Long-term in vivo integrity and safety of 3D-bioprinted cartilaginous constructs

Long-term stability and biological safety are crucial for translation of 3D-bioprinting technology into clinical applications. Here, we addressed the long-term safety and stability issues associated with 3D-bioprinted constructs comprising a cellulose scaffold and human cells (chondrocytes and stem cells) over a period of 10 months in nude mice. Our findings showed that increasing unconfined compression strength over time significantly improved the mechanical stability of the cell-containing constructs relative to cell-free scaffolds. Additionally, the cell-free constructs exhibited a mean compressive stress and stiffness (compressive modulus) of 0.04 +/- 0.05 MPa and 0.14 +/- 0.18 MPa, respectively, whereas these values for the cell-containing constructs were 0.11 +/- 0.08 MPa (p= .019) and 0.53 +/- 0.59 MPa (p= .012), respectively. Moreover, histomorphologic analysis revealed that cartilage formed from the cell-containing constructs harbored an abundance of proliferating chondrocytes in clusters, and after 10 months, resembled native cartilage. Furthermore, extension of the experiment over the complete lifecycle of the animal model revealed no signs of ossification, fibrosis, necrosis, or implant-related tumor development in the 3D-bioprinted constructs. These findings confirm the in vivo biological safety and mechanical stability of 3D-bioprinted cartilaginous tissues and support their potential translation into clinical applications

Medical 3D printing, intellectual property and regulation

This chapter gives an overview of applicable legal frameworks to the main uses of 3D printing in medicine. In particular, medical device regulation and intellectual property are explored. 3D printing is not an unregulated field, but there can be ambiguities about how particular legal frameworks, developed in a pre-3D printing era, can apply. Questions also arise about whether these frameworks need to be changed to better facilitate desirable uses of 3D printing and protect against undesirable uses. This chapter presents some of these debates, and gives a summary of legal issues those using 3D printing in the medical field need to consider, focussing on intellectual property and medical device regulation

Consent in body donation

This article explores potential threats to the valid-ity of consent in body donation and potential re-sponses to such threats. To minimize abstract generalizations, the article draws particularly on United Kingdom regulations but each of the issues it explores is applicable in many countries. Meth-ods used were searches of relevant (e.g., medical ethical) literatures using pertinent search terms (e.g., consent) and discussions with multiple stake-holders (e.g., family members of body donors). The main threats identified were: (1) failing to ade-quately acknowledge relatives’ roles in donation, particularly as donation often cannot be completed without relatives’ active participation; (2) failing to ensure that donors are informed enough to be able to give valid consent, especially given ‘specification’ and ‘temporality’ problems inherent in establishing consent for body donation; and (3) failing to genuinely prioritize donors’ motives and concerns during and after obtaining their consent. Possible ways of countering these threats include layering information given and made available to potential donors and having donors consent not to ‘donation and anything that might follow’, but in-stead to ‘relative-acknowledged donation, selective explicit consent, and delegated decision-making’. The latter involves donors specifying and relatives acknowledging donors’ key preferences and prohi-bitions, among which is nomination or acceptance of specified proxies who may make decisions on donors’ behalf after their death. By making such changes, the validity of consent for body donation could be substantially improved in ways that also increase respect for both donors and their autono-my. These changes may also increase the number of completed donations

The Ten Principles of Socially Responsible Digital Health Design

We are now, more than ever, aware of the social challenges that face us globally, keeping healthy is at the top of the list. Increasingly in the last ten years, designers have turned their attention not just to designing to alleviate and prevent illness but designing specifically to increase individual and community wellness and health. Digital health design has been one of those dimensions adopted to address the challenge. In this opinion piece we posit that in the domain of digital health all design should be socially responsible in order for us to consider it good design. Drawing on the history of socially responsible design and the emergence of digital health applications we propose Ten Principles of Socially Responsible Digital Health Design

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.</p

Bioprinting and preliminary testing of highly reproducible novel bioink for potential skin regeneration

Three-dimensional (3D) bioprinting is considered as a novel approach in biofabricating cell-laden constructs that could potentially be used to promote skin regeneration following injury. In this study, a novel crosslinked chitosan (CH)–genipin (GE) bioink laden with keratinocyte and human dermal fibroblast cells was developed and printed successfully using an extruder-based bioprinter. By altering the composition and degree of CH–GE crosslinking, bioink printability was further assessed and compared with a commercial bioink. Rheological analysis showed that the viscosity of the optimised bioink was in a suitable range that facilitated reproducible and reliable printing by applying low pressures ranging from 20–40 kPa. The application of low printing pressures proved vital for viability of cells loaded within the bioinks. Further characterisation using MTT assay showed that cells were still viable within the printed construct at 93% despite the crosslinking, processing and after subjecting to physiological conditions for seven days. The morphological study of the printed cells showed that they were mobile within the bioink. Furthermore, the multi-layered 3D printed constructs demonstrated excellent self-supportive structures in a consistent manner

3D bioprinted alginate-gelatin hydrogel patches containing cardiac spheroids recover heart function in a mouse model of myocardial infarction

Epicardial transplantation of 3D bioprinted patches represents a promising protective strategy against infarction-induced myocardial damage. We previously showed that 3D bioprinted tissues containing cardiac spheroids [in alginate/gelatin (AlgGel) hydrogels] promoted cell viability/function and endothelial cell tubular self-assembly. Here, we hypothesise that bioprinted cardiac spheroid patches improve cardiac function after myocardial infarction (MI). To determine treatment effects of hydrogel alone or with cells, MI mice were transplanted with: (i) AlgGel acellular patches, (ii) AlgGel with freely suspended cardiac cells, (iii) AlgGel with cardiac spheroids. We included control MI mice (no treatment) and mice undergoing sham surgery. We performed measurements to 28 days including echocardiography, flow cytometry and transcriptomic analyses. Our results measured median baseline (pre-surgery) left ventricular ejection fraction (LVEF%) for all mice at 66%. Post-surgery, LVEF% was 58% for Sham (non-infarcted) and 41% for MI (no treatment) mice. Patch transplantation increased LVEF%: 55% (acellular; p = 0.012), 59% (cells; p = 0.106), 64% (spheroids; p = 0.010). Flow cytometry demonstrated host cardiac tissue immune cell population changes with treatments. RNAseq transcriptomes demonstrated similar gene expression profiles for Sham and mice treated with cardiac spheroid patches. Extrusion 3D bioprinting permits hydrogel patch generation even preserving microtissue cardiac spheroids directly suspended in the bioink. Inflammatory and genetic mechanisms may play important roles in regulating host responses after patch transplantation in infarcted hearts. Future studies are needed to elucidate the possible immune cell and gene expression-related molecular mechanisms underlying these initial findings