The Era of Regenerative Medicine Is Here: Could it Mean a Cure for Heart Failure?

Dr. Robert Matheny, chief scientific officer at CorMatrix, explains the CorMatrix ECM (extracellular matrix), a technology that enables a person's own stem cells to repair damaged cardiovascular tissues by serving as scaffolding. This interview was conducted on March 16 following a tour, guided by Dr. Matheny, of the lab facilities at St. Joseph's Translational Research Institute in Atlanta, GA, where CorMatrix animal studies are conducted.

What types of research are carried out at St. Joseph’s Translational Research Institute

CorMatrix does some of our initial feasibility and testing here. The company was founded in 2000, although I’ve been working in extracellular matrices since 1993, when I was at Perdue and recognized the potential of the extracellular matrices. We eventually got some funding and started manufacturing products that are on the market now.

But we were noticing the remodeling and regenerating properties of the matrices long before we could describe the mechanism, which was a problem because humans (mammals in general) are not supposed to be able to regenerate tissue, yet we were regenerating tissue. But the mechanism has been elucidated fairly well and continues to be. First, we recognized that progenitor cells were migrating to the matrix and causing the remodeling. Everybody understands stem cells now because of the public war over them, and everybody understands their potential, but they have been used to a large extent outside of their normal physiology, which means they function by attaching to an ECM and getting their cues from the environment through the ECM.

This is an enabling technology for patients’ own inherent stem cells circulating within the niches of every organ. When there’s an injury in the area of inflammation, stem cells don’t function, and that’s why we scar rather then have regenerative capacities. What people have come to recognize is that when you have injury and inflammation, not only are the cells nonfunctional, but the ECM in that injury is destroyed, and that has to be re-grown as well as the cells. Initially, your platelets and fibrin provide rudimentary scaffolding for the function of cells, but they only produce scar. We provide a normal extracellular matrix in the area of injury, and the stem cells are capable or doing what they normally do.

We’ve started out with the pericardium, which has turned out to be a fascinating area. It was meant to be more of a feasibility, giving into the area of ECM in cardiovascular surgery, but now we’re finding that it is very much an integral part of normal cardiac function, and it is a very exciting story how the pericardial applications are growing. Then we had the intra-cardiac applications approved by the FDA, and in Europe, for fixing intra-cardiac defects within the pericardium—ascending aorta, valve leaflets for bacterial endocarditis, ASDs, VSDs, and patches of different sorts now becoming normal tissue instead of using a synthetic that remains a synthetic forever.

Did you start CorMatrix, or did the company come to you?

I founded the company and then, with the help of David Camp in 2001 who came on board as CEO, we started CorMatrix Cardiovascular. That is the parent company, and for the patches we were using—the sheets of the ECM—we have been demonstrating for a number of years how they’ve been able to grow myocardium, which you aren’t supposed to be able to do because the dogma up until recent years is “the heart doesn’t regenerate.” Now we know that it does, and we’ve been able to do it with the help of the ECM quite effectively in patches.

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electronic version that demonstrates that when we inject it, it repolymerizes within the substance of the infarct, it attracts progenitor cells and initiates an angiogenesis that then attracts the cells that turn into cardiomyocytes. For the first time, we are enabling stem cells to repair cardiac myocardial infarctions, and we think we can really, in this way, impact congestive heart failure and the formation of congestive heart failure, the number one disease killer in the country.

The question was “can we emulsify this so that we can inject it into infarcts and repair those; we just had an article come out today in the

Right now, we have really poor answers for treating CHF: transplantation, which is very limited; ventricular assist devices, which are also limited (and expensive and really exchange one disease for another via ventricular pacing); and drug therapy, none of which cure the problem. Rather than assisting the heart, we think we can actually cure CHF, the number one Medicare expenditure and a growing problem that doesn’t have a real answer; that’s why I’m hear dealing with the pigs. And we’re infarcting them, causing CHF in both acute and chronic models, and then injecting them with the emulsion. We’ve been in discussions with the FDA to some extent, and we want to have them as our partner as we approach curing this problem.

What is the CorMatrix ECM made of?

