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Robotic Mouse Massage: Is It “Regenerative” and “Anti-Inflammatory”? (Member Post)

 •  • by Paul Ingraham
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Massage science rarely makes a big splash, but a strange new study did in early October with this extraordinary claim: “robotic” massage of mice supposedly helped their little muscles heal. “Massages feel good, but do they actually speed muscle recovery? Turns out, they do,” says the Harvard Gazette. Lead researcher Bo Si Reo:

“This has promise for regenerating a wide variety of tissues including bone, tendon, hair, and skin, and can also be used in patients with diseases that prevent the use of drug-based interventions.”

Sounds like a big deal. The hair growth market alone is probably worth billions! And you thought those scalp massagers were just for relaxation!

This seems like an extremely good news story for massage. And because it comes from Harvard, this good-news cake has a thick and delicious icing of credibility. The complexity and sophistication of the experiment itself also make it look good (and harder to critically appraise).

And so the headlines were credulously shared by countless massage therapists on social media, while the massage gun industry rejoiced. I rolled my eyes and started warming up my debunking muscles.

Confession: Even I got a little infected by the hype

Despite my well-earned reputation for being a wet blanket about massage pseudoscience, I actually got an optimistic buzz from this news. I love massage. Skepticism about it is not a reflex for me; my natural enthusiasm for massage has to be tamed with mental discipline, and hype like this gets to me too. Hype is a potent drug.

And so there I was, a few hours later, banging away at my burning Achilles tendons with a massage gun. Yes, of course I own one: I love massage! As my tendons vibrated, my brain produced giddy, hopeful rationalizations: Maybe I can squeeze the inflammatory cells out! It worked on those mice, didn’t it? Plus it’s like I’m doing more research! If it works, I can tell my readers!

Dear reader: It didn’t work. Surprise surprise!

“Squeeze the inflammatory cells out”? Seriously? But that is actually how The Harvard Gazette explained the results.

The science is dubious. The hype is hilarious. And, in today’s premium post, I will break it all down: the most generous possible interpretation, the bad news about the technical limitations of the study, and the deal-breaker that no one’s even talking about.

An overview of the study and its major malfunction

The study:

“Skeletal muscle regeneration with robotic actuation-mediated clearance of neutrophils”
Seo et al. Science Translational Medicine. Volume 13, Number 614, eabe8868. Oct 2021.

Seo et al injured mice legs (“severely”) then applied a tiny custom vibrating massage machine (a “robot”). They reported improved “regeneration” of muscle tissue by a couple reckonings — not just healing, mind you, but “regeneration,” and an “anti-inflammatory” effect.

There could be something interesting to learn from this study, but “how massage works” probably isn’t it, for a simple reason: it tries to shed light on how something works that … does not happen at all in humans. No kind of massage is known to accelerate any kind of tissue recovery or have any kind of anti-inflammatory effect. No one even claims that massage is a treatment for grossly injured muscle, and all competent massage therapists avoid massaging muscle tears or contusions, let alone “severe” ones. The overwhelming majority of massage is performed not to “heal” injured muscles, but to try to relieve sensations of aching and stiffness unrelated to trauma.

So what phenomenon were these researchers trying to understand? And did they learn anything of interest at all?

“For science”: What exactly was done to these poor mice?!

Seo et al built a mouse-sized vibrating massage tool, which they called “robotic.” It was fancy as these things go — precise and “computer controlled” — but it was ultimately just one of these:

They injured some mice — a chemical injury to their muscles, not a mechanical one. They tied them down and applied a “consistent, repeated force” for two weeks. I assume the mice got breaks, but we’re talking about really a lot of vibrating massage here.

The pictures of the experimental setup look like animal torture, but I cannot share them here (copyright). They are publicly accessible in the “Supplementary Materials” for the paper. (Also, the mice look like rats to me — extremely uncomfortable rats.)

Many and varied measurements of the victims’ muscles were taken. The complete list is substantial and technical. Their search for signs of any effects on the muscle was extensive.

What did Seo et al. find?

Despite the laundry list of measurements, the researchers didn’t actually find much. But what they did find, they certainly boasted about:

  1. More muscle cells that looked bigger, “juicier,” with a different mixture of cell types. If you squint. You can see the difference, but it’s like comparing two bowls of ramen, one with 5mm wide noodles, and the other with 4mm.
  2. Fewer neutrophils, the immune cells that rush to the cite of injury and cause inflammation. In this case, the illustrative image is much clearer: it really does look like a lot fewer neutrophils. Okay.

Anything else?

Nope, that’s it: just two specific signs of “regeneration” in the treated muscle tissue. Juicier muscles cells and fewer neutrophils in chemically injured mouse muscles that got vibrated. Not exactly smoking gun evidence of a clinical benefit, not even in mice, let alone humans.

It’s also worth noting that they report a dose-response effect: more massage produced larger effects, laughably summarized by The Harvard Gazette as “the greater the force… the stronger the injured muscles became.” This flirtation with a no-pain-no-gain message is a bit worrisome — plenty can go wrong when people believe that more intensity is better. But my point here is just that the dosage was non-trivial: they vibrated these mice thoroughly to get their allegedly regenerative results.

What do the results mean? Hype-factor nine, Mr. Sulu!

