My Knee, Regenexx, and the FDA

Brian Sanderson

In the beginning

Many years ago, there was a rugby-crazy boy who lived in an enchanting land that is far far away. When the coach said "push harder, there is no way you can hurt yourself", I actually believed him. Exhausted, I pushed harder and harder --- and then the cartilage was torn in my right knee.

Back in the old days, the prevailing wisdom was "if in doubt, take it out". It worked for an inflamed appendix, why not a knee cartilage? In the course of things, surgery was performed. I never really knew exacty what was done but it certainly didn't make things better. Indeed, my knee was worse. Still, everyone cheerfully said it was all for the best and that I'd probably get arthritis by the age of 35 but in the meantime I should go ahead and make the most of things.

Prophecy fulfilled

At the age of 35 I was a full-time scientist and a part time athlete. Perhaps I would be spared the scourge of arthritis? Optimism is no match for reality and the reality was that surgical interference with the meniscus is a fine way to induce osteoarthritis. Ten years later, the knee was worse and my sporting options were becoming very limited. With each activity curtailed, I put on pounds (or should I say kilograms). Gaining weight is another excellent way to improve your odds of getting osteoarthritis.

Four years ago, I was a fat 52 year-old giving my axe a workout down in my little piece of Australian bush. I was rushing to cut through a hardwood log before being drenched by an approaching thunderstorm. Too late, it was a doozy, crashing thunder, lightening and belting rain. One more blow... and I slipped, my right foot jamming between fallen tree-trunks. The knee twisted, stretched and then made a horrifying clunk as it snapped back into place.

Well, those were busy times. I had a kid with his whole leg in plaster and a wife who had just moved to her dream job in Canada. I gritted my teeth and got on a plane. Months went by and that damn knee wasn't getting better. It was getting worse. I became a master of the art of climbing stairs on my bum.

Physiotherapy helped but, by my own standards, I was crippled. Standing to make dinner or wash a few dishes had become an unwelcome pain-wracked chore --- as had many other things that I used to do without a moments thought or hesitation. I was put on a waiting list to see a specialist. After about 3 months, the specialist took a careful look and said, "we need an MRI". After another long wait I finally got close-up and personal with an MRI machine. A week later, I got a phone call. Prophesy fulfilled, I had osteoarthritis in the medial compartment of my right knee.

Palliative care and an uncertain future

The treatment options from Nova Scotia Health were: "Take NSAIDs, and if you want we can give you a cortisone injection. If it becomes unbearable, we'll put you on a 1-3 year waiting list for an artificial joint." I also got a couple of good suggestions about what I could do to help myself. Keep riding that bicycle, the specialist said. My local GP also told me to get on my bike and go down to the weight room and strengthen those quadraceps. And, as an afterthought: "Don't be a wimp, push through the pain."

Exercise is the sort of advice I like to hear. I'm a bit wary about pushing through the pain, though. Cortisone was another matter. I'd had a cortisone shot many years ago for another injury and it had only made things worse. Cortisone works by killing off a layer of cells. I wasn't going down that track.

As for a lifetime of NSAIDs, I wasn't sure what to think. Every second TV advertisement seemed to be pushing one or the other of the prominant NSIAD brands as being everyones solution for their osteoarthritic pain. Nothing makes me more suspicious than advice from the TV. One great thing about Google is that you can quickly get at many abstracts of scientific/medical publications. My suspicions were quickly confirmed. NSAIDs are purely palliative. NSAIDs do nothing to fix the problem. NSAIDs may even make things worse in the long term... and it's all FDA-approved. No wonder the drug companies push this stuff so hard!

Fighting back

I set my old Connondale up on a wind-trainer, down the basement. It was a lot more comfortable than ploughing through the snow outside. (Oh, sometimes I missed Australia --- so bad.) At first I could only ride for 5-15 minutes at a time, so the boredom was not unbearable. Neither was the discomfort in my seat. There is a big difference between riding on the road and riding on a wind-trainer. A wind trainer does not give you the same gradient in resistance and this makes it difficult to relieve oneself from the steady pressure of the bicycle seat on your rear end. (For the technically-minded, wind-trainers rely on friction resistance which scales roughly as speed squared. On the road, inertial forces play a bigger role and they scale according to change in speed.)

