We thank staff members at the UCLA Translational Research Imaging Center and the Department of Laboratory Animal Medicine at University of California, Los Angeles, CA, USA for their assistance. This work is supported in part by the Department of Radiology and Medicine at David Geffen School of Medicine at UCLA, the American Heart Association (18TPA34170049), and by the Clinical Science Research, Development Council of the Veterans Health Administration (VA-MERIT I01CX001901).

We conducted the experiments according to the guidelines by the Animal Welfare Act, the National Institutes of Health, and the American Heart Association on Research Animal Use. Our Institutional Animal Care and Use Committee approved the animal study protocol.
1. Preprocedural preparation of 3D printed coronary stenosis implants
<ol>
	<li>Using tweezers, dip-coat the printed implants in a 25% heparin solution to prevent thrombus formation and allow to air dry for 24 h.</li>
</ol>
2. Preprocedural preparation of animal subjects
<ol>
	<li>Have male Yorkshire swine (SNS Farms, 30&#8211;45 kg) arrive at the institution 1 week prior to the experiment date and allow them to acclimate.</li>
	<li>Keep the swine in a fasting state after midnight the day prior to the procedure.</li>
</ol>
3. Procedural anesthesia
<ol>
	<li>Sedate the swine with intramuscular ketamine (10 mg/kg) and intravenous midazolam (1 mg/kg).</li>
	<li>Ventilate the animals with an oxygen-isoflurane (1&#8211;2%) mixture.</li>
	<li>Perform endotracheal intubation once the animal subject is sedated.</li>
	<li>Infuse intravenous (IV) rocuronium (2.5 mg/kg/h) and give additional boluses (1&#8211;3 mg/kg IV every 20&#8211;30 min) when needed to achieve diaphragmatic immobilization.</li>
	<li>Maintain a surgical plane of anesthesia throughout the procedure by checking for awakening, movements, wide fluctuation in vital signs, and other signs of distress or discomfort throughout the duration of the experiment. We monitored the swine for roughly 6 h under anesthesia.</li>
</ol>
4. Vascular access
<ol>
	<li>Using the Seldinger technique, insert the arterial and venous sheaths into the bilateral femoral arteries and veins of the subjects.</li>
	<li>Flush all catheter ports continuously with heparinized normal saline.</li>
</ol>
5. Preprocedural medication administration
<ol>
	<li>Administer amiodarone intramuscularly (1.5 mg/kg), lidocaine intravenously (2 mg/kg), and esmolol intravenously (1 mg/kg) as needed for prophylaxis against arrhythmia. Give repeat dosages of amiodarone, lidocaine, and esmolol as needed throughout the course of the experiment to suppress ventricular rhythms and control heart rate response.</li>
	<li>After vascular access is obtained, administer heparin (5,000&#8211;10,000 units) to keep an activated clotting time (ACT) &#62;300 s. Check the ACT every hour during the course of the experiment and give additional intravenous heparin as needed to maintain the ACT goal.</li>
</ol>
6. Hemodynamic monitoring
<ol>
	<li>Use a single lateral electrocardiography (ECG) chest lead for recording changes in ST segment, T-waves, and heart rate during the entire experimental period.</li>
	<li>Use a pressure transducer to record continuous femoral arterial pressure throughout the procedure.</li>
	<li>Attach a pulse oximeter to the animal&#39;s ear or lip for continuous pulse oximetry recordings.</li>
</ol>
7. Preparation of implant delivery equipment
<ol>
	<li>Prior to performing coronary angiography, insert a deflated NC Trek over-the-wire coronary balloon through a mother-and-child catheter of the desired size such that the balloon tip extends beyond the tip of the catheter.</li>
	<li>Mount the 3D printed implant onto the deflated angioplasty balloon such that the implant is positioned between the markers of the balloon and close to the proximal marker (Figure 1B).</li>
	<li>Inflate the balloon with an insufflator to 2&#8211;3 atm in order to fix the implant onto the balloon. Verify that the implant is positioned closer to the proximal half of the balloon so it will be closest to the mother-and-child catheter when ready for removal (Figure 1B).</li>
</ol>
8. Coronary angiography and deployment of coronary implant
<ol>
	<li>Position the fluoroscopic C-arm in the anteroposterior (AP) projection.</li>
	<li>Attach a control valve (see Table of Materials) to a left or right coronary guide catheter (see Table of Materials).</li>
	<li>Introduce the guide catheter over a J-tipped wire through the right femoral artery sheath and, under fluoroscopic guidance, advance the catheter to the aortic root.</li>
	<li>Selectively (or nonselectively) engage the catheter into the left main coronary artery (LMCA) and inject 5 mL of iodinated contrast under fluoroscopy to visualize the left coronary system.</li>
	<li>Position the guide catheter towards the LMCA for the second angiogram (Figure 2). If coronary artery engagement proves difficult, due in part to the short aortic arch of the swine, consider performing non-selective angiograms as long as they provide adequate visualization of the vessels.</li>
	<li>Once engaged within, or positioned near the LMCA, under fluoroscopy, advance a 0.014&#34;, 300 cm coronary wire (see Table of Materials) into the LMCA and further advance the wire to the distal left anterior descending artery (LAD) or left circumflex coronary artery (LCX) if desired (Figure 3).</li>
	<li>Under fluoroscopic guidance, insert the previously assembled mother-and-child catheter with the inflated coronary angioplasty balloon and implant over the coronary wire and advance to the desired location along the coronary vessel. Inject 5 mL of iodinated contrast to visualize a discrete narrowing at the desired location where the coronary implant should be deployed (Figure 4).</li>
	<li>Once the implant is in position, advance the mother-and-child catheter to the proximal marker of the inflated balloon.</li>
	<li>Deflate the balloon and retract it through the mother-and-child catheter. This process allows the mother-and-child catheter to shear the implant off the balloon as it is retracted and fixes the position of the implant in the designated segment of the vessel.</li>
	<li>Remove the balloon, mother-and-child catheter, and coronary wire.</li>
	<li>Perform final angiograms to document the location of the new artificial stenosis within the vessel. When feasible, angiograms should be performed in two orthogonal views to acquire visual estimation of stenosis severity. A final angiography (Figure 5) can also be performed with subselective positioning of the mother-and-child catheter in the proximal vessel, which provides excellent opacification with minimal contrast.</li>
	<li>Immediately transfer the animal to the MR suite to undergo cardiac stress perfusion MRI using gadobutrol (0.1 mM/kg) injected at a rate of 2 mL/sec. 
	NOTE: The stress agent used was a 4 min infusion of adenosine at 300 &#181;g/kg/min. The imaging protocol included 1) cine imaging (field of view [FOV] = 292 x 360 mm, matrix size = 102 x 126, repetition time [TR] = 5.22 ms, echo time [TE] = 2.48 ms, slice thickness = 6 mm, pixel bandwidth = 450 Hz, flip angle = 12&#730;); 2) first-pass perfusion at rest and at peak adenosine vasodilator stress using a spoiled gradient echo sequence (FOV = 320 x 320 mm, matrix size = 130 x 130, TR = 2.5 ms, TE = 1.1 ms, slice thickness = 10 mm, pixel bandwidth = 650 Hz, flip angle = 12&#730;; and 3) late gadolinium enhancement imaging using an ECG-gated, segmented, spoiled gradient-echo phase-sensitive-inversion-recovery sequence (FOV = 225 x 340 mm, matrix size = 131 x 175 mm, TR = 5.2 ms, TE = 1.96 ms, slice thickness = 8 mm, inversion time (TI) = optimized to null the myocardium, pixel bandwidth = 465 Hz, flip angle = 20&#730;). An illustrative first-pass perfusion image is shown in Figure 6.</li>
	<li>After completion of the MRI protocol, euthanize the swine by an infusion of sodium pentobarbital (100 mg/kg).</li>
	<li>Perform a lateral thoracotomy, excise the heart, and dissect the ex vivo heart to expose the coronary vessels. Note the location of the implant in relationship to either the diagonal branches (LAD territory) or obtuse marginal branches (LCX territory), and retrieve the implants.</li>
	<li>Using blunted and curved Metzenbaum scissors, open the coronary vessel and inspect the vessel for gross injury (see Figure 7). Photograph the heart tissue for gross pathology and stain with triphenyltetrazolium chloride to exclude myocardial infarction (see Figure 8).</li>
</ol>

