Name: novel percutaneous approach for deployment of 3d printed coronary stenosis implants in swine models of ischemic heart disease
Uploaded: 2020-02-18T16:00:00
Description: 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

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>
<p class="...

<ol>
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T., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+bottleneck+stent+model+for+chronic+myocardial+ischemia+and+heart+failure+in+pigs.">The bottleneck stent model for chronic myocardial ischemia and heart failure in pigs.</a> American Journal of Physiology. 305 (9), 1297-1308 (2013).</li><li>Bamberg, F., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Accuracy+of+dynamic+computed+tomography+adenosine+stress+myocardial+perfusion+imaging+in+estimating+myocardial+blood+flow+at+various+degrees+of+coronary+artery+stenosis+using+a+porcine+animal+model.">Accuracy of dynamic computed tomography adenosine stress myocardial perfusion imaging in estimating myocardial blood flow at various degrees of coronary artery stenosis using a porcine animal model.</a> Investigative Radiology. 47 (1), 71-77 (2012).</li><li>Schwitter, J., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=MR-IMPACT:+comparison+of+perfusion-cardiac+magnetic+resonance+with+single-photon+emission+computed+tomography+for+the+detection+of+coronary+artery+disease+in+a+multicentre,+multivendor,+randomized+trial.">MR-IMPACT: comparison of perfusion-cardiac magnetic resonance with single-photon emission computed tomography for the detection of coronary artery disease in a multicentre, multivendor, randomized trial.</a> European Heart Journal. 29, 480-489 (2008).</li><li>Mahrholdt, H., Klem, I., Sechtem, U. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Cardiovascular+MRI+for+detection+of+myocardial+viability+and+ischaemia.">Cardiovascular MRI for detection of myocardial viability and ischaemia.</a> Heart. 93 (1), 122-129 (2007).</li><li>Herr, M. D., McInerney, J. J., Copenhaver, G. L., Morris, D. L. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Coronary+artery+embolization+in+closed-chest+canines+using+flexible+radiopaque+plugs.">Coronary artery embolization in closed-chest canines using flexible radiopaque plugs.</a> Journal of Applied Physiology. 64, 2236-2239 (1988).</li><li>Rochitte, C. E., Kim, R. J., Hillenbrand, H. B., Chen, E. L., Lima, J. A. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Microvascular+integrity+and+the+time+course+of+myocardial+sodium+accumulation+after+acute+infarction.">Microvascular integrity and the time course of myocardial sodium accumulation after acute infarction.</a> Circulation Research. 87, 648-655 (2000).</li><li>Krombach, G. A., Kinzel, S., Mahnken, A. H., G&#252;nther, R. 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C., Ikeno, F. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=The+representative+porcine+model+for+human+cardiovascular+disease.">The representative porcine model for human cardiovascular disease.</a> Journal of Biomedical Biotechnology. 2011, 195483 (2010).</li><li>Eldar, M., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+closed+chest+pig+model+of+sustained+ventricular+tachycardia.">A closed chest pig model of sustained ventricular tachycardia.</a> Pacing Clinical Electrophysiology. 17, 1603-1609 (1994).</li><li>Reffelmann, T., et al. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+novel+minimal-invasive+model+of+chronic+myocardial+infarction+in+swine.">A novel minimal-invasive model of chronic myocardial infarction in swine.</a> Coronary Artery Disease. 15 (1), 7-12 (2004).</li><li>Haines, D. E., Verow, A. F., Sinusas, A. J., Whayne, J. G., DiMarco, J. P. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Intracoronary+ethanol+ablation+in+swine:+characterization+of+myocardial+injury+in+target+and+remote+vascular+beds.">Intracoronary ethanol ablation in swine: characterization of myocardial injury in target and remote vascular beds.</a> Journal of Cardiovascular Electrophysiology. 5, 422-431 (1994).</li><li>Kraitchman, D., Bluemke, D., Chin, B., Heldman, A. W., Heldman, A. W. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=A+minimally+invasive+method+for+creating+coronary+stenosis+in+a+swine+model+for+MRI+and+SPECT+imaging.">A minimally invasive method for creating coronary stenosis in a swine model for MRI and SPECT imaging.</a> Investigative Radiology. 35 (7), 445-451 (2000).</li></ol>

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 ...

