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Additive fabrication technologies applied to medicine and health care: a review
J. Giannatsis & V. Dedoussis
Received: 26 April 2007 /Accepted: 6 November 2007 / Published online: 18 December 2007 # Springer-Verlag London Limited 2007
m a Abstract Additive fabrication (AF) and rapid prototyping (RP)i l 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,v however, they have also been employed in various non-manufacturing
d e applications. A field that attracts increasingly more attention by thed scientific community is related to the application of AF technologies ino @ medicine and health care. The associated research is focused both on u the development of specifically modified or new methods and systemsn based on AF principles, as well as on the applications of existing i p systems assisting health care services. In this paper, representative i case studies and research efforts from the field of AF medical. applications are presented and discussed in detail. The case studiesg included cover applications like the fabrication of custom implants andr
investigation of human bones or of new medical techniques, drug delivery devices fabrication, as well as the development of new AF1 techniques specifically designed for medical applications.
Additive fabrication (AF) is a relatively new concept that emerged during the last decade in order to describe a set of new
Keywords Additive fabrication . Rapid prototyping . Rapid manufacturing . Biomodelling . Scaffold fabrication . Medical applications
methods, pro-cesses and technologies that function through material addition, in contrast to the established traditional cutting, forming or casting methods. Rapid prototyping (RP) technologies are the most widely applied and known fabrication methods that are based on additive fabrication principles. Some of
: V. Dedoussis (*)
Center for Product Development and Rapid Prototyping, University of Piraeus, 80 Karaoli & Dimitriou str.,
18534 Piraeus, Greece e-
the major RP technologies used worldwide are stereolithography (SL),manufacturing technologies, like for selective laser sintering (SLS), fused deposition modelling (FDM), 3Dinstance printing (3DP), multijet modelling (MJM) and laminated objectsystems
CNC machin-ing, RP can fabricate parts of manufacturing (LOM). The main applications of RP include thealmost any geometrical complexity fabrication of various kinds of models and prototypes for conceptin relatively lower time and with evaluation and presentation as well as functional testing of newreduced cost and without significant products early in the product development process . The continuousrequirements in technical expertise. improvement of RP systems accuracy and materials, expand graduallyThis kind of geometric flexibility, their applications to other areas of the industrial sector like rapidwhich is mostly a consequence of manufacturing (RM - the actual manufacturing of products in smalltheir additive nature, is the main batches) and rapid tooling (RT - fabrication of manufacturing tools andreason that RP technologies are increasingly used or tested in nonmoulds). industrial applications like medical and architectural modelling  or What makes RP particularly appealing for all of the above artistic creation . The applications is the fact that compared to alternative
Int J Adv Manuf Technol (2009) 40:116–127 medical branch in particular has attracted the attention of many researchers and scientists process since the first introduction of RP technologies, and has been the topic of various EU research which programs (e.g., Phidias – EC Funded Network
of these physical models, are nowadays often called biomodels, involves three phases :
Project on Rapid Prototyping in Medicine). What makes RP technologies even– The first step is to obtain the data of the more appealing is that they utilize medical imaging data (obtained by patient’s area of interest with the use of techniques like com-puted tomography - CT or magnetic resonance imaging the previously mentioned techniques MRI), almost directly, for the production of customized patient specific parts. (CT, MRI, etc.), which provides an The reported medical applications of RP technologies can be classified to the indirect representation of the patient’s following categories: anatomy through a series
(stack) of 2D images. – Biomodelling, which involves the fabrication of phys-ical models of parts of the human anatomy and biological structures in general,– The images are next manipulated for surgery planning or testing. employing special software, which
– Design and fabrication of customized implants for prosthetic operations, rehabilitation, and plastic surgery – Fabrication of porous implants (scaffolds) and tissue facilitate the separation and highlight-ing of the tissues (soft or hard) 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.
– – Fabrication of specific surgical aids and tools Drug delivery and micron-scale medical devices
Despite their great flexibility and potential, RP technol-ogies have not yet been widely adopted in the medical and health-care sectors. This can be attributed to the high cost and justified in relatively complex medical cases . 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 biocompatibil-ity . Nevertheless, RP technologies and AF in general time required for the fabrication of corresponding models which at present can only be
Finally, the biomodel is fabricated via an RP system followed by possible (if it is necessary) manual finishing.
