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INTRODUCTION
The rapid development of medical imaging modalities such as computed tomography (CT), magnetic resonance imaging (MRI), and various ultrasonic apparatuses has provided improved patient-specific anatomy information while reducing diagnostic invasiveness (12). With the help of advanced image post-processing technologies (34), radiological techniques can be combined with a variety of tools, such as multiplanar reformation, three-dimensional (3D) visualization, and image navigation, which is pivotal in both diagnosis and treatment (4). The advent of 3D printing (3DP) technology, sometimes called rapid prototyping (RP), has provided a more advanced tool with an intuitive and tangible 3D fabricated model that goes beyond a simple 3D-shaded visualization on a flat screen (5).
For its use in medical fields, the most important of the many advantages of 3DP technology is the "zero lead time" between design and final production. Furthermore, compared with industrial approaches, 3D model design for 3DP medical applications is easier, because most can be acquired using 3D surface reconstruction of medical images with the help of image post-processing. In the clinical setting, the possibility of one-stop manufacturing from medical imaging to 3DP has accelerated the recent medical trend towards "personalized" or "patient-specific" treatment. Secondly, 3DP, as an additive manufacturing technology (6), exhibits the characteristics of "zero constraint and zero skill" for 3D fabrication, which are perfect for medical applications, because the shape of 3D models derived from patient-specific medical images is usually too complex to be manufactured by conventional fabrication methods. Hence, 3DP machines have since the early 2000s been used in a variety of medical applications. The technique has been used mainly for hard tissue applications due to the hardness of most 3D printable materials (7).
The cost of 3DP systems has decreased recently because several 3DP mechanisms have become off-patent. Moreover, as 3D printable multi-materials with transparent, full-colored, and flexible characteristics are now commercially available, 3DP technologies have been applied to various fields of medicine, including personalized treatment, medical research, and premedical education, for both soft and hard tissues (78910). The present article discusses the generation of 3D reconstructed models, covering medical imaging, the post-processing of 3D models, and the recent developed 3DP systems, and reviews various related medical applications, especially those that use the recently commercialized 3DP technologies and multi-materials.
3D Modeling from Medical Images and Computer-Aided Design
For medical use, after patient scanning by CT and/or MRI, the DICOM data can be exported and processed into stereolithography data files such as stereolithography or other 3D file formats by using segmentation, surface extraction, and 3D model post-processing. Less than a 1-mm CT slice thickness and voxel with isocubic spacing are recommended. The time required depends mainly on the clinical application. In particular, segmentation is a vital procedure for improving the overall accuracy and requires considerable time. No satisfactory fully automated medical image segmentation algorithms have been developed. Therefore, manual or semi-automated segmentation algorithms have generally been used, which have increased the importance of operator experience. After segmentation, a surface model should be generated by a marching cube (1112) or other 3D contour extraction algorithm (13). For medical visualization, these types of shaded surface display techniques are well developed. However, this 3D model itself is not good enough for 3DP, due to, for example, too many mesh units and incomplete topological soundness. Therefore, topological correction (14), decimation (15), Laplacian smoothing (16), and local smoothing (17) are needed to create a 3D model for 3DP. In addition, virtual simulation, including determination of the entry point and direction of the screw and surgical line, is performed for patient-specific surgical planning. Based on such planning, surgical guides are designed using computer-aided design (CAD) software. After generation of a 3D model, the most suitable 3D printer for the application should be selected. The 3D model file is uploaded into the 3D printer. The 3D printer uses layer-by-layer stereolithographic accumulation to fabricate the 3D physical model. The overall procedure is presented in Figure 1. In general, the accuracy of the 3DP object depends on the combination of the accuracy of the medical image, which should be as thin as possible, the appropriate imaging process for 3D modeling, and the 3DP accuracy of the system.
3DP Systems for Medicine
The 3DP technology used in medicine (18) can be classified by the technique, the material, or the aimed deposition process used. The technical type classification includes stereolithography apparatus (SLA), multi-jet printing (MJP), PolyJet printing, digital light processing (DLP), selective laser sintering (SLS), direct metal laser sintering (DMLS), color-jet printing (CJP or binder-jet), fused deposition modeling (FDM), laminated object manufacturing, and electron beam melting. The material classification includes thermoplastic, metal powder, ceramic powder, eutectic metals, alloy metal, photopolymer, paper, foil, plastic film, and titanium alloys. The aimed deposition process classification includes PolyJet printing based on drop-on-drop deposition and FDM based on continuous deposition. We briefly summarize the 3D printers applicable to the medical field in Table 1.
