Joe Maroon’s knee was giving way to osteoarthritis. After years of running, biking and swimming, Maroon’s cartilage had significantly deteriorated, causing constant pain. Doctors told the 63-year-old triathlete that he needed knee replacement surgery, but as a doctor himself, a neurosurgeon at the University of Pittsburgh, he was well aware of what that might entail. Had he been just a few years younger, his doctor might not have even presented that option, since artificial hips or knees wear out after about a decade and then need to be replaced again: hence, doctors like their patients to defer that first operation for as long as possible.
The only alternative seemed to be a lifetime of steroid injections and the overwhelming likelihood of having to end his competitive sporting activities.
During his years of trying to figure out how to deal with this worsening condition, Maroon chanced upon the Centeno-Schultz Clinic’s orthopaedic alternative, Regenexx™, to heal damaged joints. Maroon was impressed enough to investigate.
Owner and medical director of the Centeno-Schultz Clinic, in Broomfield, a suburb of Denver, Colorado, Dr Chris Centeno, a 51-year-old pain-management specialist, has pioneered a technique that uses the patient’s own stem cells to restore damaged tissue – cartilage, bone, ligaments and tendons – largely ending the need for surgery.
After some of Joe’s stem cells were extracted from his bone marrow, they were cultured and so multiplied in the lab over several weeks before being re-injected into his damaged knee. The result was such a reduction of pain that Maroon, by that time aged 68, was able to compete in the Ironman Hawai’i triathlon six months later.
Most joint issues are caused by deterioration of cartilage (which cushions the movement of bones, especially in the hips and knees), usually owing to inflammation; and as cartilage is poorly supplied with blood, it ordinarily doesn’t regenerate.
Medicine makes tacit recognition of this fact with the few alternatives to joint replacement it offers. Surgery to repair cartilage either attempts to ‘injure’ it to prompt the bone beneath it to initiate a repair response, or else chunks of healthy cartilage are implanted into areas of damage as a form of tissue engineering.1
Cartilage repair has a spotty record of success,2 since transplants are often destroyed by the body’s own natural inflammatory response.
After the turn of the millennium, Centeno, profoundly dissatisfied with the state of orthopaedic medicine and its reliance on steroids and surgery, became interested in animal research on stem cells,3 and wondered whether it might apply to people too. The research was showing that when damaged joints were injected with the animal’s own stem cells, the cells, as if responding to some hidden blueprint, would differentiate into the appropriate tissues required to heal the damage. Even more encouraging, the tissue continued to do its repair job over time.
Centeno wanted to test whether the ready supply of malleable mesenchymal stem cells (MSCs), which are already likely to turn into bone, cartilage and connective tissue cells, present in the bone marrow of most patients, could be used to rebuild damaged joints. His revelation came when he realized that adding a solution of the patient’s own blood platelets to the brew would ‘supercharge’ the MSCs to replicate and also to differentiate into more cartilage and bone to repair the joint. Centeno partnered with Dr John Schultz, an orthopaedic specialist and anesthesiologist, and the Centeno-Schultz Clinic opened its doors in Broomfield.
Early on, Centeno had also decided to substantiate the clinic’s work by carrying out painstaking research and follow-up on all their patients and publishing the findings, ultimately spending $500,000 of his own funds on mainly research programmes. So far, Centeno has carried out more research on stem-cell orthopaedic repair than any other research centre.
Stem cells are nothing less than shape-shifters – precursor cells that go on to differentiate into whatever kind of cell tissue is required. They have most controversially been harvested from human embryos and adipose (fat) tissue, but those with the best record of success and safety for treating joint problems are the so-called mesenchymal stem cells (MSCs), found in large numbers in bone marrow tissue. Although other clinics use stem cells from adipose tissue in joints, Centeno believes that MSCs are considered superior because these cells are already partially committed to becoming bone, muscle, ligament or tendon, are easily harvested from bone marrow and reproduce rapidly, making them ideal candidates for repairing those very structures. According to Centeno, under certain conditions MSCs can be prompted to differentiate into the specific sort of tissue needed; when implanted into affected joints, these cells work to repair cartilage and bone, and the connective tissues in between. Indeed, there’s even evidence they can protect against inflammation-related tissue damage and have the ability to modulate autoimmune responses too.4
In 2008, he published the results of an early trial for his procedure. His guinea pig was a man who’d suffered for years from knee pain that hadn’t improved with surgery. Centeno harvested MSCs from the patient’s hip bone, then multiplied and ‘boosted’ them by culturing the cells with factors from the patient’s blood platelets. After a few days, he injected this brew into the patient’s knee.
The results were unequivocal. Just a month after the procedure, the patient’s knee cartilage surface area had expanded by more than 20 per cent, and the joint meniscus – the cushiony cartilaginous pad that bears the brunt of the thighbone’s weight – was also 29 per cent larger after six months.5 The patient’s previously limited range of motion was now nearly normal and his pain level, formerly assessed as 4 out of a possible 10, had plummeted to 0.4.
In the intervening six years, Centeno and his colleagues (including doctors he has trained around the world) have performed some 10,000 procedures on all manner of orthopaedic and soft-tissue injuries, hundreds of them involving patients with diseased knee and hip joints. The results are impressive – even more so because his patients continue to improve over months, even years.
