Additive Fabrication Technologies Applied to

Additive Fabrication Technologies
Applied to Medicine and Health Care: A
review
J. GIANNATSIS AND V. DEDOUSSIS
Center for Product Development and Rapid Prototyping
University of Piraeus
80 Karaoli & Dimitriou str., 18534 Piraeus, Greece
Tel: + 30 210 41.42.320
Fax: + 30 210 41.42.356
e-mail: [email protected], [email protected]
ABSTRACT
Additive Fabrication (AF) and Rapid Prototyping (RP) technologies are mostly associated with
applications in the product development and the design process as well as with small batch
manufacturing. Due to their relatively high speed and flexibility, however, they have also been
employed in various non-manufacturing applications. A field that attracts increasingly more
attention by the scientific community is related to the application of AF technologies in medicine
and health-care. The associated research is focused both on the development of specifically
modified or new methods and systems based on AF principles, as well as on the applications of
existing systems assisting health care services. In this paper representative case studies and
research efforts from the field of AF medical applications are presented and discussed in detail.
The case studies included cover applications like the fabrication of custom implants and scaffolds
for rehabilitation, models for pre-operating surgical planning, anatomical models for the
mechanical testing and investigation of human bones or of new medical techniques, drug delivery
devices fabrication, as well as the development of new AF techniques specifically designed for
medical applications.
Keywords: Additive Fabrication; Rapid Prototyping; Rapid Manufacturing;
Biomodelling; Scaffold Fabrication; Medical applications
1
INTRODUCTION
Additive fabrication (AF) is a relatively new concept that emerged during the last
decade in order to describe a set of new or under development manufacturing
methods, processes and technologies that function through material addition, in
contrast to the established traditional cutting, forming or casting methods. Rapid
1
Prototyping (RP) technologies are the most widely applied and known fabrication
methods that are based on additive fabrication principles. Some of the major RP
technologies used worldwide are Stereolithography (SL), Selective Laser
Sintering (SLS), Fused Deposition Modelling (FDM), 3D printing (3DP), MultiJet
Modelling (MJM) and Laminated Object Manufacturing (LOM). Main
applications of RP include the fabrication of various kinds of models and
prototypes for concept evaluation and presentation as well as functional testing of
new products, early in the product development process [1]. The continuous
improvement of RP systems accuracy and materials, expand gradually their
applications to other areas of the industrial sector like Rapid Manufacturing (RM the actual manufacturing of products in small batches) and Rapid Tooling (RT fabrication of manufacturing tools and moulds).
What makes RP particularly appealing for all of the above applications is
the fact that compared to alternative manufacturing technologies, like for instance
CNC machining, RP systems can fabricate parts of almost any geometrical
complexity in relatively lower time and with reduced cost and without significant
requirements in technical expertise. This kind of geometric flexibility, which is
mostly a consequence of their additive nature, is the main reason that RP
technologies are increasingly used or tested in non-industrial applications like
medical and architectural modelling [2] or artistic creation [3]. The medical
branch in particular has attracted the attention of many researchers and scientists
since the first introduction of RP technologies, and has been the topic of various
EU research programmes (e.g. Phidias – EC Funded Network Project on Rapid
Prototyping in Medicine). What makes RP technologies even more appealing is
that they utilize medical imaging data (obtained by techniques like Computed
Tomography-CT or Magnetic Resonance Imaging-MRI), almost directly, for the
production of customised patient specific parts. The reported medical applications
of RP technologies can be classified to the following categories:
• Biomodelling, which involves the fabrication of physical models of parts
of the human anatomy and biological structures in general, for surgery
planning or testing.
• Design and fabrication of customised implants for prosthetic operations,
rehabilitation and plastic surgery
• Fabrication of porous implants (scaffolds) and tissue engineering
2
• Fabrication of specific surgical aids and tools
• Drug delivery and micron-scale medical devices
Despite of their great flexibility and potential, RP technologies have not yet
been widely adopted in the medical and health-care sector. This can be attributed
to the high cost and time required for the fabrication of corresponding models
which at present can only be justified in relatively complex medical cases [4].
Besides time and cost, there is the issue of accuracy of RP systems, which is not
sufficient for some applications due, mainly, to poor or inaccurate medical
imaging data, as well as the issue of materials and their properties, i.e. flexibility,
strength and biocompatibility [5]. Nevertheless, RP technologies and AF in
general have great potential in the area of medical and health-care applications
due to their distinct features, and have been therefore the subject of various
studies worldwide. The corresponding research covers various areas such as the
cost-efficient application of established technologies, the development of new
technologies, the virtual modelling/representation of medical data and the
development of biocompatible materials. The purpose of the present work is to
present and discuss in detail the most representative case studies, covering the
main research areas of AF applications in medicine according to the classification
given above.
