POSTNOTE

Number 620 March 2020

3D bioprinting in medicine
Overview
◼ 3D bioprinting is a type of 3D printing that
prints an ink made from biological material,
such as living cells and proteins.
◼ This technology could potentially be used to
print new and bespoke organs, such as skin
or bladders, on demand for transplantation
to relieve the donor organ shortage.
◼ It is currently unclear whether the EU
Advanced Therapy Medicinal Products and
Medical Devices regulations would apply to
3D printing in medicine is usually associated bioprinted organs or whether such products
with the production of medical devices such as would be considered an entirely new class
hip implants and prosthetic limbs. However, of medicines.
new research is applying 3D printing to living ◼ The adoption and widespread use of this
cells and proteins, to print new tissues and technology would raise a range of logistical,
organs for medical use in a process known as financial and ethical challenges, such as
3D bioprinting. This POSTnote gives an manufacturing dynamics, treatment
overview of 3D bioprinting and the associated accessibility and human enhancement.
biological, manufacturing, regulatory and
ethical implications.

Background such as collagen.8 Currently licenced TE therapies available on

The current strategy for treating organ damage or failure is to the NHS include limbal stem cell transplantation to treat some
replace the organ with one from a donor. While the current forms of blindness,9 and autologous chondrocyte implantation
donation rate is improving, the waiting time for an organ can be for arthritis.10,11 Many scientists consider the ultimate goal of TE
several years.1 Patients who receive donor organs face a to be the creation of whole synthetic tissues and organs, 12 but
lifetime regimen of immunosuppressive drugs, lifestyle changes the field is still in the early stages of development.
and a high risk of organ rejection.2,3
Applying tissue engineering to medicine
Regenerative medicine is the branch of medicine that looks at A key advantage of TE therapies is that they are tailored
regenerating or replacing cells, tissues or organs to repair individually to each patient. Although this approach improves
damage caused by trauma or disease, rather than using donor treatment efficacy, it is also a factor restricting the pace of
organs.4 The government supports regenerative medicine research and development within TE, as personalisation is slow,
through UK Research and Innovation (UKRI), which since 2012 expensive, and requires specialist laboratories. 13 As a result,
has provided £80m of funding for regenerative medicine and this research is currently limited to small-scale applications.
supporting technologies, with a further £44m coming from the There is increasing interest in technologies that can scale-up
National Institute for Health Research (NIHR).5 Research is also and standardise production of TE therapies to overcome these
driven in this area by the Cell and Gene Therapy Catapult and issues and accelerate the pace of research.14 An example of
its Cell Therapy Manufacturing Centre, established in 2018.6 such a technology is an applied form of 3D printing known as
3D bioprinting.15
One branch of regenerative medicine, known as tissue
engineering (TE), aims to replace diseased tissues by 3D printing and 3D bioprinting
developing implantable, synthetic tissue substitutes. 7 These 3D printing is a form of additive manufacture whereby objects
tissues are made from the natural biological building blocks are produced by the selective, incremental layering of material
found within the body, including cells and structural proteins to form a 3D structure.16 There are three main ways that 3D

The Parliamentary Office of Science and Technology, Westminster, London SW1A 0AA
02072192840 [email protected] parliament.uk/post @POST_UK
POSTNOTE 620 March 2020 3D bioprinting in medicine Page 2

