Virginia Cartilage Institute.

The adoption of this cell-based technology (Denovo NT) has transformed the cartilage world.  Based upon presentations at meetings, my own experience,  and a preview of some articles about to appear in the medical literature, there is general concensus that this is an effective and safe product; this appears to be true for at least one five year knee study, and for a large cohort of about 100 cases in the ankle.  Some of the studies may have histologic (biospy) results as well as clinical outcomes data.  When available, I will share that here on this web site. We now have a single stage cartilage repair technique with favorable outcomes and a good safety profile.

The major risk of live allograft has been and always will continue to be: infection.  Thusfar, I know only of superficial infections in a very few cases; since the implant cannot be sterilized- it would kill the cells- this will require continued monitoring.

Patients should know that NO SURGERY WILL EVER BE RISK FREE . Quite a few folks also want guaranteed results, and that is just not going to be the case with any technology for any health problem that I know of.

Denovo NT still faces substantial problems of re-imbursement, i.e. will insurance cover it? I think we are just now getting to the point where the case can be made to the various payers; good outcomes,  low risk, single stage…and a price less than 1/10 of ACI (Carticel).

This week I performed a Denovo NT (live cells) and a Chondrofix (no cells) in two different patients. We went with the Chondrofix due to immediate weight bearing, i.e. crutches for only a few days, and this was the patient’s decision. My Chondrofix implants are looking just fine at 2 years now, but as readers of this blog will know the Denovo NT results are about 3 1/2 years out and I have a prejudice for live cells that grow over time. But I am open to various concepts, so this is by no means hard and fast…

Enter Arthrex, with a new product called BioCartilage. This is lyophilized (powdered) allograft from the Miami Tissue Bank, no cells.(http://www.arthrex.com/orthobiologics/biocartilage-micronized-cartilage-matrix)

As I understand it, the powder is used to supplement microfx and is glued in place with fibrin glue (also used for DenovoNT). the option of adding PRP to the implant is present, and I like that.

Now the cost of BioCartilage is low, and it may be done through the scope; both good things.  However, it is unclear that adding a powder to microfx plus a glue is any different from adding a glue alone. That is essentially what we did in the Chondux Study. (http://stm.sciencemag.org/content/5/167/167ra6)

It could be that most any jelly placed over microfx holes helps the bone marrow cells to have a higher residence time, hence improves the chances of “seeding”. IOW, the bone marrow stem cells don’t get wiped off as easily as the joint moves and is walked upon.

So the experiment to do…might be… microfx with fibrin glue..? Or perhaps a better glue with PRP?

Notice how the trinity of cells, scaffolds and growth factors begins to assert itself in various products.

Our team worked for many years to invent this medical device and then perform experiments in the lab, on animals and then finally a human clinical trial to prove efficacy and safety.  It worked! One way to repair cartilage is to stimulate marrow elements (“stem cells”) and cap the defect with a gel, which acts as a sponge and as a cover to hold the cells in place. Nature does the rest. The gel in question was invented by Jennifer Elisseeff and members of her lab at Johns Hopkins. For more info, see Science Translational Medicine; see this link for the article abstract.

I am now at about 40 cases and 40 months (on the first case) of Denovo NT implantation. The first patient keeps in touch and is the skier video on the home page of this site. She continues to do great, is without any symptoms whatsoever, and after a couple of years of heavy hiking is now training for a 10K. As she has been living out of the country until recently I do not have followup MRI scans, but stay tuned.

To my knowledge none of the Denovo NT cases have as yet required reoperation.  Four of my cases are in the ankle, the remainder in the knee. At least one patient was not satisfied with pain relief even though 3T MR scanning showed defect fill; there have been no documented infections of which I am aware.  I am concluding that we are in the 85-90% range of good to excellent results (so far), and that compares favorably with Carticel (ACI) or any other cartilage procedure.

As with all cartilage repair, durability can only be assessed after more time passes.  At my seminars I am frequently asked about “second look” procedures, which would imply that there is a reason to go back inside the joint and examine the implant.  I have yet to do this on my own cases because there has been no reason to do so.

In the latest edition of the ICRS (International Cartilage Repair Society) newsletter (winter 2012) there are no fewer than 21 papers on the use of mesenchymal stem cells for some aspect of cartilage repair. This level of interest mirrors the popularity of stem cells in the news, and the number of patients who are doing self-directed ‘research’ on the internet and have concluded that this is the way to go. As I have said  before in this blog, there remains a wide gulf  between fascinating lab studies and the clinical application of cell therapy. nevertheless, in a consumer market, this does not prevent people from using them.

Caveat Emptor, let the buyer beware, is not a phrase that occurs to all people who are shopping for medical treatments.  But it should. The average person is just not capable of assessing the validity of an experimental claim, most especially one tried only in animals.  But I fully understand how a glimmer of hope can lead to less than rational conclusions.

