biomolecules

Review Clinical Applications of Patient-Specific 3D Printed Models in Cardiovascular Disease: Current Status and Future Directions

Zhonghua Sun

Discipline of Medical Radiation Sciences, School of Molecular and Life Sciences Curtin University, GPO Box, U1987, Perth 6845, Australia; [email protected]; Tel.: +61-8-9266-7509; Fax: +61-8-9266-2377


Received: 26 September 2020; Accepted: 19 November 2020; Published: 20 November 2020


Abstract: Three-dimensional (3D) printing has been increasingly used in medicine with applications in many different fields ranging from orthopaedics and tumours to cardiovascular disease. Realistic 3D models can be printed with different materials to replicate anatomical structures and pathologies with high accuracy. 3D printed models generated from medical imaging data acquired with computed tomography, magnetic resonance imaging or ultrasound augment the understanding of complex anatomy and pathology, assist preoperative planning and simulate surgical or interventional procedures to achieve precision medicine for improvement of treatment outcomes, train young or junior doctors to gain their confidence in patient management and provide medical education to medical students or healthcare professionals as an effective training tool. This article provides an overview of patient-specific 3D printed models with a focus on the applications in cardiovascular disease including: 3D printed models in congenital heart disease, coronary artery disease, pulmonary embolism, aortic aneurysm and aortic dissection, and aortic valvular disease. Clinical value of the patient-specific 3D printed models in these areas is presented based on the current literature, while limitations and future research in 3D printing including bioprinting of cardiovascular disease are highlighted.

Keywords: 3D printing; computed tomography; image processing; medicine; model; segmentation; visualization

1. Introduction Although three-dimensional (3D) printing is not a new technology, it has experienced rapid developments over the last decade with increasing studies available in the literature documenting its clinical value in different areas. Patient-specific or personalized 3D printed models accurately replicate normal anatomical structures and pathologies, thus serving as a valuable tool in medical applications ranging from the initial orthopaedics and maxillofacial domain to cardiovascular disease and tumours [1–10]. 3D printed physical models provide useful information in pre-operative planning and simulation of complex surgical procedures, education of medical students and residents, intraoperative orientation, and physician-patient communication [8–14]. Evidence of 3D printed models in these applications is dominated by case reports and case series, while multi-centre studies and randomized controlled trials (RCTs) are increasingly reported in the literature [15–20]. 3D printed models augment clinicians’ confidence in managing different clinical situations by improving their understanding of complex spatial relationship between the normal anatomy and pathologies which cannot be accurately achieved by the traditional image visualizations. With growing interest of 3D printing in the medical community, guidelines are beginning to emerge about the appropriate use of 3D printing for medical scenarios as recommended by several societies

Biomolecules 2020, 10, 1577; doi:10.3390/biom10111577 www.mdpi.com/journal/biomolecules Biomolecules 2020, 10, x 2 of 34 beginning to emerge about the appropriate use of 3D printing for medical scenarios as recommended Biomolecules 2020, 10, 1577 2 of 34 by several societies such as the Radiological Society of North America (RSNA) 3D printing Special Interest Group or the new Society for Cardiovascular Magnetic Resonance (SCMR) 3D working group [21,22].such as Thus, the Radiological it is important Society toof have North a clear America understanding (RSNA) 3D printing of the clinical Special Interestvalue of Group 3D printing or the new and potentialSociety for limitations. Cardiovascular Magnetic Resonance (SCMR) 3D working group [21,22]. Thus, it is important to haveThe areview clear understanding article aims to of provide the clinical an overview value of 3D of printing3D printed and models potential in limitations. medical applications, specificallyThe review focusing article its value aims toin providecardiovascular an overview disease of since 3D printed its clinical models applications in medical in applications, orthopaedics andspecifically maxillofacial focusing areas its value are well in cardiovascular explored and disease confirmed since its in clinical the literature applications [23–25]. in orthopaedics Further to and the commonlymaxillofacial reported areas are usefulness well explored of 3D and printed confirmed mode in thels, use literature of 3D [23 printed–25]. Further models to thefor commonlydeveloping optimalreported computed usefulness tomography of 3D printed (CT) models, scanning use of parame 3D printedters in models cardiovascular for developing disease optimal is discussed computed and futuretomography research (CT) directions scanning are parameters highlighted. in Figure cardiovascular 1 is a summary disease of is 3D discussed printing andin the future cardiovascular research applications.directions are highlighted. Figure1 is a summary of 3D printing in the cardiovascular applications.

FigureFigure 1. Flow 1. Flow chart chart shows shows 3D 3D printing printing applications applications in in medicine medicine covering covering a range a range of areas. of areas.

2. Steps to Create 3D Segmentation Volume Data for 3D Printing 2. Steps to Create 3D Segmentation Volume Data for 3D Printing The first and important step to generate a 3D printed model is to acquire high-quality imaging data, The first and important step to generate a 3D printed model is to acquire high-quality imaging mainly CT or magnetic resonance imaging (MRI) volumetric images, although ultrasound or invasive data, mainly CT or magnetic resonance imaging (MRI) volumetric images, although ultrasound or angiography images are also used in some studies for 3D printing [11–13]. Volume datasets first undergo invasive angiography images are also used in some studies for 3D printing [11–13]. Volume datasets a series of image post-processing and segmentation (automatic or semi-automatic segmentation) steps first undergo a series of image post-processing and segmentation (automatic or semi-automatic to remove unwanted or irrelevant structures while keeping the regions of interest for 3D printing. segmentation) steps to remove unwanted or irrelevant structures while keeping the regions of Semi-automatic or manual editing is usually needed for further editing to only preserve the anatomical interest for 3D printing. Semi-automatic or manual editing is usually needed for further editing to structures that are finally used for 3D printing. Figure2 is a flow chart showing the steps from original only preserve the anatomical structures that are finally used for 3D printing. Figure 2 is a flow chart imaging data editing or segmentation to create a Standard Tessellation Language (STL) file and print showinga physical the model. steps from original imaging data editing or segmentation to create a Standard TessellationThe physical Language model (STL) can file be printedand print with a physical different model. materials, depending on many factors, such as clinicalThe purpose physical and model requirements, can be printed availability with different of 3D printers materials, and printing depend materialsing on many and associated factors, such costs. as clinicalReaders purpose are referred and torequirements, some review articlesavailability providing of 3D a printers good summary and printing of the 3Dmaterials printing and technologies associated costs.and 3DReaders printed are models referred with to usesome of areview range articles of printing providing materials a good [11–14 summary,26]. Some of of the the 3D materials printing technologiesused for printing and 3D cardiovascular printed models tissues with in termsuse ofof a ra mechanicalnge of printing properties materials and biocompatibility [11–14,26]. Some will of be the materialsdiscussed used in the sectionfor printing of bioprinting. cardiovascular tissues in terms of mechanical properties and biocompatibility will be discussed in the section of bioprinting. Biomolecules 2020, 10, 1577 3 of 34

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FigureFigure 2. Steps 2. Steps to create to create 3D printed 3D printed model frommodel segmentation from segmentation of original of coronaryoriginal CTcoronary volume CT data to volume data to generation of segmented data containing only regions of interest (coronary generation of segmented data containing only regions of interest (coronary artery tree and ascending artery tree and ascending aorta in this example) and STL file for 3D printing. The coronary aorta in this example) and STL file for 3D printing. The coronary model was printed with Visijet M2 model was printed with Visijet M2 ENT material by 3D Systems. ENT material by 3D Systems.

3. Clinical3. Clinical Applications Applications of of 3D 3D Printing Printingin in CardiovascularCardiovascular Disease Disease 3D printing has shown great promise in many medical applications covering a spectrum of 3D printing has shown great promise in many medical applications covering a spectrum of areas, depending on the location, type and severity of pathologies. For example, in the domain of areas,tumour depending diagnosis on theand location,treatment, type its application and severity mainly of pathologies. lies on the pre-surgical For example, planning in the and domain of tumoursimulation diagnosis or intraoperative and treatment, orientation its applicationto guide surgical mainly procedures, lies on thus the achieving pre-surgical more planning effective and simulationoutcomes or while intraoperative reducing complications orientation to[14,27,28]. guide surgical Whereas procedures, in the field of thus cardiovascular achieving disease, more e ffinective outcomesparticular, while congenital reducing heart complications disease, the clinical [14,27 value,28]. Whereasof 3D printing in the focuses field on of education cardiovascular of medical disease, in particular,students congenitalor junior doctors heart disease,or residents, the clinicalimproves value physician-patient of 3D printing communication focuses on education and increases of medical studentsconfidence or junior of cardiologists doctors or or residents, cardiac surgeons improves in dealing physician-patient with complex cardiac communication conditions [10–13,26]. and increases confidence3D printing of cardiologists is useful to develop or cardiac medical surgeons devices in in dealing the treatment with complexof aortic or cardiac valvular conditions diseases [26,29– [10–13,26]. 32]. In the following sections, clinical value of 3D printing is discussed with regard to each specific 3D printing is useful to develop medical devices in the treatment of aortic or valvular diseases [26,29–32]. area based on the current literature. In the following sections, clinical value of 3D printing is discussed with regard to each specific area based on the current literature. 3.1. 3D Printing in Congenital Heart Disease 3.1. 3D PrintingSince 3D in printing Congenital can provide Heart Disease an outstanding view of complex anatomical details, it has played an important role in treating patients with congenital heart disease (CHD). Diagnosis and treatment Sinceof CHD 3D requires printing a comprehensive can provide an and outstanding good understanding view of complexof complex anatomical spatial relationship details, itbetween has played an importantnormal cardiac role inanatomy treating and patients disease, with and 3D congenital printing is heart a transformative disease (CHD). technology Diagnosis that has and shown treatment of CHDto change requires the acurrent comprehensive practice in the and management good understanding of CHD. of complex spatial relationship between normal cardiacPrecise anatomypre-surgical and planning disease, of and CHD 3D can printing be achieved is atransformative with use of 3D printed technology models, that and has this shown to changeis reported the current in recently practice published in the systematic management reviews of and CHD. meta-analyses and a number of other studies Precise[13,33–40]. pre-surgical Of 24 eligible planning studies of in CHD the systematic can be achieved review conducted with use of by 3D Lau printed and Sun, models, 15 of andthem this is reportedreported in recentlythe 3D printed published models systematicin the pre-operative reviews planning and meta-analyses of CHD treatment, and provided a number how of3D other printed models assisted the planning of surgical procedures and surgeons’ opinion on the 3D printed studies [13,33–40]. Of 24 eligible studies in the systematic review conducted by Lau and Sun, 15 of them models [13]. The 3D printed models were found to assist surgeons define the best surgical approach, reported the 3D printed models in the pre-operative planning of CHD treatment, provided how 3D printed models assisted the planning of surgical procedures and surgeons’ opinion on the 3D printed models [13]. The 3D printed models were found to assist surgeons define the best surgical Biomolecules 2020, 10, 1577 4 of 34

