memorandum - qed · 3d printing medical revolution manufacturing technologies and ... future. the...

Memorandum 3D Printing Medical Revolution

manufacturing technologies and

supply chains.Additive Manufacturing techniques

started to be implemented in 1982 in US, and officially in 1984 by the filing of the US patent 4,575,330 by Chuch

Hull, the founder of 3D Systems w h o s e i n v e n t i o n r e l a t e d “ t o improvements in apparatus for forming

three-dimensional objects from a fluid medium and, more particularly, to

stereol i thography involv ing the application of lithographic techniques to production of three-dimensional

objects, whereby such objects can be formed rapidly, reliably, accurately and

economically.”All AM production processes share five similar manufacturing phases, starting

(1) from a CAD- based 3D Model, then (2) converted to a specific file

(generally in STL format, while other formats are in development as to

overcome STL limitations) and (3) sliced into layers: such information is then passed to an AM system which –

using different techniques – (4)

Giorgio MagistrelliProject Manager 3D printing, QED (Moderator)

I n h i s o p e n i n g r e m a r k s , t h e conference moderator introduced the speakers coming from the Academia,

the corporate sector and public institutions, presenting an overview of

3D Printing (3DP) and specifically of its applications, future development and opportunities on the medical

sector. 3DP encompasses a series of techniques and is also called Additive

Manufacturing (AM): while 3DP is typically associated to B2C and people

printing at home or in the community, AM is mainly related to B2B,

materially produces the object then (5) finished/polished.The main advantages of AM are

related to the new solutions offered to high tech equipment challenges,

specifically for the medical sector are design freedom, weight reduction, increased relative strength, complex

parts production, deduction/elimination of tooling (less parts and assembly work) , reduct ion/e l iminat ion of

production steps, shorter product development / project time / time to

market, unique coding of parts (track a n d t r a c e , d o c u m e n t a t i o n ) , personalization/customization and

d i s t r i b u t e d a n d o n - d e m a n d manufacturing (spare parts, long tail

items).When talking about AM multiple techniques are to be considered the

main categories and subcategories: 1) POWDER BED FUSION is an

additive manufacturing process in which focused thermal energy is used

to fuse materials by melting as they are being deposited. According to American Society for Testing and

Materials (ASTM International) Shane Collins, Managing Director of Directed

Manufacturing, and chairman of F42.05 subcommittee, powder bed fusion describes a 3D printing process

in which electron beams and laser beams grow engineered parts from polymer and metal powders in a

powder bed. Specification for Additive Manufacturing Titanium-6 Aluminum-4

Vanadium with Powder Bed Fusion, was developed by Subcommittee F42.05 on Materials and Processes.

2) DIRECTED ENERGY DEPOSITION is an AM process in which focused

thermal energy is used to fuse materials by melting as they are being deposited.

3) SHEET LAMINATION is an additive manufacturing process in which sheets

of material are bonded to form an object.


4) BINDER JETTING is an AM process in which a liquid bonding agent is selectively deposited to join

powder materials.Metal AM Technologies currently

seems to be having their golden years because metallic printing has growth by 75.8 per cent in 2013 yty and 348

3D metal printers have been sold in 2013 (vs. 198 in 2012).There are mainly three sectors of

application: Automotive, Aerospace & Defence and Medical.

For the automotive industry, AM opened doors for newer designs cleaner, lighter, and safer products,

shorter lead times and lower costs. While automotive original equipment

manufacturers (OEMs) and suppliers primarily use AM for rapid prototyping, the technical trajectory of AM makes a

strong case for its use in product innovation and high-volume direct

manufacturing in the future. New developments in AM processes, along

with related innovations in fields such as advanced materials, will benefit production within the automotive

industry as well as alter traditional manufacturing and supply chain

pathways.The Aerospace and Defence (A&D) industry was an early adopter of AM

technology contributing about 10.2 per cent of AM’s $2.2 billion global revenues in 2012. Several reasons

underlie AM’s relatively widespread adoption in A&D. AM provides the

flexibility to create complex part geometries that are difficult to build using traditional manufacturing; it can

build parts with designs such as internal cavities and lattice structures

that help reduce parts’ weight without compromising their mechanical performance. Furthermore, AM

machines produce less scrap than traditional machines, a critical attribute

when using expensive aerospace materials such as titanium. Finally,


AM’s impact on economies of scale and scope make it a natural fit for A&D, which, in contrast to other mass

production industries, is largely geared toward customized production. AM’s

current applications in the A&D industry range from manufacturing simple objects such as armrests to

complex parts such as engine components. Applications such as printing aircraft wings and parts in

microgravity are foreseeable in the future.