The liquid-based 3DP technology of SLA is the most widely used 3D technique for surgery and was first applied to grafting of a skull defect in 1994 (19). The SLA system consists of a bath of photosensitive resin, a model-building platform, and an ultraviolet (UV) laser for curing the resin (Fig. 2). A computer-controlled mirror is used to focus the UV laser onto the surface of the resin and cure the resin on a slice-by slice basis. These slice data are fed into the RP machine, which directs the exposure path of the UV laser onto the surface of the resin. The layers are cured sequentially and bind together to form a solid object, beginning from the bottom of the model and building upward. Each new layer of resin is wiped across the surface of the previous layer using a wiper blade before being exposed and cured. The model is then removed from the bath and cured for a further period in a UV cabinet (18). Generally, SL is considered to provide the greatest accuracy and best surface finish of any RP technology. The model material is robust, slightly brittle, and relatively light (2021). Choi et al. (20) found that the absolute mean deviation between an original dry skull and an SLA model over 16 linear measurements was 0.62 ± 0.5 mm (0.56 ± 0.39%) (22). Schicho et al. (22) compared the accuracy of CT and SL models. The accuracy for SL models expressed as the arithmetic mean of the relative deviations ranged from 0.8% to 5.4%, with an overall mean deviation of 2.2%. The mean deviations of the investigated anatomical structures ranged from 0.8 mm to 3.2 mm. An overall mean of deviations (comprising all structures) of 2.5 mm was found.
The liquid-based 3DP technology of MJP uses a print head to disperse an acrylic photopolymer (part) and wax (support) simultaneously. The injected materials are cured by UV light (Fig. 3). In the front view of the equipment, material is injected to the assigned location while the tray moves backward and forward, and they are stacked layer-by-layer in the z-axis. MJP is the highest-precision 3DP technique. The transparency of the main material of the acrylic photopolymer resins can be controllable but its strength is relatively weak. In addition, shape deformation occurs at 65 degrees or more.
PolyJet printing is performed by jetting state-of-the-art photopolymer materials in ultra-thin layers of 16 µm onto a build tray layer-by-layer until the model is completed. Each photopolymer layer is cured by UV light immediately after it is jetted, producing fully cured models that can be handled and used immediately without post-curing (Fig. 4). A gel-like support material that is specially designed to maintain complicated geometries and is easily removed by hand and water jetting is used (18). In fact, there is little difference between the MJP and PolyJet methods. PolyJet printing can avail of a variety of materials, including a rubber-like material, and its post-processing stage is shorter and simpler. At present, this technique is overly time consuming and, therefore, too expensive to be used in surgical applications. Ibrahim et al. (23) reported a dimensional error of 2.14% when reproducing a dry mandible using this technique (23).
The liquid-based 3DP method of DLP uses a conventional DLP projector as a light source. In the first step, it projects a two-dimensional (2D) image into a light-curable resin in a vat (Fig. 5). This method shows excellent surface finish and the fastest printing. The mechanical properties of the used material are good but the type of material and its color are limited. Moreover, the material and printing system are expensive.
The powder-based 3DP technology of SLS uses a CO2 laser beam to selectively fabricate models in the following way. First, the 2D slice data are fed into the SLS machine, which directs the exposure path of the laser over a thin layer of powder previously deposited on the build tray and leveled with a roller (Fig. 6). The laser heats the powder particles, fusing them to form a solid layer, and then moves along the X and Y axes to design the structures according to the CAD data. After the first layer fuses, the build tray moves downward, and a new layer of powder is deposited and sintered. The process is repeated until the object is completed. The prototype surface is finished by sandblasting (18). The SLS prototype is opaque, and its surface is abrasive and porous. The prototype fabrication time is 15 hours. The accuracy of the SLS model is relatively high, with maximum standard errors of 0.1 to 0.6 mm. Because of the high cost of the materials, several parts are fabricated simultaneously. The long fabrication time for the SLS technique (16 hours) is similar to that required for fabrication with the SL system (24). The equipment is expensive, but a low-cost SLS system (Norge Company, Seynod, France) was recently developed due to patent expiration.