Biomolecules 2020, 10, x 4 of 34 approach, in particular in dealing with complex CHD cases such as double outlet right ventricle (DORV)in particular (Figure3)[ in dealing13]. Personalized with complex therapeutic CHD cases strategy such as double can be outlet achieved right andventricle the best(DORV) surgery (Figure option can be3) made [13]. Personalized with the aid therapeutic of patient-specific strategy can 3D be printed achieved models and the as reportedbest surgery by option a recent can study be made [41]. with the aid of patient-specific 3D printed models as reported by a recent study [41].

FigureFigure 3. 3D 3. printed 3D printed heart modelsheart models showing showing normal normal anatomy anatomy and pathology. and pathology. (a) Normal (a) Normal heart model createdheart from model cardiac created CT and from is partitioned cardiac intoCT threeand is pieces partitioned allowing into visualization three pieces of interventricular allowing septum.visualization (b) Repaired of Tetralogy interventricular of Fallot (ToF)septum. from (b an) Repaired adult patient. Tetralogy The model of Fallot was created(ToF) from from cardiacan adult patient. The model was created from cardiac magnetic resonance imaging (MRI) and magnetic resonance imaging (MRI) and separated into two pieces allowing for clear visualization of separated into two pieces allowing for clear visualization of overriding aorta and overriding aorta and pulmonary infundibular stenosis. (c) Unrepaired ToF heart model from an infant. pulmonary infundibular stenosis. (c) Unrepaired ToF heart model from an infant. The The model was created from 3D echocardiographic images and partitioned into two pieces showing model was created from 3D echocardiographic images and partitioned into two pieces the ventricular septal defect (VSD). (d) Unrepaired ToF heart model from an infant with superior showing the ventricular septal defect (VSD). (d) Unrepaired ToF heart model from an infant and inferior portions showing VSD and the aortic overriding in relation to the VSD. Reprinted with with superior and inferior portions showing VSD and the aortic overriding in relation to permissionthe VSD. under Reprinted open access with frompermission Loke et under al. [17 open]. access from Loke et al. [17].

AnotherAnother common common application application of of 3D 3D printing printing inin CHDCHD is is about about its its usefulness usefulness in medical in medical education. education. This isThis noticed is noticed in 50% in of50% the of studiesthe studies in the in samethe same systematic systematic review review [13 [13].]. Of Of these these studies, studies, therethere areare four RCTsfour comparing RCTs comparing the 3D printed the 3D models printed withmodels traditional with traditional teaching teaching methods methods in CHD in CHD for medical for medical students and residentsstudents [and16– 18residents,42]. While [16–18,42]. the study While by the Wang study et by al. Wang did not et showal. did any not significant show any significant improvement in theimprovement 3D printing groupin the 3D when printing compared group towhen the compared control group to the [ 42control], the group other three[42], the studies other indicatedthree that 3Dstudies printed indicated models that served 3D printed as a useful models tool served in teaching as a useful and tool learning in teaching of complexand learning CHD of situationscomplex as opposedCHD to situations the control as opposed group using to the standardcontrol group teaching using standard tools (Figure teaching4)[ 16tools–18 (Figure]. This 4) is [16–18]. consistent This with is consistent with other studies reporting the utility of 3D printed models in the education of other studies reporting the utility of 3D printed models in the education of healthcare professionals, healthcare professionals, patients or families [43–45]. patients orLess families commonly [43–45 reported]. areas but also showing clinical value of 3D printing in CHD include Lesscommunication commonly between reported doctor areas and but patients also showing or parents clinical of patients, value ofand 3D pr printinge-surgical in simulation. CHD include communicationDespite only between a few studies doctor available and patientswith qualitative or parents results, of most patients, of the and participants pre-surgical agreed simulation. to the Despiteconclusion only a that few 3D studies printed available models augmented with qualitative doctor-patient results, or doctor-doctor most of the communication. participants agreed High to the conclusionsatisfaction that was 3Dfound printed with use models of 3D printed augmented models doctor-patient during patient’s or consultation doctor-doctor with communication.their doctors High satisfaction was found with use of 3D printed models during patient’s consultation with their doctors [17,36,43]. This highlights the complementary role of 3D printed models in improving the doctor-patient communication. Biomolecules 2020, 10, x 5 of 34

[17,36,43].Biomolecules 2020 This, 10 highlights, 1577 the complementary role of 3D printed models in improving the doctor-5 of 34 patient communication.

Figure 4. ImpactImpact of of 3D 3D printed printed heart heart models models on on me medicaldical education. education. Improvement Improvement was found in residents’ knowledgeknowledge on on congenital congenital heart heart disease disease with usewith of use 3D printedof 3D modelsprinted whenmodels compared when comparedto 2D images. to 2D A statisticallyimages. A statistically significant disignificantfference was difference noticed was in satisfaction noticed in ratingssatisfaction in the ratings group inhaving the group 3D printed having heart 3D models printed when heart compared models to when the control compared group to (p the= 0.03). control While group residents (p = 0.03). in the While3D printed residents model in group the 3D had printed higher self-emodelfficacy group scores had (self-reported higher self-efficacy confidence), scores this (self-reported did not reach confidence),significant di ffthiserence did compared not reach to significant the control diffe grouprence using compared 2D images to/drawings the control (p = group0.39). Reprintedusing 2D withimages/drawings permission under (p = open0.39). accessReprinted from with Loke permission et al. [17]. under open access from Loke et al. [17].