◼ hold the right physical properties in order to be printed,35

Box 1: 3D liver cells to restore liver function
◼ react (gel) on demand, to form a 3D shape,36
Work at the University of Edinburgh has shown that liver
cells (hepatocytes and endothelial cells) derived from human ◼ be biocompatible, and not degrade into toxic products,37
stem cells can be grown into small 3D self-assembled ◼ have mechanically similar properties to living tissue,38
spheres for researching human liver disease. These may also ◼ support the growth of cells in the ink and in the body.39
have potential clinical uses: recent studies have shown that
when liver spheres were implanted under the skin of immune Examples of materials with these properties include natural
competent mice with a type of liver disease, human liver proteins such as gelatin and silk. These are made into a liquid
proteins were detected in their blood, and recipients solution that can gel on demand to form a semi-solid material
displayed substantially better liver function. 17 Work is
once printed.40 As the bioink will form a tissue-like structure it
ongoing to investigate the use of bioprinting to scale up the
number of spheres that can be produced for clinical studies. may also contain living cells, but the addition of cells to the
bioink makes it more delicate and thus more difficult to print.
printing can be applied in medicine: printing of
pharmaceuticals;18 printing of structural medical devices; and Box 2: Novel bioprinting techniques
3D bioprinting, which uses living cells and biocompatible New applications have been developed to enable the
materials (biomaterials) to print living tissue-like structures in production of quicker, more defined bioprinted structures
three dimensions. The following section defines and using existing bioprinting methods. These include:
◼ Reactive jet impingement. Developed at Newcastle
distinguishes the latter two techniques and highlights some of
University. It uses a multivalve printhead to eject two
the main technical challenges associated with the bioprinting different liquid bioinks. These collide and react in mid-air,
process. forming a gel which falls onto the print substrate. This
allows quick valve printing of a gel bioink with cell
3D printing of structural medical devices concentrations approaching those found in some human
3D printing is currently used to produce customised surgical tissues.41
implants to replace knees and hip joints,19–21 external supports ◼ Suspended layer additive manufacturing. Developed
(orthoses),16,22 and surgical guides for clinicians.23 These at the Universities of Huddersfield and Birmingham. It
uses a microextrusion printer to print delicate 3D
devices may be printed with polymers or metals.24,25 Recent
structures within a bed of supportive gel. Once the print
innovations in 3D printed joint replacements involve the has solidified, the gel can be washed away, leaving the
incorporation of microscopic sponge-like designs onto the printed structure intact.42
product surface to encourage bone cells to grow into the device
when implanted, or the addition of antibacterial compounds Printing and Maturation
such as silver.26 Various bioprinting techniques are available, with each using a
different mechanism for ejecting the bioink. 33 Three commonly
3D bioprinting used bioprinting methods include:
3D bioprinting is a technology that prints biomaterials and cells ◼ Inkjet printing. Uses liquid bioinks that gel after printing.
to form a tissue-like material. The cells and biomaterials used in They work by increasing the pressure of the bioink to jet it
this technique are referred to as the “bioink”, which is printed out of the printhead. They print at the highest detail
to generate complex biological structures capable of mimicking (resolution) due to their ability to print single cells, but
the tissues found within the body.27 Bioprinting techniques are cannot print bioinks with a high cell concentration as the
currently under study to produce tissue models for disease cells can clump and block the printhead.43,44
research. These models can also be used for testing potential ◼ Valve printing. Also uses liquid bioinks. This works by
new drugs as an alternative to animal testing. 28,29 Work is also opening/closing the print nozzle on demand to allow the
underway to apply these techniques to the creation of new bioink to be deposited. They print at a lower resolution than
medical treatments (see Box 1).30,31 The use of bioprinting inkjet printers but can print bioinks of a larger range of cell
processes to produce tissue-like materials is part of a process concentrations.45
known as ‘biofabrication’.32 ◼ Microextrusion. Uses gel bioinks that are extruded (pushed
out) by the printer using pressure. They handle the highest
Stages of the biofabrication process cell concentrations due to their increased print nozzle
There are three important stages in the development of a diameter but have the lowest resolution. Most commercial
biofabricated construct (printed tissue or organ): imaging and bioprinters use this technology as it is the cheapest and most
design, bioink selection, and printing and maturation.32,33 accessible bioprinting method.34
Imaging and design
There is ongoing research into the above methods as each is
The first stage of the process requires the creation of a virtual
likely to be suited to different applications. However, they all
computer-aided design (CAD) file. This contains the necessary
have two main limitations. First, the natural density of cells
3D information needed to inform the printer where and what to
present within body tissues is high, and these methods can
print during manufacture.34 The CAD software can translate
struggle to print to this concentration.46 Second, current
medical images, such as MRI scans, into virtual 3D formats.
limitations on resolution means that it may be difficult to
Bioink selection produce the more intricate structures found in the human body,
A critical element of the bioprinting process is the design of the such as blood capillaries.45 Research is underway to develop
bioink, which is the component printed to make the structure. new bioprinting methods to address these limitations (Box 2).
The ideal bioink should:
POSTNOTE 620 March 2020 3D bioprinting in medicine Page 3

