Virginia Cartilage Institute.

There is an ongoing clinical study of 25 patients with Denovo NT, and the two year results are in on the first four patients.

(Cartilage, online edition, print edition pending:pages 1-8, 2011 Farr, J. & Yao, J: Chondral Defect Repair with Particulated Juvenile Cartilage Allograft)

Pain scores are going down, and activity scores have gone up nicely so far. This is just what one would expect with a successful repair technique.   Furthermore, MRI studies confirm my own

personal results, showing excellent “fill” of the cartilage lesions.

Four patients do not (yet) make a persuasive argument, but the trend is clear. All indications so far are that partculate

cartilage grafting can product very good early term results; no doubt critics will then ask for 5 year and then 10 year results.

Only time can address issues of that nature.

In part due to this web site I receive numerous inquiries about cartilage repair in unique circumstances- for example, various genetic diseases. The end result of many of these diseases emulates osteoarthritis in terms of the X-ray appearance, but it is obvious that the causal factors may be different. Recently this was the case with a patient who had a disorder affecting the growth plates of the bones, hence the cartilage. It is always difficult to advise someone looking for treatment under such circumstances, because the sum total of medical experience for such patients may be zero.

Nevertheless, a method for going forward may be evolving.  We have done some work on gene and protein expression (see the curriculum vitae section of this web site) sufficient to make clear that cartilage abnormalities in disease are numerous and not simple.  Very soon, we will be able at modest cost to obtain genomic information on any person (see www.pacificbiosciences.com ) and hopefully to analyze that information.  When I say hopefully, the concern is that so much information is produced it becomes very difficult to sort through it all and make legitimate conclusions.  This information may make possible the era of personalized medicine, where treatments are actually based upon the specific person and not just the patient as a member of a group- say, the group with “diabetes” or “breast cancer”.  The hope is- as yet unproven- that specific treatment will provide better outcomes.

A recent effort at cancer treatment using similar methods has not worked out at all, so this is not a slam dunk. But for genetic diseases, suppose we know the mutation(s), then what?  The technology to correct mistakes in DNA has been worked out (see www.sangamo.com) and is presently being used in a trial for HIV treatment.  It is not unrealistic to believe that this technology could be used to repair all sorts of DNA mistakes, including those that produce abnormal cartilage.

Application may be decades away. But the first step- that of finding out the abnormalities in DNA- is far closer. So before we hype the era of personalized medicine, lets get some more information, lets find out our own gene sequences. The price should be around $1000 pretty soon. The task of interpreting this information is left to another post.

In part due to this web site I receive numerous inquiries about cartilage repair in unique circumstances- for example, various genetic diseases. The end result of many of these diseases emulates osteoarthritis in terms of the X-ray appearance, but it is obvious that the causal factors may be different. Recently this was the case with a patient who had a disorder affecting the growth plates of the bones, hence the cartilage. It is always difficult to advise someone looking for treatment under such circumstances, because the sum total of medical experience for such patients may be zero.

Nevertheless, a method for going forward may be evolving.  I have done some work on gene and protein expression ( see the curriculum vitae section of this web site) sufficient to make clear that cartilage abnormalities in disease are numerous and not simple.  Very soon, we will be able at modest cost to obtain genomic information on any person (see www.pacificbiosciences.com ) and hopefully to analyze that information.  When I say hopefully, the concern is that so much information is produced it becomes very difficult to sort through it all and make legitimate conclusions.  This information may make possible the era of personalized medicine, where treatments are actually based upon the specific person and not just the patient as a member of a group- say, the group with “diabetes” or “breast cancer”.  The hope is- as yet unproven- that specific treatment will provide better outcomes.

A recent effort at cancer treatment using similar methods has not worked out at all, so this is not a slam dunk.(http://pipeline.corante.com/archives/2011/07/08/the_duke_cancer_scandal_and_personalized_medicine.php)

But for genetic diseases, suppose we know the mutation(s), then what?  The technology to correct mistakes in DNA has been worked out (see www.sangamo.com) and is presently being used in a trial for HIV treatment.  It is not unrealistic to believe that this technology could be used to repair all sorts of DNA mistakes, including those that produce abnormal cartilage.

