Cardiovascular Tissue Engineering Models for Atherosclerosis Treatment Development

Abstract

In the early years of tissue engineering, scientists focused on the generation of healthy-like tissues and organs to replace diseased tissue areas with the aim of filling the gap between organ demands and actual organ donations. Over time, the realization has set in that there is an additional large unmet need for suitable disease models to study their progression and to test and refine different treatment approaches. Increasingly, researchers have turned to tissue engineering to address this need for controllable translational disease models. We review existing and potential uses of tissue-engineered disease models in cardiovascular research and suggest guidelines for generating adequate disease models, aimed both at studying disease progression mechanisms and supporting the development of dedicated drug-delivery therapies. This involves the discussion of different requirements for disease models to test drugs, nanoparticles, and drug-eluting devices. In addition to realistic cellular composition, the different mechanical and structural properties that are needed to simulate pathological reality are addressed.

Keywords: atherosclerosis; disease models; drug-coated balloons; drug-eluting stents; nanoparticles; tissue engineering.

Figure 1

Histological sections of three different human lower limb arteries stained with Movat pentachrome staining. Nuclei are colored in black, fibrin and muscle in red, collagen in yellow and elastic fibers in blue/black. (A) vessel in early disease state with an organized layered structure (close up) and slightly visible intimal hyperplasia (B) atherosclerotic vessel with severe stenosis due to intimal hyperplasia (red arrow) (C) diseased vessel with disrupted vascular structure with calcification (black arrows) and lipid core. Images were allocated by CBSET Inc., Lexington, MA, USA (CBSET = Concord Biomedical Engineering and Emerging Technologies incorporated).

Figure 2

Upper part: Overview of key model attributes. In this review we evaluate existing tissue engineering models according to their ability to mimic healthy and diseased vascular tissue focusing on three attribute categories: biological–biochemical environment, hemodynamic–microstructural conditions (blue arrows), and mechanical–geometric (orange arrows) properties. Lower part: Overview of the minimal necessary set of attributes that a model has to represent for testing three different treatment approaches. While testing of drugs can be performed on models that replicate the biological–biochemical environment of the tissue, therapeutics that are based on nanoparticles need to also include a hemodynamic-microstructural aspect of the vascular environment, since the delivery and attachment of the particles is influenced by blood flow. Testing of therapies based on drug–eluting endovascular devices requires models that holistically replicate the biological–biochemical, hemodynamic–microstructural and mechanical–geometrical structure of the vascular system, since drug delivery is also dependent on device tracking and mechanical inflation.

Figure 3

Overview mechanism of action of drugs and nanoparticles. Drugs targeting atherosclerosis are designed to have a non-selective effect on specific cell types and are screened on simple cell cultures. For studying and testing of new drugs, mimicking the biological–biochemical tissue environment is sufficient. Nanoparticles circulate in the blood flow, approach their specific target tissue selectively, and release their molecule of interest (drug or nanoprobe). To study and optimize nanoparticles of atherosclerosis treatment, not only the biological–biochemical environment but also the hemodynamic–microstructural conditions need to be simulated. Impact due to biological–biochemical attributes are indicated with green arrows, impact due to hemodynamic–microstructural conditions are indicated with blue arrows.

Figure 4

Overview mechanism of action of endovascular device drug delivery in stenosed blood vessels. Endovascular devices are coated with cytostatic drug coating that is locally delivered. Drug-eluting stents are permanently implanted at the target lesion and can slowly release their drug load from rate-limiting coatings. The implantation of stents is associated with safety concerns, since these can injure the endothelium leading to restenosis and malapposition increases the risk of thrombosis. In contrast, drug-coated balloons transfer their drug coating during a short inflation period and rely on slow coating dissolution to sustain local drug dosing within the tissue. For studying and assessing both devices, the biological–biochemical (green arrows) environment for drug effect, hemodynamic–microstructural (blue arrows) conditions for retention versus wash-out, and mechanical–geometrical properties (orange arrows) for expansion/inflation efficiency need to be mimicked by a tissue-engineered model.