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 border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<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&#34; 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 &#181;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 su...

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 ...

Our MRI-compatible minimally invasive closed chest swine model. It facilitates a more rapid translational study of ischemic heart disease. We've shown that a mother-and-child catheter can be used to precisely deploy coronary implants in a safe and quick manner, limiting adverse effects to the animal subjects.Our method can be used to develop new diagnostic imaging techniques in ischemic heart disease. With some slight modifications, it can also be applied to other vascular disease states. Although it can be difficult to selectively cannulate the left main coronary artery in smaller pigs, using a mother-and-child catheter allows excellent quality angiograms to be obtained.Our method allows us to induce a focal coronary lesion in the vessel of our choice and to conduct an MRI study on the same day. Visual demonstration of the technique will help reduce trial and error in future investigations, resulting in more reproducible results. The day before the procedure, use tweezers to dip coat printed implants in a 25%Heparin solution.And allow the implants to dry for 24 hours. On the day of the procedure confirm an appropriate level of sedation in a 30 to 45 kilogram Yorkshire swine, and use the Seldinger technique to insert the arterial and venous sheaths into the bilateral femoral arteries and veins of the animal. Then flush all of the catheter ports continuously with Heparinized normal saline.After vascular access has been obtained, administer 5, 000 to 10, 000 units of Heparin to maintain an activated clotting time of greater than 300 hundred seconds. For hemodynamic monitoring, use electrocardiography chest feeds for recording changes in the ST segment, T waves, and heart rate during the entire experimental period. Use a pressure transducer to record the continuous femoral arterial pressure throughout the procedure.Attach a pulse oximeter to the animal's ear for continuous pulse oximetry recordings. 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. 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.Then use an Instaflator to inflate the balloon to two to three atmospheres to fix the implant onto the balloon and verify that the implant is positioned closer to the proximal half of the balloon so it'll be closest to the mother-and-child catheter when ready for removal. To induce a coronary angiography with a fluoroscopic C-arm in the antero posterior projection, attach a control valve to a left or right coronary guide catheter. 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. Selectively engage the catheter into the left main coronary artery, and inject five milliliters of iodinated contrast under fluoroscopy to visualize the left coronary system. Position the guide catheter toward the left main coronary artery for the second angiogram.Once engaged within or position near the left main coronary artery, advance a 0.014 inch 300 centimeter coronary wire into the left main coronary artery and further advance the wire to the distal left anterior descending artery. Insert the previously assembled mother-and-child catheter with the inflated coronary angioplasty balloon and implant over the coronary wire and advance the assembly to the desired location along the coronary vessel. Inject five milliliters of iodinated contrast to visualize a discreet narrowing at the desired location where the coronary implant should be deployed.Once the implant is in position, advance the mother-and-child catheter to the proximal marker of the inflated balloon. The geometric constraints of the delivery system allow the stenosis to be positioned within the proximal to mid portion of the pig coronary artery. Deflate the balloon and retract it through the mother-and-child catheter to shear the implant off the balloon as it is retracted, fixing the position of the implant within the designated segment of the vessel.Then perform final angiograms to document the location of the new artificial stenosis within the vessel and two orthogonal views as possible to acquire visual estimation of the stenosis severity. After harvest, dissect the ex-vivo heart to expose the coronary vessels. Note the location of the implant in relation to the branches it was positioned next to to retrieve the implants and inspect the vessel for gross injury.Then photograph the heart tissue for gross pathology and stain with TTC to exclude myocardial infarction. In these stress cardiac profusion magnetic resonance images of a coronary implant deployed in the proximal to mid left anterior descending artery, the implanted vessel can be observed at rest and at peak adenosine vasodilator stress. Note the inducible perfusion defects in the segments subtended by the left anterior descending artery.Remember to ensure that the mother-and-child catheter is flush against the implant in a stable position prior to deflation of the coronary balloon to allow for shearing of the balloon upon withdrawal. We can now deploy an implant and conduct an entire MR imaging study start to finish in a single day, drastically cutting down on the timing and logistical challenges for these experiments.

