diagnostic purposes in pediatric cases of developmental delay (DD). Yet policy guidelines for informed consent and return of UFs are not well equipped to address specific moral challenges that may arise in these children's situations. DISCUSSION: In previous empirical studies conducted by our research group, we found that it is sometimes uncertain how children with a DD will develop and whether they could come to possess capacities for autonomous decision-making in the future. Parents sometimes felt this brought them into a Catch-22 like situation when confronted with choices about UFs before undergoing WES in trio-analysis (both the parents' and child's DNA are sequenced). An important reason for choosing to consent to WES was to gain more insight into how their child might develop. However, to make responsible choices about receiving or declining knowledge of UFs, some idea of their child's future development of autonomous capacities is needed. This undesirable Catch-22 situation was created by the specific policy configuration in which parents were required to make choices about UFs before being sequencing (trio-analysis). We argue that this finding is relevant for reconfiguring current policies for return of UFs for WES/WGS and propose guidelines that encompass two features. First, the informed consent process ought to be staged. Second, differing guidelines are required for withholding/disclosing a UF in cases of DD appropriate to the level of confidence there is about the child's future developmental of autonomous capacities. CONCLUSION: When combined with a dynamic consent procedure, these two features of our guidelines could help overcome significant moral challenges that present themselves in the situations of children undergoing genomic sequencing for clarifying a DD.

Personalized 3D printed scaffolds: The ethical aspects.

Personalized 3D printed scaffolds are a new generation of implants for tissue engineering and regenerative medicine purposes. Scaffolds support cell growth, providing an artificial extracellular matrix for tissue repair and regeneration and can biodegrade once cells have assumed their physiological and structural roles. The ethical challenges and opportunities of these implants should be mapped in parallel with the life cycle of the scaffold to assist their development and implementation in a responsible, safe, and ethically sound manner. This article provides an overview of these relevant ethical aspects. We identified nine themes which were linked to three stages of the life cycle of the scaffold: the development process, clinical testing, and the implementation process. The described ethical issues are related to good research and clinical practices, such as privacy issues concerning digitalization, first-in-human trials, responsibility and commercialization. At the same time, this article also creates awareness for underexplored ethical issues, such as irreversibility, embodiment and the ontological status of these scaffolds. Moreover, it exemplifies how to include gender in the ethical assessment of new technologies. These issues are important for responsible development and implementation of personalized 3D printed scaffolds and in need of more attention within the additive manufacturing and tissue engineering field. Moreover, the insights of this review reveal unresolved qualitative empirical and normative questions that could further deepen the understanding and co-creation of the ethical implications of this new generation of implants.

How Smart are Smart Materials? A Conceptual and Ethical Analysis of Smart Lifelike Materials for the Design of Regenerative Valve Implants.

It may soon become possible not just to replace, but to re-grow healthy tissues after injury or disease, because of innovations in the field of Regenerative Medicine. One particularly promising innovation is a regenerative valve implant to treat people with heart valve disease. These implants are fabricated from so-called 'smart', 'lifelike' materials. Implanted inside a heart, these implants stimulate re-growth of a healthy, living heart valve. While the technological development advances, the ethical implications of this new technology are still unclear and a clear conceptual understanding of the notions 'smart' and 'lifelike' is currently lacking. In this paper, we explore the conceptual and ethical implications of the development of smart lifelike materials for the design of regenerative implants, by analysing heart valve implants as a showcase. In our conceptual analysis, we show that the materials are considered 'smart' because they can communicate with human tissues, and 'lifelike' because they are structurally similar to these tissues. This shows that regenerative valve implants become intimately integrated in the living tissues of the human body. As such, they manifest the ontological entanglement of body and technology. In our ethical analysis, we argue this is ethically significant in at least two ways: It exacerbates the irreversibility of the implantation procedure, and it might affect the embodied experience of the implant recipient. With our conceptual and ethical analysis, we aim to contribute to responsible development of smart lifelike materials and regenerative implants.

The ethical aspects of exposome research: a systematic review.

In recent years, exposome research has been put forward as the next frontier for the study of human health and disease. Exposome research entails the analysis of the totality of environmental exposures and their corresponding biological responses within the human body. Increasingly, this is operationalized by big-data approaches to map the effects of internal as well as external exposures using smart sensors and multiomics technologies. However, the ethical implications of exposome research are still only rarely discussed in the literature. Therefore, we conducted a systematic review of the academic literature regarding both the exposome and underlying research fields and approaches, to map the ethical aspects that are relevant to exposome research. We identify five ethical themes that are prominent in ethics discussions: the goals of exposome research, its standards, its tools, how it relates to study participants, and the consequences of its products. Furthermore, we provide a number of general principles for how future ethics research can best make use of our comprehensive overview of the ethical aspects of exposome research. Lastly, we highlight three aspects of exposome research that are most in need of ethical reflection: the actionability of its findings, the epidemiological or clinical norms applicable to exposome research, and the meaning and action-implications of bias.

Impact of sharing Alzheimer's disease biomarkers with individuals without dementia: A systematic review and meta-analysis of empirical data.

