This is Part 2 of an interview with Dr. Chris Centeno, an international expert in regenerative medicine and the clinical use of mesenchymal stem cells (MSCs) for orthopedic applications.
He specializes in clinical use of adult stem cells for orthopedic injuries, which he treats through same-day procedures at his clinic in Denver, Colorado, and through cultured expansion of mesenchymal stem cells at a clinic in Grand Cayman. He first performed these adult stem cell procedures in the U.S. in 2005-2006, and his clinic has since has treated thousands orthopedic patients with stem cell based therapies.
As the President/CEO of a stem cell research firm and an international rugby athlete, I have both professional and personal interest in the technologies that he has developed. He is best known for the Regenexx® technology, an approach that uses needle based procedures coupled with sophisticated guidance techniques to place large numbers of stem cells at the site needing repair.
This approach can often replace the need for invasive orthopedic surgeries.
Read Part 1 of the interview here.
Part 2 – Interview with Dr. Chris Centeno of Regenexx®
Cade Hildreth: The Regenexx® procedure works very well for anterior cruciate ligament (ACL) tears that have an inch or less of retraction. How will this treatment option affect the hundreds of thousands of ACL surgeries that are currently done each year?
Dr. Chris Centeno: We have seen pretty astounding results with ACL repair, and I think there could be a reason why it works so well. The ACL has a synovial invagination that looks like a sheath. It appears to be one of the optimal applications for cell therapy, because it has a living biologic scaffold around it.
Having said that, because it’s protected by a sheath, the ligament must be directly injected under imaging guidance, a feat easier said than done, but one we’ve mastered through the years.
When first started treating ACLs, we tried injecting partial tears with our proprietary, same day bone marrow concentrate and then those healed. Then we decided to treat a complete, non-retracted tear and that healed. Next, we tried treating a small amount of retraction, and that healed. After treating several more patients, we noted that up to about a centimeter of retraction, we were getting really nice healing.
It did not make any sense until we realized it was one of those unusual body areas that had a natural living biologic scaffold for the cells. Meaning, you could literally fill it up and the cells would be perfectly positioned to bridge a gap and that they would also be nourished by the well-vascularized synovial tissue around the ACL.
As such, ACL repairs have been a “killer application” for the Regenexx technology.
What this means is that for about 70% of ACL tears that happen in athletes, these patients will be good candidates for a cell-based procedure and could avoid traditional orthopedic surgery. If our results hold up, there could be a 70% reduction in ACL surgeries in the U.S. We have published one small imaging case series, and we are now about to publish a second larger series. Additionally, we are in the middle of recruiting for a randomized, controlled ACL clinical trial right now.
So what does the future look like for knee ACL tears? There would still be a need for traditional orthopedic surgeries for really major ACL tears, but with advances in interventional orthopedic tools, even those could one day be treated through a needle in the future.
Cade Hildreth: What are the advantages of regenerating the ACL versus repairing it through traditional orthopedic surgery?
Dr. Chris Centeno: Obviously, if you do not operate on the ACL there are some huge advantages.
One problem with traditional surgery is that when you rip out that natural ACL and you put in a tendon as a substitute, the ACL has to go in at a much deeper angle, so the graft tunnels can be positioned in the right place. Meaning, you do not get the same angle or stability as a natural ACL.
In addition, those procedures are usually single bundle. The double bundle surgery is much more technically difficult, so a lot of orthopedic surgeons don’t offer it. Therefore, you do not have the rotational stability you would with a natural ligament, which would have two bundles controlling that movement.
Then, there is proprioception. Proprioception with a tendon is never going be the same as if you can keep the natural ligament. So there are all sorts of reasons to try regenerate the ACL.
Cade Hildreth: Given the unique biological properties of the knee, are there other companies investigating alternatives to ACL surgery?
Dr. Chris Centeno: As you probably know, there are a couple companies and labs working on various ACL scaffolds and other applications.
What is really interesting about that from a business standpoint is that this may be a situation in which the ACL is so easy to repair with cells that the cheapest methods (such as same-day autologous bone marrow concentrate) could “win the day” and end up getting more insurance coverage than either biologic scaffolds or a culture expanded product.