The accuracy of RP biomodels depends
have great potential in the area of medical and health-care applications due to their distinct on various factors associated with all phases features, and have been therefore the subject of various studies worldwide. The corresponding of the process. Choi et al.  analyzed the research covers various areas such as the cost-efficient application of established possible sources of error in SL biomodel-ing technologies, the development of new technologies, the virtual model-ing/representation of and identified the main sources of error in the medical data and the development of biocompatible materials. The purpose of the present second phase, namely, the translation of 2D work is to present and discuss in detail the most representative case studies, covering the data to a 3D virtual model. This has led to the main research areas of AF applications in medicine according to the classification given development of special software tools like Mimics from Materialise Inc. (http://www. above. materialise.com) and that Biobuild have process. (http://www.anatomics.com) 2D-3D data
simplified and enhanced the accuracy of the transformation
2 Fabrication of RP models based on medical data
Regarding the manufactur-ing accuracy of RP technologies, Santler et al.  concluded that
One of the major medical applications of RP is the fabrication of models of parts it is sufficient for clinical purposes. of human anatomy of a patient based on data obtained through the various wellestablished techniques of CT or MRI . The fabrication
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 . Since every patient is unique, the surgeon must fully
understand the anatomy of the patient before operation. Obtaining a full Furthermore, the pre-surgical study of a biomodel allows not only the detailed 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 complexevaluation of the operation, without the time surgical operations . In such cases, RP biomodels greatly facilitate diagnosis and treatmentpressure present during actual operation, but planning, and decrease the risk of misinterpreta-tion of the medical problem. Having a physicalalso possible problem prediction. This way, biomodel in hand also facilitates surgery planning and makes possible the rehearsal andactual operation time, and consequently simulation of the operation through marking, cutting and reassembling of the biomodel. operation cost and infection/
118 anesthesia 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 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 . The most widely reported application of RP biomodeling for surgical planning is in the field of maxillo-craniofacial surgery, which involves the surgical treatment of congenital or acquired deformations (e.g., tumor 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
Int J Adv Manuf Technol (2009) 40:116–127 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.  investigated the usefulness of cerebrovas-cular biomodels for aneurysm surgery with similar results. The feasibility of RP biomodeling for the replication of soft-tissue parts is shown in the study of Binder et al. . They applied SL for
the construction of replicates of the mitral reasonable alternative. Among RP technologies, SL is the most commonly used in craniofacial valve with good results. biomodeling. An example of an 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 who was injured in a car
Although the results of the previous mentioned studies show the accident and it has been used for pre-operative planning of the surgery as well as an aid for the usefulness of biomodels for operation design of the prosthetic implant that would restore the anatomy of the damaged area. planning and rehearsal, the high fabrication cost and time involved is in Muller et al.  investigated the usefulness of RP models of the skull in craniofacial and most cases a major drawback. In neurosurgical practice. RP biomodels of 52 patients, whose treatment required particular, SL and SLS models are very corrective/reconstructive cranioplasty or involved complex surgical operations, were expensive and the associated cost can fabricated. They report that SL models help in better understanding of the anatomy, increase be justified only in rather complex intra-operative accuracy, support accurate fabrica-tion of implants, facilitate pre-surgical cases. In order to decrease the simulation and improve education of trainees. Kermer et al.  propose in their study an fabrication cost and time, the utilization enhancement of the RP biomodeling approach by investigating the possibility of selectively of 3D printing is proposed, which is colored RP biomodels. Their findings indicated that much less expensive and timeconsuming .
4 Tools for intra-operation guidance and testing
Of course, biomodels are not used in the presurgical 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.
Fig. 1 Skull biomodel of an injured girl for surgical planning fabricated with SL
The method of stereo-taxy is a minimally invasive form of surgical intervention which
selectively colored models facilitate the management of ablative surgery anduses 3D coordinates in order to locate reconstructive procedures as well. The value of SL surgical biomodels hasspecific targets and perform on them an also been shown in the case of reconstructing of complex orbital fractures inoperation like removal, implanta-tion or injection. The location of the target is based a study by Fan et al. .