Pre-surgical simulationsimulation is is the the ultimate ultimate goal goal of surgical of surgical planning planning as it guides as it performingguides performing the complex the complexsurgical procedures,surgical procedures, thus leading thus to leading improved to improv outcomesed outcomes in the patient in the treatment. patient treatment. This is especially This is especiallyuseful for inexperienceduseful for inexperienced surgeons or juniorsurgeons doctors or tojunior practice doctors surgical to practice simulation surgical procedures simulation on 3D proceduresprinted models, on 3D thus printed creating models, intracardiac thus creating pathways intracardiac [46]. pathways [46]. 3.2. 3D Printing in Structural Heart Disease and Cardiac Interventions 3.2. 3D Printing in Structural Heart Disease and Cardiac Interventions 3D printed models have potential value in structural heart disease, especially in interventional cardiology3D printed through models simulation have potential of cardiac value interventions in structural toheart determine disease, feasibilityespecially ofin interventional cardiologyprocedures, through selection simulation of appropriate of cardiac device, interven predicttions procedure-related to determine feasibility outcomes of andinterventional follow-up procedures,of post-procedural selection device of appropriate deployment device, [34,35 pred,47–49ict]. procedure-related Specifically, 3D printed outcomes models and follow-up have played of post-proceduralan important role device in the deployment planning [34,35,47–49]. of treatment Sp ofecifically, valvular 3D disease printed and models left atrial have appendage played an importantclosure [47 role–49 ]in. Athe systematic planning of review treatment of 29 of articles valvular on disease 3D printing and left in atrial heart appendage valve disease closure shows [47– 49].that A the systematic most common review application of 29 articles of 3D on printing 3D printing is the in preoperative heart valve planningdisease shows of valvular that the disease most (63%),common followed application by surgical of 3D printing training is (19%) the preoperati and deviceve testing planning and of development valvular disease (11%) (63%), [50]. followed by surgicalWang andtraining colleagues (19%) inand their device recent testing systematic and development review analysed (11%) 43 studies[50]. about the applications of 3D printedWang modelsand colleagues in adult cardiovascular in their recent disease systemat treated withic review surgeries analysed or catheter-based 43 studies interventional about the applicationsprocedures [ 51of ].3D Of printed 43 studies, models most in ofadult them cardiovascular (35/43, 81%) focuseddisease treated on the with clinical surgeries applications or catheter- of 3D basedprinted interventional models in adult procedures cardiovascular [51]. Of 43 disease, studies, primarilymost of them assisting (35/43, cardiovascular 81%) focused on surgery the clinical and applicationstranscatheter of interventions. 3D printed models Of diff inerent adult clinical cardiova scenarios,scular disease, 3D printing primarily was reportedassisting ascardiovascular a useful tool surgeryin preoperative and transcatheter planning andinterventions. simulation Of of different the two clinical common scenarios, heart diseases, 3D printing left atrial was reported appendage as aocclusion useful tool (LAAO) in preoperative and transcatheter planning aortic and valve simulation replacement of the (TAVR). two common Of 296 patientsheart diseases, included left in atrial these appendage35 studies, half occlusion of them (LAAO) and 17.6% and underwent transcatheter the LAAO aortic and valve TAVR, replacement respectively (TAVR). [51]. For Of the 296 remaining patients includedeight students, in these 3D 35 printed studies, models half of were them used and for 17.6% simulation underwent and training the LAAO of aortic and TAVR, valvular respectively diseases to [51].improve For the surgical remaining trainees’ eight understanding students, 3D of printed the disease. models were used for simulation and training of aorticAnother valvular application diseases to ofimprove 3D printing surgic liesal trainees’ in optimal understanding preoperative of TAVR the disease. planning confirmed by a recentAnother study application reporting the of potential3D printing value lies of in using optimal 3D printedpreoperative models TAVR for assessment planning confirmed of paravalvular by a recentleak (PVL) study [ 52reporting]. Thorburn the potential et al. created value fiveof using 3D printed 3D printed models models consisting for assessment of aortic of root, paravalvular coronary leakostium (PVL) and [52]. left Thorburn ventricular et outflowal. created tract five based 3D printed on cardiac models CT images.consisting The of printedaortic root, models coronary were Biomolecules 2020, 10, x 6 of 34 ostium and left ventricular outflow tract based on cardiac CT images. The printed models were connected to a closed pressure system for measuring PVL following TAVR implantation. The amount of PVLBiomolecules measured2020, 10in, 15773D printed models was compared to that detected on echocardiography6 ofin 34 these patients who were treated by TAVR. Their analysis showed a significant correlation of the paravalvular leak volume between 3D printed models and postoperative echocardiographic measurements in connected to a closed pressure system for measuring PVL following TAVR implantation. The amount patients [52]. This study highlights the potential value of utilizing 3D printed models in predicting the of PVL measured in 3D printed models was compared to that detected on echocardiography in these paravalvular leak in patients treated with TAVR, although future studies are needed to look at more patients who were treated by TAVR. Their analysis showed a significant correlation of the paravalvular areas,leak such volume as testing between different 3D printed valve sizes models and and implantation postoperative of the echocardiographic devices in different measurements positions. in patientsHaghiashtiani [52]. This et study al. further highlights extended the potential the value3D pr ofinted utilizing aortic 3D printedmodel models to an inadvanced predicting level the of integratingparavalvular internal leak sensors in patients array treated within with TAVR,the aortic although root, future thus studiesshowing are the needed feasibility to look atof more creating dynamicareas, functionalities such as testing diofff erentthe 3D valve printed sizes andmodels implantation [53]. Authors of the devices created in two different patient-specific positions. aortic root modelsHaghiashtiani using CT images et al. further with each extended model the consisting 3D printed of anatomical aortic model structures, to an advanced such as level the ofaortic wall,integrating myocardium, internal aortic sensors valve array leaflets within and the calcifications. aortic root, thusThese showing two models the feasibility served oftwo creating purposes withdynamic model functionalities1 used for experiments of the 3D printed of fidelity models [analysis53]. Authors (Figure created 5), two while patient-specific model 2 aorticwas used root for conductingmodels usinghemodynamic CT images analysis with each following model consisting TAVR (Figure of anatomical 6). Four structures, inks were such used as the to aorticprint wall,different myocardium, aortic valve leaflets and calcifications. These two models served two purposes with anatomical structures representing different properties, including the ink for aortic wall, model 1 used for experiments of fidelity analysis (Figure5), while model 2 was used for conducting myocardium and leaflets and calcified region as well as for the supporting material. For production hemodynamic analysis following TAVR (Figure6). Four inks were used to print di fferent anatomical of thestructures models with representing integrated different sensors properties, in the aortic including root, the finer ink fornozzles aortic wall,and layer myocardium height of and 0.4 leaflets mm with high andresolution calcified regionwere used as well to as print for the the supporting sensor ar material.ray in the For lower production section of the of models the model with integrated(Figure 6). A bioprostheticsensors in valve the aortic was root, deployed finer nozzles into the and 3D layer prin heightted models of 0.4 mm to withsimulate high resolutionTAVR treatment. were used Results to showedprint the the accuracy sensor array of in3D the printed lower section model of replicating the model (Figure patient’s6). A anatomy bioprosthetic and valvephysical was deployedbehaviour as demonstratedinto the 3D by printed the postoperative models to simulate data TAVR at diff treatment.erent cardiac Results phases showed (Figure the accuracy 6D,E). of Hemodynamic 3D printed analysismodel validated replicating the patient’s potential anatomy value andof 3D physical printed behaviour models aswith demonstrated internal sensors by the postoperativefor prediction of conductiondata at didisturbancesfferent cardiac by phases providing (Figure quantitative6D,E). Hemodynamic assessments analysis of pressure validated thechanges potential in relation value to differentof 3D valve printed sizes models (Figure with 6F–H). internal Findings sensors forof predictionthis study of confirm conduction the promising disturbances role by providingof 3D printed quantitative assessments of pressure changes in relation to different valve sizes (Figure6F–H). Findings realistic models for minimizing the risks associated with TARV procedures, thus assisting the of this study confirm the promising role of 3D printed realistic models for minimizing the risks development of optimal medical devices. associated with TARV procedures, thus assisting the development of optimal medical devices.

FigureFigure 5. Anatomical 5. Anatomical fidelity fidelity analyses analyses of theof 3Dthe printed 3D printed aortic root aortic models root and models comparison and tocomparison patient postoperative data. (A) CT scan of the 3D printed aortic root model. (B) Calibrated distance map to patient postoperative data. (A) CT scan of the 3D printed aortic root model. (B) Calibrated comparing the anatomical fidelity of the 3D printed aortic root model with the patient’s anatomy. distance(C) Histogram map comparing of the calibrated the anatomical distances between fidelity the of surface the 3D points printed of the aortic 3D printed root aortic model root with the patient’smodel and anatomy. the patient’s (C anatomy.) Histogram (D) Comparison of the calibrated of the implanted distances TAVR between prosthesis inthe the surface 3D printed points of themodel 3D withprinted the patient’s aortic postoperativeroot model data.and RCA-rightthe patient’s coronary anatomy. artery; LCA- (D) leftComparison coronary artery. of the implanted(E) Comparison TAVR ofprosthesis changes in framein the diameters 3D printed of the model implanted with valve the in patient’s the 3D printed postoperative model with the data. RCA-rightpatient’s coronary postoperative artery; data at LCA- nine di leftfferent coronary node levels. artery. Reprinted (E) Comparison with permission of under changes open accessin frame from Haghiashtiani et al. [53]. diameters of the implanted valve in the 3D printed model with the patient’s postoperative data at nine different node levels. Reprinted with permission under open access from Haghiashtiani et al. [53]. Biomolecules 2020, 10, 1577 7 of 34

Biomolecules 2020, 10, x 7 of 34

Figure 6.6.3D 3D printed printed aortic aortic root modelroot model with internal with sensorinternal arrays sensor and visualization arrays and of visualization applied pressures of appliedafter valve pressures implantation. after (Avalve) Schematic implantation. of the sensor (A) arraySchematic concept of design the sensor in planar array configuration. concept design(B) 3D printedin planar aortic configuration. root model with(B) 3D internal printed sensor aortic array root (left) model and with the correspondinginternal sensor isolated array (left)sensor and region the (right). corresponding The vertical (orange)isolated andsensor horizontal region (green) (right). electrodes The vertical of the integrated (orange) sensor and horizontalarrays on the (green) model electrodes correspond of to the the integrated top and bottom sensor electrodes arrays on in the planarmodel design,correspond respectively. to the top(C) Implantationand bottom ofelectrodes the 29-mm in Evolut the planar R TAVR design, valve framerespectively. at a shallow (C) height.Implantation (D) Implantation of the 29-mm of the Evolut29-mm EvolutR TAVR R TAVR valve valve frame frame at a at shallow an intermediate height. height.(D) Implantation (E) Implantation of the of 29-mm the 29-mm Evolut Evolut R TAVRR TAVR valve valve frame frame at at an a deep intermediate height. The height. red marked (E) Implantation lines in (C–E )of correspond the 29-mm to Evolut the intermediate R TAVR valveimplantation frame at height. a deep (F )height. Implantation The red of themarked 26-mm lines Evolut in (C R– TAVRE) correspond valve at an to intermediate the intermediate height. implantation(G) Implantation height. of the ( 29-mmF) Implantation Evolut R TAVR of the valve 26-mm at an Evolut intermediate R TAVR height. valve (H at) Implantation an intermediate of the height.31-mm CoreValve(G) Implantation TAVR valve of atthe an 29-mm intermediate Evolut height. R TAVR Reprinted valve with at an permission intermediate under height. open access (H) Implantationfrom Haghiashtiani of the et al.31-mm [53]. CoreValve TAVR valve at an intermediate height. Reprinted with permission under open access from Haghiashtiani et al. [53].

