3D Printed Models in Cardiovascular Disease: An Exciting Future to Deliver Personalized Medicine

3D printing has shown great promise in medical applications with increased reports in the literature. Patient-specific 3D printed heart and vascular models replicate normal anatomy and pathology with high accuracy and demonstrate superior advantages over the standard image visualizations for improving understanding of complex cardiovascular structures, providing guidance for surgical planning and simulation of interventional procedures, as well as enhancing doctor-to-patient communication. 3D printed models can also be used to optimize CT scanning protocols for radiation dose reduction. This review article provides an overview of the current status of using 3D printing technology in cardiovascular disease. Limitations and barriers to applying 3D printing in clinical practice are emphasized while future directions are highlighted.

The use of 3D printed models in maxillofacial and orthopedics is well-explored in the literature, and its value in cardiovascular disease is showing great promise and potential to change the current practice [1,7,8,[11][12][13][14][16][17][18][19][20]. Increasing evidence has shown that the use of 3D printing in cardiovascular disease has overcome limitations that are inherent in the current image visualizations, thus playing an important role in many aspects, from education to clinical practice [6,7,11,[16][17][18][19][20]. Patient-specific 3D printed models can enhance medical and patient education and understanding of complex anatomy and pathology by demonstrating realistic spatial relationships in various cardiovascular diseases, planning or simulating complex cardiovascular procedures, and training or guiding junior or inexperienced doctors to perform cardiovascular interventional procedures so that their confidence or skills will be improved. Further, 3D-printed personalized models can be used to optimize cardiac CT imaging protocols with the aim of reducing radiation exposure to patients. With advancements in 3D printing technology, including both printers and printing materials, it is feasible to print 3D models with materials like tissue properties of the cardiovascular system, therefore, further augmenting its applications in the cardiovascular

Processes from Image Post-Processing to 3D Printed Models
It has been well described in the literature regarding the steps or processes to generate 3D printed models using CT or MRI (sometimes using echocardiography) imaging datasets [1,7,14]. Briefly, good quality imaging data with a high spatial resolution is an essential component for image post-processing and segmentation to create 3D volumetric data, as the quality of source data has a direct impact on the quality and accuracy of 3D

Processes from Image Post-Processing to 3D Printed Models
It has been well described in the literature regarding the steps or processes to generate 3D printed models using CT or MRI (sometimes using echocardiography) imaging datasets [1,7,14]. Briefly, good quality imaging data with a high spatial resolution is an essential component for image post-processing and segmentation to create 3D volumetric data, as the quality of source data has a direct impact on the quality and accuracy of 3D printed models. This is especially important for producing 3D-printed heart or vascular models for demonstrating fine details or structures such as cardiac defects or coronary artery abnormalities [7,14]. Figure 2 is a flow chart showing the steps to create a 3D reconstruction model for printing a physically realistic model of a coronary artery [21]. There is no standard requirement for software tools to perform images segmentation, although commercially available software such as Mimics (Materialise Leuven, Belgium), MeVislab (Mevismedical Solutions, Bremen, Germany) and Analyze 12.0/14.0 (AnalyzeDirect, Inc, Lexana, KS, USA) are the commonly used packages for image post-processing and segmentation. Open source software tools such as 3D Slicer and ITK-SNAP are reported to create a 3D printed heart and vascular models with high accuracy [22].
Micromachines 2022, 13, x FOR PEER REVIEW 3 of 36 printed models. This is especially important for producing 3D-printed heart or vascular models for demonstrating fine details or structures such as cardiac defects or coronary artery abnormalities [7,14]. Figure 2 is a flow chart showing the steps to create a 3D reconstruction model for printing a physically realistic model of a coronary artery [21]. There is no standard requirement for software tools to perform images segmentation, although commercially available software such as Mimics (Materialise Leuven, Belgium, MeVislab (Mevismedical Solutions, Bremen, Germany) and Analyze 12.0/14.0 (AnalyzeDirect, Inc, Lexana, KS, USA) are the commonly used packages for image post-processing and segmentation. Open source software tools such as 3D Slicer and ITK-SNAP are reported to create a 3D printed heart and vascular models with high accuracy [22]. Steps to generate 3D printed models through image post-processing and segmentation of coronary CT images to extract the ascending aorta and coronary tree from the original volume data to STL file for printing 3D model. Reprinted with permission under open access from Sun [21].

3D Printers and Printing Materials
Once image segmentation is done, the Standard Tessellation Language (STL) file is sent to a 3D printer for printing a physical model. Several 3D printers and printing materials are available in the market, allowing for printing either flexible or rigid cardiovascular models, depending on the preference of the nature of the study. Fused deposition modeling (FDM), Stereolithography (SLA), selective laser sintering (SLS) and Polyjet printers are commonly used in most of the studies and readers are referred to several nice review articles for details [1,7,21,23]. Steps to generate 3D printed models through image post-processing and segmentation of coronary CT images to extract the ascending aorta and coronary tree from the original volume data to STL file for printing 3D model. Reprinted with permission under open access from Sun [21].