The powder-based 3DP method of the DMLS technique uses a solid-state Yb fiber laser beam to selectively fabricate models in the following way (25). DMLS was first developed by the EOS Company. The method is similar to that of SLS (26) and selective laser melting, with the exception of the melting degree of the material; small variations result in marked alteration of the characteristics of the material. A variety of materials–such as aluminum, cobalt, steel, nickel alloy, stainless steel, and titanium–can be used in DMLS. Because the powder used plays a role in supporting the model, post-processing, including supporter removal, is not needed. In addition, its printing quality is generally excellent.
The CJP method uses a print head to selectively disperse a binder onto powder layers. This technology has a lower cost than similar techniques. First, a thin layer of powder is spread over a tray using a roller, similar to that used in the SLS system (Fig. 7). The print head scans the powder tray and delivers a continuous jet of a solution that binds the powder particles as it touches them. No support structures are required while the prototype is being fabricated, because the surrounding powder supports the unconnected parts. When the process is complete, the remaining surrounding powder is aspirated. In the finishing process, the prototype surfaces are infiltrated with a cyanoacrylate-based material to harden the structure (24). The printing technique enables the formation of complex geometrical structures, such as hanging partitions inside cavities, without artificial support structures (18). Because it uses a CMYK color ink cartridge, as used in conventional 2D printers, the 3D fabricated object can be printed with an almost identical range of color. The printing and infiltration processes require ~4–6 hours. The 3D printers used in this process are relatively inexpensive (25000 British pound [GBP]), have fast build times (4 hours for a full skull), and are easy to maintain. Additionally, these 3D printers are cost effective (1 GBP/cm3), associated with low waste, accurate (± 0.1 mm in the Z plane, ± 0.2 mm in the X and Y planes), have small dimensions, and can produce hard, soft, and flexible models. These printers can also be used to identify different types of body tissue depending on the predefined threshold setting selected. Silva et al. (24) reported a mean dimensional error of 2.67% in prototypes produced using 3DP technologies compared with a dry human skull (24).
The solid-based 3DP technology of FDM uses a similar principle to SL in that it builds models on a layer-by-layer basis. The main difference is that the layers are deposited as a thermoplastic that is extruded from a fine nozzle. A commonly used material for this procedure is acrylonitrile butadiene styrene (ABS). The 3D model is constructed by extruding the heated thermoplastic material onto a foam surface along a path indicated by the model data (Fig. 8). Once a layer has been deposited, the nozzle is raised by between 0.278 to 0.356 mm and the next layer is deposited on top of the previous layer. This process is repeated until the model is completed (18). As with SL, support structures are required for FDM models because time is needed for the thermoplastic to harden and the layers to bond together (27). The supports can be removed by a simple tool or can be dissolved using a special acidic solution. Although it is the most popular 3D printer technology, the surface finish is relatively poor. Hence, several post-processing options, including acetone fumigation, can be used.
Medical Applications
Since the early 2000s, 3DP technologies have been used in a variety of medical fields, from 3D phantoms for simulation to bioprinting of organs. The former can be used in personalized treatments that take into account patient-specific anatomical variations. Personalized treatment makes use of 3DP in surgical planning and simulation, surgical guidance, and implantable device creation. 3DP has also been used in various scientific studies in the biomedical field. Personalized or disease-specific 3DP phantoms can be used to better understand physiological problems. Finally, 3DP has been used for educational and training purposes.
Applications for Personalized Treatment
Surgical Planning and Guidance Tools
In surgical planning and operating processes for personalized treatment, 3D-printed patient-specific phantoms and surgical guides have recently been used increasingly frequently to enhance understanding complex procedures and to simplify the operating procedure. These phantoms assist diagnosis and pre-surgical planning. In addition, 3DP surgical guides made of temporary biocompatible materials can be attached to the surface of the hard or soft organ by 3D modeling of the surgical interface through the pre-surgical planning. To date, the benefit of 3DP for surgical planning and as a guidance tool has been demonstrated in various hard tissue surgical applications, such as craniofacial and maxillofacial surgery (282930313233), spine surgery (34), cardiovascular surgery (3536), neurosurgery (3738), pelvic surgery (3940), and visceral surgery (41).