Recently, Centeno’s own registry data showed that, of 221 overweight and older patients with knee arthritis, 80 per cent recorded more than a 25 per cent improvement after the operation, with an average of nearly 60 per cent improvement after two years. And of 999 middle-aged people who were only slightly overweight, the figures showed that 90 per cent reported a more than 50 per cent improvement, with more than 70 per cent average improvement after four years.
Although the results for hip pain are not as spectacular, more than 60 per cent of such patients still reported more than 25 per cent pain relief, with an average improvement of 42 per cent in patients under 55 (22 per cent in those older than 55).
Puzzling over why hip patients don’t do as well as knee patients, the Regenexx team studied their post-treatment registry and discovered that a patient’s total range of hip motion was connected to outcome success: the poorer the range of motion, the poorer the outcome of the standard treatment (whereby the patient’s own stem cells are not cultured, but just injected back in).
Nevertheless, both hip and knee stem-cell patients fare well when compared with joint replacement patients. According to an independent comparison made by American orthopaedic surgeon Dr Mitch Sheinkof, patients getting hip replacements showed a greater improvement in the Harris hip test (which measures pain and movement ability), but Regenexx patients enjoyed a better range of motion and a better overall risk/benefit ratio, as the stem-cell procedure is far less invasive and carries far less risk. Some 73 per cent of the hip Regenexx patients were able to return to sporting activities. Knee patients in particular show greater overall functional improvement.
In 2011, Centeno and his team published a safety and complications report on 339 patients, most of whom had arthritis of the knee and all of whom had been told they needed knee replacements. After receiving the stem-cell Regenexx treatment, only 4.1 per cent of these patients went on to get an artificial knee, while the rest did well enough with the Regenexx treatment to avoid surgery.
Not surprisingly, Centeno has been singled out by the US Food and Drug Administration (FDA), largely because his work appears to fall outside the agency’s jurisdiction. Stem-cell therapy not only threatens to revolutionize orthopaedic medicine as we know it, but also threatens to wipe away some of the £30 billion pain-management drug business and ultimately to rock the foundations of FDA control of the entire drugs marketplace.
The FDA has visited the Colorado clinic many times – sifting through Centeno’s laboratory ‘as if it were a mass drug manufacturing factory’, as he puts it. In August 2010, the Center for Biologics Evaluation and Research, a division of the FDA, filed an injunction, ordering his clinic to stop culturing patients’ stem cells. In response, he filed for multiple temporary restraining orders simultaneously in Denver and in Washington, DC. The FDA then issued another injunction against the clinic, whereupon Centeno abandoned the restraining orders and promptly countersued the FDA for interfering with his trade.
The FDA maintains that extracting, manipulating and culturing a person’s stem cells constitutes a ‘cultured drug product’ not unlike culturing an antibiotic. In 2012, in an attempt to control this new medical technique, the FDA ruled that your own stem cells should now be considered a ‘drug’ subject to the agency’s control.
The FDA’s ruling was upheld in a court case, even though Centeno argued that ‘stem cells are body parts and not the property of the government or Big Pharma’. ‘What we’re doing in our medical practice,’ claims his partner Schultz, ‘is no different, in principle, than a fertility clinic that uses in vitro fertilization’. At the time, the ruling meant that the clinic could only treat those parts of the body that receive enough blood flow to benefit from an ordinary stem cell injection – harvested from the hip and immediately injected into the damaged joint.
As Centeno and Schultz are no longer able to culture stem cells within the USA, they were forced to move that part of their practice to the Cayman Islands, which is outside FDA jurisdiction. In most cases this isn’t an impediment to the work in the Colorado clinic, as 90 per cent of their practice concerns situations where patients can benefit from having their existing MSCs harvested and injected back in. Any patients with problems requiring a larger batch of stem cells will now travel to the clinic in the Caymans, funds permitting.
Possibly because research has shown that the native stem cells in the hips aren’t as robust as those in knees and have less of an inbuilt repair mechanism, older hip patients tend to do far better with cultured stem cells than ones just taken out of the patient’s bone marrow and re-injected back in.
In October 2013, the FDA published a rider to clarify its initial ruling, allowing work like Centeno’s to carry on so long as the harvested stem cells are returned to the patient without too much manipulation and as part of the ‘same’ procedure. This amounted to a cautious stamp of approval for the clinic to carry on its work with damaged joints, using a procedure that simply harvests MSCs from the hipbone, then purifies them and injects them directly into the damaged joint.
A number of other orthopaedic specialists are also using stem-cell technology, albeit without the scientific monitoring or published data that Centeno brings to his work.
Despite the FDA’s challenges, Centeno remains confident that the sheer weight of evidence of the safety and success of his procedure will speak for itself – and prevail.
It’s well known that injecting embryo-derived stem cells into a patient can cause tumours to develop. For this reason, Centeno and his team as well as others have kept careful follow-up data on patients receiving MSCs for orthopaedic purposes. Several years ago, Centeno published follow-up data on more than 300 patients who’d been tracked for up to four years, many of whom were later scanned for procedure-related problems, including tumours.6 This is the largest study of its kind and the first of a set of similar studies. No cancerous growths or formations were found.
In a separate study, Japanese researchers went even further, following 45 patients who’d received MSC transplants to repair cartilage, for more than 11 years. They could find no evidence of either tumours or infections.