“Autologous chondrocyte implantation” (ACI) is implanting a “patch” of your own cartilage cells. This treatment depends on some biotech wizardry owned by a big biotech company, and massive biotech companies make a lot of people a bit nervous. For better or for worse, this is Big Medical Science — it takes a lot of resources to develop and deliver a technique like this, so it’s only available1 as MACI®, the brand name of an ACI product used to repair knee cartilage defects, a technology owned by Vericel (it started out as CARTICEL®, owned by Genzyme). The M is for “matrix.”
The idea is to take a small sample of your very own cartilage cells (chondrocytes) and grow them into a surplus population of several million spares on a scaffolding (matrix) that a surgeon implants back into your knee. This is somewhat like tossing some grass seed on a rough patch of lawn, only it requires a bunch of folks with advanced degrees, and it costs a lot more. Work is probably still being done on the ideal formula for getting the implanted cells to stay put and make new cartilage. The limitations of ACI today will probably not be the limitations of the ACI of tomorrow.
Here’s a video of a surgeon performing the procedure (back when it was a Genzyme product):
For my readers — particularly many of you who have chronic patellofemoral pain syndrome (kneecap pain) — I’ve got good news and bad news about MACI. It’s both amazing and disappointing.
Relationship to other cell and stem cell therapies
Stem cells are generic cells that do not yet have a job. In theory, they can become what we need them to be, which is a potentially powerful tool in medicine. Stem cell therapy is a broad concept in regenerative medicine, and it is a hot hot hot topic right now.
Stem cell therapy is identical in spirit to the other two main regenerative therapies in musculoskeletal and pain medicine: platelet-rich plasma and cartilage regeneration. Neither PRP or ACI is technically a stem cell therapy — they use mature, specialized cells, so they are just cell therapies.
But regeneration is the goal of all of these methods, and the topic of stem cell therapy overlaps so much with PRP and ACI that they are practically the same thing with regards to safety, efficacy, and the concerns of skeptical consumers and regulators. They are biologically intriguing treatments that might amount to something someday — after all, we know regeneration is possible, thanks to salamanders! — but it’s a depressing mess so far, instead of being inspiring and promising. These treatments are all being rushed to market in the same way, all sold as high-tech medicine to desperate consumers long before the science is done.
The good news about chondrocyte implantation
On the bright side, there seems to be little doubt that the MACI procedure really can grow new cartilage. Marvellously, the implanted cells produce fresh, shiny new cartilage! Which is cool! I defy anyone to be unimpressed by that. It’s a little bit of true regeneration, just like a salamander.
Cartilage just doesn’t fix easily. In the past, trying to repair degrading cartilage with surgery has involved comparatively primitive methods: polishing it (debridement), which is notoriously ineffective; trying to stimulate healing with stresses, such as creating tiny fractures in the underlying bone (microfracture), or drilling or abrading it (drilling/abrasion); transplanting chunks of bone and cartilage from somewhere (or someone) else (autograft/allograft). None of these techniques has a particularly good track record, and some of them (debridement) are basically surgical snake oil. By contrast, implanting cells seems awfully clever and advanced.
And the patient gets “sustained and clinically meaningful improvement in pain and function,” according to American Journal of Sports Medicine in January of 20092 (plus other, similar research results reviewed below). It all sounds pretty great, and makes me want to buy stock!
Chondrocytes: the cells that build & maintain cartilage
The sparseness of chondrocytes scattered throughout cartilage mean that your joints are “plagued by inherent limited healing potential.”
The bad news about chondrocyte implantation
On the other hand, as always, you’re going to sober up after reading the fine print — as always. The MACI website has a lot of fine print, just like drug ads in magazines. And you can learn some interesting things from that small print! The most interesting is that, although ACI is a treatment for regrowing cartilage, it’s not actually intended for arthritis per se.
The original version of MACI (back when it was CARTICEL) was “not indicated for the treatment of cartilage damage associated with generalized osteoarthritis.” MACI as of 2018 intended for “cartilage defects” — “arthritis” is conspicuously missing from the reasons to have the procedure, “severe” arthritis is actually a very clearly reason not to (contraindicated), and arthritis is actually one of the side effects of the procedure. Yes, you read that right: this cartilage repair treatment can actually cause arthritis in some patients.3
Er, really? That’s quite a kick in the optimism. This is definitely not what most candidates want to hear. But it’s true: by design, ACI is for younger patients with cartilage that has been damaged by injury. Why? Rehabilitation is not quick or risk-free.
