Subchondroplasty: A New Frontier?

Over the last year I have learned about an MRI finding called Bone Marrow Edema, (BME) and a new procedure developed in Philadelphia to treat joint pain coming from BME.. I have noted this finding in some patients with osteoarthritis, many patients with failed microfracture, and some patients with inflammatory arthritis. This patient was having severe knee pain and although he does have concurrent arthritis, he is not a candidate for a knee replacement at age 50, and in a high demand occupation . I performed the subchondroplasty procedure in December of 2013 and his pain dissipated to almost zero within 2-3 weeks. it is of course too soon to comment on long term results, but clear that in at least some patients we should be looking at the subsurface issues as well as the surface (cartilage) issues.

Observe the large white area in the femur

Observe the large white area in the femur

Stem Cells and Bone Marrow: the Way Forward

 

 

The concept of using Bone Marrow as a source of the patient’s own stem cells is a good one; we know that such cells are present, albeit in small quantity, and we know that under the right conditions they can differentiate into cartilage. In fact, just recently it has been shown in the lab that certain cells can be made into stem cells by simply changing the acid in their microenvironment; this, after induced stem cells have been reported using a “cocktail” of DNA regulatory factors a couple of years ago. So it seems there are various means by which our bodies ‘turn on” the regulatory mechanism that makes a cell into a stem cell. Our job is to see if we can make that happen at the right place and at the right time.

 

 

 

Harvesting bone marrow from the top of the pelvis can be performed under local anaesthetic in the office.  That bone marrow aspirate (BMA) can then be mixed  with blood from the patient, and then purified using the Angel PRP machine.  Our first task is to then measure the output of the machine by using “biomarkers” for stem cells. Ideally, we could then have a mixture of growth factors (PRP) and an enriched population (definitely NOT a pure concentrate) of stem cells. Since the Angel device is programmable, anticipate that some adjustments need to be made in order to achieve the best results.  Only then can a study be performed on efficacy; where, for example, we inject the mixture into a joint with cartilage damage.

 

 

These principles should be applied to any cell based therapy; know what you are injecting. Safety and efficacy can only then be determined.

Next Steps for Stem Cells

The most likely sources of stem cells for cartilage regeneration are adipose tissue (fat) and bone marrow.  Each of these offers the possibility of harvesting the cells from the patient and injecting them or implanting them as a component of an advanced tissue repair product.  We know that growth factors alone (PRP, or platelet rich plasma) are effective in wound healing, and we know that cell based cartilage repair (like Denovo) can be effective in cartilage repair; as also seems likely, that a combination of scaffold coordinated bone marrow stimulation can also work.  The building blocks of tissue repair are now obvious and accessible,

 

 

One continuing issue for industry is that the regulatory pathway of an advanced hybrid product will be very expensive, perhaps unrealistically so, as the orthopedic companies involved in the sales and marketing of the new biologics are not funded for nor are they comfortable with the type of clinical trials that FDA has historically required.  These trials are not required if the patient’s own cells are used and are not manipulated, changed, augmented or otherwise turned into a potentially harmful new product or device. The effect of this situation is that many or most companies are NOT interested in any product with a tough regulatory approach- this is quite the opposite from the pharmaceutical industry. I do not see this attitude changing in the near term.

 

 

So back to Stem Cells.  Inducing pluripotent stem cells is much in the news, but will run straight into the regulatory issues just mentioned and hence is not likely to be introduced into orthopedics at this time.  Adipose tissue is readily available from many patients (but not all!) and separation techniques can be performed at the bedside to separate out a cell enriched fraction. I am not sure that the average orthopedic surgeon wants to get into liposuction, so the details involved are somewhat beyond me.

