Name: in vitro 3d cell-cultured arterial models for studying vascular drug targeting under flow
Uploaded: 2021-03-14T14:30:00
Description: Watch this Scientific Journal Video about In Vitro 3D Cell-Cultured Arterial Models for Studying Vascular Drug Targeting Under Flow at JoVE.com

This work was supported by the Israel Science Foundation (ISF grant # 902/18). Maria Khoury&#39;s scholarship was supported by The Baroness Ariane de Rothschild Women Doctoral Program.

NOTE: This protocol describes the fabrication of a 3D model of the carotid artery and can be applied to generate any other artery of interest by simply modifying the geometric parameters.
1. Design and fabrication of a 3D bifurcation of the human carotid artery model
<ol>
	<li>Choose images from patients or previously studied geometries of the human carotid artery bifurcation, and create a computer-aided design model of the mold that needs to be printed. 
	NOTE: The carotid artery bifur...

<ol>
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Y., 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=Quantum+dot+interactions+and+flow+effects+in+angiogenic+zebrafish+(Danio+rerio)+vessels+and+human+endothelial+cells.">Quantum dot interactions and flow effects in angiogenic zebrafish (Danio rerio) vessels and human endothelial cells.</a> Nanomedicine: Nanotechnology, Biology, and Medicine. 13 (3), 999-1010 (2017).</li><li>Zarins, C. K., 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=Carotid+bifurcation+atherosclerosis.+Quantitative+correlation+of+plaque+localization+with+flow+velocity+profiles+and+wall+shear+stress.">Carotid bifurcation atherosclerosis. Quantitative correlation of plaque localization with flow velocity profiles and wall shear stress.</a> Circulation Research. 53 (4), 502-514 (1983).</li><li>Chien, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Effects+of+disturbed+flow+on+endothelial+cells.">Effects of disturbed flow on endothelial cells.</a> Annals of Biomedical Engineering. 36 (4), 554-562 (2008).</li><li>Malek, A. M., Alper, S. L., Izumo, S. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Hemodynamic+shear+stress+and+its+role+in+atherosclerosis.">Hemodynamic shear stress and its role in atherosclerosis.</a> JAMA. 282 (21), 2035-2042 (1999).</li><li>Glagov, S., Zarins, C., Giddens, D. P., Ku, D. N. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Hemodynamics+and+atherosclerosis.+Insights+and+perspectives+gained+from+studies+of+human+arteries.">Hemodynamics and atherosclerosis. Insights and perspectives gained from studies of human arteries.</a> Archives of Pathology &amp; Laboratory Medicine. 112 (10), 1018-1031 (1988).</li><li>Khoury, M., Epshtein, M., Zidan, H., Zukerman, H., Korin, N. <a target="_blank" href="http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&doptcmdl=Citation&defaultField=Title+Word&term=Mapping+deposition+of+particles+in+reconstructed+models+of+human+arteries.">Mapping deposition of particles in reconstructed models of human arteries.</a> Journal of Controlled Release. 318, 78-85 (2020).</li></ol>

Current approaches to study vascular targeting of particles fall short in replicating the physiological conditions present in the human body. Presented here is a protocol to fabricate 3D-reconstructed models of human arteries to study particle targeting to the ECs lining the artery under physiological flow applied using a customized perfusion system. When choosing the material for 3D printing, it is best to use a clear plastic to avoid pigment transfer to the silicone model, which should be as transparent as possible. In...