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The authors have nothing to disclose.

In this work, we focused on a novel percutaneous deployment strategy for coronary stenosis-inducing implants and showed that a mother-and-child catheter can be repurposed for effective percutaneous delivery of 3D printed coronary implants. Discrete artificial coronary stenoses of variable severity can be created quickly in swine models with a high success rate and in a minimally invasive manner using standard human percutaneous coronary interventional techniques and equipment. These implants were shown to be safe in the acute setting and were also effective at creating severe angiographic stenoses, which correlated with stress-induced perfusion defects during vasodilator stress cardiac MRI. Compared to open-chest techniques, percutaneous delivery of stenosis-inducing implants is less invasive and more humane.
There are several other minimally invasive techniques currently available to create flow reduction in large animal models. The 3D printed coronary implants differ fundamentally from balloon occlusion and coil occlusion in that the stenoses induced by the 3D printed implants do not completely occlude the vessel. This is a major difference that allows for modelling of stress-induced ischemia rather than infarction7,8. Rissanen et al.9 describe a percutaneous technique that creates flow limiting, non-obstructive stenoses in swine models using a coronary stent wrapped in a polytetrafluoroethylene tubing. The tubing could be shaped by employing needles and heat to create luminal narrowing of various degrees. It is clear that the implants we used differ in design and thorough description with full validation is beyond the scope of the current work, which is to describe the novel methodology used for delivery of 3D printed coronary implants. Utilizing the mother-and-child catheter allowed for precise deployment of the implants deep in the coronary arteries. It is difficult to compare procedural success between our studies as other investigators explored a chronic model and kept the swine alive for an extended period of time9. Bamberg et al. described a method using balloon catheters inflated within 3 mm stents to create stenoses of 50% and 75% in the left anterior descending artery. This latter method differs from our investigation in that the stenoses created required catheters to be left inside the animals. There is no way to create an artificial lesion and remove all equipment. While viable, the Bamberg method does not allow for investigation of ischemia beyond the acute setting and residual wires would cause image artifacts10.
The role of mother-and-child catheters in coronary interventions has been well established, but their use to deliver implants into vascular beds has not been previously described5,6. The two most challenging aspects of percutaneous implant delivery include selective deployment into a precise coronary segment and prevention of retrograde migration. Attempting to deploy the device over angioplasty balloons was not effective because the implant could be pulled proximally in the vessel after balloon deflation. For several reasons, the mother-and-child catheter proved to be a valuable tool for fixing the implants in place during balloon withdrawal. The mother-and-child catheters fit easily in the coronary guide catheters and their size was ideal for our intervention. They were slightly larger than the deflated coronary balloon, allowing us to shear the implant off and to prevent retrograde migration of the implant as the balloon was withdrawn. The support provided by the mother-and-child catheter enabled the implants to be deeply seated in the coronary artery with strong apposition to the vessel lumen. Additionally, the radiopaque marker on the tip of the mother-and-child catheter helped position the catheter just proximal to the implant, as identified by the marker on the delivery balloon. Though the technique was mostly effective, in one subject there was slight distal migration after implant delivery. This may have been due to injection of intracoronary nitroglycerin for coronary vasospasm and resultant vasodilation leading to distal migration of the implant. The GuideLiner catheter was chosen due to familiarity of use, but there are a number of other similar devices which could potentially be used in its place. The Guidezilla Guide Extension Catheter (Boston Scientific, Marlborough, Massachusetts, USA) is also available in a 6F size and has a similar structure to the GuideLiner. There is also a Guidion rapid exchange guide extension catheter (Interventional Medical Device Solutions, Roden, The Netherlands) which comes in sizes 5&#8211;8F and could also potentially be used in place of the GuideLiner catheter.
Our deployment technique can be performed efficiently and humanely in swine with a low procedural failure rate. In our preliminary study the procedural failure rate was 18%. There was a learning curve associated with the technique as we streamlined our interventions. However, despite the learning curve, all animal subjects survived the initial implant deployment intervention. The lesions created were focal and the narrowing ranged in severity, but they were not occlusive. These stenoses were angiographically significant and produced inducible perfusion defects during stress perfusion MRI. Figure 6 is an example of a focal perfusion defect seen on MRI after successful implant deployment to the LAD. We aimed to create ischemia rather than infarction. Figure 8 shows an example of histopathologic analysis of the myocardial tissue, which shows no evidence of infarction. The method relies on human coronary angioplasty equipment, and the similarity in swine coronary size to those of humans. The outer diameter of the 3D printed implant was based on the inner diameter of the guiding catheter and the inner diameter of the mother-and-child catheter. The minimal luminal diameter of the stenosis was based on the size of the deflated coronary balloon. The final flow-limiting severity of the discrete stenosis is based on the inner diameter and the length of the implant. Although resting angiographic flow was preserved, maximal coronary blood flow was reduced, as evidenced by the MRI perfusion scans. Future work will focus on replacing the balloon delivery wire with a pressure wire and measurement of fractional flow reserve or instantaneous flow reserve. Similarly, downstream microvascular injury can be produced by local injections of microspheres either through the delivery balloon or the mother-and-child catheter itself.