Let me describe the product we need: an injectable (not a surgical) therapy; a high safety profile;  of reasonable cost (less than $2000 would work); easy administration for the average doctor; targeted to the lesion, repeatable (if needed); widely available; moderate shelf life(say 2 weeks). In addition the cells should have along with them an appropriate scaffold replete with whatever growth factors are needed to regenerate tissue. And all of this needs to be in a single delivery system.

For example: a hand held ultrasound will some day show us the hole in the cartilage. the, under local anaesthesia, and in the doctors office, we direct a needle to the right spot and squirt in a self adhering jelly that contains all of the elements described above. It lands in the right place and starts to grow, and grows only cartilage, and stops growing when the hole is covered.

The cells to be used could be from the patient’s own bone marrow or they could be obtained from a tissue bank. The regulatory hurdles are more severe in the latter case, but that kind of scrutiny brings with it the type of convincing studies that are required to really prove a new technique is effective. So we might envision an autologous  (from the patient)product first, a pilot study, and then an allograft (from a tissue bank)  based product. Each of these would have to be predicated upon animal experiments.

This is not a far fetched concept, but we are not yet close.

Whenever a new potential therapy is in the process of development- and most especially when it is picked up by the media- many patients, including the most desperate ones, seize the opportunity to demand that new, and essentially unproven, potential treatment.  Without taking sides, this occurs with cancer treatment all the time. Some people will pay almost anything for what they perceive as new and therefore better treatment…and so, by human nature, they will be at the mercy of those who would sell such treatment for monetary reasons only. The U.S. has a history of fantastic con artists and the victims and who keep the con game going strong.

This is not just a case of caveat emptor.  In the wake of recent stem cell developments (including last week’s Nobel Prize) it was good to hear disclaimers from scientists about the present applicability of stem cells to disease.  It is early. There are legitimate trials going on right now, FDA approved, that compare stem cells in such diverse diseases as stroke, heart attack, and vascular disease- and these trials compare the stem cell treatment to a control of salt water.  That means, if you enroll in a trial you have a 50% chance of being treated with salt water and NOT with stem cells.  This is the only way we can presently separate the reality from the hype at the present time. .

I am aware of so called stem cell treatment for joint disease that have been widely advertised . Patients are charged some thousands of dollars for an aspiration of their own bone marrow. Some of the marrow cells, which contain perhaps one stem cell in ten thousand, are then injected into an arthritic joint.  This is a good example of an unapproved “treatment” that produces good cash for the doctor and no provable benefit to the patient. People need to be wary of false claims that are based upon hype and supposition; it does not take much to separate a fool from his money.

Follow the FDA sponsored trials and make good decisions based upon data. Be a scientist. And always be skeptical about new things.

The recent Nobel prize awarded for stem cell research was a good choice. The prize is split evenly between a British researcher, (Gurdon) best known for Dolly the sheep (cloning) and a Japanese researcher  (Yamanaka) who discovered how to induce stem cells from ordinary skin cells.

It is the latter achievement that should not escape our notice. All cells contain a full complement of human DNA, a set of chromosomes (in duplicate) that contains the information for the entire human being. How clever of nature to make it such that only a small portion of the genome is turned on at any one time; so a brain cell can be a brain cell and a liver cell a liver cell etc.  It is not totally obvious why this type of redundancy evolved, but there you have it.  The instruction set for the human is copied and copied and copied throughout life.

It is highly likely that many diseases occur as a result of all this copying, with its associated errors. But more on that at another time.  As far as treatment of disease goes, the race now is to unlock the potential of stem cells to treat disease. This could be accomplished in a variety of ways. To do this, it is important to understand just what factors cause the stem cells to become…brain, liver…kidney…etc. This is referred to as “differentiation”. Differentiation could be controlled by chemical signals, such as growth factors, or by the local environment itself.  One of the challenges of microfracture, for example, has been to induce stem cells from bone marrow to “become” cartilage.  As discussed elsewhere, this sometimes works and sometime does not.

Ongoing studies with stem cells for such conditions as stroke or peripheral vascular disease may rely upon lack of tissue oxygen as a trigger. One option for stem cell therapy is to anticipate that the stem cells will actually grow into and become the damaged tissue; or, they could simply secrete various growth factors and chemicals of their own and induce other cells to heal.  It is this phenomenon that  Dr. Yamanaka  demonstrated when he provided a “cocktail’ of four growth factors that cause skin cells to become stem cells. The stem cells then can be differentiated into other tissues, given the right environment.

The bottom line is that human tissue is somewhat plastic, or changeable, and to some extent it can be modified throughout life. If we can better understand this process new methods for treating disease will soon be in the offing.

At this point with almost (3) years of experience using Denovo NT it is clear that most of my patients are choosing this technique over other available methods of cartilage repair. This is true even for those who, on the opposite knee, have had a successful repair using the two-stage ACI technique.  Patients in my practice simply do not elect to have two surgeries when there is high potential for a good outcome with one surgery.