Naturally, that brings up a huge issue for the whole industry. There are a lot of expensive solutions making their way through the FDA approval process right now. Ultimately, I think we are going to see a mixed market. We are going to see some things being treated via platelet-rich plasma (PRP) or a bone marrow concentrate, because it works extremely well and it is comparatively cheap. We may also see some more expensive options, but only in applications where those demonstrate clear superiority over cheaper options.
In other words, I think that cell therapy companies pursuing expensive therapies where a less expensive therapy will serve the patient equally well will struggle with getting insurance coverage. It brings up an interesting debate for the whole industry. If a company is going to pursue an expensive treatment, then it would be wise for that solution to be the only option that will produce results.
Hence, you should be consulting with physicians who have experience using less expensive cell based therapies for that application to ensure that they are not effective.
Cade Hildreth: What determines whether an orthopedic procedure is covered by health insurance?
Dr. Chris Centeno: It is very interesting how health insurance coverage works. There are a couple different components here. You have to have some good studies, but not necessarily, because there are all sorts of procedures that have very little evidence, but they are common practice and so they get insurance coverage.
Then there are the politics of coverage. For example, if you are an insurance company, like Aetna, you have orthopedic surgeons that sit on a panel. They will go to that panel once a year or twice a year and ask, “Here’s the evidence. Should we cover this?” They either vote “yes” or “no.” Now, those doctors are voting based on the evidence, but obviously, they are also voting based on their own commercial interest.
So, you realize it is about data, but it is also about politics. Disruptive change is always difficult.
In addition, the cell therapy industry must recognize that cost is a huge factor these days. If you are producing a vial of cells that will sell for $10,000, it had better make the blind see or the crippled walk, as many insurers won’t provide coverage despite FDA approval if it offers only marginal improvement over what’s out there.
Cade Hildreth: I think there is definitely fear surrounding the disruptive change, because it could make a lot of people obsolete. Disruptive change is the perfect way to describe it.
Dr. Chris Centeno: Yes, and it is not just doctors. It is the hospitals, the device manufacturers, the anesthesiologists, and others. There are a lot of stake holders.
Cade Hildreth: You mentioned that there are companies that are exploring ACL scaffolds. Do you know their names?
Dr. Chris Centeno: I do not remember them off the top of head, but I have seen several different press releases that have come out. They may be in very early stages right now, for example, universities filling patents and talking about starting a company.
Again, we have two discovery pathways and they regrettably have become a little bit antagonistic. On the other hand, you have physicians out there trying things to help patients. Then, you have universities who are trying animal models, but they do not have clinical experience. They do not know what is needed, but they do know what is possible.
Cell therapy is one of those areas where you have the physician-driven innovation sometimes complementing what is happening in the university, which is what we did with Colorado State University (CSU).
Other times, you are going to see it conflict. As an example, once an ACL biologic scaffold is FDA approved, a physician may say, “It’s great that you have a fancy scaffold for the ACL, but it that necessary or is it an added cost that doesn’t improve outcomes? If I can inject bone marrow concentrate via precise injection in the ACL sheath and get the same results, why do I need this stuff?”
Cade Hildreth: How were you funding your early research before you got the philanthropist, John Malone, involved?
Dr. Chris Centeno: Mostly, the old fashioned way, through cash flow into the practice
To be more specific, we initially self-funded it. Then we did a “friends and family” round. We never really went beyond friends and family until Mr. Malone got involved. We have not really taken any investors since then. It has all been self-funded and grown from the ground up.
Cade Hildreth: What was your background before you got involved with these regenerative procedures?
Dr. Chris Centeno: My background is in interventional pain management.
What got me into this type of care was how limited we were. On discs, we would inject some steroids around the nerve or do an epidural that was x-ray guided, and those patients did “okay.” Then we would nurse them along. The patients would come back every couple of months and we would give them another steroid shot. They would come back again and we would give them another steroid shot.
We knew that injecting all those steroids was not good for their tissues and probably not good for the patient, but it was better than putting them on a bunch of high-dose narcotics. So, patient care back then was really choosing between the lesser of two evils.
For example, when a patient gets an ACL surgery, do we know that is the best possible solution for that person? No, it is not. If you look at the MRI, you can see that that the solution is a bit ugly. You have to drill a hole here. You have to drill a hole there. Then, you put a tendon between the two points, and then you put a screw through that or a staple through it. It is not an elegant solution.