3D Printers and Printing Materials
Once image segmentation is done, the Standard Tessellation Language (STL) file is sent to a 3D printer for printing a physical model. Several 3D printers and printing materials are available in the market, allowing for printing either flexible or rigid cardiovascular models, depending on the preference of the nature of the study. Fused deposition modeling (FDM), Stereolithography (SLA), selective laser sintering (SLS) and Polyjet printers are commonly used in most of the studies and readers are referred to several nice review articles for details [1,7,21,23].
The selection of appropriate printing materials is also important to ensure that the 3D printed heart and vascular models serve the purpose of different utilizations. In addition to printing multi-color models, mechanical properties need to be considered for producing realistic cardiovascular models to simulate similar tissue properties in terms of modulus of elasticity. In previous studies, TangoPlus FLX930, TangoGray TM and TangoBlack TM (Stratasys) are reported to produce 3D printed heart and vascular models with soft and elastic features [24]. Recent research has shown that Visijet CE-NT (3D Systems Inc., Wilsonville, OR, USA) has the same tissue properties as cardiac tissues with similar CT attenuation; thus, it is more suitable for the 3D printed heart and vascular models ( Figure 3) [25]. The selection of appropriate printing materials is also important to ensure that the 3D printed heart and vascular models serve the purpose of different utilizations. In addition to printing multi-color models, mechanical properties need to be considered for producing realistic cardiovascular models to simulate similar tissue properties in terms of modulus of elasticity. In previous studies, TangoPlus FLX930, TangoGray TM and Tan-goBlack TM (Stratasys) are reported to produce 3D printed heart and vascular models with soft and elastic features [24]. Recent research has shown that Visijet CE-NT (3D Systems Inc., Wilsonville, OR, USA) has the same tissue properties as cardiac tissues with similar CT attenuation; thus, it is more suitable for the 3D printed heart and vascular models ( Figure 3) [25].

Education Value of 3D Printed Models in Cardiovascular Disease
3D printed models are increasingly used in medical education, with promising results achieved when compared to traditional teaching methods. Studies have shown its educational value in two areas as assessed by medical students and clinicians (cardiothoracic surgeons, cardiologists, cardiac imaging specialists including radiologists and radiographers, residents or registrars, and clinical nurses) [26][27][28][29][30][31][32][33][34][35][36][37][38][39]. Table 1 summarizes studies reporting the medical education of 3D printed models compared to traditional teaching methods or other advanced tools.

Education Value of 3D Printed Models in Cardiovascular Disease
3D printed models are increasingly used in medical education, with promising results achieved when compared to traditional teaching methods. Studies have shown its educational value in two areas as assessed by medical students and clinicians (cardiothoracic surgeons, cardiologists, cardiac imaging specialists including radiologists and radiographers, residents or registrars, and clinical nurses) [26][27][28][29][30][31][32][33][34][35][36][37][38][39]. Table 1 summarizes studies reporting the medical education of 3D printed models compared to traditional teaching methods or other advanced tools. Garas et al. [26] Cross-sectional study Twenty-three students from first-year health science courses (n = 11) and third-year human biology preclinical courses (n = 12). All participants were exposed to plastinated, 3D-printed models and cadaverous specimens.

MRI and CT
3D printed models of heart, shoulder and thigh NR NR Resin 3D printed models have the potential to assist students in anatomy learning when compared to traditional teaching methods: 3D printed models were scored to be easiest to identify anatomical features than others (p<0.001). 3D printed models received the highest percentage of the preferred method of learning anatomy compared to cadavers and plastinated models (45% vs. 36% and 18%, p < 0.001).
Lau & Sun [27] Cohort study  3D printed models significantly increased the interventional group's objective tests assessing anatomy of rings and slings (p = 0.001), diagnosis of rings and slings (p< 0.001) and treatment of rings and slings (p< 0.001). While the total improvement from pre-to post-test scores did not reach statistical significance, the intervention group received the highest average score increase than the control group after the lecture (2.6 vs. 1.8, p = 0.084). NR NR 3D printed models gave higher composite learner satisfaction scores (p = 0.03). The 3D printed model group also had higher self-efficacy aggregate scores, but the difference was not statistically significant (p = 0.39). No significant difference in preand post-test scores was found in knowledge acquisition between 2D images and 3D printed models (p > 0.05).
Valverde et al. [35] Nonrandomized cross-over study One hundred and twenty-seven participants (consultants in pediatric cardiology, fellows in pediatric cardiology, and medical students) were randomly distributed into four groups (Groups 1-4) and shown as specific crisscross heart cases (Cases 1-4). Conventional imaging teaching and 3D printed models were presented to each group.