Biomodeling of soft-tissue parts of the human body using RP, are rather rare in practice. on MRI/CT data and is determined with This can be mainly attributed to the difficulty of separating the area of interest from therespect to a reference frame that is attached surrounding soft tissues, due to the relatively small differ-ences of greyscale in medicalto the patient’s body. In order to simplify the scanned images. D’Urso et al. method and enhance its accuracy, D’Urso et  have studied the possibility of biomodeling of cerebral aneurysms based on data obtainedal.
simplicity, accuracy, and versatility but [25, 26] employed SL biomodels in a neurosurgical operation. They report that with the extra cost and time biomodel-guided stereotaxy offers significant advantages in terms of speed,
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required for biomodel fabrication. Ngan et al.  also proposed the use of RP models, fabricated with SL and 3DP, for preoperative and 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 labor intensive and required expert knowledge of the pulmonary vasculature. Another application of SL models is presented by Starly et al. , 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 Fig. 2 SLS lastic and metal sprayed surgery guidance system, thus providing an image reference that accuratelyshielding masks  guides the surgeon during operation. SL has also been used for the fabrication of surgical guides for the placement of customer-specific radiation shields of dental implants, a restoration process that requires detailed planning and high is confirmed also in a study by accuracy. Sarment et al.  investigated the accuracy of dental implant Zemnick et al.  who followed a placement with the aid of SL surgical guides, which according to their findings similar process that employs 3D laser improved the implant placement. In a similar study, Di Giacomo et al.  came toscanning and SL. the same conclusion, but denoted that the technique requires improvement to Testing of new treating methods and provide better stability of the guide during the surgery, in cases of unilateral bone- technologies is another field that RP has been applied successfully. supported and non-tooth-supported guides. Johnson and Young  have 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 investigated the feasibility of using RP cancer treatment [31, 32]. The fabrication procedure proposed by De Beer et al.  comprises biomodels as expendable test parts, in of three phases: first the face geometry for the mask is captured by 3D photography, an experimental study of the response subsequently an SLS plastic mask is pro-duced, based on the mask virtual model, and finally a of the human head to impact, during a radio protective shell on the mask is applied through spraying of a special metal alloy (see Fig. car accident. In a similar manner, SL 2). The reported results show that the proposed methodology leads to quicker and more models of cancellous bones, like those by osteopo-rosis, were accurately manufactured masks compared to conventional processes, at the expense of higher caused fabricated and mechanically tested, in costs, the latter being mainly associated with the SLS fabrication phase. Howev-er, higher order to investigate the relationship accuracy and better fit of masks are expected not only to reduce the trauma experienced by between their geometry and their the patient but also to decrease production man-hours consumed, implic-itly, therefore, mechanical strength, implicitly increasing the cost-efficiency of the method. The feasibility of the proposed procedure for the assessing fracture risk . Also, RP production 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 .
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.  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 proposeconnection of medical imaging techniques and RP can lead to significant time savings in the utilization of such models as the standard for relevant studies.
operation time and much higher accuracy and quality in surgical operation . He et al.
5 Patient-specific implants
Another area in which the application of RP systems seems to have great potential is the
 presented a design method for exact-fit
construction of customized implants for reconstructive and plastic surgery. In this area, the
Int J Adv Manuf Technol (2009) 40:116–127
customized implants that employs virtual and RP models of injured or healthy directly SL Quickcast models as bones in order to reduce the associated time and cost. This methodology is expendable patterns for investment employed in a case study investigated by Truscott et al.  that focused on the casting of titanium implants. SL models use of SLS models in the design process of customized titanium elbow implants. have also been used directly as According to their findings, the complementary use of virtual and physical models expendable patterns for casting of a greatly improves the accuracy and reduces the cost of the implant design titanium implant for the replacement of process. a damaged hemi-knee joint . In the Winder et al.  present ten clinical cases in which the required titanium implants for the same study, SL has also been reconstruction of skull defects were created using RP models as masters for casting. The employed for the fabrication of an geometry of the data was obtained by comparing the defected side of the head to the expendable mould for a porous bone contralateral, so as to retain symmetry in the final result. Applying a similar method, D’Urso et substitute (see Fig. 3). Both parts were al.  used SL models of both the actual defected side and the customized implant (the latter implanted on the patient with good to be used for casting acrylic implants) in cranioplasty operations. They report reduced results in terms of functionality and fitting with the surrounding anatomy. operating time and excel-lent results at a ‘reasonable’ cost.