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3.3. 3D Printing in Coronary Artery Disease Use of 3D printed models in coronary artery disease (CAD) is mainly shown to guide treatment of complex coronary anomalies and this is dominated by case reports in the literature [54–57]. These isolated case reports showed the usefulness of 3D printed coronary models to simulate interventional coronary procedures, plan and guide treatment strategy of complex coronary disease. Another application of 3D printed coronary artery models is to improve understanding of coronary anomalies. Lee et al. in this study selected eight cases with one normal coronary artery and seven diseased coronary arteries comprising different coronary abnormalities [58]. Eight patient-specific coronary models were created and presented to nine cardiovascular researchers and eight clinicians (two cardiac surgeons and six cardiologists) with the aim of seeking their feedback on the usefulness of 3D printed models. Both groups indicated that 3D printed models enhanced understanding of coronary anatomy and pathologies, while the clinical group with more imaging experience indicated that 3D printed models are more useful than CT images alone. Further, this study suggested that 3D printed coronary models are useful in other areas such as improving patient-physician communication by better explaining conditions to patients; preoperative planning for cardiac surgeons and improving decision-making by multidisciplinary team collaboration through demonstrating the diagnostic anatomy to clinicians. An emerging research area of using 3D printed coronary models is to investigate optimal coronary CT scanning protocols for visualization of calcified plaques and coronary lumen in coronary stenting. Some recent studies by Sun and colleagues reported their experience with promising results achieved through use of personalized coronary models [59–63]. High-resolution CT imaging allows for better visualization and assessment of coronary lumen stenosis caused by calcified plaques, thus further validating previous findings about the effect of spatial resolution on diagnostic assessment of calcified coronary plaques [60]. Coronary CT angiography is widely used in the diagnosis of CAD, however, its clinical value in coronary stenting is debatable due to the beam hardening artifacts arising from coronary stents which negatively affect the accurate assessment of coronary lumen, especially the assessment of in-stent restenosis. 3D printed coronary artery models with six different stent diameters placed in the coronary arteries were used to simulate coronary stenting in the study conducted by Sun and Jansen [63]. With scans conducted on a latest 192-slice CT scanner, results showed that images reconstructed with a sharp kernel algorithm significantly improved the stent and stented lumen visibility compared to images reconstructed with a standard kernel algorithm (Figure7). Thin slab maximum-intensity projection (MIP) images allowed for better visualization of stented lumen in comparison with thick slab MIP images (Figure8). 3D volume rendering images provide clear views of the stent location in relation to the coronary anatomy as shown in Figure9. These preliminary reports along with others suggest the potential value of using 3D printed coronary or cardiac models for studying the optimal CT protocols, although further research is needed to validate these findings [59,62,63]. Biomolecules 2020, 10, 1577 9 of 34 Biomolecules 2020, 10, x 9 of 34

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Figure 7. Cont. Biomolecules 2020, 10, 1577 10 of 34 Biomolecules 2020, 10, x 10 of 34

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FigureFigure 7. 7.3D3D printed printed coronarycoronary models models with with coronary corona stentingry stenting scanned on scanned 192-slice on CT scanner192-slice and CT scannerimages and reconstructed images reconstructed with soft and with sharp soft kernel and algorithms. sharp kernel (A) images algorithms. were reconstructed (A): images with were reconstructedstandard soft with kernel standard Bv36 algorithm soft kernel showing Bv36 that algorithm right coronary showing stents that in these right 3 modelscoronary and stents left anterior descending stent (in model 3). (B) images were reconstructed with sharp kernel Bv59 of the in these 3 models and left anterior descending stent (in model 3). (B): images were same models with significant improvement of visualization of the stents and stented lumen, in particular reconstructedimproved visualization with sharp of kernel stent wires Bv59 in of models the same 2 and models 3. Arrows with refer significant to the stent wires.improvement Reprinted of visualizationwith permission of the under stents open and access stented from Sunlumen, and Jansenin particular [63].] improved visualization of stent wires in models 2 and 3. Arrows refer to the stent wires. Reprinted with permission under open access from Sun and Jansen [63].] Biomolecules 2020, 10, 1577 11 of 34 Biomolecules 2020, 10, x 11 of 34

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FigureFigure 8. 8.Comparison Comparison of thickof thick slab withslab thinwith slab thin maximum-intensity slab maximum-intensity projection projection (MIP) images (MIP) for visualizationimages for visualization of stents and stented of stents lumen and in stented 3D printed lumen models in 3D of printed right coronary models stents. of right (A) coronary Thin slab MIPstents. images (A) improveThin slab assessment MIP images of the improve stented lumenassessment compared of the to thick stented slab lumen MIP images compared (arrows), to andthick this slab is apparent MIP images in the model(arrows), 3 (B )and in the this presence is apparent of multiple in the stent model wires 3 (arrows). (B) in the Reprinted presence with of permissionmultiple stent under wires open (arrows). access from Reprinted Sun and Jansen with [permission63]. under open access from Sun and Jansen [63]. Biomolecules 2020, 10, 1577 12 of 34 Biomolecules 2020, 10, x 12 of 34

Figure 9. 3D volume rendering images of 3D printed coronary models with stents placed Figure 9. 3D volume rendering images of 3D printed coronary models with stents placed in the incoronary the coronary arteries. arteries. Reprinted Reprinted with permission with perm underission open under access open from Sunaccess and from Jansen Sun [63 and]. Jansen [63]. Further to the above-mentioned applications, 3D printed coronary artery models can also be used to simulateFurther blood to the flow above-mentioned to the coronary applications, arteries with 3D regard printed to the coronary hemodynamic artery models changes can associated also be withused theto developmentsimulate blood of atherosclerosis.flow to the coronary Sommer ar andteries colleagues with regard created to 3Dthe printedhemodynamic coronary changes models associatedaiming to simulatewith the thedevelopment distal resistance of atherosclero and compliancesis. Sommer of the and coronary colleagues arteries created [64]. Figure3D printed 10 is coronarya workflow models showing aiming the to steps simulate from creationthe distal of resi thestance 3D segmented and compliance coronary of the artery coronary tree to arteries 3D printed [64]. Figuremodel 10 for is investigation a workflow showing of the hemodynamic the steps from flow. creation The of vasculature the 3D segmented of the model coronary was artery printed tree with to 3Dsoft printed and elastic model material, for investigation Agilus, reflecting of the thehemodynamic arterial compliance, flow. The while vasculature the calcification of the model and other was printed with soft and elastic material, Agilus, reflecting the arterial compliance, while the calcification and other supporting structure were printed with hard and rigid material, Vero. A 3D printed chamber was designed to enable the 3D printed coronary model connected to a physiological flow Biomolecules 2020, 10, 1577 13 of 34 supporting structure were printed with hard and rigid material, Vero. A 3D printed chamber was designedBiomolecules to 2020 enable, 10, x the 3D printed coronary model connected to a physiological flow pump generating13 of 34 a constant flow loop. A range of catheters with different diameters and lengths were connected to the supportpump generating chamber allowing a constant for flow simulation loop. A of range hemodymics of catheters in the with thoracic different aorta diameters and coronary and lengths arteries atwere rest, connected light and moderateto the support exercise chamber situations. allowing Five for personalized simulation of 3Dhemodymics printed coronary in the thoracic models aorta were createdand coronary in their arteries study withat rest, successful light and measurements moderate exercise of pressure situations. at flowFive personalized rates ranging 3D from printed 80 to 160coronary mL/min models at three were main created coronary in their arteries, study including with successful rightcoronary measurements artery, of left pressure anterior at descendingflow rates andranging left circumflex from 80 to 160 arteries. mL/min Results at three showed main coronary the resistance arteries, of including the chamber right forcoronary these artery, three mainleft coronaryanterior arteriesdescending was and negligible, left circumflex with mean arteries. resistance Results being showed 0.65–5.86%, the resistance 1.23–6.86% of the and chamber 0.05–1.67%, for respectivelythese three correspondingmain coronary arteries to these was coronary negligible, arteries with (Figure mean 11resistance). This study being developed 0.65–5.86%, an 1.23–6.86% innovative methodand 0.05–1.67%, to simulate respectively realistic physiological corresponding blood to th flowese coronary in the coronary arteries arteries(Figure using11). This 3D printedstudy models,developed thus an creating innovative benchtop method models to forsimulate further realistic comprehensive physiological analysis blood and flow simulation in theof coronary coronary flowarteries changes. using 3D printed models, thus creating benchtop models for further comprehensive analysis and simulation of coronary flow changes.