Echocardiography and CMR
Crisscross heart is one of the most complex and extremely rare forms of congenital heart disease. All 3D printed models were based on the four patient-specific CMR datasets. 3D printed models significantly improved crisscross heart anatomy (p < 0.001). The increase in the questionnaire marks was statistically significant across all academic groups (p < 0.05). Ninety-four percent (120) and 95.2% (121) of the participants agreed or strongly agreed, respectively, that 3D models helped them to better understand the medical images of cardiac anatomy. The average score of overall satisfaction for 3D printing was 9.1 out of 10, with students providing the highest scores than clinical fellows (9.7 vs. 8.6).
White et al. [36] Randomized controlled trial Sixty pediatric and emergency medicine residents participated in 2 studies based on pathology (VSD and ToF). Twenty-six were in a VSD study ( There does not seem to be an added benefit for understanding VSDs (the control group scored higher than the intervention group [p = 0.012), but there is for ToF (the interventional group scored higher than the control group, p = 0.037). This is likely due to the increased complexity of the lesion and difficulty visualizing spatial relationships in CHD with multiple components. Randomized controlled trial One hundred and thirty-two nursing students in congenital heart surgery were randomly divided into the 3D printing group (n = 66) or traditional group (n = −66). Both groups were exposed to the same teaching environment with 3D printed model incorporated into the 3D printing group. NR 3D printed model of a patient-specific case of ASD NR NR NR In the classroom assessment of theoretical knowledge, the 3D printing group scored significantly higher than the traditional group, with corresponding sores being 7.08 ± 1.66 and 6.56 ± 1.17, respectively (p = 0.02). The 3D printing group scored significantly higher than the traditional group in the self-evaluation of comprehensive ability and teaching satisfaction score (p < 0.05). Similarly, the 3D printing group scored significantly higher than the traditional group in the critical thinking ability assessment (p < 0.05).

Biglino et al. [38]
Crosssectional study One hundred nurses (65 pediatric cardiac nurses and 35 adult cardiac nurses) attended a training course about CHD.

NR
Nine models were created, including: a healthy heart, repaired transposition of the great vessels, ToF, pulmonary atresia with an intact ventricular septum and palliated hypoplastic left heart syndrome.

NR NR NR
The majority of the nurses indicated that 3D printed models helped them to understand cardiac anatomy (86%), spatial orientation (70%) and anatomical complexity after treatment (66%). The 3D printed models were rated as useful by the cardiac nurses, with an average score of 5.1 out of 7.
Liang et al. [39] Crosssectional study Eight CHD cases were 3D printed with clinical values assessed by two groups: one group including 40 experts (20 cardiac surgeons and 20 sonographers); another group consisting of 40 3rd year postgraduate students.
CT Diagnostic value of 3D printed CHD models, which were printed with blood pool and myocardium models. Eight types of CHD were classified as simple (PDA, CoA and VSD) and complex (ccTGA, DORV, WA, CAF and ToF). Rigid white resin 3D printing improved the diagnostic rate in both the expert and student groups, with the average value being 95.9% and 91.6% after using 3D printed models vs. 88.75% and 60% before using 3D printed models (p = 0.000-0.001). 3D printed models were found to be more important in diagnosing complex CHD than simple CHD, and the demand was stronger in students than from experts. Myocardial models were found to be more advantageous in DORV and VSD by demonstrating the location and structure of the lesions, while blood pool models were more effective in assessing other CHD diseases.

Medical Student Education
Several studies based on randomized controlled trials (RCTs) and cross-sectional or cohort studies have documented the educational value of 3D printed models in cardiovascular anatomy and pathology [20,[26][27][28][29][30][31]. Most of these studies proved the significant improvements in students' knowledge and understanding of both normal cardiac anatomy and pathology (mainly in congenital heart disease) with the use of 3D printed models over the current teaching methods such as using 2D or 3D diagrams, cadavers and educational lectures. Three-dimensional printed heart and vascular models were shown to increase students' confidence in recognizing cardiac anatomical structures and congenital anomalies. One recent study investigated whether 3D printed heart models improved the immediate and long-term knowledge retention among medical students when compared to the current teaching methods [27]. Authors delivered an education workshop comprising 2D cardiac CT images and 3D digital models to both control and 3D printing groups (53 second-and third-year medical students), while the 3D printing group received 3D printed models as additional components. Four types of congenital heart disease (CHD) were presented to the medical students who completed an online quiz at the end of the session and another online quiz 6 weeks later. The results showed no significant improvements in both immediate knowledge and knowledge retention with the use of 3D printed CHD models, despite slightly higher scores obtained in the 3D printing group than in the control group ( Figure 4).

Medical Student Education
Several studies based on randomized controlled trials (RCTs) and cross-sectional or cohort studies have documented the educational value of 3D printed models in cardiovascular anatomy and pathology [20,[26][27][28][29][30][31]. Most of these studies proved the significant improvements in students' knowledge and understanding of both normal cardiac anatomy and pathology (mainly in congenital heart disease) with the use of 3D printed models over the current teaching methods such as using 2D or 3D diagrams, cadavers and educational lectures. Three-dimensional printed heart and vascular models were shown to increase students' confidence in recognizing cardiac anatomical structures and congenital anomalies. One recent study investigated whether 3D printed heart models improved the immediate and long-term knowledge retention among medical students when compared to the current teaching methods [27]. Authors delivered an education workshop comprising 2D cardiac CT images and 3D digital models to both control and 3D printing groups (53 second-and third-year medical students), while the 3D printing group received 3D printed models as additional components. Four types of congenital heart disease (CHD) were presented to the medical students who completed an online quiz at the end of the session and another online quiz 6 weeks later. The results showed no significant improvements in both immediate knowledge and knowledge retention with the use of 3D printed CHD models, despite slightly higher scores obtained in the 3D printing group than in the control group ( Figure 4).