Box 3: Examples of current biofabrication research Box 4: Regulatory bodies in biofabrication

The following cases are examples of recent research in 3D UK and EU regulatory bodies that oversee the stages of the
bioprinting. They are still proof-of-concept studies and as biofabrication process and the use of its products include:
such are a long way from human clinical trials. ◼ The Human Tissue Authority (HTA) regulates the removal,
◼ Lung (alveoli). The core functional unit of the lung is the storage and use of human tissue for research and medical
alveolus, where gases (such as oxygen) enter small blood treatment under the Human Tissue Act 200459 and EU
vessels. A group of universities in the US has developed a Tissue and Cells Directives60–62
hydrogel that can form channels mimicking vessels ◼ The Medicines and Healthcare products Regulatory
(header image, page 1). When red blood cells are pumped Agency (MHRA) regulates the safety, quality and efficacy
through the channels, they are able to take up of medicines, medical devices and blood components used
oxygen..47,48 in the UK.63 It has also set up a cross-agency Brexit task
◼ Ovary. Researchers at Northwestern University in the US force to manage the regulatory implications on the sector
have printed a gelatin structure capable of sustaining as the UK leaves the EU.64
ovarian follicles. When implanted into sterilised female ◼ The European Medicines Agency (EMA) regulates
mice, the ovaries develop blood vessels and follicles applications to market medicines and classifies advanced
mature naturally. These were capable of being fertilised therapy medicinal products in the EU.65,66
and mice were able to carry pups to full term with live
births. Mothers were also able to nurse, showing normal number of cells required for printing a tissue or organ is difficult
hormonal functions.49 if the cells are derived from each patient individually.67 The use
◼ Cornea (stroma). Researchers at Newcastle University
of allogeneic cells could overcome this, as large standardised
have printed a part of the cornea (the transparent front
area of the eye) using microextrusion printing. They batches of cells could be pre-prepared and stored in a cell bank
created a collagen and alginate bioink that contained to be made available when required. The cells could also be
human corneal cells, and printed it into a bespoke corneal produced in such numbers that they could be used to treat
mould, which, when removed, left clear corneal tissue.50 several patients.68 A disadvantage is that, as these cells come
from a donor, patients would still have to take drugs to manage
Following the printing stage, the printed 3D constructs undergo the risk of immune rejection (potentially for their lifetime).69
a period of maturation.51 This maturation period allows the cells
that were in the bioink (or were added to the biofabricated Regulatory issues
construct after printing)52 to adhere and adapt to the structure. As biofabrication is a new technology, there is no exact
Once adapted, cells may begin self-assembly of the biological regulatory definition of what a biofabricated construct is.
features that could not be printed due to technological Depending on the nature of the construct and the process used
limitations (see below). Following maturation, the construct to make it, a range of EU and UK regulations may apply. These
would be clinically evaluated for accurate functionality, and, if include regulations on medicinal products and biomaterials,70
approved, used for clinical applications. chemical components,71 or animal derived components.72
However, the UK’s alignment to the EU regulations post-Brexit
Biological challenges
is uncertain. The most relevant EU regulations that are likely to
3D bioprinting is a rapidly developing field, resulting in several
apply to biofabricated products are those that regulate:
proof-of-concept studies (Box 3). The overall aim of such
◼ advanced therapy medicinal products (ATMPs)73
research is to produce organs and tissues for use in
◼ medical devices. The Medical Device Regulation (MDR)74 is
regenerative medicine, but there are challenges to be overcome
due to be implemented by May 2020, and replaces the
before this is possible. These include:
current medical device directives.75,76
◼ Tissue heterogeneity. Tissues and organs consist of a
variety of different cell types. Isolating and then printing ATMP Regulation
each type, ensuring they occupy anatomically relevant Given that biofabrication represents an advanced therapeutic
positions and they fully function remains a challenge. 53 process, it is widely assumed that biofabricated constructs
◼ Vascularisation. Blood supply is a key feature of almost all would fall within the scope of the EU ATMP Regulation. This
tissues and without it most tissues die rapidly. Recreating regulation defines four classes of ATMPs:
this network is difficult, but work is ongoing to explore the ◼ gene therapy products (GTMPs) that contain genes that lead
printing of blood vessel (endothelial) cells or promoting their to a therapeutic, prophylactic or diagnostic effect.
growth using hormones.54,55 ◼ cell therapy products (CTMPs) that use cells or tissues to
◼ Organ and tissue rejection. The biomaterials used to print cure, diagnose or prevent diseases.
constructs may elicit an immune rejection response from the ◼ tissue-engineered products (TEPs) that contain modified cells
patient. This may be especially the case if the construct or tissues that can be used to repair, regenerate or replace
contains cells from a donor (see below).56 human tissue.
◼ combined ATMPs (cATMPs) that contain one or more medical
When printing with a bioink that contains cells, there is ongoing
devices (jointly regulated by the MDR, see below) as an
debate over the pros and cons of using the patient’s own
integral part of the medicine, for example, cells embedded in
(autologous) cells within the ink, or those from a donor
a matrix or scaffold.
(allogeneic cells).57 A key benefit of autologous cells is the low
risk of immune rejection, but if the patient has a genetic While they are still being developed, biofabricated products are
disease then their cells may need to be genetically edited to yet to be classified, but it is envisaged that they are most likely
repair them before use.58 Furthermore, sourcing the large to be TEPs or cATMPs. Classifications are decided by the
POSTNOTE 620 March 2020 3D bioprinting in medicine Page 4