So this procedure is actually not appropriate for the majority of (older) people with a lot of stubborn anterior knee pain, or even for large numbers of younger patients whose cartilage just isn’t rough enough to justify it.
In a word, bummer.
Genzyme’s original slogan for CARTICEL was remarkably restrained because of the various problems (the worst of which I haven’t even brought up yet): “the only treatment that uses your own cells to regenerate your knee cartilage that may offer a long-term solution for a knee cartilage injury.” May offer. May. Hmm …
Nicer cartilage is just not the same thing as cured knee pain
If only wishing made it so.
The American Journal of Sports Medicine has published three studies of AIC so far this year.
There have been three prominent studies of chondrocyte implantation this year that I know of, all of them in American Journal of Sports Medicine. The largest was the STAR study, referenced above, published in January: the “Study of the Treatment of Articular Repair,” which was the source of the rather glowing results quoted above. Also in January, Kon et al found it was not only “satisfactory” but produced “better clinical results and sport activity resumption” than the microfracture technique;4 and Gobbi et al concludes that the treatment resulted in “a significant decline” in lesions and pain and is a “viable” treatment.5
Indeed, ACI looks promising. Results from STAR and Kon et al seem to pretty decisively show that it is almost certainly an improvement over older techniques. However, there is an important caveat that would be easy for the casual student to miss …
All three studies show dramatic improvement in the patients’ knee cartilage, but they each also showed that patients did not recover completely from their knee pain. For instance, Gobbi et al’s subjects went from an athletic activity (Tegner) score of about 2.5 to about 4.75 — a level of activity that does not even include “recreational sports.” We’re talking about patients who are barely running or even playing beer league softball.
Or consider Kon et al’s subjects, who went from a subjective score of 41 originally to 70 five years later. That’s a nice improvement, but still well short of feeling fantastic. How “cured” of a chronic pain would you feel if you were only at 70% of healthy status? Most athletes don’t want to operate at much less than “110%” — 70% is still pretty broken as far as most seriously active people are concerned.
The STAR study had similar results: across the board, by several measures, results were a heck of a lot better than nothing, but also well short of full recovery.
So, patients who were treated with ACI definitely improved, and that is not an unimportant result. But cured? Not hardly! Despite the fact that their cartilage looks much nicer than it did, these patients are still not exactly good to go. Unfortunately, there are still more reasons for concern.
Does MACI power a placebo?
Could the MACI benefits found by researchers have been in the mind? It seems unlikely at first glance — this is cold, hard surgery we’re dealing with, and the results were strongly positive, “statistically significant” and all that. Unfortunately, a placebo effect is not an unreasonable consideration after a closer look. The value of uncontrolled studies of knee pain surgeries (and many other surgeries) should always be suspect in principle, but especially since the surprising discovery (by Moseley et al) that a surgical placebo can act strongly on patients.6 For a summary of that fascinating bit of science, see Knee Surgery Sure is Useless! Since then, many other orthopedic surgeries have failed to beat a placebo.7
Kon et al’s study was compared only to an older cartilage repair technique, and Kon et al did not compare their patients to anything at all. So neither of these surgeries was compared to a placebo, and that’s definitely a problem. Bizarre as it sounds, it’s actually quite plausible that a substantial benefits of the surgery were due to placebo.
The STAR study was larger, and it looked only at patients who had already failed to get relief from a previous, non-ACI knee surgery — a kind of compromise. If these patients already had surgery that had no effect, placebo or otherwise, it’s safer to assume that the ACI benefits were “real.” It’s safer, but still not safe: the cool-factor of a fancy new surgery can probably power a superior placebo. Remember, it’s been nicely proven that people like the taste of crappy wine when they think it’s the expensive stuff — they almost certainly think the price and über-modern cache of ACI means it must be more effective … and that absolutely has an effect on patient hopes, dreams, and placebos.
Although this is no more proven than anything else, it really is possible that the new surgery is no better than the old one: just better at generating a robust placebo effect. Crazy, eh?