So, we began to ask ourselves, “How do we start fixing people? And, if we cannot fix them, how do we at least manage them with something that’s not going to hurt them?” That is what got my attention with the regenerative approaches.
Cade Hildreth: What trends are you seeing for the utilization of adult stem cell procedures?
Dr. Chris Centeno: We are seeing much more interest in these procedures. You cannot go to an orthopedic or to a pain management conference these days without being inundated with stem cells. It started getting attention probably about 5 years ago, although it was rare to see it then. Now, stem cell discussion probably represents about 5% of these conferences.
It is starting to catch on. Additionally, major organizations are including regenerative medicine content, because they all know it is definitely “coming down the pike.”
Cade Hildreth: I have also been hearing frequent discussion about bone marrow aspirate concentrate, also called “BMAC.” What is the difference between BMAC and the components used by Regenexx?
Dr. Chris Centeno: There is a big difference, although it is similar. Meaning, bone marrow aspirate concentrate (BMAC) – also called bone marrow concentration (BMC) – is a same-day buffy coat isolation of the bone marrow. It is usually done by any one of a number of automated machines that doctors buy that are by 510(k) approved. The machines do an “okay” job at it.
The problem is that the buffy coat, which is the middle fraction of the bone marrow after you centrifuge, appears at various places within the sample based on the hematocrit of the patient, based on how hydrated they are, and other factors. So, the machine takes a cut above the buffy coat and a cut below the buffy coat and hopes for the best. So, the first big difference is we do that all by hand in the lab to get a much purer and exact isolation.
The second big difference is that about 4 years ago, we discovered a second fraction in bone marrow aspirate that has a much, much higher concentration of mesenchymal stem cells per cc (cubic centimeter) than does the buffy coat.
We figured out how to minimally process that fraction and now add it into our isolation so that we are dramatically increasing our MSC yield out of the same exact bone marrow concentrate. That is another big difference. Right now everyone else throws that away that component, because they are unaware of what it is and what it contains.
Therefore, the big differences in the Regenexx process are that we do it by hand and that we have discovered there are more stem cells in bone marrow than in the buffy coat alone.
Cade Hildreth: Is that second fraction proprietary or are you able to discuss it?
Dr. Chris Centeno: Yes, it is proprietary. We have filed some patents for its processing, but until those are issued, it is confidential.
Cade Hildreth: How many patents would you estimate that you control in total?
Dr. Chris Centeno: We have been on a run this last year, because it takes a long time for these things to wind their way through the system. Some of the patents that we got granted this year are ones that we filed during 2006 to 2010.
If you just include U.S. patents, we probably have 5 or 6 that have been issued. Obviously, if you add the international patents, it magnifies that number because each one has to be registered in multiple regions. If you add together the international patents, it is probably 10 to 15 patents.
Cade Hildreth: Are there any unknown questions yet to be answered about the Regenexx technology?
Dr. Chris Centeno: Definitely. We are exploring one area right now that is a massive project.
One of the things that is always interested me was the fact that the results for certain indications, let’s say severe knee osteoarthritis, can be “hit or miss.” You will see a patient who comes in, you look at the MRI, and you will be convinced that there is no way this patient can respond. The MRI is too severe, it is advanced stage osteoarthritis, or they are too disabled. Yet, you do the procedure and they have a great response.
Then, someone else walks in with very little damage, such as a small hole in their cartilage, and the person is active. Surprisingly, they do not respond.
So, what we have undertaken is what we call a “Knee Microenvironment Project.”
What we got our IRB approval to do is to start taking synovial fluid samples, prior to and after the procedure. We are looking at 25 different kinds of growth factors in that synovial fluid, with the goal of being able to phenotype responders based on their microenvironment.
Our goal is to be able to say, “Mr. Smith responded because he has low TNF alpha levels after the procedure and high TIMP levels, whereas Ms. Jones, did not respond because her TNF alpha and other pro-inflammatory cytokines were way too high before the procedure.” That is the first part.
The second part is, if we can phenotype good responders, can we then change the microenvironment of bad responders to look more like those of good responders and will that improve their outcome?
Figuratively, can we be like farmers and test the soil? We would like to be able to say, “The soil is missing x, y and z, so I am going to fertilize it with x, y and z. I know that this is going to make my seeds grow better than if I do not do anything to the soil.”
