A recent article in the journal NATURE from a team at the University of Washington in Seattle has shown an exciting way of using embryonic stem cells to revitalize heart tissue. The researchers took embryonic stems cells from humans and treated them with a simple growth media to induce differentiation into heart like ‘cardiomyocytes’. They then induced, in monkeys, a large ‘heart attack’ with death of a portion of the wall of the heart- mimicking the situation of a very bad heart ‘attack’ or MI. Injection of the stem cells into the dead tissue resulted in regrowth of the heart muscle- beating heart muscle.
Although this would seem to be far from our cartilage related issues, it is not. This is yet another example of how the DNA in certain cells can be re-programmed (in this case between species!) to make the type of tissue that is desired. If damaged tissue can be restored in situ, think of the consequences. The details of this kind of therapy will have to include a convenient way of introducing the cells to a target, and ‘engrafting’ or holding them in the right spot. Several previous trials at stem cell therapy, simply involving injection of cells into the bloodstream, have failed (including the recent Aldagen trial for stroke). One common factor of these failed trials is the lack of an appropriate delivery system. In this area the need for novel medical devices is obvious.
Over the last four to five years my interest in cartilage regeneration has continued to focus upon new techniques in stimulating cells to self-repair. Concurrently, biotechnology has rapidly advanced to provide us with new tools in evaluating the genome (our DNA sequences) and to explain much of cell behavior in terms of growth factors- proteins that control how our cells work, produce materials, and eventually become senescent. Technologies in the offing will be able to make DNA editing a new therapy for many diseases. Furthermore, the link between aging, cancer, and our immune systems has become increasingly obvious- this is what is driving the marketing of “personalized medicine”.
Although we are not there yet, I feel strongly that this is the (very near)future. The concept of treating all patients with the ‘same’ ostensible problem the exact same way, or with the same drug, will be seen to be quite antiquated. Most of today’s ‘guidelines’ will soon obsolesce. Both physicians and patients will need to get smarter. Part of this will come from patient empowerment, but this will only be possible if the ‘big data’ are organized into a form that makes decisions actionable and reasonable; for example, not everyone should take up marathon running (stress fractures, heart stress), and some folks would really benefit from weight lifting(to build bone mass) at an early age. The doctor will continue to be in the business of giving advice, but it will be more informed advice.
In orthopaedics, new therapies will result in much less surgery. What if: many ACL tears were made to heal in situ? many cartilage lesions and tendinopathies healed with injections? Rotator cuffs and torn meniscii could be treated in the office? Much of this is already true today.
In my practice, patients should look forward to receiving the best synthesis of advice derived from some old methods and some new possibilities. This is how progress is made and this is what keeps life interesting.
Regeneration Success and Failure
Clinical studies have recently shed some light upon cell and growth factor studies for a variety of illness, including stroke, dementia and spinal cord injury, that will certainly advance our understanding of the potential for regenerative therapy and also point out the pitfalls in developing new treatments and delivery systems. In medicine, it is never enough to have a good theory, one must make it practical and reproducible as well- and commercially viable.
The ALDH stem cell trail for stroke, in which a special set of bone marrow derived stem cells was purified and injected into the artery that feeds the brain, showed good safety and no effect whatsoever in well compared groups of 25 patients and 25 controls. The FDA allowed for 100 patients in the trial, but the study was terminated early based upon lack of any clear response over and above what would be expected for no treatment. (http://www.cytomedix.com/Portals/121782/docs/CMXI%20RECOVER-Stroke%20Phase%202%20results%20PR%20%200505%203030%20pm.pdf) This is an excellent way to perform a study, and the negative result is quite useful; there is no evidence that injected stem cells “seed” or “engraft” the desired area, although it was hoped that they might secrete growth factors to help the brain heal itself. More science is needed about delivering cells to the target organ.
Another trial on spinal cord regeneration for paraplegia (http://www.stemcellsinc.com/therapeutic-programs/spinal-cord-injury.htm) looks a bit optimistic in its early stages. Once again, the trick will be to get comparable groups of patients in order to convince ourselves that there is a real effect; when measuring very small but significant nerve return after complete paralysis, it is easy to fool yourself even with the best motives. So far, the cell therapy shows no adverse reactions, a good start.
Much in the news are studies from Harvard and UCSF on aging in mice. (http://www.washingtonpost.com/national/health-science/new-studies-show-that-young-blood-reverses-the-effects-of-aging-when-put-into-older-mice/2014/05/04/1346baac-d2eb-11e3-8a78-8fe50322a72c_story.html) Some component in the blood serum of a younger mouse is capable to reversing nerve degeneration in the brain of an older mouse- and vice versa, perhaps! One group believes this blood component is precisely one of the powerful factors in PRP (TGF Beta) ! (http://www.nature.com/nm/journal/vaop/ncurrent/full/nm.3569.html) Clearly, much work needs to be done to confirm this finding, to specify what is causing it, and to find out if it has applicability in other mammals. One interesting fact is that blood plasma is already “on the market”, so how interesting would it be to segregate blood donations by age and use just the plasma for regenerative purposes? Or of course to purify the protein(s) involved and to bioengineer them?
These concepts will proceed with fits and starts, and well done science will push the field forward, bit by bit.
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
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.
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
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.
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.
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.
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.