Application may be decades away. But the first step- that of finding out the abnormalities in DNA- is far closer. So before we hype the era of personalized medicine, lets get some more information, lets find out our own gene sequences. The price should be around $1000 pretty soon. The treasure trove of data to be found there will be the way forward.  The task of interpreting this information is left to another post.

“Reimbursement”
( tr ) to repay or compensate (someone) for (money already spent, losses, damages, etc): your fare will be reimbursed after your interview

In healthcare we have misconstrued or re-branded this word to mean “payment”, when, in fact, it really means
payment back for a loss of money. It is an insurance term, and quite revealing of the fact that insurance companies regard health care in the same way you might regard a tornado or a car accident- unfortunate, somewhat unlikely, but compensable…up to a point. This pretty much sums up all of what is wrong about private health care in the U.S.,both presently and in all current serious proposals.

Cartilage repair may improve life quality but hardly is in the same category as kidney dialysis or heart transplantation.
It is more in the category of good dental care and hygiene- what person does not know that if you want to keep your teeth, you must take care of them? The same may be true of your joints. And it is also true, like good dental hygiene, that the status of your joints has important implications for the state of your overall health.

Insurance companies care little about this. They care about NOT spending money- your money- that you have paid in premiums.

By the time a procedure is standardized for reimbursement- especially in a dynamic field like cartilage repair-
it is often yesterday’s news. Even after the regulatory authority ( the FDA) allows a product to be sold, it may be years (if ever) before an insurance company will place that procedure on its approved list.

For many years, I was told that ACI could not be done unless a microfracture surgery had been done- and failed- and the patient had suffered for at least 3 months. Whoever thought this up should have been a member of  the Inquisition.  I am quite sure that no class in medical school ever suggested that an inappropriate and failure prone procedure be performed just to help the patient get reimbursement. This is the crazy world we live in.

Recently, insurance companies have backed off on the “microfracture first” canard. Ironically, it is now not too difficult to get ACI paid for just at the time it is becoming outdated in favor of less expensive single surgery procedures.

Those of us in cartilage repair need to make the case that new procedures may be expedient for all as we strive to produce better outcomes at less cost.  This effort should be collaborative with both payers and patients,  a situation that is difficult to achieve when conversations start off in an adversarial way. After all, medical care is all about money.  The +/- approval/disapproval mode of a “reimbursement’ decision should be replaced by an analogue, risk sharing approach; for example, have the patient pay for a portion of the implant, but cover all other expenses (including paying the doctor). Make innovation possible during the multi-year period where outcomes are assessed.  Unless we do something of this nature, payment will always be based upon the view from a rear view mirror, always looking at the past.

There is an axiom in surgery that you should never be either the first or the last to try a new technique.  I have failed to take that advice on a number of occasions, most recently in January of 2011 when I began using Chondrofix implants to repair articular cartilage defects. These are allograft plugs that are sterilized- hence the cells are killed- and are fashioned into plugs, or dowels, of various sizes.  They need to be inserted perpendicular to the joint surface, so they fit flush.  Because the cartilage has good biomechanical characteristics- it is already hard, does not need to “grow”- I am allowing almost immediate weight bearing on these implants.

When a surgeon trials something new it is always good to pick cases carefully; the first group of Chondrofix patients have isolated cartilage problems, good looking radiographs, and are all super well motivated athletic types. One of the repairs was on the trochlea and the other 5 on the femoral condyles.  All of the patients chose this implant over other options and are well aware that this is a new implant without any kind of a track record in humans.

So far there have been no complications.  There is always a learning curve with a new device and I have learned that a clear angle of attack is required, with nothing (like a meniscus) in the way. Chondrofix cannot be placed in out of the way areas.

Having said  that, the implants fit quite well and  the instruments are good. On this week’s case, the incision was 1 5/8 inches long; I am definitely more comfortable implanting Chondrofix through a small incision.

Post op pain has been nominal. There have been no infections or known implant problems.  Early on- and the longest followup is now about 6 months- pain relief has been excellent.

I have now been repairing cartilage for 14 years using a variety of methods. It is a pleasure to have available an off the shelf product with good implant characteristics, a simple technique, and a relatively easy post op course for the patient. It is too soon to make any comments about durability or to have an academic discussion about cell based vs. non cell based repair methods; but in this way the field is pushed forward. Progess.