Dental applications generally seem rather SL models have been used for the fabrication of mandible titanium trays, which are suitable for RP in view of the complex implanted in the patient as a replacement of the actual bone that was lost or removed due to ageometry involved, the low volume, and the tumor . The implant SL model served as the casting pattern for the construction of a silicon requirements for customization . mould and the subsequent casting of an identical wax model, which was finally used as an According to Chang et al. , the integrated expendable pattern for the production of the titanium part by investment casting. Singare et al.use of abrasive computer tomography (ACT), , who carried out this work, report that using CT data and SL provides very accurateRP, and CNC technologies can significantly implants that have significant functional and aesthetically pleasing results. In a followingimprove the speed and quality of the orthostudy, Singare et al.  employed dontic denture production process. Eggbeer et al.  investigated the efficiency of using RP models as expend-able casting models in 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)  the case of custom-made models of removable partial denture (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 . Kruth et al.  provide an example of a direct application of RP, particularly SLS, for the fabrication of metalalloy frameworks for dental prosthesis. Selective laser melting (SLM) is another AF technology that according to Bibb et
Int J Adv Manuf Technol (2009) 40:116–127
al.  may be employed successfully for the direct fabrication of chromium- 6 Tissue and organism manufacturing cobalt customized RPD. The feasibility of the SLM produced biocompatible engineering implants was also reported in . Fabrication of titanium alloy implants with direct laser forming, an AF technology that constructs metal parts with bulkDue to the additive nature of the incorporated in RP density, have also been investigated also . Direct fabrication of porcelain processes dental restoration parts is investigated in . The proposed method involves thetechnologies, they are also ideal for the extrusion of dental powder pastes in a layer-by-layer fashion and the solidificationfabrication of implants with special geometrical characteristics, like of the extruded powder layer using a laser beam. Using RP models as models for traditional casting methods has been also scaffolds for the restoration of tissues investigated in cases concerning soft tissue implants like ears [54, 55]. In these . Scaffolds are porous supporting cases, the geometry of the unaffected ear can be mirror-imaged using reverse structures that are used as a vessel for engineering (RE) methods, for example 3D laser scanning, and reproduced with the transplantation of tissue cells into an RP method in order to take an accurate symmetrical replicate of the lost ear the body of the patient . They serve (see Fig. 4). Direct production of ‘soft’ biocompatible implants employing available as the platform for the rapid and guided RP technologies requires the develop-ment of new specialized materials. In order growth of new tissue in damaged or to address this need, Bens et al.  developed a flexible (meth)acrylate-based defective bones or even organs of the human body. As in the cases of resin for SL that could be useful in various bio-medical applications. The versatility of RP methods may enable another route for fabricating metal implants, cranioplasty and dental implants, RP which is the direct fabrica-tion of a ceramic mould. Curodeau et al.  employ this approach technologies have been used either as to fabricate ceramic shell with 3DP which are used as expendable moulds for casting the a direct method for manufacturing the desired implant. The production of moulds for implants by RP was also investigated by Hunt et scaffolds themselves or (indirectly) as al. , who employed SLS for the fabrication of moulds for the production of wax investment a ‘manufacturing tool’ of the moulds casting patterns. According to their findings, however, the bone growth in implants fabricated required for the casting of scaffolds.