The medical technology (medtech) industry has been a leader in the use of AM. In 2012, medical applications

accounted for 16.4 per cent of the total system-related revenue for the AM

market. A key reason for this is that AM capabilities align well with the needs of medtech’s medical device

segment which serves a broad, geographically distributed population

of service providers that in turn serves an even larger end market of health

care consumers. Many medical devices, such as hearing aids, dental

crowns, and surgical implants, are relatively small in size and therefore suitable for the production sizes

avai lable through common AM systems. Furthermore, these products

are value-dense with high value with relatively small physical volume and the high level of customization

avai lab le wi th AM makes th is technology well suited for custom-fitting products to individual patients,

an important factor in clinical efficacy.The medtech industry is also relatively

well funded, which gives it the r e s o u r c e s t o i n v e s t i n n e w technologies. The industry’s 2012

revenue was estimated at $121.6 billion, with an annual expected growth

rate of 5.4 per cent. The 15-year total shareholder return (1998–2012) for medtech companies was 7.8 per cent,

compared with the Standard & Poor’s 500 average of 5.2 per cent. But to

sustain this performance, the industry needs to continue to deliver innovative

solutions to address patient needs. Given the strong alignment of AM


capabilities with the medical device segment’s needs, and the medtech industry’s ability to support investment

in new technologies, it is perhaps no surprise that AM has made substantial

inroads with health care practitioners and service providers.

synergy with Materialise know-how in the field of image processing and surgery guidance, and a unique highly-

innovative approach to implant design, Mobelife products meet the highest

standards for custom implants and they maximally improve the patient’s quality of life after the most complex

reconstructive surgery. The company offers surgeons an innovative all-in-one solution for patient-specific

orthopaedic bone and joint implants. This package typically contains a truly

customized implant, a trial component, a real-size bone replica model, a patient-specific drill guide, and a clear

and individualized booklet containing surgical guidance to assist the

surgeon through the operation. In just a few years, Mobelife specialized team has expanded significantly and

continues to assist health care providers directly – and patients

indirectly – in numerous renowned European hospitals.

Materialise developed 3D printing in

Dr Jan Demol Quality Manager at Mobelife, Materialise Group

Dr Demol introduced the Materialise group and Mobelife. Founded as part of the Materialise group and active

since 1990, Mobelife is a specialist in implant design and production for

c h a l l e n g i n g b o n e a n d j o i n t reconstruction surgery. Through the


the past 24 years with constant and growing investments in R&D (around € 20 million just in the past 3 years of

which more than € 5 million funded by the European commission and from

the Government of Belgium).Underlining that Materialise is strongly committed to use AM just for legally

authorized products, developing a device to save the hearth of a young child or to rebuilt a part of a human

skull with the combined efforts of doctors, surgeons and engineers are

just few of the multiple applications of AM. As per hearing aids, for the 95% p r o d u c e d i n 3 D p r i n t i n g ,

customization, convenient production of few products and low costs are two

of the many advantages; another positive aspects, is related to the possibility to manufacture products

which could not be realized with traditional manufacturing techniques

and with fewer assembly steps.However, 3D printing is much more

t h a n “ p u s h i n g a b u t t o n ” : t o manufacture a product which could

answer to specific manufactory, quality safety and health requirements it is needed to develop engineering, to

have people capable to design a product that can be realized by

additive manufacturing technology, further than to use suitable materials and the required post production

process and finishing. Having the equipment is not always enough: it is necessary to have

engineering equipment linked to anatomical instruments; the pre-

processing phase is linked also on developing and implementing the software that will help 3DP production

plants to streamline processes together with the offer of a platform

where designers can meet to exchange ideas for designing products while the post-processing is related to

the measurements of products made. Another crucial aspect is quality

control which should present all along the value chain and is fundamental for

Materialise in general and specifically for medical applications.