Figure 10. Model development process of 3D printed coronary artery model and Figure 10. Model development process of 3D printed coronary artery model and experimental setup. (aexperimental) Coronary CT setup. angiography (a) Coronary scans of CT the angiography heart tissue andscans the of three the heart main coronarytissue and arteries the three were importedmain coronary for analysis. arteries The were coronary imported arteries for were analysis. segmented The separatelycoronary arteries from the were calcification segmented using thresholdingseparately andfrom contouring the calcification methods. (usingb) A stereolithographic thresholding and file contouring was exported methods. from volume (b) dataA andstereolithographic imported into Autodesk file was Meshmixer exported andfrom segmentation volume data errors and were imported removed. into (c )Autodesk Cylindrical meshesMeshmixer were appended and segmentation to the aortic errors root were and the removed. diseased ( coronaryc) Cylindrical artery meshes for future were pressure appended sensor connections.to the aortic (d )root The and aortic the root diseased was extended coronary at both artery the inletfor future and the pressu outlet.re (e sensor) Vessel connections. branches were extended(d) The throughaortic root each was of the extended three chambers at both and the a inlet plane and cut wasthe administeredoutlet. (e) Vessel at the branches vessel outlets were for parallelextended ends. through (f) A 2mm each wall of wasthe three generated chambers and the an lumend a plane was hollowedcut was administered out. (g) The calcification at the vessel was solidifiedoutlets for and parallel subtracted ends. from (f) the A 2mm vasculature. wall was (h) Agenerated three-chamber and the support lumen structure was hollowed was imported out. into(g) Autodesk The calcification Meshmixer. was (i) Thensolidified model and and supportsubtracted structure from are the aligned vasculature. and ready (h to) A be three- printed. (j)chamber The model support is 3D printed, structure cleaned, was and imported ready to into be attached Autodesk to a flowMeshmixer. loop. Reprinted (i) Then with model permission and undersupport open structure access from are Sommer aligned etand al. ready [64]. to be printed. (j) The model is 3D printed, cleaned, and ready to be attached to a flow loop. Reprinted with permission under open access from Sommer et al. [64]. Biomolecules 2020, 10, 1577 14 of 34 Biomolecules 2020, 10, x 14 of 34

FigureFigure 11.11. ThreeThree chamber chamber resistance. resistance. The The resistance resistance of the of chamber the chamber was determined was determined by recording by recordingthe pressure the through pressure a tube through at flow a tube rates at from flow 1.33–2.66 rates from cm 31.33–2.66/sec within cm3/sec the LAD, within LCX the and LAD, RCA LCXchambers. and RCA LAD-left chambers. anterior descending,LAD-left anterior LCX-left de circumflex,scending, RCA-right LCX-left coronary circumflex, artery. RCA-right Reprinted coronarywith permission artery. under Reprinted open access with frompermission Sommer under et al. [ 64open]. access from Sommer et al. [64]. 3.4. 3D Printing in Aortic Aneurysm and Aortic Dissection 3.4. 3D Printing in Aortic Aneurysm and Aortic Dissection Clinical value of 3D printing in aortic disease, mainly aortic aneurysm and dissection is alsoClinical dominated value of by 3D isolated printing case in aortic reports disease, showing mainly its applicationaortic aneurysm of creating and dissection realistic is aortic also dominatedmodels for by simulation isolated ofcase surgical reports procedures, showing its in application particular minimally of creating invasive realistic endovascular aortic models stent for simulationgrafting procedures of surgical of procedures, treating abdominal in particular aortic minimally aneurysm invasive (AAA) andendovascular aortic dissection stent grafting [65–74]. proceduresTam et al. analysed of treating 42 studiesabdominal in their aortic systematic aneurysm review, (AAA) with and nearly aortic 50% dissection of them [65–74]. (20 studies) Tam related et al. analysedto 3D printing 42 studies in AAA, in their eight systematic out of 42 studies review, on with thoracic nearly aorta 50% pathology, of them (20 and studies) the remaining related reports to 3D printingon 3D printing in AAA, in othereight vascularout of 42 diseases,studies on such thorac as carotid,ic aorta subclavian, pathology, celiac, and the and remaining femoral arteries reports [ 75on]. 3D printingPatient-specific in other 3Dvascular printed diseases, aortic models such as accurately carotid, subclavian, replicate aortic celiac, aneurysm and femoral and aortic arteries dissection [75]. basedPatient-specific on patient’s CT 3D imaging printed data, aortic although models some accu measurementrately replicate differences aortic at theaneurysm aortic locations and aortic and dissectiontrue lumen based are reported on patient’s to be CT more imaging than 1.0data, mm alth (Figureough some12)[65 measurement,66]. Most of thedifferences current applicationsat the aortic locationsof 3D printed and true aorta lumen models are reported are primarily to be more related than to 1.0 the mm preoperative (Figure 12) planning [65,66]. Most and simulationof the current of applicationsendovascular of repair 3D printed of AAA, aorta especially models in dealingare primarily with complex related cases, to the such preoperative as fenestrated planning stent grafts and simulationor aortic arch of aneurysmendovascular [68–73 repair]. These of situationsAAA, especi presentally challengesin dealing for with vascular complex surgeons cases, to such manage as fenestratedthe patients, stent thus 3Dgrafts printed or aortic models arch serve aneurysm as an additional [68–73]. toolThese to simulatesituations endovascular present challenges aortic repair for vascularprocedures surgeons and facilitate to manage decision-making. the patients, thus Huang 3D et printed al. first models reported serve the useas an of 3Dadditional printed tool model to simulateto guide stentendovascular grafting fenestrationsaortic repair inprocedures a juxtarenal an aorticd facilitate aneurysm decision-making. [69]. A 3D printed Huang skin et template al. first reportedbased on the CT datause of was 3D created printed to locatemodel theto fenestrationguide stent positiongrafting onfenestrations the stent graft. in a Thejuxtarenal skin template aortic aneurysmwas then used [69]. to A cover3D printed the stent skin graft template prior to based the surgical on CT proceduredata was created for providing to locate accurate the fenestration location of positionfenestration on the holes stent on thegraft. stent The graft. skin This template novel was approach then forused improving to cover fenestrationthe stent graft accuracy prior onto the the surgicalstent graft procedure was further for confirmedproviding byaccurate Rynio location et al. who of producedfenestration a 3D holes printed on the aortic stent arch graft. template This novel from approachCT angiographic for improving data to improvefenestration accuracy accuracy and on eff ectivethe stent management graft was offurther thoracic confirmed aortic aneurysms by Rynio byet al.the who fenestrated produced and a 3D modified printed stent aortic grafts arch [ 74template]. from CT angiographic data to improve accuracy and effectiveKarkkainen management and colleagues of thoracic created aortic a realistic aneurysms 3D printed by AAAthe fenestrated model for simulationand modified of endovascular stent grafts [74].aneurysm repair by surgical trainees with different experiences [76]. Their 3D printed AAA model consists of three layers: inner rigid layer and soft flexible outer layer with each having 3 mm Biomolecules 2020, 10, 1577 15 of 34 thickness and the thin 1 mm inside layer covering the rigid one. The model was connected to a fluid pump with endovascular stent grafting procedures performed under angiography. Twenty trainees (13 were less experienced and seven were experienced) participated in performing 22 simulations with experienced trainees having significantly lower procedural time and fluoroscopic exposure time than inexperienced ones (p < 0.05). All experienced trainees completed the procedures independently and in less than 45 min, in contrast, only two of the less experienced trainees completed the entire procedures independently and six out of 13 completed the procedures in less than 45 min. This study presents another opportunity of using 3D printed aorta models for simulation and training of surgical procedures [76]. Biomolecules 2020, 10, x 15 of 34

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Figure 12. Cont. Biomolecules 2020, 10, 1577 16 of 34 Biomolecules 2020, 10, x 16 of 34

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Figure 12.12.3D 3D printed printed model model of abdominalof abdominal aortic aortic aneurysm aneurysm from CTfrom angiographic CT angiographic data. (A )data. Anterior (A) Anteriorreview of thereview 3D printed of the AAA 3D printed model showing AAA model an infrarenal showing AAA an extending infrarenal to commonAAA extending iliac arteries. to (commonB) Posterior iliac view arteries. of the aneurysm(B) Posterior and renalview arteries. of the aneurysm The mode wasand printed renal arteries. with ‘Strong The andmode Flexible was printedPlastic’ material with ‘Strong by Shapeways. and Flexible Plastic’ material by Shapeways.