this way is less than in porous implants directly fabricated with SLS. Chen et al.  present a case where an 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 morpho-genic 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 Fig. 4 Ear model manufactured with 3D printing to serve as vacuum casting pattern for the fabrication of an ear substitute  is presented by Taylor et al.  that investigates aortic valves collagen scaffold construction. Chen et al.  employed 3DP in a multi-phase of elaborate production with process nano-fibrous scaf-folds
controlled architecture in macro-, micro- and nano-scale. 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 wellwhich showed that cells proliferated as new AF methods have been investigated. In most cases, the methods well into the scaffold, showing the employed are based on jet printing (3DP, MJM) or liquid deposition techniques efficiency of this method for scaffold (FDM), that seem to be more appropriate for direct scaffold fabrication, due to the fabrication. HA scaffolds have also ‘flexibility’ in the selection of raw materials. Seitz et al.  presented a method ofbeen fabricated employing the FDM direct 3DP of scaffolds from hydroxyapatite (HA), a biocompatible implantable  and robocasting methods . ceramic material. The printed ceramic ‘green bodies’ are next cured in a high- Chim et al.  temperature furnace to allow sintering of the powder. In a subsequent study Leukers et al.  performed a histolog-ical evaluation of 3D-printed HA scaffolds
Int J Adv Manuf Technol (2009) 40:116–127
employed FDM for the construction of scaffolds with poly-e-caprolactone (PCL) and HA-PCLmodel according to user selected scaffold scaffolds in order to study different scaffold architectures and materials. Dellinger et al. elements and porosity, and based on a used robocasting, an AF method that consists of the robotic deposition of highly concentratedsurface model that provides the outer colloidal suspensions in layers to form the scaffold structure, which is subsequently sinteredgeometry of the scaffold. A micro-SL system in high tempera-ture. Miranda et al.  also investigated robocasting for the construction ofthat could be used for scaffold architecture bioceramic scaffolds for bone tissue engineering. The application of SLS technology for thestudies is presented in . According to Lee direct fabrication of biocompatible ceramic scaffolds has also been extensively investigated.et al. , the redesigned system is capable Williams et al.  assessed the direct fabrication of PCL porous scaffolds. According to their of fabricating highly accurate 3D polymer findings, the fabricated scaffolds had sufficient mechanical strength and provided a soundstructures that could aid the scaffold design platform for the generation of the new bone. PCL-sintered scaffolds SLS with a powder blendprocess. of polyetheretherketone (PEEK) and hydroxyapatite (HA) has also been tried with promising Due to the material physical and chemical of the models, RP-assisted results . The construction of liver tissues, based on SLS-fabricated PCL scaffolds, has properties future, lead to the development of an implantable liver tissue equivalent for humans.
been investi-gated by Huang et al. , who suggested that this approach could, in the near scaffold fabrication has been mainly focused on bone (hard) tissue engineering. For the fabrication of soft tissue scaffolds, new techniques like 3D-bioplotting are under A problem apparent in most studies of RP-manufactured scaffolds is the time required for investigation and development . 3Dthe virtual design and modeling of the scaffolds. 3D scaffold modeling is a trade-off design bioplotting is a technique that resembles process (porosity versus structural strength) that requires considerable time and effort continuous deposition RP technologies like employing standard mechanical design software. In order to circumvent this problem, Chua et FDM and allows 3D dispensing of liquids and al.  suggested utilizing libraries of application-specific polyhedral shapes that are used as pastes in liquid media through a pressureconstructing elements of the scaffolds. A prototype system that makes use of such primary controlled dispenser. Moroni et al.  scaffold elements (see Fig. 5) was proposed by Naing et al. . The system utilizes special employed 3D-bioplotting in the fabrication algorithms that construct the CAD scaffold process of 3D hollow fiber scaffolds from biocompatible hollowing is polymeric achieved blends. by Fiber selective
Fig. 5 3D models of possible scaffold structures for CAD scaffold modeling 
dissolution of the fiber inner core polymer by extensive immersion of the initial scaffold in solvent. Viscoelastic mechanical properties of the for obtained scaffolds can be modulated to accomplish requirements tailored tissue engineering applications . 3D fiber deposition of metallic scaffolds for orthope-dic reported . 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 technology that utilizes the principles and methods and of life modern science manufacturing science applications has also been