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Research

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Medicine

Gene Transfer for Ischemic Heart Failure in a Preclinical Model

Various emerging technologies are being developed for patients with heart failure. Well-established preclinical evaluations are necessary to determine their efficacy and safety.
Gene therapy using viral vectors is one of the most promising approaches for treating cardiac diseases. Viral delivery of various different genes by changing the carrier gene has immeasurable therapeutic potential.
In this video, the full process of an animal model of heart failure creation followed by gene transfer is presented using a swine model. First, myocardial infarction is created by occluding the proximal left anterior descending coronary artery. Heart remodeling results in chronic heart failure. Unique to our model is a fairly large scar which truly reflects patients with severe heart failure who require aggressive therapy for positive outcomes. After myocardial infarct creation and development of scar tissue, an intracoronary injection of virus is demonstrated with simultaneous nitroglycerine infusion. Our injection method provides simple and efficient gene transfer with enhanced gene expression. This combination of a myocardial infarct swine model with intracoronary virus delivery has proven to be a consistent and reproducible methodology, which helps not only to test the effect of individual gene, but also compare the efficacy of many genes as therapeutic candidates.

A method of gene transfer for the treatment of ischemic heart failure is described using a swine model of myocardial infarction. Our simple and reproducible method enables us to readily evaluate the efficacy of various gene transfers with a very simple and reproducible way.

Various emerging technologies are being developed for patients with heart failure. Well-established preclinical evaluations are necessary to determine ...

Implantation of Total Artificial Heart in Congenital Heart Disease

In patients with end-stage heart failure (HF), a total artificial heart (TAH) may be implanted as a bridge to cardiac transplant. However, in congenital heart disease (CHD), the malformed heart presents a challenge to TAH implantation. 
In the case presented here, a 17 year-old patient with congenital transposition of the great arteries (CCTGA) experienced progressively worsening HF due to his congenital condition. He was hospitalized multiple times and received an implantable cardioverter defibrillator (ICD). However, his condition soon deteriorated to end-stage HF with multisystem organ failure. 
Due to the patient's grave clinical condition and the presence of complex cardiac lesions, the decision was made to proceed with a TAH. The abnormal arrangement of the patient's ventricles and great arteries required modifications to the TAH during implantation.
With the TAH in place, the patient was able to return home and regain strength and physical well-being while awaiting a donor heart. He was successfully bridged to heart transplantation 5 months after receiving the device. This report highlights the TAH is feasible even in patients with structurally abnormal hearts, with technical modification.

This is a case report of a patient with congenitally corrected transposition of the great arteries (CCTGA) who received a total artificial heart (TAH) as a bridge to heart transplant. The TAH was successfully implanted with modifications to accommodate the patient's congenitally malformed heart.

In patients with end-stage heart failure (HF), a total artificial heart (TAH) may be implanted as a bridge to cardiac transplant. However, in congenital ...

Quantitative 3D In Silico Modeling (q3DISM) of Cerebral Amyloid-beta Phagocytosis in Rodent Models of Alzheimer's Disease

Neuroinflammation is now recognized as a major etiological factor in neurodegenerative disease. Mononuclear phagocytes are innate immune cells responsible for phagocytosis and clearance of debris and detritus. These cells include CNS-resident macrophages known as microglia, and mononuclear phagocytes infiltrating from the periphery. Light microscopy has generally been used to visualize phagocytosis in rodent or human brain specimens. However, qualitative methods have not provided definitive evidence of in vivo phagocytosis. Here, we describe quantitative 3D in silico modeling (q3DISM), a robust method allowing for true 3D quantitation of amyloid-&#946; (A&#946;) phagocytosis by mononuclear phagocytes in rodent Alzheimer&#39;s Disease (AD) models. The method involves fluorescently visualizing A&#946; encapsulated within phagolysosomes in rodent brain sections. Large z-dimensional confocal datasets are then 3D reconstructed for quantitation of A&#946; spatially colocalized within the phagolysosome. We demonstrate the successful application of q3DISM to mouse and rat brains, but this methodology can be extended to virtually any phagocytic event in any tissue.