2
FABRICATION OF RP MODELS BASED ON
MEDICAL DATA
One of the major medical applications of RP is the fabrication of models of parts
of human anatomy of a patient based on data obtained through the various well
established techniques of CT or MRI [6]. The fabrication process of these
physical models, which are nowadays often called biomodels, involves three
phases [7]:
• The first step is to obtain the data of the patient’s area of interest with
the use of the previously mentioned techniques (CT, MRI, etc.), which
provide an indirect representation of the patient’s anatomy through a
series (stack) of 2D images.
• The images are next manipulated employing special software, which
facilitate the separation and highlighting of the tissues (soft or hard)
3
that represent the area of the biomodel, and allow the conversion of the
2D image information to a 3D representation. Usually, the standard
STL representation is utilized for the latter.
• Finally the biomodel is fabricated via an RP system followed by
possible (if it is necessary) manual finishing.
The accuracy of RP biomodels depends on various factors associated with
all phases of the process. Choi et al. [8] analyzed the possible sources of error in
SL biomodelling and identified the main sources of error in the second phase,
namely, the translation of 2D data to a 3D virtual model. This has led to the
development of special software tools like Mimics from Materialise Inc.
(www.materialise.com) and Biobuild (www.anatomics.com) that have simplified
and enhanced the accuracy of the 2D-3D data transformation process. Regarding
the manufacturing accuracy of RP technologies, Santler et al. [9] concluded that it
is sufficient for clinical purposes.
3
RP BIOMODELS FOR SURGICAL PLANNING
Among the first (and major) applications of AF/RP in medicine and health-care is
the production of (physical) biomodels that can be used as an aiding tool for
surgical planning and rehearsal [10]. Since every patient is unique, the surgeon
must fully understand the anatomy of the patient before operation. Obtaining a
full understanding of the patient’s anatomy only by the study of a stack of
CT/MRI images in these cases requires great experience from the surgeon,
especially in complex surgical operations [11]. In such cases RP biomodels
greatly facilitate diagnosis and treatment planning, and decrease the risk of
misinterpretation of the medical problem. Having a physical biomodel in hand
also facilitates surgery planning and makes possible the rehearsal and simulation
of the operation through marking, cutting and reassembling of the biomodel.
Furthermore, the pre-surgical study of a biomodel allows not only the detailed
evaluation of the operation, without the time pressure present during actual
operation, but also possible problem prediction. This way, actual operation time,
and consequently operation cost and infection/anaesthesia risk are decreased.
Biomodels are also very useful as a communication tool between medical
personnel. They are also very useful for the presentation of operation details to
4
people with no medical expertise (e.g. the patient or its relatives), thus increasing
consent and trust.
In most cases, RP is applied for the fabrication of models of hard tissue
parts of the human body, i.e. bones [12]. The most widely reported application of
RP biomodelling for surgical planning is in the field of maxillo-craniofacial
surgery, which involves the surgical treatment of congenital or acquired
deformations (e.g. tumour resections or trauma defections) both for functional and
aesthetic purposes [13-19]. The geometry of the skull is quite complex and cannot
be easily reproduced in a physical model using cutting manufacturing methods
like CNC milling. RP, therefore, presents a reasonable alternative. Among RP
technologies, SL is the most commonly used in craniofacial biomodelling. An
example of a SL skull model, fabricated at the Center of Product Development
and Rapid Prototyping of the University of Piraeus, is presented in Fig.1. This SL
model is an accurate replicate of the damaged skull of a young girl, which was
injured in a car accident and it has been used for pre-operative planning of the
surgery as well as an aid for the design of the prosthetic implant that would
restore the anatomy of the damaged area.
Figure 1
Muller et al. [19] investigated the usefulness of RP models of the skull in
craniofacial and neurosurgical practice. RP biomodels of 52 patients, whose
treatment required corrective/reconstructive cranioplasty or involved complex
surgical operations, were fabricated. They report that SL models help in better
understanding of the anatomy, increase intra-operative accuracy, support accurate
fabrication of implants, facilitate pre-surgical simulation and improve education
of trainees. Kermer et al. [17] propose in their study an enhancement of the RP
biomodelling approach by investigating the possibility of selectively coloured RP
biomodels. Their findings indicated that selectively coloured models facilitate the
management of ablative surgery and reconstructive procedures as well. The value
of SL surgical biomodels has also been shown in the case of reconstructing of
complex orbital fractures in a study by Fan et al. [20].