Recently, as transparent, full-color, and flexible 3D printable materials have become available, the level of realism of the 3D phantoms for surgical planning and treatment of soft organs has improved significantly. Increased diversity due to improved transparency, color, and softness facilitates improved comprehension of complex 3D anatomical structures and guidance functions for soft tissues (42). Yang et al. (43) used a full-colored and flexible 3DP phantom as a pre-planning simulator for extended septal myectomy. From the cardiac CT data, a myocardial 3D model was generated using in-house software (A-view Cardiac; Asan Medical Center, Seoul, Korea). Using a 3D printer (Connex3 Objet500; Stratasys Corporation, Rehovot, Israel), the left ventricular (LV) myocardium, papillary muscle, and intraventricular muscle band (including accessory papillary muscle) were manufactured using differently colored materials, whose flexibility could be controlled by adding a rubber-like and transparent material (Fig. 9). The authors stated that the 3DP phantom provided intuitive information on the LV geometry, including the extent of the hypertrophied septum, and the location and length of the papillary muscle and intraventricular muscle band, which enabled preoperative simulation of the surgical myectomy.
Transparent 3D printed kidney phantoms have been used to enhance preoperative planning and intraoperative orientation of risk structure and target tissue in partial nephrectomy. All renal units with renal mass were modeled using in-house software (A-view; Asan Medical Center, Seoul, Korea), which also provides information on the renal anatomy, mass, and volume (Fig. 10). The virtual resection simulation followed an adequate safety margin with –5 mm distance from the renal mass. 3D-printed kidney phantoms were fabricated using a 3D printer (Connex3 Objet500; Stratasys Corporation, Rehovot, Israel). The 3DP phantoms were used to improve surgical outcome and may also improve the patient's understanding of their disease and improve satisfaction.
Even the softest 3D printable materials cannot be directly used as surgical simulators because they are too hard for scalpel incision and suturing. Therefore, additional post-processing using gelatin or silicon molding techniques or a novel 3DP system that can directly jet a variety of silicon materials needs to be developed.
Implantable Devices
Three-dimensional printing techniques are also used in implant design to create patient-specific prostheses, which open new treatment opportunities for patients outside the standard range of ready-made commercial implants. In addition, this approach has improved surgical performance by enabling the creation of patient-specific anatomy-based implants (7). For hard tissue structures, metal implants have, in particular, been successfully used for various applications (4445), most of which were Food and Drug Administration approved, such as mandible (33) and dental (46) restoration and hip (47), femoral (48), and hemi-knee joint reconstruction (4445). In addition, the biocompatible ceramic hydroxyapatite (49) and the biodegradable polymer polycaprolactone (50) have been used in 3DP-based applications to replace hard tissues with customized implants.
Beyond hard tissue applications, customized implants created using 3DP have recently been used in the interventional field. Amerini et al. (51) demonstrated the feasibility of a personalized interventional treatment for tricuspid regurgitation using a braided stent in an animal study. Using cardiac CT data, a 3D reconstructed model of the right-sided cardiac cavities of a pig was obtained (OsiriX® Imaging Software; Pixmeo, Switzerland). A solid Alumide® mold was manufactured using a 3DP system and a personalized compressible nitinol stent was then subsequently produced and fitted onto the 3DP mold (Fig. 11). This customized stent was almost completely fitted onto the right atrium and an additional tubular stent component containing a tissue valve prosthesis was developed. From the feasibility study conducted in animals, they found that the 3DP-based stent could stabilize the biological valve prostheses by force transmission from the annulus to the atrial wall and the adjacent vena cava.
Another example of a 3DP-based medical implantable application is the use of medical-grade silicon material for soft tissue. Figure 12 shows a pilot study to develop a patient-specific soft implant for filling a dead zone of lung after pneumonectomy. From the CT data, the volume of the dead zone was three-dimensionally reconstructed (A-view, Asan Medical Center). In this pilot study, a 3D printer system (Fortus 250 mc, Stratasys Corporation, Eden Prairie, MN, USA) was used to manufacture the patient-specific phantom of the dead zone, which was used as a mold to produce a negative mold with silicon material. The final dead zone phantom with silicon material was cast by using the negative mold and the softness of the 3D-printed material was evaluated by clinicians. In the near future, the final implantable device could be manufactured using a medical-grade silicon material through an additional molding process and evaluated in a prospective clinical trial.