Normal healthy cartilage is built for exercise, to include loading bearing exercise such as running.  There is good evidence that chondrocytes, the cells that maintain the cartilage matrix, actually grow better in response to pressure- certain chambers (called bioreactors) have been designed to promote cell growth under these conditions.

It is therefore with mixed emotions that I sometimes advise patients to exercise less, or at least to consider a modification of what type of exercise they are performing.  This apparent contradiction comes because cartilage that is damaged already is not the same as normal, healthy cartilage.  In spite of many advances in cartilage repair, it is just not appropriate to think that any repair is as good as the original.

All patients are encouraged to stay active. One frequent recommendation is to substitute sports with lower stresses.

Advice for professional athletes may be somewhat different than advice for the ordinary athlete or the ordinary person. If someone is getting paid to perform a sport- or, indeed any type of work- it is not uncommon for them to expose themselves to risks that would not normally occur to other people.  This is true whether we are talking about an astronaut or a coal miner or an oil rig worker.  As a general rule, professional athletes are very protective of their bodies even though they purposely expose themselves to risk; and they understand the consequences of injury. (I am writing this as Tiger Woods has just withdrawn from the US Open due to “leg injuries”.) It is ironic to see that some non professionals readily accept risks that the pros would never consider.

One frequent mistake occurs when the patient erroneously thinks that if the knee feels better it really is better, and the somehow the healing process is ahead of schedule. Everyone wants to believe they are a fast healer. Some take this as a license to avoid rehab, because “I can do it at home”.  Well, that seldom works, and it is a great way to undo an expensive procedure.

Any situation that disconnects expectations from reality  should be discussed before cartilage repair is attempted. Almost any surgical solution can be subverted by a patient who does not comply with the post-operative rehabilitation plan. It would be better for all concerned for such a person not have surgery.  In medical jargon we call this compliance, but what it really means is bad behavior.

The need for post op rehab was advocated many years ago by Dr. Richard Steadman, one of the original advocates of marrow stimulation for cartilage repair. I must confess that at the time I thought it was a bunch of hooey, but now I am a believer; and there is no faith like that of the converted. The originator of total hip replacement, Sir John Charnley, was once quoted as saying that a perfect operation requires no aftercare. Well, either he was wrong, or cartilage surgery is not perfect, or both.

At a recent cartilage seminar I was asked by an orthopedic surgeon about the durability of a particular type of cartilage repair, and specifically how the longevity of one type of implant might compare with another.

A fair question, but one that does not permit an easy answer. The answer is totally complicated by the size of the lesion, the location of the lesion and the stresses placed upon the new implant; not to mention how one defines durability. Implant durability is completely different issue than assessing subjective surgical results . I suppose the only unambiguous way of defining durability would be the probability of having a repeat procedure within a specific period of time. This type of scientific answer may only be possible after a decade or more experience with a given implant, and for that reason it totally eludes us in fast moving medical fields; by the time the study is complete, the product is obsolete!

We should be maintaining databases and conducting post-marketing research on all types of medical devices. Companies may be hesitant to do this unless instructed by the FDA; the fear of a product problem is naturally repugnant to the business community, although it should not be. Many companies may feel that you do not give out more information than is required. This is just wrong, it is bad medicine and it is bad business too.IMO, the regulations for medical devices should be less restrictive on product introduction and far more firm on post marketing surveillance. In that way, issues of safety and early term success are separated from questions related to long term outcome; innovation is not stifled, but there is an obligation for the company to continually reassess its product placement. This will be good for patients, in the same way 100,000 mile warranties are
good for consumers even though we all know that the parts warrantied seldom break. What the warranty really accomplishes (and medical devices are NOT going to be warrantied) is to make the company look down the road a bit, a good thing for us all.

This scenario recently happened with respect to metal on metal total hip implants. For this reason you will now find on certain TV stations lawyers trolling for clients whose implants have “failed”, and the FDA has now ordered certain post-marketing studies. We need to remove liability as a (perverse) incentive for discovering new information. It just does not serve the public well and it encourages even more secretive behavior on the part of device manufacturers rather than the open source information database we need,

I think you now see why we do not know how long any given implant will last, and why we will not have any answer any time soon. Caveat emptor!