through controlled direct or indirect 3D assembly of cells in order to manufacture live organisms to substitute or to repair human tissues and organs . According to Xiong et al. , the main principles of AF could serve as the basis of new OME
Int J Adv Manuf Technol (2009) 40:116–127
technologies for direct or indirect controlled cell assembly, and thereby provide a An example of a biomedical device that solution to the ever-increasing demand for donor organs. Yan et al.  proposedmay be used in the area of drug testing and a new process for the production of scaffolds for bone tissue engineering. TheirDNA research is reported in . The device method (low-temperature deposition manufacturing – LDM) employs the layerpresented is a biochemical laboratory in manufacturing principle and an extrusion-type system for the construction of micron-scale that may be used for cell-free synthesis. This micro-scale PLLA/TCP composite scaffolds. Compared to estab-lished methods like FDM, theprotein LDM process is reported to preserve bio-activities of scaffold materials because laboratory is assembled by biochemical chips of its non-heating liquefying processing of materials. In a following study ,fabricat-ed with the method of hybrid microLDM was investigated as a produc-tion method for implantable bioactive liverSL, in which the chip functional parts such as substitute with promising results. one-way valve, ultrafiltration membrane and
A similar extrusion-type method is proposed by Vozzi et al.  for the fabrication of PLGA photo sensor are inserted during the layer (polylactic-co-glycolic acid) scaffolds with microporosity. In the described method, material is construction-solidification process, thus deposited utilizing a pressure micro-syringe and a three-axis system with micro-scale eliminating the subsequent chip-assembly positioning accuracy. In , a comparison of four types of nozzle systems, i.e., pneumatic phase. A novel layer manufactur-ing method microvalve, solenoid microvalve, piezoelectric and precise extrusion deposition (PED) nozzles that could possibly be applied in biosensor that deposit sodium alginate and PCL solutions was carried out. The proposed multi-nozzle development, tissue engineering, drug manufacturing system can be employed used for the fabrication of bioactive tissue scaffolds, delivery, and bioma-terials, is described by automatic cell loading, and heterogeneous tissue constructs for emerging regenerative Kýzýlel et al. . The proposed method medicine. Direct fabrication of 3D neural constructs by jet printing AF has also permits the construction of the PEG-based beeninvestigated . The method proposed by Xu et al.  employs conventional inkjet hydrogel multilayer are in the mild structures. Reported of printing technology modified for alternating deposition of neural cell layers and biodegradable advantages deposited neurons maintained their basic electrophysiolog-ical functions. achieved light. The fabrication of medical microdevices or microcon-structions that are biodegradable (and therefore require no special removal operation from the patient’s body) is another possibility investigated in biocom-patibility
fibrin gel layers that form a cohesive 3D neural sheet. Examination of the sheets showed that materials and the fact that layer formation is photopolymerization conditions using visible instead of ultraviolet
7 Drug delivery and microscale devices
Another field in which RP technologies are expected to prove very useful is conjunction with AF. Methods employed the fabrication of customized micro-systems and therapeutic devices for traditionally for micro-scale manufac-turing controlled highly specific and precise drug delivery. Such devices involve like thin-film deposition, photolithography, complex micron-scale networks of fluidic and electronic components capable etching, or methods borrowed from the of operating in an integrated manner . In their study, Razzacki et al.  computer industry, are not suitable for categorized these devices into three major groups:
biodegradable polymers . In such applications, non-invasive additive
– Biocapsules and microparticles for controlled and/or site-specific drug release, – Microneedles for transdermal and intravenous delivery and – Implantable microsystems.
technologies, like micro-SL, may have great potential in both a laboratory and industry scale . Matsuda and Mizutani  liquid reported the development of two such photocurable biodegradable copolymers, one hydrophilic and another hydropho-bic. 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.  presented a novel photolithography device that could be
Fig. 6 Microneedle array fabricated with microstereolithography 
Int J Adv Manuf Technol (2009) 40:116–127
employed in the preparation of micro-patterned surfaces for biomedical applications as well as metallic LCD projector and has been tested in the construction of polyacrylamide (PAAm)
other microfluidic surfaces in a rapid prototyping manner. The device is based on a modified through patterned surfaces. Shape deposition manufacturing (SDM) is another RP method that could
or acrylic implants lost-wax or vacuum micro- casting methods.