Biomodelling of soft-tissue parts of the human body using RP, are rather
rare in practice. This can be mainly attributed to the difficulty of separating the
area of interest from the surrounding soft tissues, due to the relatively small
differences of greyscale in medical scanned images. D’Urso et al. [21] have
5
studied the possibility of biomodelling of cerebral aneurysms based on data
obtained through CT angiography (CTA) and MR angiography (MRA). Their
results indicate that the SL models are sufficiently accurate and can be quite
useful for surgical planning in complex cases or when the standard imaging is felt
to be equivocal. In a similar study Wurm et al. [22] investigated the usefulness of
cerebrovascular biomodels for aneurysm surgery with similar results. The
feasibility of RP biomodelling for the replication of soft-tissue parts is shown in
the study of Binder et al. [23]. They applied SL for the construction of replicates
of the mitral valve with good results.
Although the results of the previous mentioned studies show the usefulness
of biomodels for operation planning and rehearsal, the high fabrication cost and
time involved is in most cases a major drawback. In particular, SL and SLS
models are very expensive and the associated cost can be justified only in rather
complex cases. In order decrease the fabrication cost and time the utilization of
3D-printing is proposed, which is much less expensive and time-consuming [24].
4
TOOLS FOR INTRA-OPERATION GUIDANCE
AND TESTING
Of course, biomodels are not used in the pre-surgical phase only. They are also
used in actual surgery, during which, biomodels or images obtained by biomodels,
can be utilized to guide the operation, assuring the accuracy and the quality of
results. D’Urso et al. [25,26] investigated the possibility of using accurate SL
biomodels of the patient in planning and rehearsing stereotactic surgery. The
method of stereotaxy is a minimally-invasive form of surgical intervention which
uses 3D coordinates in order to locate specific targets and perform on them an
operation like removal, implantation or injection. The location of the target is
based on MRI/CT data and is determined with respect to a reference frame that is
attached to the patient’s body. In order to simplify the method and enhance its
accuracy, D’Urso et al. [25,26] employed SL biomodels in a neurosurgical
operation. They report that biomodel-guided stereotaxy offers significant
advantages in terms of speed, simplicity, accuracy, and versatility but with the
extra cost and time required for biomodel fabrication. Ngan et al. [27] also
proposed the use of RP models, fabricated with SL and 3DP, for preoperative and
6
intraoperative planning of pulmonary atresia surgical treatment. They report that
the surgeons found biomodels very useful in visualizing the vascular anatomy, but
construction of virtual models was relatively labour intensive and required expert
knowledge of the pulmonary vasculature.
Another application of SL models is presented by Starly et al. [28], in which
the SL model is used as a medium for the transfer of the anticipated skull
geometry in a surgical guidance system of over-laying images. In this approach
the 3D virtual model of the patient’s skull is constructed first through CT data
interpolation. The virtual model is then split in two symmetrical parts, the
undamaged half and the defective half that contains the trauma. Next, the
defective part is discarded and replaced by the mirror image of the other half and
a new virtual model of the skull with the required symmetry is constructed and
fabricated with SL. The SL model is then scanned with CT and the obtained stack
of images is transferred to the surgery guidance system, thus providing an image
reference that accurately guides the surgeon during operation.
SL has also been used for the fabrication of surgical guides for the
placement of dental implants, a restoration process that requires detailed planning
and high accuracy. Sarment et al. [29] investigated the accuracy of dental implant
placement with the aid of SL surgical guides, which according to their findings
improved the implant placement. In a similar study Di Giacomo et al. [30] came
to the same conclusion, but denoted that the technique requires improvement to
provide better stability of the guide during the surgery, in cases of unilateral bonesupported and non-tooth-supported guides.
SLS and Reverse Engineering (RE) methods have been employed for the
construction of protective patient-specific shielding masks that may be used as
protective shields during cancer treatment [31,32]. The fabrication procedure
proposed by De Beer et al. [31] comprises of three phases: first the face geometry
for the mask is captured by 3D photography, subsequently an SLS plastic mask is
produced, based on the mask virtual model, and finally a radio protective shell on
the mask is applied through spraying of a special metal alloy (see Fig.2). The
reported results show that the proposed methodology leads to quicker and more
accurately manufactured masks compared to conventional processes, at the
expense of higher costs, the latter being mainly associated with the SLS
fabrication phase. However, higher accuracy and better fit of masks are expected
7
not only to reduce the trauma experienced by the patient but also to decrease
production man-hours consumed, implicitly, therefore, increasing the cost
efficiency of the method. The feasibility of the proposed procedure for the
production of customer-specific radiation shields is confirmed also in a study by
Zemnick et al. [32] who followed a similar process that employs 3D laser
scanning and SL.