The first Chondrofix in my practice, performed in January 2011, was for a defect of the medial condyle.
The patient is now without knee symptoms of any kind and is back to recreational athletics. Based on this early experience I am now allowing almost immediate weight bearing on this implant. There are now several other patients in the pipeline, doing well thusfar. A release of this implant to the general orthopedic community is anticipated later this year.

Normal healthy cartilage is built for exercise, to include loading bearing exercise such as running. There is good evidence that chondrocytes, the cells that maintain the cartilage matrix, actually grow better in response to pressure- certain chambers (called bioreactors) have been designed to promote cell growth under these conditions.

It is therefore with mixed emotions that I sometimes advise patients to exercise less, or at least to consider a modification of what type of exercise they are performing. This apparent contradiction comes because cartilage that is damaged already is not the same as normal, healthy cartilage. In spite of many advances in cartilage repair, it is just not appropriate to think that any repair is as good as the original.

Advice for professional athletes may be somewhat different than advice for the ordinary athlete or the ordinary person. If someone is getting paid to perform a sport- or, indeed any type of work- it is not uncommon for them to expose themselves to risks that would not normally occur to other people. This is true whether we are talking about an astronaut or a coal miner or an oil rig worker. As a general rule, professional athletes are very protective of their bodies even though they purposely expose themselves to risk; and they understand the consequences of injury.

One frequent problem is that certain recreational athletes take themselves quite seriously;
they want to be treated as if they were professional athletes-, which they are not. This is a common situation that disconnects expectations from reality and should be discussed before cartilage repair is attempted. Almost any surgical solution can be subverted by a patient who does not comply with the post-operative rehabilitation plan. It would be better for all concerned for such a person not to have surgery.

Rehab regimens are individually tailored to each specific situation. Most include a period of limited or non weight bearing, followed by a gradual increase in loading activities. Early swimming is a feature I really encourage. Where some patients fall off the path is somewhat later on, when they are typically feeling good, and think that just because they feel better that the cartilage repair is progressing more rapidly than expected. Some people think they are superman! A better view is that cartilage repair is a biology experiment we are conducting inside the body, and that time is an important parameter- often more important than symptoms.

Why do some cells divide and duplicate, some grow out of control, and some grow not at all? A better understanding of these mechanisms will no doubt shed light upon such apparently unconnected processes like wound healing, cancer biology, tissue repair, and aging. Do not be surprised if the control mechanisms turn out to be similar, but the instructions different.

In cartilage repair, we are faced with a situation where the predominant cell, the chondrocyte, is relatively quiescent. In adulthood, its main job is to support the matrix that lies in between cells and comprises about 95% of the tissue. If things are going well, there is little to do, the chondrocyte is happy just chugging along at a low metabolic rate and in a low oxygen environment. When cartilage is damaged- and this may occur either through trauma or because the chondrocyte is a little lazy in supporting the matrix- these cells cannot readily be coaxed into a more active state (see Denovo NT, based upon more active juvenile chondrocytes). It is for this reason that cartilage in adults does not repair itself.

There are several methods to making cells “turn on” their manufacturing plants and repair tissue, much as they did in childhood. The source material- the DNA- is definitely there. Control triggers can be proteins such as TGF Beta, a factor also found in platelet rich plasma. Scientists have been able to turn normal cells into stem-like cells by using a “cocktail” of nuclear transcription factors that penetrate the cell nucleus and turn on DNA, hence protein synthesis. These are called induced pluripotent cells, a hot topic now in molecular biology. Can we induce cartilage cells to grow?

A company called TissueGene is trying to do just that. They are conducting a trial where the gene for TGF Beta is transfected into the patient’s cells- a form of genetic engineering- and potentially those cells will make more cartilage matrix. If present methods of cartilage repair can be likened to repairing potholes in the road, the TissueGene approach is more akin to building an entirely new road.

Many questions need to be answered, not the least of which is safety. Might there be unintended consequences of manipulating genes in cells? No doubt, we have seen this already in other diseases. Recent exciting work on HIV,
however, shows the other side of the story- a potential cure in some patients (see Sangamo, Inc) who have had their own cells altered and made resistant to the virus.

Since cartilage loss is not a fatal disease, we will have to find ways of evaluating such bold therapy lest it remain on the blackboard forever. But I am optimistic. Once the toolkit of gene control becomes better understood, the science will be applied.