Several approaches have recently been applied utilizing 3D models of human arteries1,2,3,4,5. These models replicate the physiological anatomy and environment of different arteries in the human body in vitro. However, they have been mainly used in cell biology studies. Current studies on vascular targeting of particles to the endothelium include in silico computational simulations6,7,8, in vitro microfluidic models9,10,11, and in vivo animal models12. Despite the insights they have provided, these experimental models have failed to accurately simulate the targeting process that occurs in human arteries, wherein blood flow and hemodynamics constitute dominant factors. For example, the study of particle targeting to atherosclerotic regions in the carotid artery bifurcation, which are known for their complex recirculation flow pattern and wall shear stress gradient, may impact the journey taken by the particles before they reach the endothelium13,14,15,16. Therefore, these studies must be performed under conditions that replicate the physiological environment, i.e., size, dimension, anatomy, and flow profile.
Recently, this research group fabricated 3D-reconstructed human arterial models to study the deposition and targeting of particles to the vasculature17. The models were based on geometrical 3D replicas of human blood vessels, which were then cultured with human ECs that subsequently lined their inner walls. In addition, when subjected to a perfusion system that produces physiological flow, the models accurately replicated physiological conditions. The perfusion system was designed to perfuse fluids at a constant flow rate, using a peristaltic pump in both closed and open-circuit configurations (Figure 1). The system can be used as a closed-circuit to map particle deposition and targeting to the cells seeded inside the carotid model. In addition, it can be used as an open circuit to wash out non-adherent particles at the end of the experiments and to clean and maintain the system. This paper presents protocols for the fabrication of 3D models of the human carotid bifurcation, design of the perfusion system, and mapping of the deposition of targeted particles inside the models.

<table border="1" fo:keep-together.within-page="1" fo:keep-with-next.within-page="always">
	<tbody>
		<tr>
			<td>3D printer</td>
			<td>FormLabs</td>
			<td>PKG-F2-REFURB</td>
			<td></td>
		</tr>
		<tr>
			<td>Acetone, absolute (AR grade)</td>
			<td></td>
			<td></td>
			<td></td>
		</tr>
		<tr>
			<td>Connectors</td>
			<td>Nordson Medical</td>
			<td>FTLL013-1</td>
			<td>Female Luer</td>
		</tr>
		<tr>
			<td></td>
			<td></td>
			<td>FTLL230-1</td>
			<td>Female Luer</td>
		</tr>
		<tr>
			<td></td>
			<td></td>
			<td>FTLL360-1</td>
			<td>Female Luer</td>
		</tr>
		<tr>
			<td></td>
			<td></td>
			<td>LP4-1</td>
			<td>Male Luer Integral Lock</td>
		</tr>
		<tr>
			<td>Damper</td>
			<td>Thermo-Fisher Scientific</td>
			<td>DS2127-0250</td>
			<td>Nalgene Polycarbonate, Validation Bottle</td>
		</tr>
		<tr>
			<td>Damper Cover</td>
			<td>Thermo-Fisher Scientific</td>
			<td>2162-0531</td>
			<td>Nalgene Filling/Venting Closures</td>
		</tr>
		<tr>
			<td>Elastosil Elastosil RT 601 A</td>
			<td>Wacker</td>
			<td>60003805</td>
			<td></td>
		</tr>
		<tr>
			<td>Elastosil RT 601 B</td>
			<td>Wacker</td>
			<td>60003817</td>
			<td>The crosslinker</td>
		</tr>
		<tr>
			<td>Endothelial Cell Media</td>
			<td>ScienCell</td>
			<td>1001</td>
			<td></td>
		</tr>
		<tr>
			<td>Fibrontectin</td>
			<td>Sigma Aldrich</td>
			<td>F0895-5mg</td>
			<td></td>
		</tr>
		<tr>
			<td>HUVEC</td>
			<td>Lonza</td>
			<td>CC-2519</td>
			<td></td>
		</tr>
		<tr>
			<td>Isopropyl alcohol, AR grade 99.5%</td>
			<td></td>
			<td></td>
			<td>Remove plastic dust from the sanded model</td>
		</tr>
		<tr>
			<td>Lacquer</td>
			<td>Rust-Oleum</td>
			<td></td>
			<td>2X-Ultra cover Gloss Clear</td>
		</tr>
		<tr>
			<td>Matlab</td>
			<td>Mathworks</td>
			<td></td>
			<td>https://www.mathworks.com/products/matlab.html</td>
		</tr>
		<tr>
			<td>Microscope</td>
			<td>Nikon</td>
			<td>SMZ25</td>
			<td></td>
		</tr>
		<tr>
			<td>Microscope Camera</td>
			<td>Nikon</td>
			<td>DS-Qi2</td>
			<td></td>
		</tr>
		<tr>
			<td>Peristaltic pump</td>
			<td>Watson Marlow</td>
			<td>530U IP31</td>
			<td>With 2 pumpheads: 313D</td>
		</tr>
		<tr>
			<td>Plastic tube clamp</td>
			<td>Quickun</td>
			<td>1-2240-stopvalve-2pcs</td>
			<td></td>
		</tr>
		<tr>
			<td>Polystyrene Particles</td>
			<td>&#160;Thermo-Fisher Scientific</td>
			<td>&#160;F8827</td>
			<td>&#160;Diameter = 2 &#181;m</td>
		</tr>
		<tr>
			<td>Printer resin</td>
			<td>FormLabs</td>
			<td>RS-F2-GPCL-04</td>
			<td></td>
		</tr>
		<tr>
			<td>Rotator</td>
			<td>ELMI Ltd.</td>
			<td></td>
			<td>Intelli-Mixer RM-2</td>
		</tr>
		<tr>
			<td>Solidworks&#160;</td>
			<td>SolidWorks Corp.,&#160;Dassault Syst&#232;mes</td>
			<td></td>
			<td>https://www.solidworks.com/</td>
		</tr>
		<tr>
			<td>Tubing</td>
			<td>Watson Marlow</td>
			<td>933.0064.016</td>
			<td>Tubing for the pump: 6.4 mm ID</td>
		</tr>
		<tr>
			<td></td>
			<td></td>
			<td></td>
			<td>All the other tubing: Silicon tubing: 4 mm ID</td>
		</tr>
	</tbody>
</table>