In this article, only clinical applications that can be realized by the already developed 3DP technologies are discussed, but there are other approaches for personalized implants, including bio-printing of tissues and organs (105253) and organ-on-a-chip (5455).
Phantom Fabrications for Medical Research
For better understanding of complex pathologies, a variety of in vitro and ex vivo studies have investigated phantoms fabricated by 3DP (56575859). These tangible 3DP phantoms themselves provide more intuitive information than mere 3D visualizations. Furthermore, various in vitro studies have been more beneficial, such as for assessing the hemodynamics or aerodynamics of cardiovascular or airway diseases (6061), because abnormal interactions between fluids and organs in a disease model can be delicately investigated through patient-specific fluid phantom studies. The detailed fluid dynamic information, including that of disease models, provided by these experimental studies may also facilitate postoperative simulation for clinicians.
A 3D compliant model mimicking the elastic properties of vessels has also been manufactured using silicon or polyurethane material (3562). Recently, a descending aortic dissection phantom fabricated by 3DP used a two-mold process to mimic the intimal flapping motion of aortic dissection (6364). From the CT data, a 3D reconstructed model of descending aortic dissection was generated and modified to manufacture a 3DP mold for silicon casting (Fig. 13). A 0.5 mm layer was first cast on the true lumen mold, and the second casting was then performed over the initial cast to produce the false lumen. Four-dimensional flow MRI was used to quantitatively measure the local velocity profiles of both lumens.
In addition, a fluid dynamic study of paramedian pontine infarction caused by atheroma obliteration of the perforators of the basilar artery (BA) was performed. Using the MRI data, a stenotic BA model was generated using dedicated software (A-view; Asan Medical Center) and was then 3D printed with ABS thermoplastic material by a 3DP system (Fortus 400 mc; Stratasys Corporation) (Fig. 14). The 3DP BA phantom was cast with a polydimethylsiloxane (PDMS) silicone compound, and then the ABS material was dissolved out from the PDMS in acetone. The fabricated PDMS phantom with a hollow BA artery morphology was applied to a fluid dynamic experiment using particle image velocimetry, which is a quantitative velocity field measurement technique that uses optical scanning. This experimental study verified the hypothesis (65) that perforator infarction can be caused by a hemodynamic mechanism that is triggered by stenosis-induced recirculation flow in the poststenotic area.
Simulation for Medical Education and Training
Traditionally, human cadavers have been used to teach students anatomy and the morphological relationships of various organs in medicine. Using this approach, however, it is difficult to accumulate sufficient experience of surgery for a variety of diseases. Assisting and observing surgical operations gives a trainee indirect experience, but this approach is insufficient to improve operating skills and intuitive understanding of complex pathologic and disease-specific anatomical details, especially in surgeries that use laparoscopy and endoscopy. Hence, many trainees must develop their surgical skills during real surgical procedures. In addition, it is increasingly difficult to dissect human cadavers or observe medical treatment, for such reasons as cultural disapproval of dissection of the human body and enhanced patient rights.
Patient-specific 3D models fabricated by the 3DP system have been used to train young surgeons in surgical procedures, including bone surgery (66), endovascular stent implantation (35626768), and ex vivo biliary drainage surgery (59). The recently developed multi-material 3DP technology provides more realistic phantoms that mimic real hard and soft tissues (6970). Waran et al. (69) used multi-material neurosurgical phantoms with a pathological entity with varying consistencies and densities for their trainees (Fig. 15). Based on the CT data, in-house software (Biomodroid; CBMTI, Universiti of Malaya, Malaysia) was used to generate a 3D reconstructed model of the skin, bone, dura, and tumor and manufactured 3DP phantoms using a 3D printer (Objet500; Stratasys Corporation, Rehovot, Israel). They stated that their trainees could practice the basic steps from navigation and planning of skin flaps to the initial steps in a craniotomy and simple tumor excision. Similarly, a 3DP phantom for training in the transcatheter aortic valve implantation (TAVI) procedure was demonstrated (Fig. 16). From the cardiac CT data, LV with a calcified bicuspid aortic value and aorta covering the catheterization root was reconstructed in 3D using dedicated software (A-view Cardiac; Asan Medical Center). Using a 3D printer (Connex3 Objet500; Stratasys Corporation), a 3DP phantom with multi-materials was manufactured in which the soft tissue of the aorta and leaflet was composed of flexible material and the calcification comprised hard material for a more-accurate representation of the in vivo situation. Catheterization intervention using a TAVI (SAPIEN; Edwards Lifesciences Corporation, Irvine, CA, USA) was simulated using the fabricated 3DP phantom.