INTRODUCTION: We conducted a systematic literature review and meta-analysis of empirical evidence on expected and experienced implications of sharing Alzheimer's disease (AD) biomarker results with individuals without dementia. METHODS: PubMed, Embase, APA PsycInfo, and Web of Science Core Collection were searched according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Results from included studies were synthesized, and quantitative data on psychosocial impact were meta-analyzed using a random-effects model. RESULTS: We included 35 publications. Most personal stakeholders expressed interest in biomarker assessment. Learning negative biomarker results led to relief and sometimes frustration, while positive biomarkers induced anxiety but also clarity. Meta-analysis of five studies including 2012 participants (elevated amyloid = 1324 [66%], asymptomatic = 1855 [92%]) showed short-term psychological impact was not significant (random-effect estimate = 0.10, standard error = 0.23, P = 0.65). Most professional stakeholders valued biomarker testing, although attitudes and practices varied considerably. DISCUSSION: Interest in AD biomarker testing was high and sharing their results did not cause psychological harm. HIGHLIGHTS: Most personal stakeholders expressed interest in Alzheimer's disease biomarker assessment. Personal motivations included gaining insight, improving lifestyle, or preparing for the future. There was no short-term psychological impact of sharing biomarker status, implying it can be safe. Most professional stakeholders valued biomarker testing, believing the benefits outweigh the risk. Harmonized guidelines on biomarker testing and sharing results are required.

The boundary problem: Defining and delineating the community in field trials with gene drive organisms.

Despite widespread and worldwide efforts to eradicate vector-borne diseases such as malaria, these diseases continue to have an enormous negative impact on public health. For this reason, scientists are working on novel control strategies, such as gene drive technologies (GDTs). As GDT research advances, researchers are contemplating the potential next step of conducting field trials. An important point of discussion regarding these field trials relates to who should be informed, consulted, and involved in decision-making about their design and launch. It is generally argued that community members have a particularly strong claim to be engaged, and yet, disagreement and lack of clarity exist about how this "community" should be defined and delineated. In this paper, we shed light on this "boundary problem": the problem of determining how boundaries of inclusion and exclusion in (GDT) community engagement should be drawn. As our analysis demonstrates, the process of defining and delineating a community is itself normative. First, we explicate why it is important to define and delineate the community. Second, we demonstrate that different definitions of community are used and intermingled in the debate on GDTs, and argue in favor of distinguishing geographical, affected, cultural, and political communities. Finally, we propose initial guidance for deciding who should (not) be engaged in decision-making about GDT field trials, by arguing that the definition and delineation of the community should depend on the rationale for engagement and that the characteristics of the community itself can guide the effective design of community engagement strategies.

Duty to recontact in genomic cancer care: A tool helping to assess the professional's responsibility.

Tumour DNA and germline testing, based on DNA-wide sequencing analysis, are becoming more and more routine in clinical-oncology practice. A promising step in medicine, but at the same time leading to challenging ethicolegal questions. An important one is under what conditions individuals (patients and their relatives, research participants) should be recontacted with new information, even if many years have passed since the last contact. Based on legal- and ethical study, we developed a tool to help professionals to decide whether or not to recontact an individual in specific cases. It is based on four assessment criteria: (1) professional relationship (2) clinical impact (3) individual's preferences and (4) feasibility. The tool could also serve as a framework for guidelines on the topic.

Alleviating the burden of malaria with gene drive technologies? A biocentric analysis of the moral permissibility of modifying malaria mosquitoes.

Gene drive technologies (GDTs) have been proposed as a potential new way to alleviate the burden of malaria, yet have also raised ethical questions. A central ethical question regarding GDTs relates to whether it is morally permissible to intentionally modify or eradicate mosquitoes in this way and how the inherent worth of humans and non-human organisms should be factored into determining this. Existing analyses of this matter have thus far generally relied on anthropocentric and zoocentric perspectives and rejected an individualist biocentric outlook in which all living organisms are taken to matter morally for their own sake. In this paper, we reconsider the implications of taking a biocentric approach and highlight nuances that may not be evident at first glance. First, we shortly discuss biocentric perspectives in general, and then outline Paul Taylor's biocentric theory of respect for nature. Second, we explore how conflicting claims towards different organisms should be prioritised from this perspective and subsequently apply this to the context of malaria control using GDTs. Our ethical analysis shows that this context invokes the principle of self-defence, which could override the pro tanto concerns that a biocentrist would have against modifying malaria mosquitoes in this way if certain conditions are met. At the same time, the case study of GDTs underlines the relevance of previously posed questions and criticism regarding the internal consistency of Taylor's egalitarian biocentrism.

The ethics of gene therapy for hemophilia: a narrative review.

Gene therapy is expected to become a promising treatment, and potentially even a cure, for hemophilia. After several years of research, the first gene therapy product has been granted conditional market authorization by the European Union in August 2022. The recent progress in the field also has implications on the ethical aspects of hemophilia gene therapy. Reviews conducted in the 2000s mainly identified questions on the ethics of conducting early-phase clinical trials. However, since then, the knowledge on safety and efficacy has improved, and the field has moved toward clinical application, a phase that has its own ethical aspects. Therefore, we conducted a narrative review to take stock of the ethical aspects of hemophilia gene therapy. Based on our analysis of the literature, we identified 3 ethical themes. The theme Living up to expectations describes the existing hopes for gene therapy and the unlikelihood of the currently approved product becoming a permanent cure. In the theme Psychosocial impacts, we discuss the fear that gene therapy will impact the identity of people with hemophilia and their need for psychosocial support. The theme Costs and access discusses the expected cost-effectiveness of gene therapy and its implications on accessibility worldwide. We conclude that it may be necessary to change the narratives surrounding gene therapy, from describing it as a cure to describing it as one of the many treatments that temporarily relieve symptoms and that there is a need to reevaluate the desirability of gene therapy for hemophilia, given the availability of other treatments.