Figure 2
Testing of new treating methods and technologies is another field that RP
has been applied successfully. Johnson and Young [33] have investigated the
feasibility of using RP biomodels as expendable test parts, in an experimental
study of the response of the human head to impact, during a car accident. In a
similar manner, SL models of cancellous bones, like those caused by osteoporosis,
were fabricated and mechanically tested, in order to investigate the relationship
between their geometry and their mechanical strength, implicitly assessing
fracture risk [34]. Also, RP models of pelvic bones have been used to prove
experimentally the higher efficiency of computer assisted screw insertion
procedures over conventional ones in spinal surgery [35].
The study of exposure of the human respiratory system to dangerous or
pathogenic aerosols is another area where RP models have been used successfully.
Clinkbeard et al. [36] applied SLS for the fabrication of human tracheobronchial
airway models and carried out an experimental investigation of the location and
the amount of deposition of dangerous aerosols under different conditions. They
propose the utilization of such models as the standard for relevant studies.
5
PATIENT-SPECIFIC IMPLANTS
Another area that the application of RP systems seems to have great potential is
the construction of customized implants for reconstructive and plastic surgery. In
this area the connection of medical imaging techniques and RP can lead to
significant time savings in operation time and much higher accuracy and quality
in surgical operation [37]. He et. al. [38] presented a design method for exact-fit
customized implants that employs virtual and RP models of injured or healthy
bones in order to reduce the associated time and cost. This methodology is
employed in a case study investigated by Truscott et al. [39] that focused on the
8
use of SLS models in the design process of customised titanium elbow implants.
According to their findings the complementary use of virtual and physical models
greatly improves the accuracy and reduces the cost of the implant design process.
Winder et al. [40] present 10 clinical cases, in which the required titanium
implants for the reconstruction of skull defects were created using RP models as
masters for casting. The geometry of the data was obtained by comparing the
defected side of the head to the contralateral, so as to retain symmetry in the final
result. Applying a similar method D’Urso et al. [41] used SL models of both the
actual defected side and the customized implant (the latter to be used for casting
acrylic implants) in cranioplasty operations. They report reduced operating time
and excellent results at a ‘reasonable’ cost.
SL models have been used for the fabrication of mandible titanium trays,
which are implanted in the patient as a replacement of the actual bone that was
lost or removed because to a tumour [42]. The implant SL model served as the
casting pattern for the construction of a silicon mould and the subsequent casting
of an identical wax model, which was finally used as an expendable pattern for
the production of the titanium part by investment casting. Singare et al. [42], who
carried out this work, report that using CT data and SL provides very accurate
implants that have significant functional and aesthetically pleasing results. In a
following study Singare et al. [43] employed directly SL Quickcast models as
expendable patterns for investment casting of titanium implants. SL models have
also been used directly as expendable patterns for casting of a titanium implant for
the replacement of a damaged hemi-knee joint [44]. In the same study, SL has
also been employed for the fabrication of an expendable mould for a porous bone
substitute (see Fig. 3). Both parts were implanted on the patient with good results
in terms of functionality and fitting with the surrounding anatomy.
Figure 3
Dental applications generally seem rather suitable for RP in view of the
complex geometry involved, the low volume and the requirements for
customization [45]. According to Chang et al. [46] the integrated use of Abrasive
Computer Tomography (ACT), RP and CNC technologies can significantly
improve the speed and quality of the orthodontic denture production process.
Eggbeer et al. [47] investigated the efficiency of using RP models as expendable
casting models in the case of custom made models of removable partial denture
9
(RPD) metal alloy frameworks. These frameworks serve as a medium to retain
artificial replacement teeth in the oral cavity. According to their method, RP
models of the framework, which are fabricated based on digitally scanned data of
an impression of the patient’s mouth, can be used as models for lost-wax casting
of the actual framework with great success. Fabrication of titanium replicates of
the actual teeth is also reported possible using RP models and vacuum casting for
the production of teeth wax models for lost-wax casting [48]. Kruth et al. [49]
provide an example of a direct application of RP, particularly SLS, for the
fabrication of metal alloy frameworks for dental prosthesis. Selective Laser
Melting (SLM) is another AF technology that according to Bibb et al. [50] may be
employed successfully for the direct fabrication of chromium-cobalt customized
RPD. The feasibility of the SLM produced biocompatible implants was also
reported in [51]. Fabrication of Titanium alloy implants with Direct Laser
Forming, an AF technology that constructs metal parts with bulk density, have
been investigated also in [52]. Direct fabrication of porcelain dental restoration
parts is investigated in [53]. The proposed method involves the extrusion of dental
powder pastes in a layer-by-layer fashion and the solidification of the extruded
powder layer using a laser beam.