in vitro 3d cell-cultured arterial models for studying vascular drug targeting under flow

The use of three-dimensional (3D) models of human arteries, which are designed with the correct dimensions and anatomy, enables the proper modeling of various important processes in the cardiovascular system. Recently, although several biological studies have been performed using such 3D models of human arteries, they have not been applied to study vascular targeting. This paper presents a new method to fabricate real-sized, reconstructed human arterial models using a 3D printing technique, line them with human endothelial cells (ECs), and study particle targeting under physiological flow. These models have the advantage of replicating the physiological size and conditions of blood vessels in the human body using low-cost components. This technique may serve as a new platform for studying and understanding drug targeting in the cardiovascular system and may improve the design of new injectable nanomedicines. Moreover, the presented approach may provide significant tools for the study of targeted delivery of different agents for cardiovascular diseases under patient-specific flow and physiological conditions.

This paper presents a new protocol to map the deposition of particles inside real-sized 3D human artery models, which may provide a new platform for drug delivery research. Using a 3D printing technique, a model of the human carotid bifurcation artery was fabricated (Figure 2). The model was made of silicone rubber and seeded with human ECs (Figure 3). Importantly, this protocol enabled the replication of physiological conditions, especially with respect to flui...

Watch this Scientific Journal Video about In Vitro 3D Cell-Cultured Arterial Models for Studying Vascular Drug Targeting Under Flow at JoVE.com

In Vitro 3D Cell-Cultured Arterial Models for Studying Vascular Drug Targeting Under Flow

Here, we present a new protocol to study and map the targeted deposition of drug carriers to endothelial cells in fabricated, real-sized, three-dimensional human artery models under physiological flow. The presented method may serve as a new platform for targeting drug carriers within the vascular system.

In Vitro 3D Cell-Cultured Arterial Models for Studying Vascular Drug Targeting Under Flow

The use of three-dimensional (3D) models of human arteries, which are designed with the correct dimensions and anatomy, enables the proper modeling of ...