The setup for single stage cartilage repair

This point of view is informed by the results illustrated in this blog, including some remarkable MRI scans. Having said that, we do not have the 10 year outcome data that is available for ACI, and this will continue to remain a fact for at least 6 years to come (the first Denovo NT performed  was in 2007).  Patients in my practice have a busy- not to say hyperkinetic- lifestyle. Even though cartilage repair is now an outpatient, mini-incision, and considerably less costly procedure…it still is difficult to get some people to use crutches, to protect their knee or ankle, to attend physical therapy, or to take simple measure to avoid complications like blood clots. As a rule, when they are offered a quicker and less costly road to recovery, they will take it. And they still want it to be even quicker!

I would also point out that so far in (3) years there has been only one secondary procedure in my Denovo NT patients, and that was early on for a possible infection. No germs were discovered in that case and the patient subsequently did well.  Therefore, the “take-back” to surgery rate is exceedingly low in my series.

This case demonstrates the “single-stage” nature of Denovo NT; The implant is now being approved by some insurance companies based upon MRI evidence alone, as in this case. Therefore, I had the implant ordered in advance, which is crucial.  First, I arthroscoped the knee and verified the location of the lesion, seen here. Note the large flap of cartilage coming off of the lateral femoral condyle. This may cause severe pain.

The flap of cartilage is held in the tweezers, showing the hole beneath.

The incision is less than 2 inches long and the exposure is excellent. Because of the mini-incision, recovery from this type of surgery is essentially the same as an ordinary arthroscopy.

If you take a 15 year view, we have so much more to offer patients at this time as compared to the late 1990s.  There is no question that better imaging, less invasive surgery, better techniques, and a clear understanding of how cartilage can heal has moved the field forward quite significantly.

Denovo NT particulated cartilage in place

I am now pleased to be able to offer patients a new facility that combines the latest tools in ultrasound imaging technology with the latest developments in regenerative medicine. My aim is to have both the most effective equipment and also the most congenial atmosphere for the non-surgical treatment of  joint disease and tendinitis.

To this end we have re-designed part of the office as shown below. For platelet rich plasma injections (PRP), first we draw the patient’s blood and then analyze it using the cell counter.  There are several reasons for this; each of us has a different level of platelets in the blood, and we are calculating the correct dose. Also, the number of white cells that are present turns out to be very important in the modulation of inflammation; the technology I use is capable of reducing or eliminating white cells in the injection if that is desired.  (It is programmable, in other words.)  Many other PRP technologies on the market do not have this capability and are not comparable to the material I use.

The New facility includes ultrasound, cell counting technology and several PRP separators.

Then, after the PRP is concentrated, I measure the amount of concentration as a quality control measure. Since we know the volume and we know the concentration, we can calculate the dose.  Ongoing studies are being conducted to determine the correct dose for different problems. In this way the use of PRP will become more personalized and specific to each patient.

DENOVO NT ANKLE RESULTS AT 13 MONTHS

My experience with foot and ankle surgery for cartilage repair is limited and certainly not comparable to the large number of cases I have performed in the knee.  The demand for cartilage repair of the talus, the main bone supporting the ankle, is large and growing. It is likely that a large number of these problems have been caused by sports in youth, and that small areas of cartilage loss (“osteochondritis”) have enlarged with the aging of the patient.  Even so-called simple ankle sprains can do this. Ankle problems can be quite severe as the surface area of the talus is quite small in proportion to body weight and thus the amount of stress per square cm is far greater than, for example, the knee.  This is another way of saying that small holes in the dome of the talus really can hurt, and large defects are a major handicap.

Historically it has been felt than some approaches to the ankle require osteotomies, the cutting of bone, in order for the surgeon to see well. Although this can sometimes be true, in my lecture travels around the country I learned that just a small incision coupled with distraction of the ankle may be sufficient to expose the entire top of the talus. This is where the problem lies.

Therefore, the knee experience with Denovo NT led me to try this technique on the ankle.

Here is the pre-op MRI view of a large talar dome lesion, which was very painful in an active 31 year old man.

The patient is 6 foot 4 inches tall and weighs 250 pounds, attesting to the amount of force this relatively small bone is under. (Under load that would be well over 1000 lbs. per square inch).

Here is the post op view at 13 months:

I think you can easily see the lesion is filled in with cartilage. The patient at this point is pain free and back to all activities.

This is quite an amazing result and is holding up nicely now at 15 months. Although the story is an anecdote, and I do not yet have sufficient number of cases to apply statistics, I think anecdotes are OK if they are true and if there is no known downside to the repair. In other words, should this type of cell-based repair ever fail, all options are still available to this patient; no bridges are burned.  This fact is important in all phases of regenerative medicine.