By 2050, better performing biomaterials-based implants will improve life. They will help restore the contractile function of a failing heart or create heart valves that grow with the patient–by Marc Gozlan
Engineering a tissue injured by growing cells from a donor or the patient himself, introduced to the patient on the site of the lesion. The production of biomaterials that can be used for cardiovascular regeneration is certainly a debut, but it is full of promise on the horizon for 2040-2050.
One of the most promising approaches is for researchers to introduce these cells within an implantable biomaterial that will foster the regeneration of damaged tissue. The vocation of this material is to mimic the extracellular matrix, a more or less dense mesh surrounding the cells, in the natural state, composed mainly of collagen fibers, a thousand to ten thousand times smaller than a hair tangled with a diameter of 10 to 300 nanometers.
The biomaterial can be composed of natural, synthetic or composite polymers. It is therefore for the biologists, engineers in biomaterials and chemists to produce a three-dimensional scaffold able to accommodate cells which promote tissue regeneration after implantation of a biomaterial. “The goal is to seed the scaffold with cells that can be set and in which they can proliferate and differentiate themselves,” said Dr. Catherine Le Visage of the cardiovascular bioengineering Inserm laboratory at Hôpital Bichat (Paris). “The scaffold must be biodegradable, but its degradation must be pretty slow so it can serve as a support for regeneration. It aims to disappear as new tissue secretes its own extracellular matrix”, she added.
Nanofabrication techniques allow one to obtain the biomaterials in which the 3D architecture mimics the natural environment of the cells. The morphology of the surface of the biomaterial scaffolding also depends crucially on the behavior of the seeded cells. Several nanofabrication technologies shape bumps, grooves, edges, pits and pores. The scale of these structures is in the order of tens or hundreds of nanometers; a nanometer is equal to one billionth of a meter! Despite their small size, these reliefs allow a dramatic increase in the surface area available within a given volume, while mimicking the topography of the extracellular matrix, which gives the biomaterial physical, chemical, structural and biological properties able to serve as support for cells that are introduced. Indeed, these nanostructures on the surface of the biomaterial influence the adhesion, migration, proliferation and differentiation of cells in the scaffolding.
Thus, pillars with a width of 150 nanometers and 400 nanometers in height, greatly promote the accession of heart cells from a scaffold with a smooth surface. Similarly, Nano lines with a height of 15 nanometers increase the adhesion of stem cells to a flat surface. The diameter and spacing between wells also affects cell adhesion. Their size of 30 nanometers is also more effective than deeper wells. Finally, while 35 nanometer grooves promote the alignment of heart cells along the surface of the biomaterial, deeper grooves can slow down the proliferation of cells or be fatal. Obtaining an alignment relatively homogeneous for cells in the scaffolding is essential insofar as electrical impulses through the heart travel preferentially in the longitudinal axis of the cell bundles to ensure cardiac contraction.
HEART AND VESSELS
The biomaterial mimicking cardiac extracellular matrix is mostly a hydrogel, capable of holding a large amount of water. Some research teams have designed a hydrogel which releases growth factors favoring the growth of cells in the implant. Thomas Webster, Professor of chemical engineering at Northeastern University in Boston, hopes the market by 2020-2025 is compatible with cardiac conductive injectable nanomaterials simulating the direction of propagation of electrical impulses in the heart.
While synthetic grafts are used successfully to replace large caliber arteries, they are not suitable for vessels less than 6 mm in diameter. These small vessels are involved in disabling pathologies, such as Arthritis of the lower limbs. The registry of vessels taken on another site (chest, leg) of the patient remains the solution of choice, but these plugins are not always healthy or available. In this case, the surgeon has to resort to synthetic grafts for which the failure rate is high, the plugin will often end up clogging due to the formation of a clot.