For the fabrication of biomodels for
be potentially employed for micro-scale manufacturing. Cheng and Lin  presented such an surgery planning and evaluation purposes, less ‘expensive’ or time-consuming RP application of SDM in the fabrication of valve-less micro-pumps with micro channels. technologies, like multicolor 3DP and FDM AF may provide alternative ways for the fabrication of drug-delivery devices like oralseem to be the most suitable choice. Another tablets. Rowe et al.  presented an application of 3DP technology for the fabrica-tion of oraladvantage of these two technologies is that devices where two different release mechanisms, erosion and diffusion, are mixed in a singlethey are office-friendly and can process device. Other possible applications are tablets with a quick dissolve region that break into biocompatible materials with some minor controlled subunits and pulsatory devices. The SLS process has been also used for themodifications. Further reduction in the fabrication of porous cylindrical disc matrices that may be used as drug delivery devices by fabrication time involved can be achieved Low et al. . They reported that it is possible to use SLS for producing drug-delivery devices through higher automation of the medical that have variable porosity and micro-features. Leong et al.  investigated the possibility ofimaging data manipulation process that is building biodegradeable controlled drug-delivery devices with SLS. Their experi-ments withrequired for the construction of the virtual PCL and PLLA as test materials showed that varying porosity discs can be produced by model. The virtual model construction phase controlled variance of SLS fabrication parameters. 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
8 Discussion and concluding remarks
In this paper, applications of AF/RP technologies in medicine and current SLS technology has the greatest research issues in the field of rapid medical prototyping are presented. The potential among commercial RP review of the international specialized literature showed that customtechnologies or direct fabrication of biomodels fabricated with RP technologies are quite useful for planning and implants. This is mainly due to the fact the rehearsal of complex surgical operations. According to the results of that SLS can fabricate implants from a most studies, RP biomodels aid the surgeons in diagnosis, planning, problem variety of materials including metals, prediction and communication, thus reducing operation time infection riskceramics and thermoplastics with sufficient accura-cy. In this context, the and improving the results of the operation.
Among the RP technologies applied to medicine, SL seems to have attracted the attentionmain research issue is to develop and of most researchers. SL is not only relatively more accurate but also the number of installed SLtest materials that are biocompatible so systems worldwide is very big. Also, SL resins provide the advantage of biomodel clarity andthat can be used safely for direct transparency that can be quite useful in surgery rehearsal. However, they are notfabrication of implants. biocompatible and require special handling; a fact that makes adoption of SL systems in the biomodels makes them ideal as casting patterns for the fabrication of customized hospital environment difficult. Both the accuracy and the low surface roughness of SL scaffolds
Fabrication of custom-made is another appli-cation 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
Due to adverse materials properties direct fabrication is mostly directed to hard-tissue scaffolds (bone tissue
engineering). As far as the fabrication of soft-tissue scaffolds new manufacturing methods thattechnologies apply the principles of AF are currently under development. These new methods employavailability
mostly the jet-printing or deposition operational principles for the construction of layers fromsystems (Bio-CAD) that enable design and biocompatible or biodegradable materials. An aspect that should be considered in scaffoldmanipulation of the relatively complex geomfabrication with powder based RP technologies is the removal of trapped material within the etries of scaffolds. Scaffolds also present a scaffold (trapped volume problem). Also, the minimum grain size sets a limit in the porositychallenge in 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
Int J Adv Manuf Technol (2009) 40:116–127 terms of virtual representation that cannot be easily manipulated by currently available industrial CAD systems. 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 support-ing 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. Although RP is faster and more flexible than other manufacturing methods (e.g., CNC machining) it 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 up to 2 days, which may be 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 fabrica-tion applications, e.g., for orthopedic 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 surgical operation itself . Considering, therefore, these compensating costs, the initial investment cost in RP may be well justified. Regarding 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.
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