Our low procedural failure rate in a closed-chest swine model shows promise for future implementation. Because complete total occlusion was not performed, myocardial infarction was avoided, and may have contributed to the lower rate of malignant arrhythmias. In our study only 1 subject developed ventricular fibrillation. After an initial period of optimization, we cut down procedural time to roughly 30 min per case.
In summary, our results demonstrate a novel technique for deployment of 3D printed coronary implants and show the feasibility of creating a closed-chest swine model of discrete focal coronary stenosis. This minimally invasive technique can be used for testing and development of new diagnostic imaging techniques in ischemic heart disease. We used stress cardiac perfusion MRI, but other modalities may include nuclear imaging, ultrasound, and computed tomography. Although this model is immediately applicable to ischemic heart disease, with minor modifications, the technique can be employed for other occlusive vascular disease states.

Ischemic heart disease continues to be the number one cause of death in the United States1. Large animal models have been used experimentally to understand and characterize mechanisms driving coronary artery disease (CAD) and associated complications (including myocardial infarction, arrhythmic events, and heart failure), as well as for testing of new therapeutics or diagnostic modalities. Results from these studies have helped to broaden the understanding, diagnosis, and monitoring of ischemic heart disease and to advance clinical practice2. Several animal models including rabbits, dogs, and swine have been used. However, coronary stenoses, particularly discrete lesions, occur very rarely in these animals and are difficult to induce reproducibly3. Prior work described the creation of artificial coronary stenoses using ligation, occluders, or external clamps. Recently, we described how to use 3D printing technology to manufacture coronary implants that can be used to percutaneously create discrete artificial coronary narrowing4. Using computer-aided design software, we designed coronary artery implants as hollow tubes with varying inner and outer diameters as well as implant length and then fabricated them using commercially available additive materials. The implants are smooth, hollow, 3D printed tubes with rounded edges. We designed a library of implant sizes with a range of inner diameter, outer diameter, and length. The outer diameter of the implant is based on the size of the coronary guide catheter. The inner diameter is based on the size of a deflated coronary angioplasty balloon. We varied the length of the implant to tailor the desired severity of perfusion. However, safe percutaneous delivery of such devices can be challenging due to the lack of wires and catheters manufactured specifically for large animal use. In contrast, an extensive collection of catheters, wires, and supportive equipment are available for clinical use in human coronary arteries. In this work, we show how to repurpose a clinical grade mother-and-child coronary guide catheter for the delivery of the 3D printed coronary implants.
The GuideLiner catheter (Figure 1A) was developed for percutaneous coronary intervention (PCI) to allow for deep catheter seating and increased support for complex cases5. In our investigation, the GuideLiner catheter was chosen due to familiarity of use and availability, but similar catheters, where available, may also be considered. Considered a &#34;mother-and-child&#34; guide catheter (Figure 1B), the device fits inside a typical coronary guide catheter (&#34;mother&#34;) and is a coaxial flexible tube (&#34;child&#34;). This catheter can be inserted over a guidewire and effectively lengthens the reach of a typical coronary guide catheter by extending beyond the end of the coronary guide. The GuideLiner or a similar mother-and-child catheter can be used as added support for deployment of the 3D printed coronary implants. Because the implants are mounted over angioplasty balloons to be inserted as a unit over a coronary wire into the vessel (Figure 1B,1C), the catheter offers additional support to deliver the implant to the desired site. By positioning the mother-and-child catheter just proximal to the balloon, the implant remains at the desired location during balloon deflation and retraction. Despite having some firmness to its structure, the mother-and-child catheter&#39;s unique ability to be advanced deep into coronary arteries over a guidewire and the radiopaque marker at the catheter tip were essential characteristics for implantation.
Our assembled delivery apparatus consisted of a typical coronary guide catheter, the mother-and-child catheter, and a 3D printed implant fixed onto a deflated coronary angioplasty balloon (Figure 1B). As a functional delivery unit, the mother-and-child catheter not only provided stable additional support for the delivery of the equipment but was also uniquely applied as a shearing device to keep the implants in place during deflation and removal of the balloon. The radiopaque marker at the catheter tip served as a positioning guide for the assembled apparatus and sits proximal to the angioplasty balloon. These characteristics allowed for precise deployment of the flow-limiting implants. The process was designed to be reproducible, efficient, and humane for the animal subjects.
In our application, the mother-and-child percutaneous delivery technique was used to create swine models with focal coronary stenosis for evaluation of contrast-enhanced stress cardiac perfusion magnetic resonance imaging (MRI). However, the technique may be employed in other investigations including vascular systems outside the coronary vessels.