Quantitative 3D In Silico Modeling q3DISM of Cerebral Amyloid-beta Phagocytosis in Rodent Models of Alzheimer&#039;s Disease

We developed a methodology for quantitative 3D in silico modeling (q3DISM) of cerebral amyloid-&#946; (A&#946;) phagocytosis by mononuclear phagocytes in rodent models of Alzheimer&#39;s disease. This method can be generalized for the quantitation of virtually any phagocytic event in vivo.

Neuroinflammation is now recognized as a major etiological factor in neurodegenerative disease. Mononuclear phagocytes are innate immune cells responsible ...

Model of Ischemic Heart Disease and Video-Based Comparison of Cardiomyocyte Contraction Using hiPSC-Derived Cardiomyocytes

Ischemic heart disease is a significant cause of death worldwide. It has therefore been the subject of a tremendous amount of research, often with small-animal models such as rodents. However, the physiology of the human heart differs significantly from that of the rodent heart, underscoring the need for clinically relevant models to study heart disease. Here, we present a protocol to model ischemic heart disease using cardiomyocytes differentiated from human induced pluripotent stem cells (hiPS-CMs) and to quantify the damage and functional impairment of the ischemic cardiomyocytes. Exposure to 2% oxygen without glucose and serum increases the percentage of injured cells, which is indicated by staining of the nucleus with propidium iodide, and decreases cellular viability. These conditions also decrease the contractility of hiPS-CMs as confirmed by displacement vector field analysis of microscopic video images. This protocol may furthermore provide a convenient method for personalized drug screening by facilitating the use of hiPS cells from individual patients. Therefore, this model of ischemic heart disease, based on iPS-CMs of human origin, can provide a useful platform for drug screening and further research on ischemic heart disease.

We present a model of ischemic heart disease using cardiomyocytes derived from human induced pluripotent stem cells, together with a method for quantitative evaluation of tissue damage caused by ischemia. This model can provide a useful platform for drug screening and further research on ischemic heart disease.

Ischemic heart disease is a significant cause of death worldwide. It has therefore been the subject of a tremendous amount of research, often with ...

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 ...

Use of a Percutaneous Ventricular Assist Device/Left Atrium to Femoral Artery Bypass System for Cardiogenic Shock

The left atrial to femoral artery bypass (LAFAB) system is a mechanical circulatory support (MCS) device used in cardiogenic shock (CS) that bypasses the left ventricle by draining blood from the left atrium (LA) and returning it to the systemic arterial circulation via the femoral artery. It can provide flows ranging from 2.5-5 L/min depending on the size of the cannula. Here, we discuss the mechanism of action of LAFAB, available clinical data, indications for its use in cardiogenic shock, steps of implantation, post-procedural care, and complications associated with the use of this device and their management.
We also provide a brief video of the procedural component of device therapy, including the pre-placement preparation, percutaneous placement of the device via transseptal puncture under echocardiographic guidance and the post-operative management of device parameters.

The following article describes the stepwise procedure for placement of a device (e.g., Tandemheart) in cardiogenic shock (CS) that is a percutaneous left ventricular assist device (pLVAD) and a left atrial to femoral artery bypass (LAFAB) system that bypasses and supports the left ventricle (LV) in CS.

The left atrial to femoral artery bypass (LAFAB) system is a mechanical circulatory support (MCS) device used in cardiogenic shock (CS) that bypasses the ...

Large Animal Model for Evaluating the Efficacy of the Gene Therapy in Ischemic Heart

Coronary artery disease is one of the significant causes of mortality and morbidity worldwide. Despite the progression of current therapeutics, a considerable proportion of coronary artery disease patients remain symptomatic. Gene therapy-mediated therapeutic angiogenesis offers a novel therapeutic method for improving myocardial perfusion and relieving symptoms. Gene therapy with different angiogenic factors has been studied in few clinical trials. Due to the novelty of the method, the progress of myocardial gene therapy is a continuous path from bench to bedside. Therefore, large animal models are needed for evaluating the safety and efficacy. The more the large animal model identifies the original disease and the endpoints used in clinics, the more predictable outcomes are from clinical trials. Here, we introduce a large animal model for evaluating the efficacy of the gene therapy in the ischemic porcine heart. We use clinically relevant imaging methods such as ultrasound imaging and 15H2O-PET. For targeting the gene transfers into the desired area, electroanatomical mapping is used. The aim of this method is: (1) to mimic chronic coronary artery disease, (2) to induce therapeutic angiogenesis at hypoxic areas of the heart, and (3) to evaluate the safety and efficacy of the gene therapy by using relevant endpoints.