Several research teams have built tubular scaffolding from natural or synthetic polymers. They have introduced smooth vascular muscle cells and (including skin fibroblasts) collagen producing cells. The inside of these tubes, designed to be in contact with blood, are seeded with endothelial cells to prevent the formation of a clot. Of neovessels, having a mechanical resistance comparable to those of natural vessels, vascular pressure and elasticity were thus obtained. They have been implanted successfully in animals, causing no clot formation after several months. ‘The evaluation of the clinical efficacy of neovessels incorporating nanostructured biomaterials will impose to conduct clinical trials with long-term follow-up, thrombosis may occur long after the introduction of the neovessels”, says Dr. Catherine Le Visage. According to Professor Thomas Webster, a specialist of nanomaterials in regenerative medicine in Boston, “blood vessels equipped with a rough nanostructured surface could be used regularly by 2020. However, it will not be until 2030 or 2040-2050 that using perfect blood vessels will become routine and using cells from the patient will take longer to be validated by the regulatory authorities.”
“Once implanted, current valvular prostheses cannot grow or remodel. This is a major drawback in particular with children who will no doubt need surgery to receive new valves when they grow. In addition, these valves may calcify and be a source of thrombosis’, says Dr. Robert Gauvin, researcher in the Division of science and biomedical technology at Harvard Medical School and the Massachusetts Institute of Technology.
For Professor Ali Khademhosseini, who directs the laboratory, “nanostructured biomaterials employment represents a way that would create a viable heart valve prosthesis, with increased biocompatibility, having the ability to grow and shape inside the patient after implantation”. A prototype of a valve consisting of a synthetic polymer whose functional area is conducive to adhesion, growth and proliferation of endothelial cells, has recently been developed. Other experimental valves also incorporate nanoparticles containing active substances, whose release is controlled, in order to stimulate the growth of cells in the scaffolding.
According to Thomas Webster, “valve making nanostructured polymers already approved by the Food and Drug Administration will be routinely used in the clinics in five years”. It will take longer for valves that would use new polymers or the patient’s own cells. Indeed, these autologous cells should be grown in the laboratory before being introduced into the valvular replacement used biomaterial. The availability of safe and effective heart valves, manufactured from nanomaterials, will no doubt be possible in 2045-2050.
Laboratories are now working on the manufacture of a patch which architecture mimics the cardiac extracellular matrix. Applied surgically, this patch would stimulate the production of functional cardiac cells on a failing myocardium. According to Professor Philippe Menashé, surgeon at the Hôpital Européen Georges-Pompidou (Paris) and a specialist in cardiovascular cell therapy,[we] must “wait a decade before in clinical cardiac patches are routine for the inorganic promoting cell adhesion of neurons” (below). Nanocablage of the Harvard researchers planted 3D scaffold porous nanoelectronics with cells, creating a type of fabric ‘cyborg’. Patients with chronic heart failure that escape the conventional medical treatments and which, for various reasons, are with a left ventricular assist device or heart transplantation, while adding that “this could go faster in the light of the rhythm to which it leads clinical trials using stem cells in other pathologies.”
The source of cells to implant in these nanostructured patches remains a problem, because it is difficult to get heart cells from the patient. The track of the heart stem cells, able to differentiate into mature heart cells (cardiomyocytes), appears promising.
A research project, called NanoCARD, coordinated by the Max Planck Institute for Intelligent Systems in Stuttgart (Germany), aims to develop a nanostructured, porous, biomimetic material, composed of a degradable biopolymer that can accommodate strains and cardiac progenitor cells to differentiate into functional cardiac cells. Nanostructured surfaces are designed to promote the adhesion and differentiation of cells.
Intended to be implanted on the failing myocardium for improved contractile function, this device is part of the 7th Framework Programmed for research of the European Union. This project is for a period of 24 months ending late 2013. It combines seven research centers including Swiss, Swedish, Israeli and Italian, as well as German, French, and Israeli biotech companies. However, it will probably not be until years 2045-2050 to make the installation of a patch (also banal today) for coronary angioplasty or the laying of a stent (a metal device used to hold open the body cavity).
Does this mean that the future of nanomaterials in cardiovascular regenerative medicine lies in the long term? Certainly not. The first application of nanomaterials in this area could quickly emerge. It could involve the PLGA polymer commonly used in biodegradable sutures. “We have created PLGA of surfaces that mimic the nanotopography of cardiac tissue and observed cardiac tissue regeneration,” says Professor Thomas Webster. This nanostructured material could be approved within one to two years.
Le Monde article on “Nanomaterials to Repair Man” by Marc Gozlan. (pdf version)