<table><tbody><tr><td>3D-Printed coronary implants</td><td>Study Site Manufactured</td><td></td><td></td></tr><tr><td>Amiodarone IV solution</td><td>Study Site Pharmacy</td><td></td><td></td></tr><tr><td>Amplatz Left-2 (AL-2) guide catheter (8F)</td><td>Boston Scientific, Marlborough, Massachusetts, USA</td><td></td><td></td></tr><tr><td>Balance Middleweight coronary wire (0.014&amp;rdquo; 300cm)</td><td>Abbott Laboratories, Abbott Park, Illinois, USA</td><td></td><td></td></tr><tr><td>COPILOT Bleedback Control valve</td><td>Abbott Laboratories, Abbott Park, Illinois, USA</td><td></td><td></td></tr><tr><td>Esmolol IV solution (1 mg/kg)</td><td>Study Site Pharmacy</td><td></td><td></td></tr><tr><td>Formlabs Form 2 3D-printer with a minimum XY feature size of 150 &amp;micro;m</td><td>Formlabs Inc., Somerville, Massachusetts, USA</td><td></td><td></td></tr><tr><td>Formlabs Grey Resin (implant material)</td><td>Formlabs Inc., Somerville, Massachusetts, USA</td><td></td><td></td></tr><tr><td>Gadobutrol 0.1 mmol/kg</td><td>Gadvist, Bayer Pharmaceuticals, Wayne, NJ</td><td></td><td></td></tr><tr><td>GuideLiner catheter (6F)</td><td>Vascular Solutions Inc., Minneapolis, Minnesota, USA</td><td></td><td></td></tr><tr><td>Heparin IV solution</td><td>Surface Solutions Laboratories Inc., Carlisle, Massachusetts, USA</td><td></td><td></td></tr><tr><td>Ketamine IM solution (10 mg/kg)</td><td>Study Site Pharmacy</td><td></td><td></td></tr><tr><td>Lidocaine IV solution</td><td>Study Site Pharmacy</td><td></td><td></td></tr><tr><td>Male Yorkshire swine (30-45 kg)</td><td>SNS Farms</td><td></td><td></td></tr><tr><td>Midazolam IV solution</td><td>Study Site Pharmacy</td><td></td><td></td></tr><tr><td>NC Trek over-the-wire coronary balloon</td><td>Abbott Laboratories, Abbott Park, Illinois, USA</td><td></td><td></td></tr><tr><td>Oxygen-isoflurane 1-2% inhaled mixture</td><td>Study Site Pharmacy</td><td></td><td></td></tr><tr><td>Rocuronium IV solution</td><td>Study Site Pharmacy</td><td></td><td></td></tr><tr><td>Sodium Pentobarbital IV solution (100mg/kg)</td><td>Study Site Pharmacy</td><td></td><td></td></tr><tr><td>Triphenyltetrazolium chloride stain</td><td>Institution Pathology Lab</td><td></td><td></td></tr></tbody></table>

novel percutaneous approach for deployment of 3d printed coronary stenosis implants in swine models of ischemic heart disease

Minimally invasive methods for creating models of focal coronary narrowing in large animals are challenging. Rapid prototyping using three-dimensionally (3D) printed coronary implants can be employed to percutaneously create a focal coronary stenosis. However, reliable delivery of the implants can be difficult without the use of ancillary equipment. We describe the use of a mother-and-child coronary guide catheter for stabilization of the implant and for effective delivery of the 3D printed implant to any desired location along the length of the coronary vessel. The focal coronary narrowing was confirmed under coronary cineangiography and the functional significance of the coronary stenosis was assessed using gadolinium-enhanced first-pass cardiac perfusion MRI. We showed that reliable delivery of 3D printed coronary implants in swine models (n = 11) of ischemic heart disease can be achieved through repurposing mother-and-child coronary guide catheters. Our technique simplifies the percutaneous delivery of coronary implants to create closed-chest swine models of focal coronary artery stenosis and can be performed expeditiously, with a low procedural failure rate.