Clinician Education
Due to the complexity and wide heterogeneity of CHD lesions, it is difficult to fully understand the complex 3D anatomy and pathology on a 2D flat screen, thus rendering 3D printed models a valuable tool for the education of clinicians or healthcare professionals. Most of the studies reported the educational value of using 3D printed CHD models in pediatric or medical residents [32][33][34][35][36], with some involving pediatric cardiologists [35] ( Table 1). There is consistent agreement among these studies that 3D printed models significantly increased the participants' knowledge of cardiac anatomy and CHD pathology when compared to conventional education or imaging approaches. Significantly higher scores were achieved in the 3D printing groups than those in the control groups, and this is especially apparent when complex CHD was involved [36,39], and 3D printed models were rated as an excellent tool for anatomy teaching, as well as improving diagnostic rate assessed by both experts and students [39].
Interestingly, a recent study by Lau et al. compared 3D printing with virtual reality (VR) technologies in 4 selected CHD cases among 29 participants [32]. All participants received a 15-min session of 2D/3D visualizations plus 3D printed CHD models and VR. There was no significant difference between these two tools in medical education and preoperative planning of CHD. Thus, this study highlights the potential value of using VR in combination with 3D printing technology in medical education. In addition to VR, advanced innovative tools, including augmented reality (AR) and mixed reality (MR), have also been applied in medical education by providing immersive learning experiences that may enhance the teaching and learning of complex content such as cardiovascular anatomy and pathology [40][41][42][43]. Barteit et al. conducted a systematic review of VR, AR and MR in medical education through an analysis of 27 studies comprising 956 participants [44]. Medical students (59.9%) and residents represented (30.2%) most of the participants with AR and MR mainly implemented in surgery training (48%) and anatomy learning (15%). This review and other research studies highlighted the effectiveness of using VR, AR or MR tools in teaching cardiac anatomy and pathology [42][43][44]. The use of 3D-printed physical models, along with these novel visualization tools, will further enhance medical education.
Two studies investigated the educational value of 3D printed models for cardiac nurses or nursing students. Tan et al., in their RCT, randomly allocated 132 nursing students of congenital heart surgery to the 3D printing or traditional groups to assess their knowledge and critical thinking of a real case of atrial septal defect [37]. Significant higher scores were found in the 3D printing group than those in the traditional group regarding students' comprehensive thinking ability of cardiovascular anatomy and congenital heart disease ( Table 2). Biglino et al. showed that the 3D printed heart and CHD models enhanced cardiac nurses' knowledge of understanding cardiac anatomy and pathology [38]. There was no significant difference regarding the usefulness of 3D printed models in understanding different cardiac defects.

Clinical Applications of 3D Printed Models in Cardiovascular Disease
Clinical applications of using 3D printed models in cardiovascular disease are manifested in four areas: assisting pre-surgical planning of complex cardiac surgery procedures, simulation of surgical or interventional radiology procedures for medical residents or trainees, improving doctor-to-patient communication and development of optimal CT scanning protocols for reduction of radiation dose. The following sections will review these applications based on the current research studies.

Pre-Surgical Planning of Complex Cardiac or Cardiovascular Procedures
Application of 3D printed models in pre-surgical planning of complex cardiac or cardiovascular procedures represents the most common applications, and this is shown in a recent review article with nearly 50% of the applications on the assessment of the clinical value of 3D printed models in pre-surgical planning or simulation of cardiovascular procedures [45,46]. Table 3 summarizes some recent studies based on single and multicenter reports on the clinical value of 3D printed models in pre-surgical planning, with most of them focusing on CHD surgeries [24,[47][48][49][50][51][52]. The multi-center study by Valverde et al. is a well-recognized report involving ten international centers with the inclusion of 40 complex CHD cases. In nearly half of the cases (47.5%), a surgical decision was changed with the use of 3D printed heart models, while in 28 cases conventionally considered for surgery, the surgical approach was modified in 15 cases (53.6%) after evaluating the 3D printed models [47].
Three single-center studies documented their three years and eight years of experience in using 3D printed models in CHD surgeries with the creation of more than 100 models [22,50,52]. Gomez-Ciriza and colleagues developed 138 affordable 3D printed models (an average cost per model is EUR85.7) and presented similar findings as Valverde et al., with 47.5% of surgical planning modified with the use of 3D printed models when compared to the original surgical plan. Further, these 3D printed models were scored useful for communicating with patients and parents when assessed by cardiac surgeons and pediatric cardiologists [22]. Ryan et al. reported their three years of experience with the generation of 164 models for a range of purposes [50]. When compared to the standard of care pre-procedural planning, 3D printed models reduced the operating length of time, 30-day mortality and readmission rate, although this did not reach statistical significance. Ghosh et al. reviewed the growth and development of using more than 100 3D printed models in their practice over a period of 3 years, with 96 of the models used for operative planning of CHD cases. Their experience shows that 3D printing can be incorporated into the pre-procedural planning of CHD in a pediatric clinical center [52].
Other studies based on case series or case reports (<30 cases) from a single-center experience showed consistent findings that 3D printed models assisted pre-surgical planning and simulation of CHD and cardiomyopathy (Table 3). Russo et al. applied 3D printed models of aortic stenosis to simulate transcatheter aortic valve replacement (TAVR) for predicting the risk of developing coronary artery obstruction or complications. The simulation results of 3D printed models correlated well with clinical outcomes and thus can be used to plan TAVR procedures for reducing potential risks or complications [53].
Lau et al. further compared 3D printed models with VR in the clinical value of these two tools in preoperative planning and education of CHD [32]. Interestingly, both VR and 3D printed models are useful for understanding complex CHD conditions and preoperative planning when compared with the standard 2D or 3D visualizations, although VR scored higher than 3D printed models with no significant difference. Similar findings were reported by Chen et al. with VR and MR using Hololens enhanced understanding of intracardiac anatomy when compared to 3D printed models [48]. This could highlight the potential value of using VR/MR in pre-surgical planning of cardiovascular disease when a 3D printing facility is not available or using a combination of both methods [44].  The most common applications of 3D printed models were to evaluate intracardiac anatomy for complex biventricular repair (31%) and preoperative evaluation of extracardiac pathology (20%), followed by repair of multiple ventricular septal defects (12%). In about one-third (34%) of cases, 3D printed models were requested prior to patients undergoing CT or MRI imaging. 3D printed models can be incorporated into the pre-procedural care of patients with CHD. TAVR was successfully stimulated in all 13 printed models with a high risk of CAO. The 3D model simulations correlated well with clinical outcomes by accurately replicating specific anatomy and procedural outcomes. 3D printed models serve as a useful simulation platform in high-risk TAVR patients to predict complications.
Abbreviations are the same as shown in Table 1.