 

As for bone marrow, that is accessible in all of us. The usual donor site is from the prominences of the iliac bone, just below the skin. Under local anaesthesia, a needle device can be introduced into the bone; what hurts is the aspiration of the marrow.  I am currently working on ways of minimizing the discomfort ( translation = pain) to make this more tolerable.  These marrow cells are quite diverse, and the stem cell population may only be 1 in 10000.  Nevertheless, with the PRP technology currently available, we can mix the marrow with some peripheral blood and develop a purified concentrate for “bone marrow aspirate” and PRP in a very low volume.  In this way we now have an enriched population of cells that should be an excellent construct for cartilage repair, growth factors inc

Second BioCartilage Case/ 9 months

Case number two is now without pain of any kind, able to exercise and do both up/down stairs without pain, a marked change from her pre-op condition.  This was a 1.5 cm sq. patellar facet cartilage lesion (hole). the patient has decided not to get a post-op MRI.

A testimonial from her will be forthcoming on this web site.

BioCartilage MRI results

The first MRI results from Biocartilage implantation are now coming in. Case #1, a 1.5 cm patellar lesion, has 100% fill at 10 months and the patient is without symptoms.  There is a bit of undulation of the surface and the overall integration to the surrounding tissues looks good. Will post the images on this web site soon.

Stem Cell Questions

In my clinic I often see patients who have researched various claims made on the internet. These claims include the use of BONE MARROW ASPIRATE (BMA) which is often referred to as STEM CELL THERAPY. Here are the facts.

True stem cells (a.k.a mesenchmyal stem cells or MSCs) are a small population within the bone marrow of a healthy person; perhaps 1 in 10000 cells. So, without purification using pretty fancy equipment (for example a cell sorter based upon biomarkers on the cell surface) a BMA has very few stems cells in it. I wish it were otherwise. There is at least one clinical trial taking place (see the Aldagen Company) where BMA is sent to the facility and a purification is performed; this is costly and NOT available except on a research basis at the present time.As an alternative, it is possible to take BMA from the patient, mix it with blood, and use the PRP type systems to purify a component with “monomuclear cells” that may contain at least some of the MSC population mixed in with the platelets.  This concentrate could then be placed in a cell counter to see (a) what the platelet concentrate is and (b) are there any mononuclear cells in it. Is this a shortcut with scientific validity? We don’t really know. We do know that if you advertise it as a stem cell therapy, the FDA will not be pleased. It is definitely a way to avoid regulatory scrutiny, and it may even “work”; but without careful experiments we really will never know. How about some good imaging studies before and after? Where is the data?  Depending upon the testimonials of “cured patients” is not the way to move the field forward; it didn’t work in the 19th century and it won’t work now!

So caveat emptor; do your research, and always be skeptical.

 

BioCartilage at 6 months

Recent developments in cartilage repair have focused upon the use of allograft material combined with growth factors and the patient’s own stem cells- a composite material, if you like- that can be an inexpensive and substantially better product than microfracture alone.  In spite of laudable success with products like Denovo NT, reimbursement issues on this and other products (in the 4- 8K range) remain daunting for most patients and providers, to the point where many needed surgeries just do not get done. As the projected U.S need for cartilage repair is well over 100,000 patients per year, we have to be realistic about this (and all other medical devices) in addressing options for the future.

 

 

As reported here earlier, I started using BioC early in 2013.  This is an acellular matrix that is glued into position with the addition of growth factors (PRP), and combined with marrow stimulation.  It can be performed either through a keyhole incision or through the scope, depending upon the location of the problem. Importantly, the implant kit can be kept on the shelf and is returnable if not used. The overall cost is around 1K. This number is within the parameters of most all facilities; translation: the surgicenter can allow the case to be performed, pay for the implant, and still make money.

 

 

In view of our national dialogue about economics the latter point should be understood by all.

 

 

Here is a link to the technique: http://www.arthrex.com/resources/video/Kg9hsjoIQkqS8wE7U0lJKA/biocartilage-preparation

 

 

Although it is early, I am pleased to report that at about six months the first group of BioC  patients look quite good in terms of pain relief.  Check this site in a couple of months for early MRIs. There have been no complications thusfar.  One of the major issues with all kinds of cartilage repair is duration of followup; it will still be some years before I am able to make statements with confidence about longer term outcomes.