Myocardial gene therapy for ischemic heart disease holds great promise for future therapeutics. Here, we introduce a large animal model for evaluating the efficacy of gene therapy in the ischemic heart.

Coronary artery disease is one of the significant causes of mortality and morbidity worldwide. Despite the progression of current therapeutics, a ...

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 ...

Combining 3D-Printing and Electrospinning to Manufacture Biomimetic Heart Valve Leaflets

Electrospinning has become a widely used technique in cardiovascular tissue engineering as it offers the possibility to create (micro-)fibrous scaffolds with adjustable properties. The aim of this study was to create multilayered scaffolds mimicking the architectural fiber characteristics of human heart valve leaflets using conductive 3D-printed collectors.
Models of aortic valve cusps were created using commercial computer-aided design (CAD) software. Conductive polylactic acid was used to fabricate 3D-printed leaflet templates. These cusp negatives were integrated into a specifically designed, rotating electrospinning mandrel. Three layers of polyurethane were spun onto the collector, mimicking the fiber orientation of human heart valves. Surface and fiber structure was assessed with a scanning electron microscope (SEM). The application of fluorescent dye additionally permitted the microscopic visualization of the multilayered fiber structure. Tensile testing was performed to assess the biomechanical properties of the scaffolds.
3D-printing of essential parts for the electrospinning rig was possible in a short time for a low budget. The aortic valve cusps created following this protocol were three-layered, with a fiber diameter of 4.1 &#177; 1.6 &#181;m. SEM imaging revealed an even distribution of fibers. Fluorescence microscopy revealed individual layers with differently aligned fibers, with each layer precisely reaching the desired fiber configuration. The produced scaffolds showed high tensile strength, especially along the direction of alignment. The printing files for the different collectors are available as Supplemental File 1, Supplemental File 2, Supplemental File 3, Supplemental File 4, and Supplemental File 5.
With a highly specialized setup and workflow protocol, it is possible to mimic tissues with complex fiber structures over multiple layers. Spinning directly on 3D-printed collectors creates considerable flexibility in manufacturing 3D shapes at low production costs.

The presented method offers an innovative way for engineering biomimetic fiber structures in three-dimensional (3D) scaffolds (e.g., heart valve leaflets). 3D-printed, conductive geometries were used to determine shape and dimensions. Fiber orientation and characteristics were individually adjustable for each layer. Multiple samples could be manufactured in one setup.

Electrospinning has become a widely used technique in cardiovascular tissue engineering as it offers the possibility to create (micro-)fibrous scaffolds ...

Fully Endoscopic Mitral Valve Repair with Percutaneous Cannulation of Groin Vessels

Endoscopic mitral valve surgery (EMS) has become a standard of care at specialized heart centers, further reducing surgical trauma compared to a traditional minimally invasive, thoracotomy-based approach. Exposure of the groin vessels for the establishment of cardiopulmonary bypass (CPB) via surgical cutdown in minimally invasive surgery (MIS) may result in wound healing disorders or seroma formation. The avoidance of surgical exposure of the groin vessels by using fully percutaneous techniques for the insertion of a CPB cannula with the implementation of vascular pre-closure devices has the potential to reduce these complications and improve clinical results. Herein, we present the utilization of a novel plug based vacsular closure device with a resobable collagen plug and the absence of suture material for closure of the arterial access for CPB in MIS. While this device was initially predominantly used in transcatheter aortic valve implantation (TAVI) procedures, with its safety and feasibility shown, we herein show that it can be used in CPB cannulation, since it is capable of closing arterial access sites up to 25 French (Fr.) in size. This device may be suitable to significantly reduce groin complications in MIS and simplify the establishment of CPB. Here, we describe the fundamental steps of EMS, including percutaneous groin cannulation and decannulation using a vascular closure device.

This protocol demonstrates in detail how to perform fully endoscopic mitral valve surgery (EMS) with percutaneous cannulation of the groin vessels, using a percutaneous plug-based vascular closure device. Fundamental steps and useful instructions are described in detail for each step.