Simulation of Surgical or Interventional Procedures
The use of 3D printed models in simulating cardiac surgeries or interventional procedures is another area that has been well explored in the literature, with promising results reported. Table 4 summarizes some representative studies documenting the value of using 3D-printed personalized models in this field.
One of the common applications of 3D printing lies in guiding left atrial appendage occluder device selection to improve treatment outcomes and reduce potential complications associated with LAA occluder procedures. RCT, case-control and cross-sectional studies have shown the significant advantages of 3D printing guided procedures over traditional methods based on imaging (CT, echocardiography or intraoperative angiography), with key findings, including: good agreement between 3D printed model-based sizes and finally implanted occluder device sizes; reduced procedure time with no major adverse events or mortality and reduce radiation exposure to patients when compared to the control group without having 3D printed models [54][55][56][57] (Table 4). Further, it seems the clinical value of 3D printed models depends on the type of occluder devices, as the correlation between 3D printed models and inserted device size was different for different occluders [58]. This may need to draw attention to clinicians when choosing different devices in planning the treatment of LAA.
Another common application of 3D printing is to simulate cardiac or cardiovascular procedures, in particular, interventional cardiology or radiology procedures, for training surgeons or trainees to perform complex or challenging procedures. The use of personalized 3D printed vascular models aims to increase the confidence and surgical skills of surgeons prior to operating on real patients [59][60][61][62][63][64][65]. Endovascular aneurysm repair (EVAR) is a widely used, less invasive procedure for treating aortic dissection and aneurysm, and the use of 3D printed models in simulating EVAR procedures has significantly reduced fluoroscopy time, procedure time, contrast medium and cannulation time when compared to the control group using standard training approach [60,63,[66][67][68][69]. Similar findings are also reported by a recent study on the use of 3D printed CHD models for a hands-on training program to simulate interventional cardiology procedures [65] (Figures 5 and 6).
Printing materials have an impact on the user's performance when performing a simulation of interventional procedures as 3D models printed with soft and elastic materials allow the user to acquire a similar tactile experience to human vascular tissue, and this is especially important for structures like vessels and cardiac valves as highlighted in some studies [64,65]. Current developments in 3D printing technologies and printing materials have enabled achieving this goal with the selection of appropriate materials to replicate human cardiovascular tissue properties [25,70]. Evidence strongly recommends that 3D printed vascular models serve as a valuable tool for simulating and rehearsing cardiac or interventional radiology procedures. Rynio et al., in their recent study, tested the effect of sterilization on 3D printed aortic templates, which are used in aortic stent grafting. They chose a complex case of aortic arch dissection and printed 11 models with use of six common materials. The sterilization was performed under three different methods and temperatures to determine the change of 3D printed model geometry and dimensions. Figure 7 shows the effect of high temperature on the deformation of 3D printed aortic templates printed with different materials [66]. This study presented important findings on the relationship between 3D printing materials and sterilization methods. The implantation success was 100% and 93.1% in retrospective and prospective groups. The prospective group with the use of 3D printed models achieved shorter procedural time, few devices used for the procedure (p < 0.05 for all) with no procedure complications. There were no major adverse cardiac events or mortality in the prospective group at a mean follow-up of 9.4 months, while there were three major adverse events and nine deaths in the retrospective group at a mean follow-up of 3 years.

Hell et al. [55]
Cross-sectional study A high correlation was found between 3D printed models and the inserted device size for the AMPLATZER occluder (p = 0.001) but was a poor correlation between 3D printed models and the WATCHMAN device (p = 0.203).  Practicing on 3D printed models led to a significant reduction in the mean fluoroscopy time. All participants gave 3D printed models very positive ratings as a training tool for the simulation of interventional cardiac procedures.
Rynino et al. [66] Cross-sectional study Eleven models of aortic dissection cases were printed using different materials and distributed into four groups: autoclave 121 • C sterilization, plasma sterilization, gas sterilization, 105 • C autoclave sterilization.
CT Effect of sterilization methods on the geometric changes of the 3D printed aortic template. 3D printed models made from PLA, PETG and PP were deformed during sterilization at high temperatures (autoclave 121 • C). However, 3D-printed models made with nylon or flexible and rigid resin did not undergo filament deformities during high-temperature sterilization. All mean geometry differences were less than 0.5 mm.
Abbreviations are the same as shown in Table 1.