European Medicine Agency’s (EMA, Box 4) Committee for this route as a way of circumventing the clinical trial data
Advanced Therapies (CAT) or by the relevant country’s requirements of market authorisation.81 In response to this, the
Competent Authority on a case-by-case basis.77,78 In the UK, House of Commons Science and Technology Committee has
the Competent Authority is the Medicines and Healthcare recommended that the Government should review how hospital
products Regulatory Agency (MHRA, Box 4). Once approved exemptions are used for ATMPs across the UK, and assess how
and classified, ATMPs can be used clinically in one of two main they might be adapted for the UK post-Brexit to provide a
ways.77 First, developers can apply through the EMA’s balance between safety and accelerated access to cutting edge
centralised system for market authorisation to commercialise technologies.5
the product across all EU member states. Applications must be
backed up with evidence from clinical trials of the product’s Establishing GMP-compliant hubs
safety, quality and efficacy.77 Otherwise, ATMPs may be RDM requires the creation of a series of local production
delivered to clinic via a ‘hospital exemption’ route. This centres equipped with advanced facilities that adhere to GMP
circumvents market authorisation on the basis that they are standards, however, establishing these centres would likely be
one-of’ customised products that address an unmet need, and expensive. The UK currently has 26 GMP-compliant facilities
are not derived from an industrial source.79,80 This route is that are operating at close to full capacity (~73%).86 One of
intended to allow for bespoke treatments in a single member these centres, based at the Royal Free Hospital in London, was
state. opened in 2015 and cost £2.1 million to establish - this total
excludes costs associated with bioprinting equipment or staff
Medical Devices Regulation training.87 Expanding the GMP network to enable UK-wide RDM
If biofabricated constructs are classified as cATMPs, then these for biofabrication would thus require significant investment.88,5
are co-regulated by the new MDR. Compliance with the MDR
brings extra regulatory challenges to biofabrication, and may Ethical and legal issues
add extra complexity and cost to production processes.74,81 Risks of early adoption
Some stakeholders have concerns about the high expectations88
Regulations on the use of human cells of 3D bioprinting and the potential for bioprinted constructs to
The biofabrication process may also fall under regulations be deployed in a medical setting without full knowledge of their
covering human cell use, and standards for the manufacture long-term impacts on human health. This may be exacerbated
and distribution of cell-based medicines. The donation and use in cases where the bioprinted organ would be serving as a
of human cells in the UK is regulated by the Human Tissue replacement (due to the likely irreversible nature of the
Authority (HTA, Box 4), which oversees cell and tissue storage, procedure)89 or where products are used within a hospital
processing and sample traceability requirements.59 The MHRA exemption capacity, where the requirement for clinical trials
also produces standards for the manufacturing and distribution evidence may be lower than for ATMP market authorisation.
of cell-based medicines, which are known as the Good Practice There are reports of historical cases where tissue engineering