Using RP models as models for traditional casting methods has been also
investigated in cases concerning soft tissue implants like ears [54,55]. In these
cases the geometry of the unaffected ear can be mirror-imaged using Reverse
Engineering (RE) methods, for example 3D Laser Scanning, and reproduced with
an RP method in order to take an accurate symmetrical replicate of the lost ear
(see Fig. 4). Direct production of ‘soft’ biocompatible implants employing
available RP technologies requires the development of new specialized materials.
In order to address this need Bens et al. [56] developed a flexible (meth)acrylatebased resin for SL that could be useful in various bio-medical applications.
Figure 4
The versatility of RP methods may enable another route for fabricating
metal implants, which is the direct fabrication of a ceramic mould. Curodeau et al.
[57] employ this approach to fabricate ceramic shell with 3DP which are used as
expendable moulds for casting the desired implant. The production of moulds for
implants by RP was also investigated by Hunt et al. [58], who employed SLS for
the fabrication of moulds for the production of wax investment casting patterns.
10
According to their findings however, the bone growth in implants fabricated this
way is less than in porous implants directly fabricated with SLS.
6
TISSUE AND ORGANISM MANUFACTURING
ENGINEERING
Due to the additive nature of the processes incorporated in RP technologies, they
are also ideal for the fabrication of implants with special geometrical
characteristics, like scaffolds for the restoration of tissues [59]. Scaffolds are
porous supporting structures that are used as a vessel for the transplantation of
tissue cells into the body of the patient [60]. They serve as the platform for the
rapid and guided growth of new tissue in damaged or defective bones or even
organs of the human body. As in the cases of cranioplasty and dental implants, RP
technologies have been used either as a direct method for manufacturing the
scaffolds themselves or (indirectly) as a ‘manufacturing tool’ of the moulds
required for the casting of scaffolds.
Chen et al. [61] present a case where a SL mould of the intended scaffold
geometry was used to cast an artificial bone through injection of calcium
phosphate cement (CPC), which is a non-toxic soluble material and bone
morphogenic protein. Tests performed on animals showed that the artificial bone
scaffold accelerated the growth of the actual bone. The same approach has also
been used in other studies with similarly successful results in terms of cell growth
on the scaffold [62,63]. Scaffold moulds for soft tissue implants have also been
fabricated by inkjet printing technology with successful results [64,65]. In this
case, the collagen scaffold was cast in the expendable RP mould, which was
subsequently removed by ethanol bathing. A possible application of the method is
presented by Taylor et al. [66] that investigate aortic valves collagen scaffold
construction. Chen et al. [67] employed 3DP in a multi-phase elaborate
production process of nano-fibrous scaffolds with controlled architecture in
macro-, micro- and nano-scale is presented. In the proposed process 3DP is used
for the production of the moulds of PLLA scaffolds that could be used in bone
tissue engineering.
For direct fabrication of biocompatible scaffolds several RP methods, as
well as new AF methods have been investigated. In most cases the methods
employed are based on jet printing (3DP, MJM) or liquid deposition techniques
(FDM), that seem to be more appropriate for direct scaffold fabrication, due to the
11
‘flexibility’ in the selection of raw materials. Seitz et al. [68] presented a method
of direct 3DP of scaffolds from Hydroxyapatite (HA), a biocompatible
implantable ceramic material. The printed ceramic ‘green bodies’ are next cured
in a high temperature furnace, so to allow sintering of the powder. In a subsequent
study Leukers et al. [69] performed a histological evaluation of 3D printed HA
scaffolds, which showed that cells proliferated well into the scaffold, showing the
efficiency of this method for scaffold fabrication. HA scaffolds have also been
fabricated employing the FDM [70] and Robocasting methods [71]. Chim et al.
[70] employed FDM for the construction of scaffolds with poly-e-caprolactone
(PCL) and HA-PCL scaffolds in order to study different scaffold architectures and
materials. Dellinger et al. [71] used Robocasting, an AF method that consists of
the robotic deposition of highly concentrated colloidal suspensions in layers to
form the scaffold structure, which is subsequently sintered in high temperature.
Miranda et al. [72] also investigated Robocasting for the construction of
bioceramic scaffolds for bone tissue engineering. The application of SLS
technology for the direct fabrication of biocompatible ceramic scaffolds has been
also extensively investigated. Williams et al. [73] assessed the direct fabrication
of PCL porous scaffolds. According to their findings the fabricated scaffolds had
sufficient mechanical strength and provided a sound platform for the generation of
the new bone. PCL sintered scaffolds SLS with a powder blend of
polyetheretherketone (PEEK) and hydroxyapatite (HA) has been also tried with
promising results [74]. The construction of liver tissues, based on SLS fabricated
PCL scaffolds, has been investigated by Huang et al. [75], who suggested that this
approach could, in the near future, lead to the development of an implantable liver
tissue equivalent for humans.