But the bottom line is always that patellofemoral pain is multifaceted
An even more obvious explanation for the imperfect results of the surgeries is this: the condition of your cartilage is only one of many factors in anterior knee pain. Patellar bone fatigue and synovial membrane irritation, for instance, are two other major candidates — and likely involved to some degree in many cases of knee pain.
Most of the knee pain information on PainScience.com is about patellofemoral syndrome and iliotibial band syndrome, the two most common runner’s knee conditions, typically causing pain on the front and side of the knee respectively (learn more about the difference). Arthritis is not my usual subject matter, although I do keep tabs on it (particularly because of the way it is routinely confused with patellofemoral pain).
- Massage Therapy for Your Quads — Perfect Spot No. 8, another one for runners, the distal vastus lateralis of the quadriceps group
- IT Band & Patellofemoral Pain Defy Common Sense — The science shows that you can’t blame runner’s knee on structural quirks that seem like “obvious” problems
- Do Women Get More Knee Pain? — The relationship between gender and knee pain, especially runner’s knee (IT band syndrome, patellofemoral pain)
- What Can a Runner With Knee Pain Do at the Gym? — Some training options and considerations for runners (and others) with overuse injuries of the knee
- Patellofemoral Pain Diagnosis with Bone Scan — If you have anterior knee pain, should you bother x-ray, MRI, CT scan, or bone scan?
- Diagnosing Runner’s Knee — It usually starts with lateral knee pain during and after runs, but there are two major types
- Should You Get A Lube Job for Your Arthritic Knee? — Reviewing the science of injecting artificial synovial fluid, especially for patellofemoral pain
- Does Hip Strengthening Work for IT Band Syndrome? — The popular “weak hips” theory is itself weak
- Patellofemoral Pain & the Vastus Medialis Myth — Can just one quarter of the quadriceps be the key to anterior knee pain?
- Patellofemoral Tracking Syndrome — The beating heart of the conventional wisdom about patellofemoral pain is mostly nonsense
- Knee Surgery Sure is Useless! — Evidence that arthroscopic knee surgery for osteoarthritis is about as useful as a Nerf hammer
- Is Running on Pavement Risky? — Hard-surface running may a be risk factor for running injuries like patellofemoral pain, IT band syndrome, shin splints, and plantar fasciitis
- Kinesio Taping Review — A quick analysis of that colourful therapy tape that was so popular at the Olympics. Does it help?
Articles about other kinds of regenerative medicine:
- Does Platelet-Rich Plasma Injection Work? — An interesting treatment idea for arthritis, tendinopathy, muscle strain and more
- Salamander and Regeneration Science — Why does PainScience.com have a salamander mascot? Their regenerative superpower is an inspiring, profound example of what is possible in biology and healing
- Don’t Believe Everything You Hear about Stem Cells, by Deepak Srivastava, president of the International Society for Stem Cell Research. “The science is progressing rapidly, but bad actors have co-opted stem cells’ hope and promise by preying on unsuspecting patients and their families.”
About Paul Ingraham
I am a science writer in Vancouver, Canada. I was a Registered Massage Therapist for a decade and the assistant editor of ScienceBasedMedicine.org for several years. I’ve had many injuries as a runner and ultimate player, and I’ve been a chronic pain patient myself since 2015. Full bio. See you on Facebook or Twitter.
What’s new in this article?
Five updates have been logged for this article since publication (2009). All PainScience.com updates are logged to show a long term commitment to quality, accuracy, and currency. more
Like good footnotes, update logging sets PainScience.com apart from most other health websites and blogs. It’s fine print, but important fine print, in the same spirit of transparency as the editing history available for Wikipedia pages.
I log any change to articles that might be of interest to a keen reader. Complete update logging started in 2016. Prior to that, I only logged major updates for the most popular and controversial articles.
See the What’s New? page for updates to all recent site updates.
Jan 28, 2020 — Added a footnote to clarify the source of claims about autologous chondrocyte implantation side effects.
2019 — New section, “Relationship to other cell and stem cell therapies.”
2018 — Updated references to CARTICEL and Genyzme to MACI and Vericel, and a bunch of other miscellaneous minor improvements.
2016 — Added citation to Louw 2016. Converted all inline citations to footnotes.
2016 — Miscellaneous minor improvements and updates.