Enhancement of Doctor-to-Patient Communication
The role of using 3D printed models in enhancing doctor-patient communication has been reported in the literature, although only a limited number of studies are available, according to a recent scoping review. Traynor et al. conducted a comprehensive review of the current literature and identified 19 studies on the use of 3D printing in patient communication [71]. Of these studies, seven studies were related to cardiology and cardiovascular surgery [49,[72][73][74][75][76][77], of which four studies were reported from the same research group [72][73][74][75]. Biglino and colleagues investigated the impact of 3D printed CHD models on communication from the perspectives of different stakeholders, including clinicians (cardiologists), patients and the parents of patients. Results of these studies presented consistent findings that 3D printed models facilitated communication with colleagues, patients and parents, with a significant improvement in patients' and parents' knowledge or understanding of the disease condition, or satisfaction [74] (Figures 8 and 9). The other three studies also supported the improvement between doctor-patient or between clinicians' communication with the use of 3D printed models heart models [49,76,77]. More research needs to be done on patient engagement in decision-making through understanding their disease conditions by use of 3D printing.

Enhancement of Doctor-to-Patient Communication
The role of using 3D printed models in enhancing doctor-patient communication has been reported in the literature, although only a limited number of studies are available, according to a recent scoping review. Traynor et al. conducted a comprehensive review of the current literature and identified 19 studies on the use of 3D printing in patient communication [71]. Of these studies, seven studies were related to cardiology and cardiovascular surgery [49,[72][73][74][75][76][77], of which four studies were reported from the same research group [72][73][74][75]. Biglino and colleagues investigated the impact of 3D printed CHD models on communication from the perspectives of different stakeholders, including clinicians (cardiologists), patients and the parents of patients. Results of these studies presented consistent findings that 3D printed models facilitated communication with colleagues, patients and parents, with a significant improvement in patients and parents' knowledge or understanding of the disease condition, or satisfaction [74] (Figures 8 and 9). The other three studies also supported the improvement between doctor-patient or between clinicians' communication with the use of 3D printed models heart models [49,76,77]. More research needs to be done on patient engagement in decision-making through understanding their disease conditions by use of 3D printing.

Development of Optimal CT Scanning Protocols
Application of 3D printed models in developing optimal CT scanning protocols is a new research direction with only a few studies available in the literature, but with promising results achieved. Cardiac CT is a widely used modality for diagnostic assessment of cardiovascular disease, most used in coronary artery disease, aortic aneurysm or dissection and pulmonary embolism [78][79][80]. The main concern of cardiac CT is a high radiation dose; hence, the use of appropriate CT scanning protocols is clinically important for the reduction of patient radiation exposure without compromising image quality. Despite commercially available anthropomorphic human phantoms for dose reduction and image

Development of Optimal CT Scanning Protocols
Application of 3D printed models in developing optimal CT scanning protocols is a new research direction with only a few studies available in the literature, but with promising results achieved. Cardiac CT is a widely used modality for diagnostic assessment of cardiovascular disease, most used in coronary artery disease, aortic aneurysm or dissection and pulmonary embolism [78][79][80]. The main concern of cardiac CT is a high radiation dose; hence, the use of appropriate CT scanning protocols is clinically important for the reduction of patient radiation exposure without compromising image quality. Despite commercially available anthropomorphic human phantoms for dose reduction and image