As to guarantee the requi red standards, Mobelife creates a so-called “Surgical Guide”, a patient

specific medical device that is manufactured on the basis of one

person’s anatomy. It is not to be implanted, but it is to aid the surgeon in the placement of an implant. Under

the “Medical Devices Directive” and the implementing Belgian law, there is a category dedicated to these devices,

i.e. the invasive medical devices. On this point Materialise prepared a

“White Paper” focused on a proposal for a regulation of medical devices adopted by the European Parliament

in order to overcome the flaws and gaps in the existing medical device

r e g u l a t o r y f r a m e w o r k , w h i l e addressing innovation within the medical device industry.

The Materialise Group recommends that the directive includes AM

techniques into the legislation to ensure that the use of AM technology

in the medical device industry continues to effectively contribute to a

better and more personalized health care. In the adopted proposal, invasive and/or implantable patient-specific

medical devices designed and manufactured by means of additive

manufac tu r ing techno logy a re currently classified as “custom-made medical devices”. However, the current

proposal of the Medical Device Regulation does not cover the specific characteristics and associated risks of

the use of AM for purposes of designing, producing and using

patient-specific medical devices. To enable a safe use of the AM technology in the medical device

i n d u s t r y , M a t e r i a l i s e h i g h l y r e c o m m e n d s a s t a n d a r d i z e d

regulatory environment throughout the EU as well as a harmonized regulatory supervision and verification. This

would not only best serve public health, but would also allow the

industry itself to further develop in a consistent manner throughout the 28

Members States. Dr Demol concluded his intervention


presenting a practical case, and a video of a 15-year-old Swedish girl facing a lifetime in a wheelchair

because of Neurofibromatosis, a congenital disease also known as ‘Von

Recklinghausen’s disease’, which left her with a severe skeletal deformation o f the le f t h ip because o f a

neurofibroma that destroyed her pelvis and which was causing a lot of pain. In 2012, Prof Rydholm from the Skane

University Hospital in Lund, Sweden came to Mobelife with the case: the

girl had been suffering from her hip condition since childhood and in 2010 the neurofibroma was surgically

removed. After a femur fracture a few months later, her situation took a turn

for the worse, forcing her to leave school to be home educated for the next 2 years. Her doctors initially saw

very limited or no treatment options for her hip and she was looking at a life in

a wheelchair. Prof Rydholm took this case to Mobelife and their team of

engineers set to design a custom

implant, based on the patient's CT scan, to fit the bony situation of the patient and to reconstruct the defect.

In September 2012, the Mobelife aMace® 3D printed titanium implant

was delivered to the hospital in Sweden and the girl was operated. Almost immediately after surgery, she

was pain free. By Christmas, she was out of her wheelchair and walking with just one crutch, pain free: now she is

walking without crutches and back to school like a normal teenager.


Dialing in to the conference from the FDA Head Quarters, Dr Pollack intervened on the existing regulations

on Medical Devices, which are categorized according to risk-based

criteria. The first class includes simple, low risk devices, subject to general controls and most exempt from

premarket submission (as surgical scissors, clamps etc.); the second class is related to more complex

devices with higher risk and which require special controls, premarket

Notification (with form “510k”), substantial equivalence, clinical data and 90 days for FDA to review (as

electronic medical instruments etc.); the third and last class is represented by most complex, highest risk medical

devices which require a Premarket Application (PMA), evaluations to

establish safety and effectiveness which might include post-approval study requirements and 320 total days

for FDA to review. There are also specific cases of Investigational Device Exemption (IDE) when the

investigational device is used in a clinical study in order to collect safety

and effectiveness data. Clinical studies are most often conducted to support a PMA. Only a small percentage of

