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Supramolecular chemistry and the development of a living heart valve replacement
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by Frederick Schoen, MD, PhD
Current options for heart valve replacement, whether mechanical or biological, are far from perfect solutions. In fact, patients who have undergone previous valve replacement surgery account for more than 25% of patients with valvular heart disease, emphasizing the high rate of failure of contemporary valve substitutes.
Mechanical prosthetic devices, which include tilting-disc and bileaflet devices fabricated from synthetic biomaterials, require anticoagulation therapy for the patient who receives them, whereas biological valves fabricated from either human tissue, including homografts or pulmonary autografts, or animal tissue, such as porcine, bovine or equine pericardial bioprostheses, deteriorate over time. Further, the challenges can be more acute when treating pediatric patients, given their small size, more active metabolism and the additional factor that the patient’s body continues to develop and enlarge.
We have been investigating heart valves for many years, looking at how natural heart valves work, the mechanisms by which heart valves stay healthy, as well as the mechanisms that contribute to disease and dysfunction of natural and substitute heart valves, creating the need for replacement or repair.
Understanding heart valve health and disease
The mechanisms of both health and disease heavily involve valve cells and the extracellular matrix that surrounds and supports them. Coupled with data that show how heart valves evolve and mature in the fetus and during growth and aging, we have developed a better understanding of the mechanisms of how heart valve tissue is created, changes with age and various stresses, and how this tissue remains healthy.
The goal of the work that we’ve done in Boston, in conjunction with John Meyer in Boston, Michael Sacks in Austin, Texas, Simon Hoerstrup in Switzerland, and others, has sought to translate this understanding into the creation of improved tissue-engineered heart valves.
The hope with an engineered tissue valve replacement is that it would be composed of living tissue that is actually fabricated from the cells of the individual who needs the valve and, therefore, the living natural tissue would function and evolve much more like the natural heart valve. In theory, this would result in less risk of degradation of the implanted tissue, and potentially enlarge and repair damage as the recipient grows and ages.
Potential to grow a heart valve
There is now a project underway in Europe that takes the premise of an engineered tissue valve replacement in a new direction because it relies on a polymer medical device, derived from the concepts and practice of supramolecular chemistry, to encourage the body to grow a valve, physiologically, from new, native tissue.
Four fundamental requirements are required to make this work: First, biocompatibility; the implant cannot cause any adverse effects. Second, the implant would need to stimulate and support the growth of tissue in a natural way. Third, and this is where the novelty comes in, is that the implant would need to dissolve at an appropriate rate as it is replaced by natural tissue. Fourth, the implant would need to perform the mechanical work of a natural valve from the moment it is implanted and transfer stresses to the new tissue as it is created.
Supramolecular polymers
The device under development by Xeltis is based on progress in a scientific field that was termed supramolecular chemistry, the chemistry of assembled molecules, by Jean-Marie Lehn, PhD, from the University of Strasbourg, who shared the Nobel Prize in chemistry in 1987 with two other chemists for their pioneering work in the field. The Lehn group initiated the use of hydrogen bonds for linking the monomer molecules to make supramolecular polymers. Polymers, using these bonds, were further developed by E.W. Meijer, PhD, and his time in Eindhoven, which formed the basis for the Xeltis technology.
The polymers marked the breakthrough for using these supramolecular polymers in a variety of applications. They fine-tuned the rate of exchange and the stability of the bonds to create a polymer with quadruple hydrogen bonds, bonds that are not so strong as covalent bonds, like those in normal macromolecule, but also not so weak that the material is still a liquid. The dynamics of the exchange of the quadruple hydrogen bonds are making a polymer strong enough for biomedical materials applications, but being labile enough to disappear in time.
Interestingly, there was initially much skepticism about the work on supramolecular polymers. The skepticism also extended to how these polymers would behave once implanted in the human body. It appears that these polymers can be biocompatible and eventually simply disappear (ie, they are resorbed and metabolized by the body).
New technology
The new technology created by Xeltis utilizes biodegradable matrices that are designed to stimulate and guide the body’s natural healing response without the need for stem cells, growth factors or animal tissue delivered from outside the patient. These polymers are “programmed” so that as the natural and functioning tissue grows, they disappear and no foreign material is left behind.
The process for creating the device begins with the assembling of the polymers fabricated using supramolecular principles into nanofibers. After this step, a process called “electrospinning” is used to assemble the nanofibers into fibers about one-tenth the width of a human hair, which are then intertwined to create a porous polymer matrix. The resulting matrix, which is shaped in the macroscopic configuration of the valve, is made of a single fiber close to 100 km that is flexible, yet strong enough, to meet the demands of a beating heart.
The hope is that the Xeltis technology will stimulate the growth of tissue in the individual who receives the implant and eventually this implant will be replaced by healthy, living, natural tissue that resembles the natural heart valve of the patient.
Open questions
Although this technology certainly seems interesting, a strong body of clinical evidence remains to be built to prove that the four fundamental requirements are being met. A feasibility clinical trial currently underway should provide the first clinical observations testing these hypotheses.
Although considerable work needs to be done to validate the principles and prove clinical benefit, this work has the potential to be an enormous step forward for using these types of materials in the body.
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