1 Source of materials

Researchers have long been culturing and reproducing cells in laboratories, including skin tissues, blood vessels, and other cells from various organs. There is a wide range of materials that could be used in bioprinting. In addition to cells and collagen, autologous stem cells are an attractive option for use as bio-ink for printing different organs and tissues, as they may adapt easily to host tissues.

The 3D bioprinted product using bio-ink developed from autologous cells would reduce the patient’s rejection rate, though in certain circumstances it is also possible to use allogeneic cells for fabrication. Cells and tissues are first acquired from a patient or a donor before the initial processing of cell releasing from tissue matrix, cell isolation/enrichment, cell culture, harvest, and encapsulation of cells in hydrogel.Footnote ⁷ In order to ensure the quality and safety of cell and tissue material, the early stage of donation, procurement, and testing of tissue and cells is governed in the UK by the Human Tissue Act 2004 (following the EU Tissues and Cells Directive (EUTCD) 2004/23).Footnote ⁸ This Directive is applied through two separate implementing Directives: the First Technical Directive covering the actions just listedFootnote ⁹ and the Second Technical Directive covering storage and distribution of tissues and cells.Footnote ¹⁰ In fact, a third Directive was introduced later, in 2012, making amendments in particular with respect to testing regimes.Footnote ¹¹

Establishments carrying out the above activities are required to meet the standards that are detailed in the Guide to Quality and Safety Assurance of Human Tissues and Cells for Patient Treatments, as implemented by HTA Directions 003/2010. “HTA Directions 003/2010” consolidate and clarify the standards required under the Human Tissue (Quality and Safety of Tissues and Cells for Human Application) Regulations 2007.Footnote ¹² These directions concern especially the requirement for clean processing environments, quality control processes for source materials and their storage, responsibilities of production managers, traceability, and protocols for record-keeping and inspection by regulators.

Regulation of biotechnology is based upon principles of bioethics such as “do no harm”, confidentiality, informed consent, and benefit sharing. According to the Human Tissue Act 2004, only a licensed person is allowed to remove a living person’s transplantable material. Such removal would need to be non-commercial. A full informed consent process should minimise the risk of harm and possible violation of ethical considerations. Express consent from the donor is required to remove, store, and use his or her tissues. Consent could be given by the donor (in his/her lifetime or after death if such consent is expressed by will), a nominated person, or the next of kin. A child is to give consent him/herself but, in situations where a child is incapable of giving consent or where it involves the mentally incapacitated, a parent or guardian is to give express consent. Consent will not be required if the donor or the next of kin could not be traced. The ethics committee may approve the research without consent. Donors should be informed of the current and future use of his or her cells and tissues. It is suggested that complete details about the composition of the bioprinted product, the implantation process, all conflicts of interest, and all potential outcomes and adverse effects are noted in the consent form.Footnote ¹³ It is noteworthy that a “presumed consent” (opt-out) model of the deceased is applied in Wales.Footnote ¹⁴

In preparation of the materials for fabrication, the use of Human Embryonic Stem Cells (HESCs) as bio-ink once again touches on the social and religious taboos of cloning, and the interpretation of humanity and human dignity. The ATMP Regulation states that the regulation of ATMP at EU level should not interfere with decisions made by individual member states on whether or not to allow the use of any specific types of human cells, such as embryonic stem cells or animal cells (i.e the principle of subsidiarity). In view of potential objections, researchers may now pursue the more recently developed “Induced Pluripotent Stem Cells” (iPSC) technologies, or collect multipotent stem cells (adult/somatic stem cells) for producing pluripotent stem cells for 3D tissue engineering in order to bypass the destruction of human embryos.

The ATMP Regulation also acknowledges the respect of fundamental rights by making reference to the Council of Europe Convention for the Protection of Human Rights and Dignity of the Human Being with regard to the Application of Biology and Medicines: Convention on Human Rights and Biomedicine. It is recognised that the same regulatory principles for other types of pharmaceutical medicinal products should be applicable to ATMP where they are comparable, and that specific technical requirements with regard to quality and clinical data to ensure quality, safety and efficacy, may also be required. The central Committee for Advanced Therapies (CAT), which implements the ATMP Regulation by assessing newly-notified products, acts as an advisory body to the over-arching European Medicines Agency. The ATMP Regulation stresses that the procurement of human cells or tissues used in ATMP should be derived from voluntary and unpaid donation, and that the anonymity of, and solidarity between, donor and recipient should be respected.