510(k)s requires clinical data to support the application. Investigational

use also includes clinical evaluation of certain modifications or new intended uses of legally marketed devices. All

clinical evaluations of investigational devices, unless exempt, must have an

approved IDE before the study is initiated, which permits a device to be

shipped lawfully just for the purpose of

Dr Steven Pollack Director of Center for Devices and Radiological Health (CDRH) Office of Science and Engineering Laboratories, FDA


conducting investigations of the device and without complying with other requirements of the Food, Drug, and

Cosmetic Act (FD&C Act) that would apply to devices in commercial

distribution. Sponsors need not submit a PMA or Premarket Notification 510(k), register their establishment, or

list the device while the device is under investigation. Dr Pollack indicated that subtractive

manufacturing is what has traditionally been used to make medical devices

(and everything else) and relies on removing materials, much like as a sculpture with the chain saw. This is in

contrast with AM techniques, which build layer-by-layer, only uses material

where necessary and u t i l i zes additional support material without requiring moulds or tooling, and can

produce low quantities.AM manufacturing characteristics,

specifically useful for the medical sector, consist in creating parts using

engineering drawing software, while

the pat ient ’s anatomy can be accounted for via MRI/CT scanning and porosity or internal reinforcements

can be added. Thereafter, the entire component (comprising solid & porous

features) is built layer-by-layer from a digital model. He also brought the example of the so-called “robohand”,

designed in 2012 to address the needs for prosthetics for children suffering from amniotic banding syndrome:

using open source software and a low cost commercial printer, a mechanical

prosthetic hand can be made to the proper size and allows for a quick, low cos t a l te rna t i ve to t rad i t iona l

prosthetics near the patient. The unpowered hand prosthetics are Class

I devices and are exempt from pre-market review. Another example has been related to

the “Trancheobronchomalacia”: a baby’s bronchus collapsed regularly

and a CT scan taken of bronchus allowed creating a splint designed

from patient’s anatomy; a tracheal


splint was therefore 3D printed from degradable polymer and designed to degrade and to become bioresorbable

over 3 years. The patient was successfully removed off ventilator

after just 21 days and the splint received emergency device clearance from the FDA.

In terms of regulatory approvals of 3D printed medical devices, the FDA cleared patient matched implants (as

skull plates, orthopaedic implants, emergency and custom devices),

orthopaedic devices (hip cups, spinal cages and knee trays), patient matched surgical guides (craniofacial,

knee and ankle) and dental (temporary bridges and reconstructive surgery

support).The world's first patient-specific jaw implant was built in 2012 when an 83

year old woman with osteomyelitis of the jaw had it replaced with a 3D

printed titanium implant patient: she had MRI and therefore the implant was

an anatomical match. The jaw was

printed from titanium powder in a two- day print and the patient was eating, drinking, and speaking within 4 hours

of surgery.When receiving an application, the

FDA specifically evaluates three key aspects: the imaging (the type of imaging used and the image fidelity

must be established and maintained under quality control to generate consistent results); the digital design

(the base model for the medical device will be designed digitally in the same

way as traditional medical devices, while the algorithms will change the shape and dimensions to fit a given

patient but there must be bounds on those changes so that the structural

integrity, function, and safety of the device are maintained and these steps often require clinician input and

concurrence); and the printing (the printer specifications and printing

process parameters can have a significant effect on the final product;

depending on the type of printer, with


concern to finishing steps and cleaning processes, additional information may be required to support a premarket

submission).W h e n e v a l u a t i n g d e v i c e s

manufactured with AM techniques, the FDA attains specific importance to mechanical properties (as with

concern to the printing process and pos t p rocess ing p rocedu res ) , biocompatibility (as per the cleaning of

finished parts and material recycling) and design compatibility.

The FDA internal AM Working Group encompasses the Office of Science and Engineering Laboratories, the

Office of Devices Evaluation, Office of Compliance and the representatives of

the Center for Biologics Evaluation and Research (CBER) and the Center for Drug Evaluation and Research

(CDER) and its main functions are to coordinate across the CDRH, with

CBER and CDER, to improve the consistency of devices reviews, to

intervene on related policies and

research priorit ization (modules addressing specific and immediate regulatory questions and informing

sc ien t ific dec is ion mak ing fo r regulatory submissions), while being

the point of contact for Additive Manufacturing.FDA is also a key point of reference in

terms of innovative researches in the medical field with specific relation to AM techniques and their applications.