After initial optimization of the procedure, the intervention component was completed within 30 min. The implants were successfully delivered in all 11 subjects (100%). The implant was retrieved at the autopsy in all 11 subjects (100%). Using the diagonal branches (along the LAD) or obtuse marginal branches (along the LCX) as positional markers, we found the position of the implant at fluoroscopic-guided deployment and at autopsy to be consistent in 10 of the 11 (91%) subjects where the implant was retrievable. In one subject, there was slight distal migration of the implant, which may be related to vasodilation induced by intracoronary nitroglycerin injection for coronary spasm. Of the 11 subjects studied, 9 survived for the entire catheterization and completed the MRI protocol, giving us an 82% procedural success rate. Two subjects died after the implants were deployed. The first subject developed ventricular fibrillation in the MRI suite well after deployment of the implant. The second died in the MRI scanner in the setting of hypotension midway through the experiment. At the time of dissection, we did not see thrombus within the implants or other signs of structural injury to the vessels. The high survival rate (2 deaths, 9 of 11 survived) highlights the importance an effective anti-arrhythmic prophylaxis regimen. An illustrative example of stress cardiac perfusion MRI is provided in Figure 6. Detailed implant design and full results of the MRI validation will be reported separately.
<img alt="Figure 1" class="xfigimg" src="/files/ftp_upload/60729/60729fig01.jpg" /> 
Figure 1: Catheter design and assembled apparatus with mounted coronary implant. (A) Diagram of the components of the mother-and-child catheter6. (B) Assembled apparatus showing the coronary balloon inflated with the 3D printed implant mounted and fixed at the leading head of the catheter, which protrudes through the guide catheter. (C) A magnified image of the 3D printed implant is shown mounted onto the angioplasty balloon. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/60729/60729fig01large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 2" class="xfigimg" src="/files/ftp_upload/60729/60729fig02.jpg" /> 
Figure 2: Coronary angiogram in the anteroposterior projection shows selective contrast-enhancement of the left main coronary artery system. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/60729/60729fig02large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 3" class="xfigimg" src="/files/ftp_upload/60729/60729fig03.jpg" /> 
Figure 3: Coronary angiogram in the anteroposterior projection shows the 0.014&#34; 300 cm coronary wire in the left anterior descending artery. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/60729/60729fig03large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 4" class="xfigimg" src="/files/ftp_upload/60729/60729fig04.jpg" /> 
Figure 4: Coronary angiogram in the anteroposterior projection. The image on the left shows the assembled mother-and-child catheter with the inflated coronary balloon and implant in the mid to distal segment of the left anterior descending artery. A higher magnification of the assembled apparatus within the coronary vessel is shown in the right panel. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/60729/60729fig04large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 5" class="xfigimg" src="/files/ftp_upload/60729/60729fig05.jpg" /> 
Figure 5: Anteroposterior angiogram. The image on the left shows a focal stenosis in the distal left anterior descending artery after deployment of the implant. A higher magnification of the discrete coronary narrowing induced by the implant is shown in the right panel. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/60729/60729fig05large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 6" class="xfigimg" src="/files/ftp_upload/60729/60729fig06v2.jpg" /> 
Figure 6: Stress cardiac perfusion magnetic resonance images of a coronary implant deployed in the proximal to mid left anterior descending artery. The images at rest (upper panel) and peak adenosine vasodilator stress (lower panel) show inducible perfusion defects in the segments subtended by the left anterior descending artery. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/60729/60729fig06large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 7" class="xfigimg" src="/files/ftp_upload/60729/60729fig07v2.jpg" /> 
Figure 7: Autopsy images. (A) The implant at the distal left anterior, descending artery. (B) The absence of gross injury to the coronary vessel. (C) Implant without thrombus. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/60729/60729fig07large.jpg" target="_blank">Please click here to view a larger version of this figure.</a>
<img alt="Figure 8" class="xfigimg" src="/files/ftp_upload/60729/60729fig8a.jpg" /> 
Figure 8: Histopathology of swine myocardial tissue. (A) Gross pathology and (B) triphenyltetrazolium chloride stains in one subject showed no evidence of myocardial tissue infarction. <a href="https://www-jove-com.remotexs.ntu.edu.sg/files/ftp_upload/60729/60729fig8alarge.jpg" target="_blank">Please click here to view a larger version of this figure.</a>

Watch this Scientific Journal Video about Novel Percutaneous Approach for Deployment of 3D Printed Coronary Stenosis Implants in Swine Models of Ischemic Heart Disease at JoVE.com

Novel Percutaneous Approach for Deployment of 3D Printed Coronary Stenosis Implants in Swine Models of Ischemic Heart Disease

We describe a novel, cost-effective, and efficient technique for percutaneous delivery of three-dimensionally printed coronary implants to create closed-chest swine models of ischemic heart disease. The implants were fixed in place using a mother-and-child extension catheter with high success rate.

Minimally invasive methods for creating models of focal coronary narrowing in large animals are challenging. Rapid prototyping using three-dimensionally ...

novel-percutaneous-approach-for-deployment-3d-printed-coronary

Nanyang Technological University

Research

JoVE Journal

Medicine

6.8K Views.  University of California Los Angeles. Onze MRI-compatibele minimaal invasieve gesloten borst varkens model. Het vergemakkelijkt een snellere translationele studie van ischemische hartziekten. We hebben aangetoond dat een moeder-en-kind katheter kan worden gebruikt om nauwkeurig te implementeren coronaire implantaten in een veilige en snelle manier, het beperken van nadelige effecten voor de dierlijke onderwerpen.Onze methode kan worden gebruikt om nieuwe diagnostische beeldvormingstechnieken te ontwikkelen bij ischemische ...

Video: Novel Percutaneous Approach for Deployment of 3D Printed Coronary Stenosis Implants in Swine Models of Ischemic Heart Disease

A Murine Model of Stent Implantation in the Carotid Artery for the Study of Restenosis

Despite the considerable progress made in the stent development in the last decades, cardiovascular diseases remain the main cause of death in western countries. Beside the benefits offered by the development of different drug-eluting stents, the coronary revascularization bears also the life-threatening risks of in-stent thrombosis and restenosis. Research on new therapeutic strategies is impaired by the lack of appropriate methods to study stent implantation and restenosis processes. Here, we describe a rapid and accessible procedure of stent implantation in mouse carotid artery, which offers the possibility to study in a convenient way the molecular mechanisms of vessel remodeling and the effects of different drug coatings.