Karkkainen3D printing and models colleagues of aortic created dissection, a realistic in particular, 3D printed reproducing AAA model the intimal for simulation flap is very of endovascularchallenging due aneurysm to the very repair thin by structure surgical separating trainees with true different lumen from experiences false lumen [76]. (Figure Their 3D 13)[ printed64,65]. AAALimited model research consists is done of three in this layers: area inner and a rigid study layer by Hossien and soft etflexible al. reported outer layer interesting with each findings having [67 3]. Threemm thickness cases of and type the A dissectionthin 1 mm wereinside selected layer covering with involvement the rigid one. of aorticThe model branches was toconnected some extent. to a fluid3D aortic pump models with wereendovascular printed usingstent polylacticgrafting pr acidocedures materials performed demonstrating under angiography. true and false Twenty lumen traineesin relation (13 to were the aortic less branches.experienced Intimal and flapseven was were also experienced) printed to separate participated true lumen in performing from the false 22 simulationslumen in their with case experienced report. Similar trainees to other having aortic significantly disease, the lower 3D printedprocedural models time allowand fluoroscopic for surgical exposuresimulation time of complex than inexperienced endovascular ones repair (p < of0.05). aortic All dissection, experienced although trainees further completed research the isprocedures needed to independentlytest its clinical valueand in moreless than cases. 45 min, in contrast, only two of the less experienced trainees completed the entire procedures independently and six out of 13 completed the procedures in less than 45 min. This study presents another opportunity of using 3D printed aorta models for simulation and training of surgical procedures [76]. 3D printing models of aortic dissection, in particular, reproducing the intimal flap is very challenging due to the very thin structure separating true lumen from false lumen (Figure 13) [64,65]. Limited research is done in this area and a study by Hossien et al. reported interesting findings [67]. Biomolecules 2020, 10, x 17 of 34

Three cases of type A dissection were selected with involvement of aortic branches to some extent. 3D aortic models were printed using polylactic acid materials demonstrating true and false lumen in relation to the aortic branches. Intimal flap was also printed to separate true lumen from the false lumen in their case report. Similar to other aortic disease, the 3D printed models allow for surgical simulationBiomolecules 2020 of ,complex10, 1577 endovascular repair of aortic dissection, although further research is needed17 of 34 to test its clinical value in more cases.

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FigureFigure 13.13.3D 3D printed printed model model of typeof type B aortic B aortic dissection. dissection. (A) Anterior (A) Anterior view of view the 3D of printedthe 3D modelprinted of modelaortic arch of aortic and descending arch and descending aorta. Arrows aorta. refer Arro to thews intimal refer flapto the separating intimal flap true lumenseparating from true false lumenlumen. from (B) Inferior false viewlumen. of the (B) intimal Inferior flap view and trueof the and intimal false lumen flap compartments. and true and The false mode lumen was compartments.printed with ‘strong The and mode flexible was plastic’ printed material with by Shapeways.‘strong and flexible plastic’ material by Shapeways. Tong et al. expanded the application of 3D printing aorta models to guide surgical planning of fenestrationTong et al. expanded for treatment the application of patients of with 3D printing thoracoabdominal aorta models aortic to guide aneurysm surgical (TAAA) planning [77 of]. fenestrationTheir retrospective for treatment study comprisedof patients 34with patients thoracoabdominal who received aortic fenestrated aneurysm endovascular (TAAA) [77]. stent Their graft retrospectiverepair (fEVAR) study for thoracoabdominalcomprised 34 patients aortic who disease received (19 fenestrated had aortic dissectionendovascular and stent 15 had graft thoracic repair (fEVAR)abdominal for aorticthoracoabdominal aneurysms). aortic CT angiographic disease (19 had images aortic were dissection used to and create 15 had patient-specific thoracic abdominal models aorticwhich aneurysms). were printed CT using angiographic materials forimages biocompatibility were used to and create transparency. patient-specific The aortic models stent which graft were was printeddeployed using in each materials 3D printed for biocompatibility model in the operatingand transparency. room to The determine aortic stent the exactgraft was position deployed of each in eachfenestration 3D printed or branchmodel in which the operating was marked room on to thedete stentrmine graft the exact (Figures position 14 and of each15). Thisfenestration allows foror branchaccurate which planning was marked of personalised on the stent fEVAR graft based (Figures on measurements 14 and 15). This of allows the size for of accurate the fenestrations planning forof personalisedindividual arterial fEVAR branches, based on thus measur reducingements the of riskthe size of complications of the fenestrations such as for endoleak. individual Following arterial branches,customization, thus thereducing fenestrated the risk stent of graft complications was reloaded such into as the endoleak. delivery sheathFollowing for patient customization, development. the fenestratedResults showed stent graft the successful was reloaded treatment into the of delive thesery complicated sheath for patient thoracoabdominal development. aortic Results disease showed by thecustomized successful fenestrated treatment stent of graftsthese withcomplicated a mean follow-upthoracoabdominal of 8.5 months aortic in thisdisease case series.by customized All of the fenestratedbridged visceral stent vesselsgrafts with were a patent mean withfollow-up no enlargement of 8.5 months of the in aneurysm this case series. during All the of follow-up the bridged [77]. visceralThis study vessels proves were the patent clinical with value no of enlargement 3D printed aortic of the models aneurysm in guiding during treatment the follow-up of aortic [77]. disease This studyby fEVAR, proves although the clinical further value research of 3D onprinted a large aortic sample models size in with guiding long follow-uptreatment ofof clinicalaortic disease outcomes by is warranted. Biomolecules 2020, 10, x 18 of 34

BiomoleculesfEVAR, although2020, 10, 1577 further research on a large sample size with long follow-up of clinical outcomes18of is 34 warranted.

FigureFigure 14. 14.Use Use of 3D of printed 3D printed model tomodel guide fenestratedto guide fe stentnestrated graft repair stent of graft a thoracoabdominal repair of a aorticthoracoabdominal aneurysm (TAAA). aortic (A) Accordinganeurysm to (TAAA). the measurements (A) According determined to inthe EndoSize measurements or 3mensio, (Bdetermined) a 3D model in of EndoSize the TAAA or was3mensio, printed. (B) ( aC )3D The model main of aortic the TAAA stent-graft was wasprinted. completely (C) The released main inaortic the 3D stent-graft model, and was the positioncompletely of each released fenestration in the or 3D branch model, was marked.and the (Dposition) The fenestration of each wasfenestration cut using or an branch electric was pen, marked. and a wire (D) was The sutured fenestration around was its cut edge. using (E) Intraoperativean electric pen, images and showinga wire thewas calibrated sutured catheteraround (left)its edge. in the ( TAAAE) Intraoperative and the fenestrated images stent-graft showing (right) the calibrated in position. (Fcatheter) Completion (left) ofin thethe procedure TAAA and with the addition fenestrated of the stent-graft proximal stent-graft.(right) in position. Reprinted (F with) Completion permission fromof the Tong procedure et al. [77]. with addition of the proximal stent-graft. Reprinted with permission from Tong et al. [77]. Biomolecules 2020, 10, 1577 19 of 34 Biomolecules 2020, 10, x 19 of 34

Figure 15.15.Use Use of 3D of printed 3D printed model to guidemodel fenestrated to guide stent fe graftnestrated repair ofstent a thoracoabdominal graft repair aorticof a thoracoabdominaldissection. (A,B) A thoracoabdominal aortic dissection. aortic (A,B dissection) A thoracoabdominal after prior thoracic aortic endovascular dissection aorticafter repair.prior thoracic(C) The main endovascular aortic stent-graft aortic was repair. completely (C) The released main aortic in the 3Dstent-graft model of was the lesion,completely and the released position inof eachthe 3D fenestration model of or the branch lesion, was and marked. the position (D,E) Intraoperative of each fenestration images showing or branch the fenestrations was marked. for (theD,E visceral) Intraoperative branches. (F )images Completed showing procedure the showing fenestrations the bridging for stentgraftsthe visceral in the branches. target vessels (F) Completedand obliteration procedure of the false showing lumen. Reprinted the bridging with permission stentgrafts from Tongin the et al.target [77]. vessels and obliteration of the false lumen. Reprinted with permission from Tong et al. [77]. 3.5. 3D Printing in Pulmonary Artery Disease

3.5. 3DApplication Printing in ofPulmonary 3D printing Artery in pulmonaryDisease diseases mainly lies in the pre-surgical planning for treatment of congenital heart disease involving anomalies such as pulmonary atresia or stenosis or Application of 3D printing in pulmonary diseases mainly lies in the pre-surgical planning for coronary-pulmonary artery fistula [78–81]. With patient-specific 3D printed models incorporated into treatment of congenital heart disease involving anomalies such as pulmonary atresia or stenosis or the management plan, it was found useful to assist decision making and reduce the contrast volume coronary-pulmonary artery fistula [78–81]. With patient-specific 3D printed models incorporated into during angiography and improve the performance efficiency by interventional cardiologists. the management plan, it was found useful to assist decision making and reduce the contrast volume An emerging area is to use 3D printing for detection of pulmonary embolism aiming to develop during angiography and improve the performance efficiency by interventional cardiologists. optimal CT pulmonary angiography (CTPA) protocols [82–84]. Our experience has shown its value An emerging area is to use 3D printing for detection of pulmonary embolism aiming to develop in this aspect. A 3D printed pulmonary artery model using normal CTPA images was generated optimal CT pulmonary angiography (CTPA) protocols [82–84]. Our experience has shown its value comprising the main pulmonary arteries [82]. The model was scanned on a 64-slice CT scanner with in this aspect. A 3D printed pulmonary artery model using normal CTPA images was generated different protocols. There was high accuracy between the 3D printed model and original CT images comprising the main pulmonary arteries [82]. The model was scanned on a 64-slice CT scanner with with respect to replication of normal anatomy with mean difference between original CT images, different protocols. There was high accuracy between the 3D printed model and original CT images STL and 3D printed model less than 5%. Low-dose CTPA protocol such as use of 80 kilovoltage peak with respect to replication of normal anatomy with mean difference between original CT images, STL and 3D printed model less than 5%. Low-dose CTPA protocol such as use of 80 kilovoltage peak (kVp) with 0.9 pitch was recommended with resultant lower radiation dose while still acquiring Biomolecules 2020, 10, 1577 20 of 34