In fact, FDA evaluates how does print configurat ion affect mechanical

properties and this research area seeks to evaluate the effect of printer type (laser vs. electron beam metal

sintering) and print orientation on the mechanical performance of printed

test specimens - specifically, on the static and dynamic properties under axial, torsion, and axial/torsion loading.

Another research area is related to the regulatory requirements for 3d

printable hydrogels, used extensively as medical devices. Their chemical

and material properties are highly


tuned and integral to their function, but not optimized for 3D printing. The material properties and chemistry

affect the printing process, which in turn affects final device performance.

This examination will characterize the effects of raw material properties as well as gelation time and chemistry on

common hydrogels. Furthermore, 3D printed models can support and enhance diagnostic

imaging validation and the FDA is analysing more realistic test methods

for innovative clinical bio photonic imaging systems, as to develop 3D p r i n t e d p h a n t o m s b a s e d o n

segmented images of vascularized tissue (i.e., acquired with optical

coherence tomography) printed with realistic optical properties. The final phantoms will be validated with micro-

C T a n d u s e d t o a s s e s s t h e performance of a hyper spectral

imaging system.Considering that there is no guidance

for evaluation of additively

manufactured devices and some traditional bench tests will not capture the effects of powder-based additive

manufacturing, the FDA is also researching what biocompatibility tests

are required. This research area will identify methods to determine what bench tests are sufficient to ensure

safety through evaluating cellular response to various materials and cleaning levels.

Another unexplored area of analysis is the comparison between patient-

matched and standard devices: experience level, task completion time, and c l in ica l outcomes wi l l be

evaluated. In conclusion of his intervention, Dr

Pollack informed the audience that in October 2014 the FDA organized an “ Interact ive Discussion on the

Technical Considerations of 3DP of Medical Devices”, whose purpose was

to provide a forum for FDA, medical device manufactures, AM companies,

and academia to discuss technical


challenges and solutions of 3DP. As direct outcomes, most devices to date are rev iewed through ex is t ing

regulatory pathways, the agency is proactively gathering expertise and

developing policy to address this technology and AM holds great promise for personalized medicine and

innovative medical solutions.

supply chain, warranties, liabilities and Intellectual Property Rights.According to a report of Gartner, “by

2016, 3D printing of tissues and organs (bio printing) will cause a

global debate about regulating the technology or banning it for both human and nonhuman use”: there are

in fact numerous aspects to consider, in terms of ownership, compliance, R&D and Supply chain issues.

IPR protection is the main driver and the starting point for a successful

business plan to market. IP rights inc lude mater ia ls , methods of production, hardware, software and

data and manufacturing outputs. With concern to materials, products of

nature are in principle not patentable: in the US isolated human genes are not patentable, but there have been

numerous controversial cases as the “Association for Molecular Pathology v.

Myriad Genetics”, challenging the validity of gene patents in the United

States, and specifically certain claims

Ernst-Jan Louwers Attorney-at-law, Louwers IP- Technology Advocaten

Mr Louwers introduced the legal aspects of Additive Manufacturing with specific relations to medical devices,


in issued patents owned or controlled by Myriad Genetics that cover isolated DNA sequences, methods to diagnose

propensity to cancer by looking for mutated DNA sequences, and

methods to identify drugs using isolated DNA sequences. Prior to the case, the U.S. Patent Office accepted

patents on isolated DNA sequences as a composition of matter. In Europe, until now they are patentable and

comparable to plant breeding.With concern to methods, technologies

of bioprinting and products directly resulting from method are patentable, as are hardware covered by patents

and software and design/database rights protected by copyrights: the

debate is going on with relation to the protection of tissue and parts.Prostheses and dental implants can be

protected in terms of method and outputs as “products by process while

mixture and intermediate results may be patentable.