 

 

 

 

 

The Fallacies of Genomic testing

 

 

 

When physicians (and investors) look at the potential for genomic testing, the emphasis should be on the word potential.  It is an understatement to say that we are just not there yet, and the abundance of data to be analyzed from sequencing 5B bases pairs of DNA (and roughly 20000 genes) will lead to confusion and possibly bad decisions.  So of course, this being America, we are already seeing the “marketing” of gene testing by various cancer centers.  I also note that my local hospital is reinventing itself as a “Genomics Center”. It cannot be an accident that vulnerable and frightened patients are first singled out

for tests that are not covered by insurance.

 

 

 

And of course as Mencken said: No One ever went broke underestimating the intelligence of the American public.

 

 

 

Firstly, it must be understood that DNA sequence does not in and of itself describe all the ails a human being.

 

Second, we do not know what most of our genes encode for, or how they interrelate, or become modified by the environment.

 

Third, we are only just beginning the process of what to do if a SNP, or an isolated bad sequence of DNA is detected.

 

Fourth, there are very specific diseases for which some patients may benefit from gene testing.

 

 

 

As for the use of DNA sequence to treat all cancers, this too is early; BRCA is a good example of a gene that is only of interest in a small percentage of all breast cancers. Other biomarkers for cancer that are protein based (like PSA) are such poor indicators that many have questioned whether they do more harm than good. Only when there is a certain drug for a certain tumor does it currently make sense, and this does not require sequencing the entire genome.

 

 

 

As regards arthritis, I have been involved in a project that showed about 100 proteins aberrant in that disease.  This finding is likely to recur in other diseases,  where it is the sum total of all the “mistakes’ in DNA that eventually result in a real problem. The classic genetic diseases, like sickle cell anemia, will look simple in comparison.

 

 

 

Which is NOT to say that gene testing is not of interest; it just should not be marketed to all patients as important for treatment.  Not yet.

 

 

 

 

 

 

 

 

 

To Cell or Not to Cell, that is the Question

Common in my clinic now are discussions comparing cellular and acellular implants for chondral repair.  I definitely started off with a bias towards cell based repair, for several reasons including a large experience with ACI (Carticel). However, all cell based methods prove to be (a) more expensive and (b) predicated on using the material based upon the order; that is you order it, you own it.

The virtue of an acellular product was demonstrated yet again this week when a potential patient for cartilage repair- and one with a very excellent pre-op MRI- proved NOT to require cartilage repair.  Since the implant was returnable and has a long shelf life, no worries.

It may be far too simplistic to advise one product for all patients, but surely this is a consideration.  When one combines the issues of cost and “returnability (or shelf life) “with efficacy over the long haul, we are certain to have to re-think how we best match a given implant to a given patient. the good news is that now in 2013 there are many more choices than just a few years ago, and clearly the field is advancing…although not always in a straight line!

3 D Printing for cartilage repair

There has been a flurry of articles in the news recently about using 3D printing technology to spew out organs and tissues for purposes of replacement or repair. This all sounds like a consequence of the digital age where the boundary between the virtual and the real is increasingly blurred.

But at surgery, we still need a real device to be implanted. A 3D printer can use inkjets or nozzles to spew out a material in layers, and basically sculpt it.

Robotic technology can use a motorized router type device to carve into dense materials and make complex 3D forms out of metal or plastic.

So in a sense, design on the computer can already be converted into real shapes or models. Imagine designing a cartilage implant that perfectly fit into the space to be reconstructed!  Issues develop when we reconsider reality.  How long does it take? can it be done in advance? And of course, who will pay for this and can you prove it is “better”.

I remember the days when total hip replacements came in 3 sizes and most everyone was a “medium’.  Custom made does NOT mean better success, this is NOT a Savile Row suit. In fact, quality control is far better in many consumer items than it ever was in the old bespoke days; would a hand made automobile be more or less reliable?

So my take on this, as with certain kinds of “robotic” surgery, is that 3D printing for cartilage repair may be a cool science project but is most likely not a product