A model of stent implantation in mouse carotid artery is described. Compared to other similar methods, this procedure is very rapid, simple and accessible, offering the possibility to study in a convenient way the vascular wall reaction to different drug-eluting stents and the molecular mechanisms of restenosis.

Despite  the considerable progress made in the stent development in the last decades,  cardiovascular diseases remain the main cause of death in western ...

Transplantation of a 3D Bioprinted Patch in a Murine Model of Myocardial Infarction

Testing regenerative properties of 3D bioprinted cardiac patches in vivo using murine models of heart failure via permanent left anterior descending (LAD) ligation is a challenging procedure and has a high mortality rate due to its nature. We developed a method to consistently transplant bioprinted patches of cells and hydrogels onto the epicardium of an infarcted mouse heart to test their regenerative properties in a robust and feasible way. First, a deeply anesthetized mouse is carefully intubated and ventilated. Following left lateral thoracotomy (surgical opening of the chest), the exposed LAD is permanently ligated and the bioprinted patch transplanted onto the epicardium. The mouse quickly recovers from the procedure after chest closure. The advantages of this robust and quick approach include a predicted 28-day mortality rate of up to 30% (lower than the 44% reported by other studies using a similar model of permanent LAD ligation in mice). Moreover, the approach described in this protocol is versatile and could be adapted to test bioprinted patches using different cell types or hydrogels where high numbers of animals are needed to optimally power studies. Overall, we present this as an advantageous approach which may change preclinical testing in future studies for the field of cardiac regeneration and tissue engineering.

This protocol aims to transplant a 3D bioprinted patch onto the epicardium of infarcted mice modeling heart failure. It includes details regarding anesthesia, the surgical chest opening, permanent ligation of the left anterior descending (LAD) coronary artery and application of a bioprinted patch onto the infarcted area of the heart.

Testing regenerative properties of 3D bioprinted cardiac patches in vivo using murine models of heart failure via permanent left anterior descending (LAD) ...

Bioengineering

A Chronic Cardiac Ischemia Model in Swine Using an Ameroid Constrictor

Cardiovascular disease remains the number one cause of mortality in the United States. There are numerous approaches to treating these diseases, but regardless of the approach, an in vivo model is needed to test each treatment. The pig is one of the most used large animal models for cardiovascular disease. Its heart is very similar in anatomy and function to that of a human. The ameroid placement technique creates an ischemic area of the heart, which has many useful applications in studying myocardial infarction. This model has been used for surgical research, pharmaceutical studies, imaging techniques, and cell therapies.
There are several ways of inducing an ischemic area in the heart. Each has its advantages and disadvantages, but the placement of an ameroid constrictor remains the most widely used technique. The main advantages to using the ameroid are its prevalence in existing research, its availability in various sizes to accommodate the anatomy and size of the vessel to be constricted, the surgery is a relatively simple procedure, and the post-operative monitoring is minimal, since there are no external devices to maintain. This paper provides a detailed overview of the proper technique for the placement of the ameroid constrictor.

The purpose of this protocol is to demonstrate the placement of a delayed constricting device (an ameroid constrictor) around a coronary artery in a swine model. This device creates an ischemic area of the heart that is useful for studying new diagnostic imaging techniques and new methods of treatment.

Cardiovascular disease remains the number one cause of mortality in the United States. There are numerous approaches to treating these diseases, but ...

Implantation of Human-Sized Coronary Stents into Rat Abdominal Aorta Using a Trans-Femoral Access

Percutaneous coronary intervention (PCI), combined with the deployment of a coronary stent, represents the gold standard in interventional treatment of coronary artery disease. In-stent restenosis (ISR) is determined by an excessive proliferation of neointimal tissue within the stent and limits the long-term success of stents. A variety of animal models have been used to elucidate pathophysiological processes underlying in-stent restenosis (ISR), with the porcine coronary and the rabbit iliac artery models being the most frequently used. Murine models provide the advantages of high throughput, ease of handling and housing, reproducibility, and a broad availability of molecular markers. The apolipoprotein E deficient (apoE-/- ) mouse model has been widely used to study cardiovascular diseases. However, stents must be miniaturized to be implanted into mice, involving important changes of their mechanical and (potentially) biological properties. The use of apoE-/- rats can overcome these shortcomings as apoE-/- rats allow for the evaluation of human-sized coronary stents while at the same time providing an atherogenic phenotype. This makes them an excellent and reliable model to investigate ISR after stent implantation. Here, we describe, in detail, the implantation of commercially available human coronary stents into the abdominal aorta of rats with an apoE-/- background using a trans-femoral access.

This protocol describes the implantation of human coronary stents into the abdominal aorta of rats with an apoE-/- background using a trans-femoral access. Compared with other animal models, murine models carry the advantages of high throughput, reproducibility, ease of handling and housing, and a broad availability of molecular markers.

Percutaneous coronary intervention (PCI), combined with the deployment of a coronary stent, represents the gold standard in interventional treatment of ...