Further than considering legislative

issues, Ernst-Jan Louwers also focused on the enforcement of IPR: they are in principle protected by

national laws but 3D designs can be easily shared on internet.

Supply Chain can also be deeply affected by AM techniques and also in the medical sector changes are

happening: in fact hospitals can become factories, doctors engineers and engineers doctors, while dentists

can print implants and the industry becomes suppliers of human tissue

and spares. It is therefore required that a company, on the occasion of an AM related business plan and strategy,

reconsiders its role and relationships and at which point of the value chain

of the future can position itself. In terms of risks, products can be defective; should that be the case, in

the medical sector it is required a specific legislation related to the

responsibilities and roles of the various actors as producers, distributors,

materials providers, hospitals,


surgeons etc., considering also the timing of the market entry of related products (which can be generally

assumed in 3-5 years for the adoption of the technology and 5-7 for the

commercialization) and the need to legally cover all the different steps.

Sirris is a nonprofit, Industry owned collective Centre of the technology industry with EUR 24 million turnover

and 130 experts and high-tech infrastructure; the AM centre has

n o w a d a y s 2 2 e n g i n e e r s a n d technicians, 15 high-tech additive technologies in house and is the most

complete and largest machine park in Europe with two locations in Liège and Charleroi, covering the main AM

techniques.Leading appl icat ions of AM in

biomedical are related to personalized/complex devices and implants (as skulls implants, jaws, spinal case

studies in ceramics, scaffolds and lattice porous structures), surgery tools

(with custom cutting instruments that can allow surgery time reduction of 20-70% and costs reduction from EUR

3,000 to 30,000 per intervention), in vitro testing tools (as flexible devices),

communication and education tools.Bioprinting is an emerging technology

and relates to the process of printing

Dr Gregory Nolens Biomedical Project Manager, SIRRIS

Dr Nolens explained that, being one technological field where Sirris started to invest in 1990, 3DP is considered

by Sirris as one of the key high technologies which could support the

transformation of Belgian companies becoming factories of the future.


biologically relevant materials (such as cells, tissues, and biodegradable biomaterials) that will accomplish one

or more biological functions though the utilization of specific customized

machines.Considering the numerous barriers related to technics, ethics, validation

time and standards, the Bioprinting strategy of SIRRIS follows a step by step approach, targeting the most

promising and nearest markets and combining the existing knowledge to

succeed faster. Main business opportunities and interests for the private sector cover

drug/cosmetic discovery and assays, cell therapy and tissue engineering,

bio production, in vitro diagnostic/research and food. With concern to drug/cosmetic

discovery and assays, bio printing could open effective possibilities of

cost savings and less deviations in experiments, considering that 90-95%

of drugs approved on animals (mouse,

rabbit, etc.) did not prove effectiveness on humans with an understandable loss of money (the overall costs are in

the range of USD 10—100 million), beside the related ethical issues;

f u r t h e r m o r e , t h e E u r o p e a n Commission approved a full banning on animal testing for cosmetics and

the next reform could extend such limitations to the pharmaceutical sector.

The Cell therapy industry market offers business opportunities specifically in

terms of raising cell therapy barriers of large defect repairing, combining stem cells and biomaterial scaffolds.

Biotechnologies and bioprocesses are also developing and more and more

treatments are using biomolecules instead of small drugs: however at present the products are very

expensive and cost reduction can be achieved through production.

In vitro diagnostic and Research involve biomarkers, biosensors, drugs

kinetics and pathogen reactions.


Food and Agriculture represent sent also new frontiers for biomaterials and tissue engineering.

In terms of regulations, medical devices are under general standards

as ISO 13485, 10993 etc. and further regulations are under discussion, being medical devices faster and

easier to label than drugs; advanced therapy medicinal products (ATMP) are under Regulation 1394/2007

following the same procedure for drugs, which requires long clinical

process (6-10 years plus post market) and faces heavy process constraints.