(kVp) with 0.9 pitch was recommended with resultant lower radiation dose while still acquiring Biomolecules 2020, 10, x 20 of 34 diagnostic images. This preliminary finding was supported by later experiments with simulation of pulmonarydiagnostic embolism images. This in the preliminary 3D printed finding model. was supported by later experiments with simulation of pulmonaryWith successful embolism creation in the of 3D personalized printed model. pulmonary artery model, we further tested different CTPA protocolsWith using successful the 2nd creation and 3rd of generation personalized dual-source pulmonary CTartery scanners. model, we Large further and tested small different emboli were insertedCTPA into protocols the main using and the side 2nd pulmonary and 3rd generation arteries dual-source to mimic pulmonary CT scanners. embolism Large and [ 83small,84]. emboli A series of CT scanswere inserted were performed into the main with and kVp side ranging pulmonary from arteries 70 to 80, to 100mimic and pulmonary 120, pitch embolism 0.9, 2.2 and[83,84]. 3.2. A Image series of CT scans were performed with kVp ranging from 70 to 80, 100 and 120, pitch 0.9, 2.2 and 3.2. quality was quantitatively analysed by measuring the signal-to-noise ratio and qualitatively assessed Image quality was quantitatively analysed by measuring the signal-to-noise ratio and qualitatively by two experienced radiologists. Results showed the feasibility of developing low-dose CTPA protocols assessed by two experienced radiologists. Results showed the feasibility of developing low-dose whenCTPA kVp protocols was reduced when from kVp 120was to reduced 100 or 80from and 120 pitch to 100 was or increased80 and pitch to was 2.2 orincreased 3.2 without to 2.2 significantly or 3.2 affectingwithout the significantly image quality affecting when the 128-slice image CTquality was when used (Figure128-slice 16CT)[ 83was]. Whereasused (Figure when 16) CTPA[83]. was conductedWhereas on when the latest CTPA CT was such conducted as 192-slice on scanner,the latest ultra CT such low-dose as 192-slice protocol scanner, was also ultra achievable low-dose when furtherprotocol reducing was also kVp achievable to 70 and when increasing further pitchreducing to 2.2 kVp or to 3.2 70 stilland allowingincreasing forpitch detection to 2.2 or of3.2 small still and peripheralallowing pulmonary for detection embolism of small and with peripheral no significant pulmonary effect embolism on the image with no quality significant (Figure effect 17 on)[ 84the]. image quality (Figure 17) [84].

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FigureFigure 16. Computed 16. Computed tomography tomography pulmonary pulmonary angiography angiography (CTPA) in(CTPA) the detection in the ofdetection main pulmonary of embolismmain withpulmonary different embolism scanning with protocols. different (A,B scanning) When pitch protocols. was increased (A,B): When to 3.2, imagepitch noisewas was increasedincreased with to 70 3.2, and image 80 kVp noise protocols; was increased (C,D) in with contrast, 70 and no 80 significant kVp protocols; change (C, ofD) image: in contrast, quality was notedno with significant 100 and 120change kVp of protocols, image regardlessquality was of pitchnoted values. with 100 Arrows and refer120 tokVp the thrombusprotocols, in the mainregardless pulmonary of arteries.pitch values. Reprinted Arrows with refer permission to the thrombus under open in the access main from pulmonary Aldosari arteries. et al. [83 ]. Reprinted with permission under open access from Aldosari et al. [83]. Biomolecules 2020, 10, 1577 21 of 34 Biomolecules 2020, 10, x 21 of 34

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Figure 17. Cont. Biomolecules 2020, 10, 1577 22 of 34

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FigureFigure 17. Computed17. Computed tomography tomography pulmonary pulmonary angiography angiography (CTPA) (CTPA) in the in detection the detection of peripheral of pulmonaryperipheral embolism pulmonary with diembolisfferentm scanning with different protocols. scanning (A–D): protocols. The small thrombus(A–D): The is viewedsmall as low-attenuationthrombus is fillingviewed defect as low-attenuation in the left segmental filling pulmonary defect in the artery left segmental (top arrows) pulmonary and right pulmonaryartery artery(top (bottom arrows) arrows) and right and theypulmonary are visible artery in all (bottom protocols, arrows) regardless and ofthey kVp are or pitchvisible values in all used. Reprinted with permission under open access from Aldosari et al. [84]. Biomolecules 2020, 10, 1577 23 of 34

These findings indicate the potential applications of 3D printed models in optimizing CT scanning protocols, in particular in the diagnostic detection of pulmonary embolism, given the fact that CTPA is the first line technique in the diagnosis of pulmonary embolism. 3D printed realistic models offer advantages over commercial body phantoms not only because of low cost, but also the capability of providing individualized anatomy and pathology associated with 3D printed models as opposed to the commercial ones with only showing average adult or paediatric anatomical structures. Further research should focus on developing 3D printed chest phantom with simulation of bones, lungs, heart and cardiovascular vessels as well as muscles to represent realistic anatomical environment, thus protocols including chest and cardiac CT imaging could be optimized. Another novel application of 3D printing technique is to assist management with the recent coronavirus disease 2019 (COVID-19) pandemic which results in a shortage of medical supplies, in particular, the personal protective equipment (PPE) [85–88], given the primary presentation of respiratory symptoms by COVID-19 [89–93], although it is also associated with cardiovascular disease [94–97]. 3D printing is playing an important role in providing medical devices including PPE when we are still fighting against the COVID-19 as shown in some reports documenting an overview of 3D printing applications and challenges in the COVID-19 [87,98].

3.6. 3D Bioprinting in Cardiovascular Disease Bioprinting is promising, although it is still in its early stage. Tissue engineering combined with 3D printing represents a fast developing technique in recent years with creation of scaffold structures for use in regeneration of tissues and organs [99–106]. In recent years, significant progress has been made in 3D bioprinting with studies reporting promising results of printing cardiovascular tissues and organs. Biomaterials guarantee the success of 3D bioprinting as materials must be biocompatible and non-toxic. Further, mechanical properties are equally important as they influence cell function and viability and cardiovascular structural integrity [107–109]. Bioinks used for bioprinting of cardiovascular tissues also need to mimic properties such as stiffness of the extracellular matrix of heart and other tissues [110]. Progress in 3D bioprinting and tissue engineering has made possible to generate 3D printed cardiovascular constructs, however, to achieve physiological levels of cardiomyocytes is still challenging with many obstacles to be overcome before printing tissues with the clinical sizes. Cell-laden bioprinting represents a very promising technology since it is capable of achieving well-controlled distribution of the cells (both cell density and diffusion distance) in a complex environment, mimicking the function of cardiovascular tissue and cardiomyocytes. Several studies have reported the feasibility of 3D bioprinting cardiovascular constructs, although the research was based on a small scale of vascular channels [111–116]. Miller et al. 3D printed a 1 mm diameter of vascular construct with generation of endothelial cell-line lumen but lack of perfusion to the constructs, thus, having very limited applications [111]. Kolesky and colleagues advanced the application to perfused channels in a 3D printed construct with human mesenchymal stem cells and fibroblasts embedded in an extracellular matrix [112]. They were able to inject the endothelial cells into the 3D printed channels and maintained perfusion for more than six weeks. Two research groups by Skylar-Scott and Brandenberg et al. used high-resolution laser methods to generate microvascularized constructs with a diameter of 20–50 µm simulating capillaries [113,114]. However, there is a strong demand on the use of multiplexing printheads since it requires very high resolution and fast printing to print this kind of scale scaffold. Jang et al. demonstrated the promising results of 3D printed complex vascular constructs with functional structures [115]. The 3D printed patch had 8 mm and 0.5 mm for diameter and height, respectively. In vivo animal testing, the developed stem cells improved cardiac functions, reduced cardiac fibrosis and scar formation, thus showing benefits in cardiac repair. Redd et al. presented the similar findings of developing 3D printed perfused microvascular constructs with implanted in the infarcted rat models [116]. The perfusable microvascular grafts as analysed by optical microangiography imaging Biomolecules 2020, 10, 1577 24 of 34 showed improved vascular remodelling and enhanced coronary perfusion. These results reveal the promise and opportunity for cardiac tissue engineering combined with 3D bioprinting. Hynes et al. further extended the application of bioprinting to understand the dynamics of circulating tumour cells (CTC) within the vascular beds [117]. They used 3D bioprinting technology to develop living models of the human vasculature channels that are responsive to mechanical stress enabling analysis of biological and physical factors in vitro situation. The biomaterial was planted with human brain microvasculature endothelial cells and were then perfused to generate vascular geometry structures simulating normal tissues with cell growth and formation. CTC cell lines of a metastatic mammary gland carcinoma were chosen to ensure metastatic vascular attachment. Computational fluid modelling was performed to analyse hemodynamic changes such as wall shear stress. Figure 18 shows the steps of 3D printed vascular beds with complex geometry that were embedded in a hydrogel. Results showed the significant mechanical changes in relation to vessel distensibility with presence of endothelial cells. Particle image velocity (PIV) was used to analyse flow behaviour difference between acellular and endothelialized vessels in comparison with computational simulations. There was a good agreement between predicted and experimentally determined flow patterns for these two vessels. PIV observed the flow partitioning of CTC cells toward the centre of the vessel. This study offers a unique experimental design using a combination of different novel approaches including 3D bioprinting, bioengineering and computation for studying the biophysics of endothelial cell behaviour of CTC during metastasis. Biomolecules 2020, 10, x 25 of 34

Figure 18. Cont.