After a few weeks, I was riding longer and the knee was giving me less grief. I'd limp and shuffle painfully downstairs, ride the bicycle for 20 minutes, then walk relatively pain free up the stairs. But 20 minutes was getting very boring and my bum was deteriorating faster than my knee was improving. Finding a bicycle seat that worked for me was frustrating, time consuming, and expensive... and well worth the trouble when the job was done.

We are all exceptional in some ways and the thing that is truly exceptional about me is my feet. My feet are so wide and high that footwear manufacturers find them too many standard deviations off the chart to believe. Years of squashing my feet into ill-fitting footwear has pinched a nerve. The more cycling, the better my knee, but the worse my nerve. Again, I got lucky. For a large fee, I got some custom-built D2 Cycling Shoes. Wow! D2 Cycling Shoes seem to have fixed my Morton's neuroma! (Is that practicing medicine without a licence?)

Well, the sore bum and neuroma problems were solved but I was still bored out of my skull. The boredom problem was solved by buying an inexpensive TV. OK, I can hear you, "but TV is boring". Well, yes, it's brain-dead boring --- it anaesthetises all higher brain function. So I made a pact with myself to only watch TV when bicycling. I'd have to say that was about the easiest pact I ever made. Soon, I was spinning those wheels for an hour or more every evening and that was sufficient to immunize myself from any desire to watch more of the infernal boob-tube. It also greatly relieved the pain in my knee so that I was able to free myself from NSAIDs. I could also sleep relatively pain free, providing I put a cushion between my knees (that's another trick well worth trying).

I was fighting back.

The body has its limits

Adjusting ones lifestyle to avoid the pain of osteoarthritis is not the same as being healed. Anything more than a short walk caused pain. Pain kept me off my feet. My greatest functional gain was the ability to drive the car without pain. Don't laugh, that's a big thing. I could drive into Town and buy stuff --- providing I could find a convenient parking spot. I could pick my boy up after school and even shuffle out to talk, briefly, with other parents before the knee started to bite.

I started to wonder how exactly the bicycle had worked its miracle and how much more improvement might be possible? Well, the knee is just another one of those synovial-type joints. The movement helps flood the joint with nice warmed-up synovial fluid and that's a great little lubrication system. Cartilage is really very tough stuff and even when some of it is missing the joint can be quite functional --- providing the stress on the joint is not too large. A bicycle on a wind-trainer puts most of the pressure of your weight firmly on your bum, instead of on your knee. One can work the muscles quite hard without punishing the joint.

Synovial fluid is also the joints transportation system. It squeezes in and out of cartilage, circulating nutrients, waste products, and repair cells. Yep, you read me right, I said repair cells. Not many of them mind you.

It's often said, and truthfully so, that if one puts a scratch on the surface of cartilage then its like puting a footprint on the surface of the moon. A lifetime later, it's still there. I don't dispute that for one minute, but this is not the same as saying that the cartilage remains immutable at the molecular level or even at the cellular level.

Exercise reduces weight and that takes strain off the joint. Exercise strengthens muscles and that helps support the joint. Perhaps, at a cellular/molecular level, exercise can shift the balance between repair and decay, ever so slightly.

Unfortunately, exercise could only get me so far. I was stalled, getting neither better nor worse.

Discovering Regenexx

I was a man with a problem. Nova Scotia Health didn't have solutions, so I would look elsewhere. Building upon the joint replacement option, I figured, well it's only a part of my joint that has a problem --- so why not a surgical fix for that? Indeed, there were many options whereby various plugs, mechanical devices, and tissue transplants that could be surgically fitted. For a time, I contemplated a return to Australia where seemingly advanced treatments were available. But the more I looked at the surgical options, the less I liked them. I began thinking that some sort of mechanical exoskeleton would be a far less drastic next step.

Indeed, I found the exoskeleton option on the web but I was dismayed. It looked so, well, primitive... Would it help? One doctor said yes, the other said no. I looked for scientific publications, and they said yes. About two thousand dollars later, I had my exoskeleton --- fitted by a very nice physiotherapist. I found that an exoskeleton helps with function under many circumstances but it isn't really a solution and can sometimes become a nuisance.