A problem apparent in most studies of RP manufactured scaffolds is the
time required for the virtual design and modelling of the scaffolds. 3D scaffold
modelling is a trade-off design process (porosity versus structural strength) that
requires considerable time and effort employing standard mechanical design
software. In order to circumvent this problem Chua et al. [76] suggested utilizing
libraries of application-specific polyhedral shapes that are used as constructing
elements of the scaffolds. A prototype system that makes use of such primary
scaffold elements (see Fig. 5) was proposed by Naing et al. [77]. The system
utilizes special algorithms that construct the CAD scaffold model according to
12
user selected scaffold elements and porosity, and based on a surface model that
provides the outer geometry of the scaffold. A micro-SL system that could be
used for scaffold architecture studies is presented in [78]. According to Lee et al.
[78] the redesigned system is capable of fabricating highly accurate 3D polymer
structures that could aid the scaffold design process.
Figure 5
Due to the materials physical and chemical properties of the models, RP
assisted scaffold fabrication has been mainly focused on bone (hard) tissue
engineering. For the fabrication of soft tissue scaffolds new techniques, like 3DBioplotting, are under investigation and development [79]. 3D-Bioplotting is a
technique that resembles continuous deposition RP technologies like FDM, and
allows 3D dispensing of liquids and pastes in liquid media through a pressurecontrolled dispenser. Moroni et al. [80] employed 3D-Bioplotting in the
fabrication process of 3D hollow fiber scaffolds from biocompatible polymeric
blends. Fiber hollowing is achieved in by selective dissolution of the fiber inner
core polymer by extensive immersion of the initial scaffold in solvent.
Viscoelastic properties of the obtained scaffolds can be modulated to accomplish
mechanical requirements for tailored tissue engineering applications [81]. 3D
fiber deposition of metallic scaffolds for orthopaedic applications has also been
reported [82].
An emerging concept based on the primary successful research results of AF
applications in tissue engineering is the concept of Organism Manufacturing
Engineering (OME). OME is defined as the science and technologies that utilize
the principles and methods of modern manufacturing science and life science,
through controlled direct or indirect 3D assembly of cells, to manufacture live
organisms, to substitute or to repair human tissues and organs [83]. According to
Xiong et al. [83] main principles of AF could serve as the basis of new OME
technologies for direct or indirect controlled cell assembly, and thereby provide a
solution to the ever increasing demand for donor organs. Yan et al. [84] proposed
a new process for the production of scaffolds for bone tissue engineering. Their
method (Low-temperature Deposition Manufacturing – LDM) employs the layer
manufacturing principle and an extrusion-type system for the construction of
PLLA/TCP composite scaffolds. Compared to established methods like FDM, the
LDM process is reported to preserve bio-activities of scaffold materials, because
13
of its non-heating liquefying processing of materials. In a following study [85]
LDM was investigated as a production method for implantable bioactive liver
substitute with promising results.
A similar extrusion-type method is proposed by Vozzi et al. [86] for the
fabrication of PLGA (PolyLactic-co-Glycolic Acid) scaffolds with microporosity.
In the described method, material is deposited utilizing a pressure micro-syringe
and a three-axis system with micro-scale positioning accuracy. In [87] a
comparison of four types of nozzle systems, i.e pneumatic microvalve, solenoid
microvalve, piezoelectric and precise extrusion deposition (PED) nozzles that
deposit sodium alginate and PCL solutions was carried out. The proposed multinozzle manufacturing system can be employed used for the fabrication of
bioactive tissue scaffolds, automatic cell loading, and heterogeneous tissue
constructs for emerging regenerative medicine. Direct fabrication of 3D neural
constructs by jet printing AF has been also investigated [88]. The method
proposed by Xu et al. [88] employs conventional inkjet printing technology
modified for alternating deposition of neural cell layers and biodegradable fibrin
gel layers that form a cohesive 3D neural sheet. Examination of the sheets showed
that deposited neurons maintained their basic electrophysiological functions.
7
DRUG DELIVERY AND MICROSCALE DEVICES
Another field that RP technologies are expected to prove very useful is the
fabrication of customized microsystems and therapeutic devices for controlled
highly specific and precise drug delivery. Such devices involve complex micronscale networks of fluidic and electronic components capable of operating in an
integrated manner [89]. In their study Razzacki et al. [89] categorized these
devices into three major groups:
•
biocapsules and microparticles for controlled and/or site-specific drug
release,
•
microneedles for transdermal and intravenous delivery and
•
implantable microsystems.