Figure 18. Bioprinting endothelialized vascular beds with complex geometry. (A) Schematic representation of vascular bed printing using the ink method. (B) Cytoskeletal morphology of microvascular endothelial cells shows high alignment in straight regions of the vascular bed (inset i, red border), with chaotic cytoskeletal alignment in the fork regions (inset ii, blue border). (C) Alignment of cytoskeleton in perfused engineered beds shows high actin alignment in the wall of straight vascular regions (yellow arrows), whereas fork regions exhibit weak alignment (blue arrows). AU, arbitrary units. (D) Direction of preferential alignment follows flow direction. Coloured arrows indicate principle flow direction (up, yellow; down, purple), which tends to agree with orientation direction of endothelial cell alignment. Reprinted with permission under open access from Hynes et al. [117]. Biomolecules 2020, 10, x 25 of 34

Biomolecules 2020, 10, 1577 25 of 34

Figure 18.Figure Bioprinting 18. Bioprinting endothelialized endothelialized vascular vascular beds withbeds complex with geometry.(complexA) geometry. Schematic representation (A) Schematic representationof vascular of bedvascular printing usingbed theprinting ink method. using (B) Cytoskeletalthe ink method. morphology (B of) Cytoskeletal microvascular endothelial morphology cells shows high alignment in straight regions of the vascular bed (inset i, red border), with chaotic of microvascularcytoskeletal alignmentendothelial in the cells fork regions shows (inset high ii, blue alignment border). (C) Alignmentin straight of cytoskeleton regions of in perfusedthe vascular bed (insetengineered i, red border), beds shows with high actinchaotic alignment cytoskel in theetal wall ofalignment straight vascular in the regions fork (yellow regions arrows), (inset ii, blue border).whereas (C fork) Alignment regions exhibit of weakcytoskeleton alignment (bluein perfused arrows). AU, engineered arbitrary units. beds (D )shows Direction high of actin alignmentpreferential in the wall alignment of straight follows flow vascular direction. regions Coloured (yellow arrows indicatearrows), principle whereas flowdirection fork regions (up, yellow; down, purple), which tends to agree with orientation direction of endothelial cell alignment. exhibit weakReprinted alignment with permission (blue under arrows). open access AU, from arbitrary Hynes et al.units. [117]. (D) Direction of preferential alignment follows flow direction. Coloured arrows indicate principle flow direction (up, 4. Limitations and Future Research Directions yellow; down, purple), which tends to agree with orientation direction of endothelial cell alignment.Promising Reprinted results with of permission 3D printing under in the open cardiovascular access from applications Hynes et are al. [117]. shown in the above-mentioned areas, however, a number of limitations exist which still hinder the widespread use of 3D printing in clinical practice. Prospective and multi-centre studies are still lacking with RCTs only available in the 3D printing in CHD for medical education, while in other areas, case reports or case series dominate most of the applications (66%) as shown in a recent review article on 3D printing in CHD [118]. Inclusion of a larger sample size with potential longitudinal studies of mid to long-term outcomes is necessary to validate the clinical value of 3D printing such as how 3D printed models change patient’s management and whether treatment outcomes are significantly improved with incorporation of 3D printing into practice. High cost is another issue that needs to be addressed before 3D printing is incorporated into routine clinical practice. With cost reductions in 3D printers and printing materials, 3D printing will become an acceptable technique for both patients and clinicians. Despite high accuracy and quality of 3D printed models, even with multicolour materials, most of the current models are static, thus they do not represent realistic properties similar to normal tissues. Generation of realistic and dynamic models is of clinically important for cardiovascular disease as simulation of hemodynamic blood flow in these 3D cardiovascular models plays a crucial role in creating a realistic environment that can mimic the real physiological situation. Some recent studies already demonstrated the dynamic mechanical properties of 3D printing materials in coronary artery disease and coronary stents [119–121]. 3D printed bioresorbable stents using polymer materials such as polylactic acid (PLA) or polycaprolactone (PCL) have shown good compatibility with blood and cells, and they can be used to print coronary stents for treating coronary artery disease [120]. Guerra et al. Biomolecules 2020, 10, 1577 26 of 34 produced 3D printed composite stents using PLA and PCL materials. They showed that both PLA and PCL are both biocompatible with PLA stent presenting with an average cell proliferation of 8.28% and PCL 12.46% after three days [121]. However, each of them has limitations with PLA having high modulus (high elasticity with excellent recoil ratio) but low properties restricting its implantation, while PCL having low modulus (high rigidity with best radial expansion), thus limiting its application for stenting purpose. Therefore, composite PCL/PLA stents were recommended as they improve the performance by overcoming each material’s limitations. Although extensive attempts have been made by researchers to use 3D bioprinting technologies to print heart, blood vessels, heart valves as well as cardiovascular constructs [111–116,122–126], the main technological barriers or obstacles in bioprinting are to develop suitable biomaterials (bioinks) with good mechanical strength and biocompatibility to match the biological properties of native organs [127]. Bioprinting of cardiovascular organs or cells is more challenging since the bioprinted cells/stem cells need to maintain proliferation and differentiation in a living extracellular microenvironment. Despite good resolution available with the current bioprinters, further improvement in resolution is necessary to print small vessels with high accuracy. Table1 is a summary of bioprinting processes showing comparison of different types of bioprinters, printing materials and other features. These promising findings will need to be tested in vivo situations before bioprinted models can be applied to patients for treating cardiovascular disease. Biomolecules 2020, 10, 1577 27 of 34

Table 1. Characteristics of 3D bioprinting processes. Reprinted with permission under open access from Li et al. [127].

Types of Cell Biomaterials Bioprinting Speed Cost Advantages Disadvantages Bioprinters Viability/Resolution Wide availability; low cost; high Poor vertical structure clogging Inkjet-based Low-viscosity suspension of living ~90% Fast resolution; high printing speed; characteristics; thermal and Low bioprinting cells; biomolecules; growth factors 20–100 µm (<10,000 droplets/s) ability to introduce concentration mechanical stress to cells; limited gradients in 3D constructs printable materials (liquid only) Hydrogel; melt; cells; proteins and ceramic materials; solutions, pastes, or Numerous materials that can be Limited mechanical stiffness; dispersions of low to high viscosity; printed with any dimensions; mild critical timing of gelation time; Pressure-assisted Poly Lactic-co-Glycolic Acid (PLGA); 40–80% conditions (room temperature); specific matching of the densities Slow Medium bioprinting tricalcium phosphate (TCP); collagen 200 µm use of cellular spheroids; direct of the material and the liquid and chitosan; collagenalginate-silica incorporation of cells; and medium to preserve shapes; composites coated with HA; and homogenous distribution of cells low resolution and viability agarose with gelatin Nozzle-free, noncontact process; High cost; cumbersome and time Laser-assisted Hydrogel, media, cells, proteins and >95% cells are printed with high activity consuming; requires a metal film Medium High bioprinting ceramic materials of varying viscosity >20 µm and high resolution; high control and thus is subject to metallic of ink droplets and precise delivery particle contamination Applicable to photopolymers only; Solid freeform and nozzle-free lack of biocompatible and technology; highest fabrication biodegradable polymers; harmful Light-sensitive polymer materials; >90% accuracy; compatibility with an Stereolithography Fast (<40,000 mm/s) Low effects from residual toxic curable acrylics and epoxies ~1.2–200 µm increasing number of materials; photo-curing reagents; possibility light-sensitive hydrogels can be of harm to DNA and human skin printed layer-by-layer by ultraviolet (UV) Biomolecules 2020, 10, 1577 28 of 34

5. Summary There is no doubt that 3D printing represents a fast evolving technology over the last decades with increasing reports available in different medical domains. Use of 3D printing in cardiovascular disease is one of the most exciting applications in the medical field, given the high prevalence of cardiovascular disease worldwide and associated high morbidity and mortality. Personalized 3D printed models revolutionize the current practice of planning and treating patients with different kinds of cardiovascular disease, ranging from congenital heart disease to acquired coronary, valvular, aortic and pulmonary artery diseases. These realistic physical models enhance clinician’s understanding of complex pathological situations in relation to the surrounding structures and improve their confidence in performing difficult and complex procedures, hence achieving the outcomes of better patient management with low surgery or procedure-related complications. 3D bioprinting is showing its significant impact on the development of 3D printing technology with early results of printing biocompatible cardiovascular tissues and structures. This article provides an overview of the clinical applications of 3D printing in these areas. With further improvements in 3D printing technology and advancements in printing materials in the near future, we expect to see more promising results available in the literature and witness how this technique benefits patient care and clinical practice.

Funding: This research received no external funding. Conflicts of Interest: The author confirms that he has no conflict of interest to declare for this publication.

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