That’s what we are currently doing. We have collected about 30 samples, but now we have to wait for those patients to get a little further out. We are aiming to do this with about 200 patients, and then we will have a massive computational biology problem to figure out what conditions are related to outcome.
Cade Hildreth: You will need good data analysis at that point.
Dr. Chris Centeno: Yes, we will. We have been doing these procedures for 11 years and it is time now for us to take it to the next level. It is time to take it from something that is “hit and miss” in certain applications (and quite reliable in others) to something that’s more reliable across many indications.
We will never know answers to these questions from animal models. Animal models really do not bear any resemblance to the human clinical condition of a 55 year-old “couch potato” with an awful knee microenvironment.
Cade Hildreth: When are you expecting results from this microenvironment analysis?
Dr. Chris Centeno: We will have our first results in the spring. Hopefully we can get enough information from that to start getting a little bit of knowledge about the types of phenotypes that respond well.
By the end of next year, we will have another big batch of data. By 2017, we hope to be in the phase where we are starting to see if we can change the microenvironment to improve patient outcomes.
Cade Hildreth: What do you think is the future regenerative medicine in the area of orthopedics?
Dr. Chris Centeno: It is going to be interesting. You are going see lots of different solutions. In 10 years, I think we will have a mixed market. There will be some FDA approved drug or cell drug solutions, which might be growth factors or stem cells in a vial or other progenitor cell cocktails in a vial.
You will see platelet-rich plasma (PRP) and bone marrow concentrate, and at that point, there will also be adipose SVF (stromal vascular fraction) that is 510(k) approved, as well as PMA (pre-market approved) devices.
Ten years from now there will probably be 6 or 7 or 8 different cell based or regenerative solutions for musculoskeletal injuries.
Then, the next 5 years after that will probably be about figuring out which one of those solutions works the best and is most cost effective within our insurance environment when compared “head-to-head.” There is so much pressure right now on cost that there will eventually be some washout of products. There will be winners and losers, because some of the solutions that are really expensive will not get coverage.
Cade Hildreth: How will these changes in regenerative medicine affect patients?
Dr. Chris Centeno: For patients, it is going to be pretty amazing. You are going to see surgical rates plummet. Fifteen years from now, I think the number of orthopedic surgeries done for things like knee arthroscopy will probably be down 50% or so, because the research has been pretty dismal so far on outcomes and also because you will see interventionalists injecting stem cells or growth factors who will be getting similar results to surgery. Having said that, perhaps some surgical outcomes will improve because of cell based therapies.
In the end however, I think health insurance carriers will look at that these outcomes and say, “Hmm, we get a lot less complications with these approaches and also pay a lot less for complications when we do not do the surgery. Let’s start getting rid of surgeries as covered procedures.”
Cade Hildreth: Recently, amniotic stem cells have gotten a lot of press. What is your opinion of amniotic fluid and the cells it contains?
Dr. Chris Centeno: I recently released in-vitro research that our lab performed on amniotic fluid. There are many doctors telling patients that they are injecting stem cells from amniotic fluid. However, we tested it in the lab and there is nothing living in these vials, let alone, stem cells. So, we are trying to make sure that physicians get good information, because if physicians do not get good information, then patients do not get good information.
What is really crazy is that amniotic tissue has been sold for years, mostly for ophthalmology and neurosurgery applications. However, a couple years ago, sales reps figured out that if they claimed that there are stem cells in their vials, that they could sell high volumes of the product. FDA registrations do not say that there are any living stem cells present, and in fact, many of them recognize it as devitalized (dead) tissue. The doctors buying these vials don’t have enough knowledge to know if these statements are true or not.
It is a really interesting phenomenon. There are literally medical clinics out there giving seminars to patients saying, “This little vial has 4 million stem cells.” We ask the doctor, “How do you know there are 4 million stem cells?” He or she says to us, “Well, the sales rep told me that.” When we test the vial, there is nothing living in it at all.
Here is one article where doctors and patients can learn more about this topic: http://www.regenexx.com/amniotic-fluid-stem-cells-pros-and-cons-more-scams/.
Cade Hildreth: Final and most important question. How can people get in touch with you or learn more about the Regenexx?
Cade Hildreth: I looking forward to seeing what the next 10-15 years will hold for stem cells in orthopedic applications and learning about the results of your knee microenvironment analysis. Thank you for the honor of doing this interview and for the knowledge you have shared.
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