A few years ago I stumbled upon a report where someone had grown cartilage (for an ear) in a laboratory. Further investigation indicated many difficulties: the culture needed a high pressure environment if it was to grow strong knee cartillage, and how on earth did you get lab-grown cartillage attached to where you needed it? Obviously, the ultimate solution would be to grow the stuff in vivo. Microfracture surgery pointed to some of the difficulties growing high-quality cartilage within the joint.

Then, quite by accident, I came across some most interesting publications:

The above publications ( and other published applications of autogolous MSC) make a convincing case for application of autogolous MSC to treat a range of debilitating conditions. Studies using autogolous MSC in animal models have also given positive results. There is a lot of good stuff.

Autogolous MSC therapy appeals to my way of thinking because:

  1. It actually aims to fix the problem --- whereas all the commonly available options merely mask the problem, or compensate for the problem, or replace the problem with an engineered lesser problem.
  2. It uses MY cells and MY growth factors in MY body to fix MY problem. In a real sense, THIS IS A SOLUTION THAT I OWN. Big Pharma must hate it. It's the exact opposite of their business model, and it actually works!
  3. The risks are real low because:
I also add that MSC have some very nifty features:
  1. They adhere to surfaces, quite firmly, which makes it "easy" to put them exactly where they are needed.
  2. MSC are hard-working little beavers as they grow on the damaged surface but, in the language of population dynamics, they are self-regulated surface-growers. That means that they don't grow willy-nilly out of control. They have their own in-built regulatory system --- and the MSC regulatory system works far better than the FDA and all the lawyers in the USA.
  3. MSC come with their own little localized suppression system, so they can do their work relatively unimpeded --- but not disrupt the functioning of other cells. (Contrast this with the incredibly clumbsy option of a joint replacement, where you will probably need to take antobiotics, that disrupt your entire body, just to protect the joint from infection when you get a bit of dental work done!)
  4. Finally, MSC are multipotent but moderate their own behaviour so that it remains within reasonable limits. Contrast that with the politicians, bureaucrats, and special interest groups that jump on the back of anyone who has the courage to do something useful!

I started trawling the web looking for stem cell clinics. There were a few out there that made big claims but they didn't publish their treatment methods in convincing detail and also failed to publish the results that they obtained. (Perhaps I shouldn't say "failed", more that I couldn't find evidence of credible publication.)

Eventually, I "discovered" Regenexx and the Centeno-Schultz Clinic. They seemed like a relatively open outfit, compared to all the rest. Practitioners that publish, wonderful!

Before getting too excited, it's always worth doing a back-of-the-envelope calculation to check whether or not a treatment passes a basic sanity test. The Regenexx proceedure isolates MSC from a 60 ml bone marrow draw and cultures them to yield about 5-100 million MSC for re-injection. Let's estimate how many MSC are required to fix a cartilage defect that is 2.5 mm deep and 10 mm wide and 10 mm long. Well, measurements show that each cubic millimeter of cartilage has about 15000 cells scattered amidst a lot of collagen. Let us assume that all the MSC cells construct a little house for themselves out of proteoglycan complex wrapped up with collagen rope and then turn themselves into a cartilage cell. That means we would need 2.5x10x10x15000 = 3.75 million MSC. This number compares favourably with the 5-100 million MSC cells that the Regenexx procedure makes available for re-injection. Of course, some of the injected MSC might be duds or some might reproduce further within the joint --- who knows? Regardless of complicating details, I figured Regenexx passed my back of the envelope sanity calculation.

Nevertheless, I was extremely cautious and I hovered around on the web checking out Regenexx for the best part of a year --- studying all the good stuff and well as all the muck. I stayed totally on the outside, looking, never speaking.

Everyone who does anything of consequence will be criticized. Dr Centeno seemed to answer his critics with remarkable poise. (If I'd been in his position, I would have gone straight for the jugular.) Probably the most common criticism was the lack of a large double-blind comparative study. Being a scientist, who has published across several disciplines, this is an issue that I can address, albeit briefly.

Television and radio frequently report large studies where this or that drug or disease has been studied by comparing the responses of large numbers of people who have been divided into two (or more) groups that have received different treatments. Large numbers of people and dollars are an excellent way of catching public attention. The public (and FDA?) seems to have been conditioned to think that this is the only way to scientifically address a medical question. Indeed, such studies can be the best way to address most questions that arise in some scientific disciplines. Specialists often make the mistake of thinking that their favoured methods are "the best method". It's human nature, if your only tool is a hammer then every problem is a nail. The scientific method is not so single-minded. A good scientist adapts his/her methods to the problem and knowledge at hand.