An example of biomedical device that may be used in the area of drug
testing and DNA research is reported in [90]. The device presented is a
biochemical laboratory in micron scale that may be used for cell-free protein
14
synthesis. This micro-scale laboratory is assembled by biochemical chips
fabricated with the method of Hybrid micro-SL, in which the chip functional parts
such as one-way valve, ultrafiltration membrane and photo sensor are inserted
during the layer construction-solidification process, thus eliminating the
subsequent chip assembly phase. A novel layer manufacturing method that could
possibly be applied applications in biosensor development, tissue engineering,
drug delivery and biomaterials is described by Kızılel et al. [91]. The proposed
method permits the construction of the PEG-based hydrogel multilayer structures.
Reported advantages are the biocompatibility of materials and the fact that layer
formation is achieved in mild photopolymerization conditions using visible
instead of ultraviolet light.
The fabrication of medical microdevices or microconstructions that are
biodegradable and therefore require no special removal operation from the
patient’s body is another possibility investigated in conjunction with AF. Methods
employed traditionally for micro-scale manufacturing like thin-film deposition,
photolithography, etching or methods borrowed from the computer industry, are
not suitable for biodegradable polymers [92]. In such applications non-invasive
additive fabrication technologies, like micro-SL, may have great potential in both
a laboratory and industry scale [92]. Matsuda and Mizutani [93] reported the
development of two such photocurable biodegradable liquid copolymers, one
hydrophilic and another hydrophobic. Reported results show that the developed
copolymers can be easily photocured by UV radiation and are, therefore, suitable
for use in micro-SL (see Fig. 6). Itoga et al. [94] presented a novel
photolithography device that could be employed preparation of micro-patterned
surfaces for biomedical applications, as well as other microfluidic surfaces in a
rapid prototyping manner. The device is based on a modified LCD projector and
has been tested in the construction of polyacrylamide (PAAm) micro-patterned
surfaces. Shape Deposition Manufacturing (SDM) is another RP method that
could be potentially employed for micro-scale manufacturing. Cheng and Lin [95]
presented such an application of SDM in the fabrication of valve-less micropumps
with micro channels.
Figure 6
AF may provide alternative ways for the fabrication of drug delivery
devices like oral tablets. Rowe et al. [96] presented an application of 3DP
15
technology for the fabrication of oral devices where two different release
mechanisms, erosion and diffusion, are mixed in a single device. Other possible
applications are tablets with a quick dissolve region that breaks into controlled
subunits and pulsatory devices. The SLS process has been also used for the
fabrication of porous cylindrical disc matrices that may be used as drug delivery
devices by Low et al. [97]. They reported that it is possible to use SLS for
producing drug delivery devices that have variable porosity and micro-features.
Leong et al. [98] investigated the possibility of building biodegradeable controlled
drug delivery devices with SLS. Their experiments with PCL and PLLA as test
materials showed that varying porosity discs can be produced by controlled
variance of SLS fabrication parameters.
8
DISCUSSION AND CONCLUDING REMARKS
In this paper applications of AF/RP technologies in medicine and current research
issues in the field of Rapid Medical Prototyping are presented. The review of the
international specialized literature showed that custom biomodels fabricated with
RP technologies are quite useful for planning and rehearsal of complex surgical
operations. According to the results of most studies RP biomodels aid the
surgeons in diagnosis, planning, problem prediction and communication, thus
reducing operation time infection risk and improving the results of the operation.
Among the RP technologies applied to medicine, SL seems to have attracted
the attention of most researchers. SL is not only relatively more accurate but also
the number of installed SL systems worldwide is very big. Also, SL resins provide
the advantage of biomodel clarity and transparency that can be quite useful in
surgery rehearsal. However, they are not biocompatible and require special
handling; a fact that makes adoption of SL systems in the hospital environment
difficult. Both the accuracy and the low surface roughness of SL biomodels makes
them ideal as casting patterns for the fabrication of customised metallic or acrylic
implants through lost-wax or vacuum casting methods.
For the fabrication of biomodels for surgery planning and evaluation
purposes, less ‘expensive’ or time-consuming RP technologies, like multicolour
3DP and FDM seem to be the most suitable choice. Another advantage of these
two technologies is that they are office friendly and can process biocompatible
materials with some minor modifications. Further reduction in the fabrication time
16
involved, can be achieved through higher automation of the medical imaging data
manipulation process that is required for the construction of the virtual model.