In addition, a 3DP phantom with multi-materials could provide trainees and/or surgeons with various educational and/or rehearsal simulators based on both patient-specific and disease-specific anatomy. By training and/or rehearsing with these simulating phantoms, trainees and/or surgeons may gain confidence before performing real operations.
Discussion and Conclusion
With the development of inexpensive 3D printers, 3D printable multi-materials, and 3D medical imaging modalities, 3DP medical applications have come into the spotlight. Due to the availability of transparent, full-colored, and flexible multi-materials, 3DP objects can be more realistic, mimicking the properties of the real body; i.e., not only hard tissue alone but also hard and soft tissue together.
Regarding applications for personalized medical treatments, 3DP multi-materials could provide a flexible LV phantom for pre-planning of extended septal myectomy (43) and kidney phantoms for a partial nephrectomy simulator. Beyond a surgical guide for hard tissue (30), a surgical guide with flexible material could be used in partial carcinectomy of soft organs. Regarding implantable devices, a recent study showed that 3DP-based personalized stents could be used for tricuspid regurgitation (51). In addition, a patient-specific flexible implant for filling a dead zone in the lung after pneumonectomy with a nonmedical-grade silicon material was developed. It is expected that a final implantable device composed of a medical-grade silicon material could be manufactured by means of an additional molding process. Fabrication of a phantom using a variety of 3DP methodologies for various biomedical research applications would also be useful. By applying a two-mold process to a fabricated 3DP phantom, a flow phantom constructed for descending aortic dissection that mimics the intimal flapping motion could be manufactured (63). Through this patient-specific in vitro phantom study, detailed hemodynamic information on the aortic intima layer could be acquired, which would facilitate postoperative simulation for clinicians. 3D-printable multi-materials have been used to manufacture various educational phantoms. A recent neurosurgical phantom was capable of mimicking the skin, bone, dura, cerebral parenchyma, and tumor using a mixture of soft and hard materials of various colors (69). A more-realistic material is needed to mimic a variety of real soft tissues, but this limitation can be resolved by a hybrid of the 3DP and molding techniques and using materials with enhanced properties (elasticity, tensile strength, compression strength, and fatigue failure). For trainees, these 3DP educational phantoms would play an important role in filling the gap between preclinical studies and real surgery.
Despite the substantial increase in the number of 3DP medical applications, several major limitations, such as those associated with the technology and the time and cost of manufacturing 3D phantoms, remain to be overcome. Development and optimization of the entire procedure, from image acquisition to 3DP fabrication, are required for personalized treatment, even in emergency situations. In addition, it is important to select a specific medical situation with a clear clinical implications, so that the additional costs of 3DP are outweighed by the improved rate of success and shortened operative duration. Furthermore, to produce an effective 3DP object, multidisciplinary knowledge of the entire 3DP process chain is needed; namely, image acquisition using a protocol suitable for 3D modeling, post-processing of the medical images to generate a 3D reconstructed model, 3DP manufacturing with an appropriate 3DP technique, and post-processing of the 3DP object to adapt it for medical use. We did not focus on bio-printing in this review due to a lack of radiologic relevance, but the developing technologies of bio-printing for tissues and organs (105253) and organ-on-a-chip (5455) should be noted.
In this article, we illustrate the practical medical applications of 3DP based on currently available 3DP technologies. It is hoped that this review article will enhance understanding of the various 3DP medical applications and facilitate their incorporation into clinical practice.
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