When Big Pharma comes up with some new drug they routinely do large double-blind tests. They have to. That's because they are introducing a foreign pathogen into extremely complex machines (your bodies) and all of those machines are different, and they all have a 3.5 billion year history that we have barely begun to know and probably will never really know. Treating you with your own MSC is a very different matter, as previously discussed.

Do you really need to test a new drug/treatment on a huge number of people before you can have have confidence in it? Yes and no, for at least two reasons:

  1. The drug might have many unknown and very different side effects with different people. Given that everyone is different, you need to test the drug on lots of people in order to estimate its safety. Further, you need to test it for a long time because problems may take a long time to develop. These things are obviously much less likely to be an issue for autologous MSC.
  2. The number of measurements depends very much upon what is actually being measured. Let's compare two topical examples:

In my non-specialist scientific view, enough was known to begin the practicable application of MSC to treat some osteoarthritic problems and a variety of common injuries that often degenerate into osteoarthritis. Also, I'm thoroughly convinced that present therapies will be greatly improved upon by experience gained through clinical applications of MSC. In this sense, by becoming a patient at an MSC clinic, I would also be a guinea pig. But I would be a knowledgable guinea pig with a very real chance of getting a positive outcome and a very low chance of suffering harm --- compared to the damage done by cortizone, or even NSAIDs.

I'm not a medical practitioner. I sought advice from my local GP and the specialist who had diagnosed me (and helped push me onto my bicycle). They were both interested and supportive but plainly admitted the limits of their experience.

The Regenexx cultured MSC therapy seemed to offer a good chance of a postive outcome without burning any bridges. Above all, Dr Schultz and Dr Centeno were not just practitioners, they were researchers. I knew enough about their methodology to have confidence that it was scientifically respectable. My participation in their program, even if it didn't help me, would make a small contribution towards advancing the state of the art. I checked my bank balance and started filling out forms...

Getting better

My application, MRI, and various other reports were assessed by Dr Centeno. I was assessed as a "Fair Candidate". The basic plan, draw some marrow and try to culture enough MSC for three re-injections.

I travelled from Halifax to Chicago and on to Denver on 4 April 2010. I flew United Airlines because they break guitars. The next morning, oh too early, I was at the Centeno-Schultz Clinic. I've never been stuck with so many needles in such quick succession. Blood samples, prolotherapy, IMS, and then the bone marrow draw. Dr Schultz is an expert needle man so it wasn't anywhere near as bad as you are imagining.

I was sent off with instructions to get IMS therapy for the neuro-muscular knots in my thigh and prolotherapy for all those stretched ligaments in my knee. Upon arriving back home, I discovered that prolotherapy wasn't well regarded by the local medical system. IMS, being a Canadian invention, seemed to be held in higher regard. That being said, in the whole of Nova Scotia there was only one guy who did it. I must say, that IMS treatment was real helpful... although not for wimps. Since getting my muscles unknotted, I'm now careful to give myself a deep massage from time to time. (I know, I should get someone else to do that, but she's always too busy.)

Meanwhile, Regenexx was busy helping my MSC to go forth and multiply. Multiply they did, enough for two re-injections.

Eventually I managed to find a bit of spare time for myself and on 24 June 2010 I flew back down to Colorado to reclaim my body-parts. This would be a longer stay. I had prolotherapy on the 25 June and waited until 30 June to get my MSC re-injected. With time to kill, I checked out a Better Bodies gym that was only a short walk from the hotel. They gave me a free pass for the week. So I'm giving them a rave. Better Bodies is the best gym I've ever worked out in! When not at the gym, I used my time alone to focus and solve a computational fluid dynamics problem that had been bugging me for a couple of years. Even without the re-injection, it would have been a successful trip.

The re-injection procedure was straightforward. I didn't have my glasses on, so I only got a blurred look at those little MSC before they were painted on one of the bald spots where there was full-thickness chondral loss. We'd paint the other bald patches on another day. After a couple days taking it easy, I flew home.