The virtual model construction phase is reported as the main source of observed
inaccuracies, mainly due to the low level of detail and information that can be
obtained through conventional medical imaging (diagnostic) systems.
SLS technology has the greatest potential among commercial RP
technologies or direct fabrication of implants. This is mainly due to the fact that
SLS can fabricate implants from a variety of materials including metals, ceramics
and thermoplastics with sufficient accuracy. In this context the main research
issue is to develop and test materials that are biocompatible so that can be used
safely for direct fabrication of implants.
Fabrication of custom-made scaffolds is another application in which RP
can be quite useful. Two approaches have been identified:
• Direct Methods - they employ a commercial RP system or a new AF
method for the fabrication of the actual scaffold itself (e.g. SLS of
biocompatible ceramics) and
• Indirect Methods - they employ RP for the fabrication of the tool (pattern
or mould) that will be used for the production of the actual scaffold.
Due to adverse materials properties direct additive scaffold fabrication is
mostly directed to hard-tissue scaffolds (bone tissue engineering). As far as the
fabrication of soft-tissue scaffolds new manufacturing methods that apply the
principles of AF are currently under development. These new methods employ
mostly the jet-printing or deposition operational principles for the construction of
layers from biocompatible or biodegradable materials. An aspect that should be
considered in scaffold fabrication with powder based RP technologies is the
removal of trapped material within the scaffold (trapped volume problem). Also,
the minimum grain size sets a limit in the porosity obtainable with these methods.
However, the development of finer grain powder materials could greatly alleviate
these drawbacks. Obviously, full exploitation of the advantages of AF
technologies is directly related to the availability of special design software
systems (Bio-CAD) that enable design and manipulation of the relatively complex
geometries of scaffolds. Scaffolds also present a challenge in terms of virtual
representation that cannot be easily manipulated by currently available industrial
CAD systems.
17
Micro- and nano-fabrication variants of AF technologies are expected to
make possible the fabrication of controllable drug delivery units or implants in the
micron or the submicron level. For custom implants of such fine scale require
further improvement of associated technologies such as micro-CT. Fabrication of
artificial organ substitutes is a very interesting area of research, where initial
results show that extrude-type AF may be employed successfully. Relevant
technologies under development mostly focus on deposition techniques that
enable controlled ‘assembly’ of living cells and supporting material in order to
construct the organ substitute.
In conclusion, the literature review carried out in this work showed that
although RP technologies exhibit a great potential in the field of medical
applications, they have not been widely adopted yet in standard medical practice,
because of the high cost and fabrication time involved. RP although faster and
more flexible than other manufacturing methods (e.g. CNC machining) is neither
fast enough nor cost effective to cater for emergency cases. Depending on the size
and complexity of the biomodel, RP fabrication times vary between a few hours to
two days, which maybe unacceptably long for emergency cases (depending, of
course, on the particular case). Time and cost requirements, therefore, restrict the
utilization of RP to rather complex cases where considerable cost savings and
quality benefits are expected. Indeed, this is the case with surgical planning
biomodels. Also, RP cost and time ‘expenses’ seem to be justifiable for custom
implant fabrication applications, e.g. for orthopaedic surgery, simply because in
such cases the utilization of conventional manufacturing methods, implies
significantly higher fabrication time and cost. Furthermore, the customization of
the implant assures accurate fitting, reduces operating time and enhances quality.
Ill fitted implants cause discomfort and should be replaced quite frequently, which
means that the cost of rectifying or compensating the effects of an ineffective
surgery can be far higher than the cost of the actual surgery operation itself [24].
Considering, therefore, these compensating costs the initial investment cost in RP
may be well justified. Regarding the tissue engineering, artificial organ
manufacturing and drug delivery device fields, initial experimental results show
that there is a great potential. However, a lot of research effort is still required for
the development of reliable manufacturing systems and materials, which could be
employed for the mass production of scaffolds or even organ substitutes.
18
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List of Figures
Fig. 1. Skull biomodel of an injured girl for surgical planning fabricated with SL.
Fig. 2. SLS lastic and metal sprayed shielding masks [31].
Fig. 3. The SL pattern (a) for the casting of the titanium joint (b) and the negative pattern (c) for
the corresponding porous bone (d) [44].
Fig. 4. Ear model manufactured with 3D printing to serve as vacuum casting pattern for the
fabrication of an ear substitute [54].
Fig. 5. 3D models of possible scaffold structures for CAD scaffold modeling [77].
Fig. 6. Microneedle array fabricated with micro-stereolithography [93].
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Figure 1
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Figure 2
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(a)
(b)
(c)
(d)
Figure 3
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Figure 4
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Figure 5
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Figure 6
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