2009 — Publication.
- It’s a big world, perhaps there are other options, but as of 2018, this is the only FDA-approved product of this kind available in the USA.
- Zaslav K, Cole B, Brewster R, et al. A prospective study of autologous chondrocyte implantation in patients with failed prior treatment for articular cartilage defect of the knee: results of the Study of the Treatment of Articular Repair (STAR) clinical trial. Am J Sports Med. 2009 Jan;37(1):42–55. PubMed #18927254 ❐
- Although this side effect is actually well-known, the claim seems startling on its face. The primary citation for this was provided earlier (the STAR study, Zaslav et al). That said, the adverse events associated with ACI are widely reported. For instance, Drugs.com reports multiple relevant and common harms, deriving the information from the STAR study and also “the Cartilage Repair Registry, the Swedish Series, and post-marketing adverse event reporting.” Adverse events include arthrofibrosis/joint adhesions, chondromalacia or chondrosis, and cartilage injury. These are not technically “arthritis” — that word was a simplification — but they are collectively extremely similar to it in practice. The cartilage can get damaged, and these are very much non-rare complications, with rates ranging froom 5-16% of patients.
- Kon E, Gobbi A, Filardo G, et al. Arthroscopic second-generation autologous chondrocyte implantation compared with microfracture for chondral lesions of the knee: prospective nonrandomized study at 5 years. Am J Sports Med. 2009 Jan;37(1):33–41.
- Gobbi A, Kon E, Berruto M, et al. Patellofemoral Full-Thickness Chondral Defects Treated With Second-Generation Autologous Chondrocyte Implantation Results at 5 Years’ Follow-up. Am J Sports Med. 2009 Jun;37(6):083–1092.
- Moseley JB, O’Malley K, Petersen NJ, et al. A controlled trial of arthroscopic surgery for osteoarthritis of the knee. N Engl J Med. 2002 Jul 11;347(2):81–8. PubMed #12110735 ❐ PainSci #56845 ❐
In this landmark and fascinating study, people with osteoarthritis improved equally well regardless of whether they received a real surgical procedure or a sham, which is a particularly striking example of the placebo effect and implies that belief can have an effect even on a “mechanical” knee problem. From the abstract: “In this controlled trial involving patients with osteoarthritis of the knee, the outcomes after arthroscopic lavage or arthroscopic debridement were no better than those after a placebo procedure.”
In 2008, these findings were fully supported by a Cochrane Collaboration review (Laupattarakasem) which concluded that “there is ‘gold’ level evidence that arthoscopic debridement has no benefit,” and by New England Journal of Medicine (Kirkley) which reported that “surgery for osteoarthritis of the knee provides no additional benefit to optimized physical and medical therapy.”
This study inspired more comparisons of orthopedic surgeries to shams. By 2016, at least four more popular surgeries have been shown to have no benefit (Louw 2016).
- Louw A, Diener I, Fernández-de-Las-Peñas C, Puentedura EJ. Sham Surgery in Orthopedics: A Systematic Review of the Literature. Pain Med. 2016 Jul. PubMed #27402957 ❐ PainSci #53458 ❐
This review of a half dozen good quality tests of four popular orthopedic (“carpentry”) surgeries found that none of them were more effective than a placebo. It’s an eyebrow-raiser that Louw et al could find only six good (controlled) trials of orthopedic surgeries, and all of them were bad news.
Surgeries have always been surprisingly based on tradition, authority, and educated guessing rather than good scientific trials; as they are tested properly, compared to a placebo (a sham surgery), many are failing the test. This review introduction is excellent, and does a great job of explaining the problem. As of 2016, this is the best academic citation to support the claim that “sham surgery has shown to be just as effective as actual surgery in reducing pain and disability.” The need for placebo-controlled trials of surgeries (and the damning results) is explored in much greater detail — and more readably — in the excellent book, Surgery: The ultimate placebo, by Ian Harris.
The surgeries that failed their tests were:
- vertebroplasty for osteoporotic compression fractures (stabilizing crushed verebtrae)
- intradiscal electrothermal therapy (burninating nerve fibres)
- arthroscopic debridement for osteoarthritis (“polishing” rough arthritic joint surfaces)
- open debridement of common extensor tendons for tennis elbow (scraping the tendon)