Development of Optimal CT Scanning Protocols
Application of 3D printed models in developing optimal CT scanning protocols is a new research direction with only a few studies available in the literature, but with promising results achieved. Cardiac CT is a widely used modality for diagnostic assessment of cardiovascular disease, most used in coronary artery disease, aortic aneurysm or dissection and pulmonary embolism [78][79][80]. The main concern of cardiac CT is a high radiation dose; hence, the use of appropriate CT scanning protocols is clinically important for the reduction of patient radiation exposure without compromising image quality. Despite commercially available anthropomorphic human phantoms for dose reduction and image quality experi-ments, they are not only expensive but do not represent an individual patient's situation due to the use of average adult or pediatric body sizes. The 3D-printed personalized models based on CT images overcome these limitations by producing individualized heart or cardiovascular models for studying CT protocols.
Several studies have explored the feasibility of developing 3D printed heart and vascular models for CT dose optimization [81][82][83][84][85][86][87][88][89][90]. Abdullah et al. developed an organ-specific cardiac insert phantom for the investigation of cardiac CT scanning protocols. Although it does represent the novelty of the study design with the simulation of surrounding cardiac structures as well as contrast medium during cardiac CT scan (Figure 10), the study lacks personalized 3D printed anatomical structures [81]. Morup et al. tested four different materials (gelatin mixtures, pig hearts and Ecoflex TM silicone) with the aim of determining the appropriate one to simulate human heart and vascular tissue properties. Their results showed that the contrast-filled Ecoflex TM silicone had a mean CT attenuation of 318 Hounsfield Units (HUs) which is close to the contrast enhancement CT attenuation in real patients (Figure 11), serving as a cost-effective model for CT protocol optimization [82]. quality experiments, they are not only expensive but do not represent an individual patient's situation due to the use of average adult or pediatric body sizes. The 3D-printed personalized models based on CT images overcome these limitations by producing individualized heart or cardiovascular models for studying CT protocols. Several studies have explored the feasibility of developing 3D printed heart and vascular models for CT dose optimization [81][82][83][84][85][86][87][88][89][90]. Abdullah et al. developed an organ-specific cardiac insert phantom for the investigation of cardiac CT scanning protocols. Although it does represent the novelty of the study design with the simulation of surrounding cardiac structures as well as contrast medium during cardiac CT scan (Figure 10), the study lacks personalized 3D printed anatomical structures [81]. Morup et al. tested four different materials (gelatin mixtures, pig hearts and Ecoflex TM silicone) with the aim of determining the appropriate one to simulate human heart and vascular tissue properties. Their results showed that the contrast-filled Ecoflex TM silicone had a mean CT attenuation of 318 Hounsfield Units (HUs) which is close to the contrast enhancement CT attenuation in real patients (Figure 11), serving as a cost-effective model for CT protocol optimization [82].   quality experiments, they are not only expensive but do not represent an individual patient's situation due to the use of average adult or pediatric body sizes. The 3D-printed personalized models based on CT images overcome these limitations by producing individualized heart or cardiovascular models for studying CT protocols. Several studies have explored the feasibility of developing 3D printed heart and vascular models for CT dose optimization [81][82][83][84][85][86][87][88][89][90]. Abdullah et al. developed an organ-specific cardiac insert phantom for the investigation of cardiac CT scanning protocols. Although it does represent the novelty of the study design with the simulation of surrounding cardiac structures as well as contrast medium during cardiac CT scan (Figure 10), the study lacks personalized 3D printed anatomical structures [81]. Morup et al. tested four different materials (gelatin mixtures, pig hearts and Ecoflex TM silicone) with the aim of determining the appropriate one to simulate human heart and vascular tissue properties. Their results showed that the contrast-filled Ecoflex TM silicone had a mean CT attenuation of 318 Hounsfield Units (HUs) which is close to the contrast enhancement CT attenuation in real patients (Figure 11), serving as a cost-effective model for CT protocol optimization [82].   We have developed personalized coronary artery models and aorta models using CT images for optimizing CT protocols and visualization of coronary calcified plaques and stenting [83][84][85][86]. Calcified plaques were created using a mixture of silicone, ethiodized oil and carbonate to simulate calcification in the coronary arteries. The combination of silicone and 32.8% calcium carbonate was found to produce CT attenuation of 800 HU, representing extensive calcification ( Figure 12); thus, it is suitable for studying CT protocols for assessing calcified coronary plaques ( Figure 13) [83]. We have developed personalized coronary artery models and aorta models using CT images for optimizing CT protocols and visualization of coronary calcified plaques and stenting [83][84][85][86]. Calcified plaques were created using a mixture of silicone, ethiodized oil and carbonate to simulate calcification in the coronary arteries. The combination of silicone and 32.8% calcium carbonate was found to produce CT attenuation of 800 HU, representing extensive calcification ( Figure 12); thus, it is suitable for studying CT protocols for assessing calcified coronary plaques ( Figure 13) [83].  Further, 3D printed models of type B aortic dissection were developed using CT datasets to replicate true lumen, false lumen, aortic aneurysm, and insertion of the aortic stent graft to simulate EVAR (Figure 3) [25]. CT scans were conducted to investigate the optimal aortic CT angiography (CTA) protocols in the follow-up of patients with aortic dissection following EVAR treatment. Low kilovoltage peak (80 kVp) and high pitch (2.0) can be suggested as the optimal CT protocol with a reduction of more than 20% radiation dose without affecting image quality as assessed quantitatively and qualitatively ( Figure  14) [25,88]. Since aorta CTA is the preferred imaging modality for both diagnosis of aortic Further, 3D printed models of type B aortic dissection were developed using CT datasets to replicate true lumen, false lumen, aortic aneurysm, and insertion of the aortic stent graft to simulate EVAR (Figure 3) [25]. CT scans were conducted to investigate the optimal aortic CT angiography (CTA) protocols in the follow-up of patients with aortic dissection following EVAR treatment. Low kilovoltage peak (80 kVp) and high pitch (2.0) can be suggested as the optimal CT protocol with a reduction of more than 20% radiation dose without affecting image quality as assessed quantitatively and qualitatively ( Figure 14) [25,88]. Since aorta CTA is the preferred imaging modality for both diagnosis of aortic aneurysm/dissection and follow-up of EVAR patients due to consecutive CT scans at regular periods, low-dose CT protocol is of paramount importance to minimize radiation dose. Thus, the use of 3D printed personalized aorta models will have great potential in the future to optimize current CT scanning protocols.
Another area of using a personalized 3D printed model lies in the simulation of pulmonary embolism with the model scanned using a range of CT pulmonary angiography protocols. Significant dose reduction by up to 80% was achieved with the use of low dose (70-80 kVp) and high pitch (3.2) with acceptable image quality when assessing pulmonary embolism, either in the main or side branches [89,90]. The main limitation of these studies is the lack of placing the 3D printed model in a realistic chest phantom with surrounding lungs, bones or cardiac structures. This needs to be addressed in future experiments.