Prof Dufrane focused his presentation

on bio printing, its challenges and the opportunities (as the replacement of human organs, tissue engineering

etc.). Regenerative medicine for organs and

tissues could represent a response to a large and emergency medical need, considering that there are currently

123,175 people waiting for lifesaving organ transplants in the US, and of

t h e s e 1 0 1 , 1 7 0 a w a i t k i d n e y transplants ; nearly 3,000 new patients are added to the kidney waiting list

each month, 12 people die each day

Prof Dr Denis Dufrane Head of Endocrine Cell Therapy -Unit, Université Catholique de Louvain

________________________


while waiting for a life-saving kidney transplant, every 14 minutes someone is added to the kidney transplant list

and in 2013, 4,453 patients died while waiting for a kidney transplant.

In terms of market segmentation, the most promising areas are Cell Therapy (CT) Gene Therapy (GT), Tissue

Engineer ing (TE) and Smal l molecules and biologics, while in terms of Therapy Regenerative

Medicine commercially main available products covered in 2013 non healing

wounds/skin at 46%, Musculo-Skeletal at 35%, Cancer at 10%, Ocular at 7% and Cardio-vascular at 2%.

3D bioprinting is moving in diverse directions and it is expected that in the

coming future it will further expand its horizons; there is still a much larger scope for 3DP in the medical field and

recent developments enabled 3DP of biocompatible materials, cells and

supporting components into complex 3D functional living tissues; 3D

bioprinting is also being applied to

regenerative medicine to address the need for tissues and organs suitable for transplantation.

Compared with non-biological printing, 3D bioprinting involves additional

complexities, such as the choice of materials, cell types, growth and differentiation factors, and technical

challenges related to the sensitivities of living cells and the construction of tissues. Addressing these complexities

requires the integration of technologies from the fields of engineering,

biomaterials science, cell biology, physics and medicine. A t a sca f f o l d l eve l , comp lex

combinations or gradients allow a c h i e v i n g d e s i r e d f u n c t i o n a l ,

mechanical and supportive properties which can be modified or designed to facilitate bio printer deposition, while

also exhibiting desired post printing properties. The use of decellularized

tissue-specific ECM scaffolds allows to study ECM compositions, also as

printable materials.


In terms of further appropriate mater ia ls select ion for use in bioprinting, their performance in a

particular application depends on several features as printability (i.e.

properties that facilitate handling and deposition by the bioprinter may include viscosity, gelation methods

a n d r h e o l o g i c a l p r o p e r t i e s ) , biocompatibility (materials should not induce undesirable local or systemic

responses from the host and should contribute actively and controllably to

t he b i o l og i ca l and f unc t i ona l components of the construct and degradation kinet ics/byproducts

(degradation rates should be matched to the ability of the cells to produce

their own ECM while degradation byproducts should be nontoxic and materials should demonstrate suitable

swelling or contractile characteristics).With concern to structural and

mechanical properties, materials should be chosen based on the

required mechanical properties of the

cons t ruc t , r ang ing f r om r i g i d thermoplastic polymer fibres for strength to soft hydrogels for cell

compatibility.Furthermore, in terms of material

biomimicry, engineering of desired structural, functional and dynamic material properties should be based

on knowledge of tissue-specific endogenous material compositions.Cells are the smallest functional units

of life and tissues and are arranged in specific 3D orientation depending on

the functions they perform. Tissue engineering technology has used different fabrication methods for

bringing cells together to generate appropriate tissues, requires well-

characterized and reproducible source of cells further than combinations of cell phenotypes with specific functions.

W i t h t h i s c o n c e r n , g r e a t e r understanding is required of the

heterogeneous cell types present in the tissues, as well as a direct control

over cell proliferation and


differentiation with small molecules or other factors. Bioprinting technology is compatible with physiological ly

relevant materials, cells increased resolution and speed, can be scaled

up for commercial applications and it could be necessary to combine bioprinting technologies to overcome

technical challenges. With concern to vascularization, a well-developed vascular tree is required for large

t issues and might have to be engineered in the b io pr in ted

construct, with capillaries and micro vessels required for tissue perfusion together with suitable mechanical

properties for physiological pressures and for surgical connection.