2 Bioprinting triggered by computer-aided manufacturing

The printing process is triggered by the instructions generated by CAD or CAM systems. The customised CAD file is generated by 3D scanning and image segmentation. The medical use of 3D printers involves a digital file generated from 3D scanning of a human body part, and reprinting at the wound site for repair. In medical use, researchers could use the digital data acquired from Computer Tomography (CT) or Magnetic Resonance Imaging (MRI) scans to make a 3D design model of an organ or other tissue. It is then used in the software designing process in order to modify the design for customisation. The next step is to convert the design or data into an STL file. The STL file is then imported into the printer software package to set up the machine for printing. It is then to be reviewed and verified by a surgeon to make possible patient-specific tailoring decisions, before triggering the CAM process.

Mass digitisation and dissemination of STL files poses risks to the regulatory framework of consumer safety, product liability (quality control), and data protection, confidentiality, and safety. A major issue is that the design involves multiple translation and compilation steps between different software applications, each having different error sensitivities, hence errors in customisation settings are likely to occur. The current computer-aided process planning still relies on human expertise and manual interaction so that the manufacturer will need to verify and account for the accuracy of the image.Footnote ¹⁵ These errors would consequently have direct impact on the mechanical strength of the finished 3D bioprinted product. A key question, then, is how could the translation and compilation steps better ensure reproducibility and comparability of printed products?

It is also noteworthy that if the software and hardware set-ups for bioprinting are regarded as “medical devices” that fall within the auspices of new EU Medical Device Regulations (MDR),Footnote ¹⁶ then they will need certification before being released on the market. Once a software is qualified as a medical device (as it should be if it affects medical decision-making) it will fall subject to safety and performance requirements when used for diagnosis, prevention, monitoring, treatment or alleviation of disease, injury or disability, and the “investigation, replacement or modification of the anatomy or of a physiological or pathological process or state”.Footnote ¹⁷ With regard to the classification of the software as a medical device, the new MDR further explains that standalone software that drives a device will fall into the same class as the device. But if standalone software is independent of any other device, it is classified in its own right.Footnote ¹⁸ The use of software in the process raises data protection issues. Extra caution needs to be paid to the protection of personal data. Information for documentation should include: manufacturing parameters; risks identified for each step of the manufacturing process; mitigations of these risks; software steps; validation and testing steps, and acceptance activities.Footnote ¹⁹

3 Bioprinted medical products

The key issue in post-printing is the classification of a bioprinted product: since organs and tissues are not “original” body parts are they to be regulated as “products”, medical devices, drugs, ATMP, or a new category? Further, when the printing process takes place at clinics or hospitals are they put “on the market” or “put into service”? The European Medicines Agency (EMA) is responsible for the regulatory framework, while the CAT acts as the scientific Committee dealing with individual submission of new proposed products. The CAT will decide the classification and evaluate the quality, safety and efficacy of an ATMP product in accordance with the scientific information submitted to the Committee.

The ATMP Regulation classifies tissue-based or cell-based products as medicinal products including gene therapies, cell therapies, and tissue engineering,Footnote ²⁰ which may or may not be regarded as regenerative medicines, a non-legal category. Many bioprinted implants will be classified as tissue-engineered products (TEPs) under the ATMP Regulation (which provides Europe’s first legal definition of TEPs), which will typically combine a cellular component with a supporting matrix of hydrogel. Cells or tissues that are subject to “substantial manipulation” are considered “engineered” and thus fall within the ATMP classification.Footnote ²¹ The ATMP regulation involves one centralised marketing authorisation pathway, or an alternative “hospital exemption” route of individual therapies under a medical practitioner’s prescription not produced “routinely” or by an “industrial method”, the aim being to separate one-off treatments to address unmet individual needs from products that could be commercialised and placed on the open market.Footnote ²² The ATMP regulation waives the requirement of pre-market approval under the “hospital exemption” where the ATMPs are prepared on a non-routine basis according to specific quality standards. Due to the experimental nature of this, so far the bioprinted products are used via this “hospital exemption” (a similar though not identical scheme is called “Specials” in the UKFootnote ²³ ). However, some aspects of its application remain unclear, especially the question of whether bioprinted products, which combine some standardised processes (e.g. in the software and machinery) with unique individual cells, will be deemed to be “routine” or “non-routine” manufacturing – an important factor for determining the regulatory measures and data requirements.

The production of ATMPs should follow the principles of good manufacturing practice, and good clinical practice when conducting clinical trials. If producers seek to market a product, clinical trials on ATMPs are required for central EMA market authorisation. It is also noteworthy that a “combined” ATMP, comprised of both medical device and viable cells or tissues, will require pre-market approval from the EMA, which involves assessment for both the medical device part and the medicinal product part. After the bioprinting process, traceability of the patient and the ATMP is required to monitor the safety of ATMP. It is required that the holder of marketing authorisation keeps the relevant data for a minimum of 30 years after the expiry date of the product for follow-up of efficacy and risk management post-authorisation.Footnote ²⁴ This places a significant onus on producers, hospitals and even physicians in data collection and storage, depending on where the liability is determined to lie.