(GxP) guidelines. Several GxP guidelines are relevant at constructs used in patients without being tested rigorously in
different stages of biofabrication, such as during manufacture animals may have contributed to patient deaths.90,91
(Good Manufacturing Practice, GMP), and clinical trials (Good
Clinical Practice, GCP).82,83 Producers of bioprinted products Accessibility of treatment and enhancement
would have to meet the GxP standards, regardless of facility The clinical application of biofabrication is potentially highly
size, location, or scale of production. bespoke, tailored to individual patients’ needs. This means that
biofabrication procedures are likely to be costly, which raises
Manufacturing challenges questions regarding accessibility and affordability. 92
A key challenge in adopting biofabrication is deciding where Furthermore, biofabrication represents a potential route to
and who will manufacture these products. While conventional human enhancement. For example, it has been suggested that
medicines are manufactured at a centralised site, the bespoke biofabricated materials could include the integration of sensor
and delicate nature of biofabricated products mean they may technologies, which could be used to detect diseases earlier.93
be better suited to local manufacturing by an approach known This raises a number of ethical questions on whether it is
as redistributed manufacturing (RDM). This involves making appropriate to modify organs in this way.
products in local biofabrication hubs based in private facilities,84
or existing healthcare settings, such as hospitals or NHS Blood Patentability and confidentiality
and Transplant Centres.85 Potential benefits of an RDM There is ongoing debate over whether certain parts of the
approach include reduced waiting times for products, lower bioprinting process are patentable.94,95 It is also not clear who
burden on major hospitals, and more accessible treatments. might be the patent holder of the various components of a
bioprinted organ, given the numerous players in the
However, some stakeholders have questioned whether the biofabrication process and the difficulty in identifying novel
routine use of biofabrication methods in such facilities would invention.96 These difficulties have implications for product
meet good quality assurance standards. 84 Others have also liability should the constructs malfunction, and for organ
questioned whether sustained production under the hospital ownership. In addition, the distribution of CAD files for
exemption pathway would be permitted, because these are biofabrication requires sensitive patient data in order to design
intended to allow bespoke treatments for individual patients. the construct. It is unclear how this stage of biofabrication
There are also general concerns that some groups are using would be compatible with current data protection legislation. 81

POST is an office of both Houses of Parliament, charged with providing independent and balanced analysis of policy issues that have a basis in science and technology.
POST is grateful to Melissa Jackson for researching this briefing, to the BBSRC for funding her parliamentary fellowship, and to all contributors and reviewers. For further
information on this subject, please contact the co-author, Pete Border. Parliamentary Copyright 2020. Image copyright Jordan Miller/Rice University
POSTNOTE 620 March 2020 3D bioprinting in medicine Page 5

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