Innervation is required for normal tissue function and might be inducible a f t e r t r a n s p l a n t a t i o n u s i n g

pharmacologic or growth factor signalling and simulation before

transplantation could be achieved using bioreactors. In vitro maturation

experiments indicate that time is still required for assembly and maturation, that bioreactors may be used to

maintain tissues in vitro and that maturat ion factors as wel l as physiological stressors with the

potential for pre-implantation testing of constructs are provided.

As a conclusion, Prof Dufrane commented on the preliminary results of 3D bioprinting which has already

been used for the generation and transplantation of several tissues, including multi-layered skin, bone,

vascular grafts, tracheal splints, heart tissue and cartilaginous structures.

Other applications include developing high-throughput 3D-bioprinted tissue models for research, drug discovery

and toxicology.The gradual evolution of bioprinting,

from the short term goal of two dimensional products could most probably evolve to hollow tubes and

hollow organs in the medium terms and to solid organs in the long terms,

notwithstanding the present limitations represented by regulation 1394-2007

on ATMP and ethical aspects which should be addressed.


Panel discussion

While underlining the participation in the aud ience o f the Brusse ls Representative of ASTM International,

the moderator, Mr Giorgio Magistrelli, informed that ASTM is a globally

recognized leader in the development and delivery of international voluntary consensus standards, and specifically

asked to Dr Pollack an overview of ASTM Committee F42 on Additive M a n u f a c t u r i n g Te c h n o l o g i e s .

Established in January 2009 to address high-priority needs for

standards in Additive Manufacturing Techno log ies , ASTM inc ludes subcommittees on: Terminology, Test

Methods, Materials and Processes, Design (including data formats) and

U.S. TAG to ISO TC 261. At present, the F42 roster includes 207 individuals and organizations from 13 countries

(more than 1/4 from outside the U.S.) and ASTM F42 and ISO TC 261

cooperate to approve uniform AM related standards.

Afterwards, the audience asked to Dr Gregory Nolens and Prof Dr Denis D u f r a n e w h i c h a r e t h e m a i n

stakeholders groups requiring specific experiments: for Sirris both the

corporate sector and universities/hospitals are requiring asking to implement research programs and

activities, while for the Unit of Professor Dufrane there is more a public structure/hospital approach.


Another question was concerning legal issues, and Ernst-Jan Louwers underl ined the importance that

companies and entities involved in bioprinting and 3D printing consider

the IPR issue very carefully and along all the business plan implementation period.

Dr Jan Demol replied to a following question related to software related issues and challenges indicating that

Mater ia l ise internal ly develops software solutions and therefore

Mobelife takes advantage of the knowledge of the parent company. On the other hand, Dr Gregory Nolens

indicated that companies requiring assistance of Sirris use their own

software, developed or licensed as the software from Materialise.A researcher from the Academia asked

the panellist to indicate the main sectors of development for 3D printing

and all panellists agreed on the opportunities represented by the

automotive, aerospace and the medical sector. However, also the B2C sector is in strong development, in

te rms o f hardware sa les and specifically in terms of service

providers’ development.A debate also started on Medical Devices regulations development at

European Level and the comparison with US FDA responsibilities. While the US regulatory process is quite

centralized, Europe legislative process is characterized by multiple levels;

another present issue is related to the uncertainty of the permanence of Medical Devices regulations in the

portfolio of DG Sanco while a recent reform – not yet implemented –

forecasts the new involvement of DG Enterprise (which will be called DG Growth after the merging with Dg

Markt).In terms of markets knowledge of AM

in the medical sector, Dr Jan Demol explained that knowledge needs to be


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raised because sometimes hospitals and patients have the idea that AM technologies can solve all the issues;

furthermore, it is also important to consider the interaction between

engineers and doctors who are developing inter-related knowledge to be applied to AM technologies

implementation.On this point, Ernst-Jan Louwers also recalled the importance of ethical

issues to be taken in consideration and how important it is to continue to have all the stakeholders meeting and

discussing on the development of the AM sectors.

With concern to medical insurance coverage, according to Dr Jan Demol the situation is quite fluid and

extremely different according to each European state.

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