Development and Evaluation of 3D-Printed Cardiovascular Phantoms for Interventional Planning and Training

Catheter-based interventions are standard treatment options for cardiovascular pathologies. Therefore, patient-specific models could help training physicians&#39; wire-skills as well as improving planning of interventional procedures. The aim of this study was to develop a manufacturing process of patient-specific 3D-printed models for cardiovascular interventions.
To create a 3D-printed elastic phantom, different 3D-printing materials were compared to porcine biological tissues (i.e., aortic tissue) in terms of mechanical characteristics. A fitting material was selected based on comparative tensile tests and specific material thicknesses were defined. Anonymized contrast-enhanced CT-datasets were collected retrospectively. Patient-specific volumetric models were extracted from these datasets and subsequently 3D-printed. A pulsatile flow loop was constructed to simulate the intraluminal blood flow during interventions. Models&#39; suitability for clinical imaging was assessed by x-ray imaging, CT, 4D-MRI and (Doppler) ultrasonography. Contrast medium was used to enhance visibility in x-ray-based imaging. Different catheterization techniques were applied to evaluate the 3D-printed phantoms in physicians&#39; training as well as for pre-interventional therapy planning.
Printed models showed a high printing resolution (~30 &#181;m) and mechanical properties of the chosen material were comparable to physiological biomechanics. Physical and digital models showed high anatomical accuracy when compared to the underlying radiological dataset. Printed models were suitable for ultrasonic imaging as well as standard x-rays. Doppler ultrasonography and 4D-MRI displayed flow patterns and landmark characteristics (i.e., turbulence, wall shear stress) matching native data. In a catheter-based laboratory setting, patient-specific phantoms were easy to catheterize. Therapy planning and training of interventional procedures on challenging anatomies (e.g., congenital heart disease (CHD)) was possible.
Flexible patient-specific cardiovascular phantoms were 3D-printed, and the application of common clinical imaging techniques was possible. This new process is ideal as a training tool for catheter-based (electrophysiological) interventions and can be used in patient-specific therapy planning.

Here we present development of a mock circulation setup for multimodal therapy evaluation, pre-interventional planning, and physician-training on cardiovascular anatomies. With the application of patient-specific tomographic scans, this setup is ideal for therapeutic approaches, training, and education in individualized medicine.

Catheter-based interventions are standard treatment options for cardiovascular pathologies. Therefore, patient-specific models could help training ...

Myocardial Infarction by Percutaneous Embolization Coil Deployment in a Swine Model

Myocardial infarction (MI) is the leading cause of mortality worldwide. Despite the use of evidence-based treatments, including coronary revascularization and cardiovascular drugs, a significant proportion of patients develop pathological left-ventricular remodeling and progressive heart failure following MI. Therefore, new therapeutic options, such as cellular and gene therapies, among others, have been developed to repair and regenerate injured myocardium. In this context, animal models of MI are crucial in exploring the safety and efficacy of these experimental therapies before clinical translation. Large animal models such as swine are preferred over smaller ones due to the high similarity of swine and human hearts in terms of coronary artery anatomy, cardiac kinetics, and the post-MI healing process. Here, we aimed to describe an MI model in pig by permanent coil deployment. Briefly, it comprises a percutaneous selective coronary artery cannulation through retrograde femoral access. Following coronary angiography, the coil is deployed at the target branch under fluoroscopic guidance. Finally, complete occlusion is confirmed by repeated coronary angiography. This approach is feasible, highly reproducible, and emulates the pathogenesis of human non-revascularized MI, avoiding the traditional open-chest surgery and the subsequent postoperative inflammation. Depending on the time of follow-up, the technique is suitable for acute, sub-acute, or chronic MI models.

Myocardial infarction (MI) animal models that emulate the natural process of the disease in humans are crucial to understanding pathophysiological mechanisms and testing the safety and efficacy of new emergent therapies. Here, we describe an MI swine model created by deploying a percutaneous embolization coil.

Myocardial infarction (MI) is the leading cause of mortality worldwide. Despite the use of evidence-based treatments, including coronary revascularization ...

Transcatheter Pulmonary Valve Replacement from Autologous Pericardium with a Self-Expandable Nitinol Stent in an Adult Sheep Model

Transcatheter pulmonary valve replacement has been established as a viable alternative approach for patients suffering from right ventricular outflow tract or bioprosthetic valve dysfunction, with excellent early and late clinical outcomes. However, clinical challenges such as stented heart valve deterioration, coronary occlusion, endocarditis, and other complications must be addressed for lifetime application, particularly in pediatric patients. To facilitate the development of a lifelong solution for patients, transcatheter autologous pulmonary valve replacement was performed in an adult sheep model. The autologous pericardium was harvested from the sheep via left anterolateral minithoracotomy under general anesthesia with ventilation. The pericardium was placed on a 3D shaping heart valve model for non-toxic cross-linking for 2 days and 21 h. Intracardiac echocardiography (ICE) and angiography were performed to assess the position, morphology, function, and dimensions of the native pulmonary valve (NPV). After trimming, the crosslinked pericardium was sewn onto a self-expandable Nitinol stent and crimped into a self-designed delivery system. The autologous pulmonary valve (APV) was implanted at the NPV position via left jugular vein catheterization. ICE and angiography were repeated to evaluate the position, morphology, function, and dimensions of the APV. An APV was successfully implanted in&#160;sheep J. In this paper, sheep J was selected to obtain representative results. A 30 mm APV with a Nitinol stent was accurately implanted at the NPV position without any significant hemodynamic change. There was no paravalvular leak, no new pulmonary valve insufficiency, or stented pulmonary valve migration. This study demonstrated the feasibility and safety, in a long-time follow-up, of developing an APV for implantation at the NPV position with a self-expandable Nitinol stent via jugular vein catheterization in an adult sheep model.

This study demonstrates the feasibility and safety of developing an autologous pulmonary valve for implantation at the native pulmonary valve position by using a self-expandable Nitinol stent in an adult sheep model. This is a step toward developing transcatheter pulmonary valve replacement for patients with right ventricular outflow tract dysfunction.

Transcatheter pulmonary valve replacement has been established as a viable alternative approach for patients suffering from right ventricular outflow ...