Once home, I got back onto the bicycle, vacuumed up large doses of Collagen MD, applied heat to my knee in spare moments (no more than 30 minutes at a time), and waited to get better. Now here I have to confess a couple of personal shortcomings. I'm not much good at changing my routine. I couldn't use the infra red heat pad when I was working because I'd forget it was there and end up overbaked. Most days, I managed to set aside a half hour of quality time with the dear little the infra red unit, but not always.

By late August I had noted improvements to my knee. I could stand for much longer without pain so kitchen work was a nuisance but not dreadful. Walking the dog had become almost enjoyable! A couple of times, while watching my boy play soccer, I felt myself on the edge of breaking into a run. There was improvement but it is the sort of improvement that only Old Crocs might appreciate. I was far from "healed". I became anxious to get my next re-injection.

Of course, I only had enough cultured MSC for 1 more re-injection and it had always been clear that I would need more than that. I figured I'd make an appointment to get another bone marrow draw along with my re-injection. If Regenexx could culture up enough cells for another 2 or 3 re-injections, heck, I might even be able to get my torn rotator cuff patched up. (The rotator cuff is another story for another day. Suffice to say that strengthening exercises maintain most function but don't actually heal the problem.)

Thwarted by bureaucrats

So I sent a message of to Jen to see if she could get shuffle me in for treatment. Checking my email, late at night, I read her reply. It knocked the wind right out of my sails! FDA and Regenexx were locked in a legal dispute. According to FDA my cultured autologous MSC were drugs!

OK, to be honest, I should have been more prepared for this outcome. From early times it seemed that FDA had been confused as to what, exactly, a drug was and what exactly they should be doing about cultured autologous MSC therapies. I saw all the stooges trolling around the web --- you can recognize them by the slime they leave behind --- making idiotic claims that culturing autologous MSC turns it into a drug. It seems that the FDA has made the mistake of believing such drivel!

FDA takes the position that when my MSC are grown in an extract of my blood then my MSC become drugs. Well, I might agree if my MSC were injected into someone else. But they are being re-injected into me! For crying out loud, why can't the FDA tell the difference between a homecoming and a drug-crazed orgy?

Look here Mr FDA, this is how I tell the difference between a drug and my body parts.

Don't get me wrong. I think that all aspects of medicine should be subject to some sensible measure of regulation. Regulation should, however, be relevant to facts and outcomes. My MSC, presently on-ice at Regenexx, are not drugs. It is farcical to regulate my MSC as a drug.

As far as I'm concerned, the facts and the outcomes should determine the rules. FDA behaves as though outcomes are nothing and procedures are everything. I only hope that Courts and politicians can imbue bureaucratic procedure with a little more scientific sense.

Sidestepping the bureaucrats

Remember I said the "the ultimate solution would be to grow autogolous MSC in vivo". Seems that is what Regenexx is going to do. I'll be giving that a go. In the words of the Terminator, "I'll be back".

FDA, take a pill and bug out!

Beyond Old Crocs

Look, I am a prematurely broken down old crocodile. It would take a miracle to cure me. I'll be real happy with a patch up job that lets me be a bit more active and keeps me away from the surgeons knife.

It would make much more sense for young people to get autogolous MSC therapy when first they are injured rather than waiting 20-30 years for them to prematurely degenerate into old crocs. All these old injuries cost a fortune in lost productivity and joint replacements. In the very near future it should be far less expensive to fix the problem early using autogolous MSC therapies. Insurance companies (and Canadian taxpayers) should be jumping with joy!

It seems that MSC do better in patients who exercise. In a very real sense, the message of autogolous MSC therapy is: You can heal yourself, with a little help from Regenexx. What a wonderful philosophical break from the pill-pushing antics of you know who!

Reverse Medical Tourism

Scientifically, it is obvious that the autogolous MSC therapies have a real future. Bureaucratically, the FDA seems to be determined to crush autogolous MSC therapies in USA. This opens up opportunity for other nations to profit. Whichever nation can provide a competent regulatory framework for this entirely revolutionary type of treatment will stand to profit handsomely.

Perhaps can we encourage Regenexx to set up a laboratories and clinics in Canada? Or perhaps they might be persuaded to set up in one of my other homelands: New Zealand or Australia?

Regenerative medicine is much more sensible than more expensive options like knee-replacement surgery or nursing a nation of cripples and feeding them palliative drugs. Regenerative medicine is the future and the future is now. Do it!

Interesting URL's from Australia