The present protocol may serve as a new platform for the study and development of drug carriers to target disease sites within the human vascular system. The main advantage of our technique is that it allows the study of drug carriers'accumulation inside human-replicated 3d arterial model. This is done under physiological conditions, including blood flow.This approach can be used to optimize drug carriers for the diagnosis and treatment of a wide range of vascular diseases, including a atherosclerotic arteries. Begin by selecting images from patients or previously studied geometries of the human carotid artery bifurcation and using the images to create a computer-aided design model of the mold. Use a 3d printer to print the design, remove the temporary printing supports and rinse the model with acetone before using sandpaper to polish and smooth the molds, especially the areas from which the supports were cut.After sanding, rinse the model with isopropyl alcohol to remove any plastic dust and allow the model to dry in a chemical hood for two to three hours. To facilitate easy disillusion of the plastic, spray the model with transparent lacquer three times, allowing the lacquer to air-dry for one hour between applications. After the last application, use a paint brush and lacquer to glue transparent, rectangular strips of smooth plastic to each side of the frame, such that the model will be sealed at the bottom and open at the top.After drying, place the mold in a desiccator and slowly poor freshly-prepared silicone rubber solution into the opening. Remove air bubbles until the mixture is clear and leave the mold inside the desiccator overnight. When the mixture is fully dry, remove the transparent slides and immerse the model in absolute acetone for 48 hours in a chemical hood until the plastic is fully dissolved.To evaporate the trapped acetone before cell seeding, incubate the model for at least four days at 60 degrees Celsius. To seed the model with cells, first sterilize the model and two inlet and outlet connectors by ultraviolet light or radiation. After 20 minutes, using a syringe to coat the model with four milliliters of 100 microgram per milliliter fibronectin for two hours at 37 degrees Celsius.At the end of the incubation, remove the fibronectin solution through the outlet and wash the model with endothelial cell medium. Use a syringe to fill the rinsed model with four milliliters of a 2.5 times 10 to the sixth endothelial cells per milliliter of endothelial cell medium cell suspension and secure the model to a rotator inside a cell culture incubator 48 hours at one revolution per minute, to ensure homogenous distribution of the cells. At the end of the incubation, use a 10 milliliter plastic syringe to wash the model with PBS.Fix the cells for 15 minutes, with four milliliters of 4%paraformaldehyde, then wash the model three times with PBS as demonstrated before storing the model at four degrees Celsius in four milliliters of fresh PBS. Before beginning an experiment, use the outlet tubing to connect an oscillation damper connected to a peristaltic pump to the inlet of the cultured carotid model and use a piece of tubing to merge the two outlets. Then split the outlet tubing to two outlet tubes and add a plastic clamp to each tube.To set up a closed circuit configuration, add 300 milliliters of PBS to a closed circuit container and place one inlet and one outlet tube inside the PBS filled container with the B and C clamps open, respectively, then place the other inlet tube into a one-liter washing container filled with distilled water, and the other outlet tube into an empty one-liter waste container with the A and D clamps closed, respectively. Place the carotid model under a stereo microscope, set the pump to a starting flow rate of 10 revolutions per minute, with five revolution per minute increment increases every four to five minutes. When the flow rate reaches 100 revolutions per minute, add 1.6 micrograms of fluorescent carboxylated polystyrene particles per milliliter of PBS to the closed circuit container and image the region of interest every 10 seconds for one and a half hours.To set up an open circuit configuration, open the A and D clamps and immediately close the B and C clamps. Let most of the water flow from the washing container to the waste container at 100 revolutions per minute. Before the water has been completely transferred, stop the pump and close the tube clamps before the inlet and after the outlet of the carotid model.Using the appropriate filters, capture images of the model at the region of interest to show the deposition and adhesion of the particles to the cells. Upon completion of the experiment, use a customized software code to analyze the images captured at the region of interest, enter the name of the image and set the estimated threshold. Then run the code.Inspect the resulting image and the counted number of particles in the image. In this representative analysis, photo micrographs of cultured endothelial cells seeded in a 3d carotid artery model can be observed by brightfield and fluorescence confocal microscopic imaging. Fluorescent 10 micron diameter glass beads, seeded into the 3d model exhibited a recirculation pattern, suggesting a successful mimicking of physiological conditions within the model.Imaging of the particle deposition revealed that a higher level of adhesion of the particles to the cells was observed outside of the recirculation area where the wall shear stress was high. Following this protocol, functionalized particles with specific binding kinetics and a core culture of cells within different human artery models may be explored to improve the model and to study specific formulations. This technique provides a new platform for studying the vascular targeting of drug carriers.We have recently used it to show how the additivity of particles can be tailored to target different diseased vessel regions.

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