Preclinical Evaluation of Coronary Artery Stents

Coronary artery disease is a major contributor to morbidity and mortality worldwide. While lifestyle changes and medication are the cornerstones of treatment, coronary artery balloon angioplasty and stenting are routinely performed on patients with acute coronary syndromes and chronic coronary artery disease who remain symptomatic with optical medical treatment. Several generations of coronary stents have been developed over recent decades. Balloon angioplasty and stenting are supported by the use of pharmaceutical agents applied onto balloons and the stent surface, either to advance the healing properties of the artery post-intervention or to prevent the formation of restenosis. New devices need to be rigorously tested for safety and efficacy before acceptance into clinical practice; thus, there is a continuing need for reliable and reproducible preclinical methods of stent evaluation. We describe here a pig coronary artery model as well as an atherosclerotic rabbit model for coronary artery stent research and describe basic steps in intravascular imaging and stent histology.

New coronary artery stent designs and materials must be tested before clinical use in relevant preclinical models. Here we describe an atherosclerotic rabbit aorta model and a pig coronary artery model for stent research with in vivo and histological analyses.

Coronary artery disease is a major contributor to morbidity and mortality worldwide. While lifestyle changes and medication are the cornerstones of ...

Delivery of Cardioactive Therapeutics in a Porcine Myocardial Infarction Model

Myocardial infarction is one of the leading causes of death and disability worldwide, and there is an urgent need for novel cardioprotective or regenerative strategies. An essential component of drug development is determining how a novel therapeutic is to be administered. Physiologically relevant large animal models are of critical importance in assessing the feasibility and efficacy of various therapeutic delivery strategies. Due to their similarities to humans in cardiovascular physiology, coronary vascular anatomy, and heart weight to body weight ratio, swine is one of the preferred species in the preclinical evaluation of new therapies for myocardial infarction. The present protocol describes three methods of administering cardioactive therapeutic agents in a porcine model. After percutaneously induced myocardial infarction, female landrace swine received treatment with novel agents through either: (1) thoracotomy and transepicardial injection, (2) catheter-based transendocardial injection, or (3) intravenous infusion via jugular vein osmotic minipump. The procedures employed for each technique are reproducible, resulting in reliable cardioactive drug delivery. These models can be easily adapted to suit individual study designs, and each of these delivery techniques can be used to investigate a variety of possible interventions. Therefore, these methods are a useful tool for translational scientists pursuing novel biological approaches in cardiac repair following myocardial infarction.

The present protocol describes three methods of administering cardioactive therapeutic agents in a porcine model. Female landrace swine received treatment through either: (1) thoracotomy and transepicardial injection, (2) catheter-based transendocardial injection, or (3) intravenous infusion via jugular vein osmotic minipump.

Myocardial infarction is one of the leading causes of death and disability worldwide, and there is an urgent need for novel cardioprotective or ...

Adjunctive Exosome Therapy: Enhancing Myocardial Recovery Post-CABG Surgery

Surgical Porcine Model of Chronic Myocardial Ischemia Treated by Exosome-laden Collagen Patch and Off-pump Coronary Artery Bypass Graft

Chronic myocardial ischemia resulting from progressive coronary artery stenosis leads to hibernating myocardium (HIB), defined as myocardium that adapts to reduced oxygen availability by reducing metabolic activity, thereby preventing irreversible cardiomyocyte injury and infarction. This is distinct from myocardial infarction, as HIB has the potential for recovery with revascularization. Patients with significant coronary artery disease (CAD) experience chronic ischemia, which puts them at risk for heart failure and sudden death. The standard surgical intervention for severe CAD is coronary artery bypass graft surgery (CABG), but it has been shown to be an imperfect therapy, yet no adjunctive therapies exist to recover myocytes adapted to chronic ischemia. To address this gap, a surgical model of HIB using porcine that is amenable to CABG and mimics the clinical scenario was used. The model involves two surgeries. The first operation involves implanting a 1.5 mm rigid constrictor on the left anterior descending (LAD) artery. As the animal grows, the constrictor gradually causes significant stenosis resulting in reduced regional systolic function. Once the stenosis reaches 80%, the myocardial flow and function are impaired, creating HIB. An off-pump CABG is then performed with the left internal mammary artery (LIMA) to revascularize the ischemic region. The animal recovers for one month to allow for optimal myocardial improvement prior to sacrifice. This allows for physiologic and tissue studies of different treatment groups. This animal model demonstrates that cardiac function remains impaired despite CABG, suggesting the need for novel adjunctive interventions. In this study, a collagen patch embedded with mesenchymal stem cell (MSC)-derived exosomes was developed, which can be surgically applied to the epicardial surface distal to LIMA anastomosis. The material conforms to the epicardium, is absorbable, and provides the scaffold for the sustained release of signaling factors. This regenerative therapy can stimulate myocardial recovery that does not respond to revascularization alone. This model translates to the clinical arena by providing means of physiological and mechanistic explorations regarding recovery in HIB.

Author Spotlight: Enhancing Coronary Artery Revascularization

This study presents a surgical porcine model of chronic myocardial ischemia due to progressive coronary artery stenosis, resulting in impaired cardiac function without infarction. Following ischemia, animals undergo off-pump coronary artery bypass graft with epicardial placement of stem cells-derived exosomes-laden collagen patch. This adjunctive therapy improves myocardial function and recovery.

Chronic myocardial ischemia resulting from progressive coronary artery stenosis leads to hibernating myocardium (HIB), defined as myocardium that adapts ...

Novel Percutaneous Approach for Deployment of 3D Printed Coronary Stenosis Implants in Swine Models of Ischemic Heart Disease

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