The ECM is mostly made up of different collagen components, as far as the majority of the bulk of it. It does have some growth factors, proteoglycans, and glycosylated glycans, all of which are necessary for the cells to receive their proper instructions. In fact, what was, and has been, the major problem is harvesting—removing the cells that cause the immune response out of the matrix and yet leaving that fine architecture in tact, because we have come to find that the fine architecture, which is on a nanometer level, is as important—if not more so—than some of it’s constituents and bio-ingredients. And if you disrupt that architecture, then you destroy what the cells normally see and respond to. If you alter that, you don’t get the normal response. Just like an inflammation when the ECM is degraded, the cells don’t recognize the environment anymore, and if you alter that before implantation, they also don’t recognize it. So, a large part of the manufacturing process has been understanding how to get it into a clinician’s hand in the lab or the OR in a form that the cells recognize.

Most of the current form are sewn in as a patch for an ASD or VSD. But we realized that wasn’t going to work for an infarct, because you can’t take out a big chunk of the left ventricle and sew in a patch; otherwise, the patient is going to need a ventricular assist device during the remodeling process, which isn’t practical.

So, we made the emulsified version so that when you inject it at 37 degrees it repolymerizes; it’s like injecting the patch and repairing the infarct from within.

When do you expect to move to human studies?

We’re looking at acute and chronic models, a number of toxicity and degradation studies, a lot of safety studies and inflammation studies, and some arrhythmia trials to make sure it doesn’t cause any arrhythmias. We haven’t noticed that in animal studies and it doesn’t seem to be a problem, but the cell therapy early on did cause some arrhythmias, so I’m sure that the FDA will want to have some assurance that that doesn’t cause a problem.

Once we satisfy those trials—and we hope to be done by the end of this year—we will work toward putting it in some human trials. The way we would like to approach that is to first make sure it’s safe by putting it in probably the safest patient cohort, which is those patients who are already on a ventricular assist device totally supporting the heart who are being bridged to transplant. We can inject it in those hearts very safely because the heart is fully supported; we’ll also get some histology on the transplanted heart at the time of transplant. Once we do those studies and know that it’s safe, then we would like to go into trials with heart failure patients and do a formal trial hopefully next year.

How far away are we from a marketable product?

A couple years. I would say we’re probably a year away from the first human implant, but that will be in a restricted trial; it will take probably a year to do that trial and cull the results together, and then after that, hopefully we can start using it for everyday applications.

Could you explain in more detail what your animal studies have shown?

We have now done studies on small, medium, and large mammals, and the results have been consistent across the board. We have done patch studies in full-thickness ventricular defects for a number of years. The emulsified version has been studied in rats, then in rabbits, and we’ve now done a number of pig studies, and they show the same thing: angiogenesis followed by recruitment of progenitor cells that emanate from the bone marrow and the heart, establish a vascular supply, and then phenotypically change into cardiomyocytes, which is phenomenal. And we’ve even seen that now by sewing the patch on the heart in some rat studies that are being done at Stanford and in Calgary. It’s working quite well, and now we’re doing this very large animal study, which is in both acute and chronic adult pigs, to add to the volume so we can go to the FDA and let them see how we’re progressing.

What should practicing cardiologists know about the technology?

They need to understand that the era of regenerative medicine is here; it’s not something that stem cells are going to provide 5 or 10 years from now. It’s on the shelf. It’s in its first current forms. They should start understanding more of the molecular events that take place in the stem cells rather than just the fact that they’re interesting play toys for the researcher. They are now going to be applying those, currently in the products that we have, and in the future with the emulsion.

And, they need to start understanding the technology behind it, which is becoming familiar with the publications on the ECM and some of the stem cells and things that are happening, because this is something in the next couple years that they’ll be dealing with every day. In fact, they’re starting to; CorMatrix has sold, since 1996, over 22,000 patches for both peri- and intra-cardial use, and the number is growing rapidly.

Now we have clinical data of patients having atrial-septal defects normal on scan, valve leaflets that are normal on reoperation—superior vena cava, right ventricular outflow tracts, pulmonary arteries, ventricular wall; it’s all doing the same thing in humans, we now know, as it did in the animals.

It’s an enabling technology for stem cells, without having to go get any stem cells. So, as far as the cost, the regulatory hurdles, the sterilization issues, and the ethical issues, it makes all of those a moot point. We’ve leapfrogged that whole problem area and kind of come in the back door while everybody was looking out front.

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different patient; that goes from class 4 to class 2, and now that’s a patient who on the right medications can go to the mall and walk around and drive the car and is functional and isn’t a burden on the healthcare dollar. And I have every expectation that we can do that.

If you take a patient who has a 15-20% ejection fraction and can get them up to a 25-30% ejection fraction, that’s a

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