Limitations, Barriers and Future Directions
Over the last decades, there have been significant advancements in the use of 3D printing technology in cardiovascular disease, with reports showing great potential in clinical applications, as well as medical education and other areas. However, there exist some limitations and barriers that need to be considered when promoting 3D printing applications in cardiovascular disease. First, despite increasing reports in the literature, robust studies are still lacking, with the majority of the current studies based on case series or relatively small sample sizes (Tables 1, 3 and 4). Further, follow-up studies of the mid

Limitations, Barriers and Future Directions
Over the last decades, there have been significant advancements in the use of 3D printing technology in cardiovascular disease, with reports showing great potential in clinical applications, as well as medical education and other areas. However, there exist some limitations and barriers that need to be considered when promoting 3D printing applications in cardiovascular disease. First, despite increasing reports in the literature, robust studies are still lacking, with the majority of the current studies based on case series or relatively small sample sizes (Tables 1, 3 and 4). Further, follow-up studies of the mid to long-term outcomes of how 3D printed models contribute to education and clinical practice are scarce. Second, technological improvements have enabled the printing of realistic heart and vascular models with high accuracy in replicating anatomy and pathology (including complex conditions such as CHD); however, most of the current 3D printed models are static ones, and they do not really represent real cardiovascular circulatory physiology. Future research will need to address this limitation by developing more realistic 3D printed models, with 3D printed models connected to a fluid pump with the simulation of cardiac pulse sequences, as shown in Karkkainen and other studies [60,87]. Third, the use of appropriate printing materials plays an important role, especially in the simulation of cardiac or interventional procedures, such as the operators need to experience a similar feeling when performing the simulation on 3D printed models so that clinicians and students can gain confidence and skills that are required to operate on real patients. This is already achievable with the current printing materials [25,63,70,88].
The main barriers to implementing 3D printing technology in routine cardiovascular practice are the relatively high costs associated with 3D printing (including image postprocessing and segmentation) and the slow turnaround time. The first barrier will be addressed by using artificial intelligence, such as machine learning (ML) or deep learning (DL), to enhance the image segmentation process [91][92][93]. With printers available at clinical sites, the use of 3D printing technology in daily practice will become possible, and clinicians can incorporate 3D printed models into their diagnosis and decision-making process.
Bioprinting is the future of 3D printing technology in medical applications, with significant progress made in printing cardiovascular constructs, cardiovascular regeneration and pharmacology over the last decades [94][95][96][97][98][99]. Figure 15 outlines the scheme of 3D bioprinting technology in the cardiovascular system. Despite promising results available in the literature, current technologies and printing materials limit the application of bioprinting to only small units of functional cardiovascular tissues. There are still many challenges to be resolved before printing complete organs, such as a fully functional heart, becomes possible [94].
A close collaboration between clinicians and academic researchers is essential to achieve the goal that clinicians are aware of the 3D printing technologies and capabilities so that their knowledge, skills and confidence in using the 3D printed personalized models are enhanced. This will play an important role in ensuring the incorporation of 3D printing technology into routine practices to benefit diagnostic strategy and clinical decision-making [100]. nificant progress made in printing cardiovascular constructs, cardiovascular regeneration and pharmacology over the last decades [94][95][96][97][98][99]. Figure 15 outlines the scheme of 3D bioprinting technology in the cardiovascular system. Despite promising results available in the literature, current technologies and printing materials limit the application of bioprinting to only small units of functional cardiovascular tissues. There are still many challenges to be resolved before printing complete organs, such as a fully functional heart, becomes possible [94]. Figure 15. Schematic diagram outlining the techniques for 3D cardiovascular bioprinting, bioengineering methods, and bio-applications in regeneration and pharmacology. Reprinted with permission from Cui et al. [94].
A close collaboration between clinicians and academic researchers is essential to achieve the goal that clinicians are aware of the 3D printing technologies and capabilities so that their knowledge, skills and confidence in using the 3D printed personalized models are enhanced. This will play an important role in ensuring the incorporation of 3D printing technology into routine practices to benefit diagnostic strategy and clinical decision-making [100].

Summary and Concluding Remarks
There is no doubt that 3D printing technology has revolutionized our current practice (both education and clinical) in the diagnosis and management of patients with cardiovascular disease. The 3D printed models assist surgical planning and the simulation of cardiac procedures, thus greatly improving understanding of anatomy and pathology, increasing clinicians', especially trainees', knowledge, skills and confidence when performing operations on patients. This has a significant clinical impact on training young and junior doctors with 3D printed personalized models. Simulation of cardiac or interventional procedures will lead to high operation success rates with few complications, thus improving patient outcomes. 3D printed models serve as a valuable education tool for medical students or graduates in learning cardiovascular anatomy and pathology; therefore, they could be used as an alternative to the current teaching methods.
An emerging area of using personalized 3D printed models is to optimize CT scanning protocols with evidence showing feasibility and promise. More research could be developed along this pathway to optimize current CT practice with the delivery of low-dose protocols. With the further development of 3D printing technology and the incorporation of other technologies, such as ML and DL and VR, AR and MR, a combination of using advanced technologies will be of great benefit to our healthcare through the delivery of personalized medicine.