Depends who you ask. Press coverage of this paper is so fawning that it turns my stomach. The Harvard Gazette’s language makes it sound like the treated mice were all flexing Popeye-like muscles by the end of the study: better, stronger, faster!

This is predictable with a certain kind of science journalist hack, just punching the clock and reporting the most “exciting” and simplistic interpretation of study results. But in this case it’s not just the journalists that are tripping over themselves to declare a meaningful victory here. The researchers themselves, as quoted, reach far beyond their evidence, making claims so outlandish that it’s hard to believe they can think rationally about anything. Consider this gem:

These findings are remarkable because they indicate that we can influence the function of the body’s immune system in a drug-free, non-invasive way.

Or this:

The fields of mechanotherapy and immunotherapy rarely interact with each other, but this work is a testament to how crucial it is to consider both physical and biological elements when studying and working to improve human health.

Or this (partially quoted above)…

Our work shows a very clear connection between mechanical stimulation and immune function. This has promise for regenerating a wide variety of tissues including bone, tendon, hair, and skin, and can also be used in patients with diseases that prevent the use of drug-based interventions.

So let me get this straight: from a study of massage of injured mouse muscles, the authors got to profound cross-disciplinary implications, namely general immunotherapy and regenerative medicine for any tissue in the body? From vibration? I hardly ever resort to an “LOL” in my writing, but … LOL! That is some cold-fusion-grade delusional optimism! Hopeless hyperbole from people who should know much better.

This casts doubt on their ability to produce and interpret data in a somewhat objective fashion. I do not think scientists need to be emotionless robots with no hopes or dream for what they find when they study things, but I worry about such a striking lack of restraint in public outreach.

The most generous possible interpretation

It might be exactly what it seems to be, in principle: mechanical stimulation is “anti-inflammatory” and “regenerative” in some meaningful sense, to some degree. Maybe injured muscles actually do heal faster when treated like this.

If it proves to also be true of mechanically or metabolically injured human muscles, with practical vibration intensities and dosages, that is indeed a big deal.

A big deal that has almost nothing to do with existing conventional massage therapy or any other kind of prevalent physical therapy. Most massage isn’t vibrating massage of injured muscle tissue! I cannot emphasize that strongly enough. Even if true, this research suggests the need for a new massage techniques and protocols, not validation of what’s already happening.

The research would still be quite interesting in principle, however. If vibration is to some degree actually regenerative, then it might be true to some lesser extent of smaller doses of virtually any kind of physical stimulation.

“Mice lie and monkeys exaggerate”

Even if the findings are what they seem to be, there are still serious concerns about the degree and meaning of the results, and their relevance to real-world healing in humans. The two most obvious weaknesses of this study are:

  1. Mice are not humans. They are much smaller. They work differently.
  2. The chasm between the biochemistry and clinical reality.

Mice can be excellent models for human physiology, but they are also infamously misleading. Hence the charming research expression: “mice lie and monkeys exaggerate.”

It’s reasonable to study mice and other animals for many purposes — it’s a good starting place — but it’s quite foolish to assume that people will work the same way. The history of medical science is littered with the corpses of “promising” effects in mice that didn’t pan out in humans.

And we’re mostly talking about inflammation here, the signature of immunity. It’s hard to imagine anything harder to make good guesses about.

The huge leap over the chasm between biochemistry and clinical reality

If immunity was a nation, inflammation would be its armed forces, and neutrophils its troops. All inflammation is a function of the immune system, but with immense variety. Immunity isn’t just “complex,” it’s “where intuition goes to die.” Rocket science is far simpler.

People tend to think of immunity as something that is either “boosted” or “suppressed” uniformly. That is not how it works.

Immunity is constantly being boosted and suppressed in many different ways at once, all with trade-offs between costs and benefits. For instance, bear in mind that a neutrophil presence is business-as-usual after injury, and we just have no idea whether rushing them is actually “accelerating healing.” The researchers did some fancy hand-waving about this:

“While the inflammatory response is important for regeneration in the initial stages of healing, it is equally important that inflammation is quickly resolved to enable the regenerative processes to run its full course.”

Is it, though? It’s possible, but that is clearly guesswork.

Not just guesswork, mind you. They actually did additional in vitro side-experiments to inform this opinion — studying cells in a petri dish. (Seriously, this paper is way too elaborate. Way too many moving parts, way too much opportunity for error and p-hacking. Focus, people, focus! If it’s not reproducible, it’s not science!)

They took that detour, and arrived at the opinion that you need a Goldilocks dose of inflammation for optimal healing. Still guesswork! This does not prove that neutrophil herding is a way to speed healing (even if it is possible).

And how do I know that? Because nothing has ever been shown to “speed healing.” As far as anyone knows, healing just can’t be rushed — all we can do is remove impediments. In that context, the hypothesis that we need a just-right inflammation dose — in humans, based on mouse cells — is just not credible.

(And never mind the extra claim that we know how to get that dose.)

The deal-breaker: an answer in search of a question

Let’s return to the most basic problem here: this is a study trying to shed light on something that does not actually happen in humans in the first place. No one was even asking “How does massage heal wounds faster?” They weren’t asking because it doesn’t.

And yet here we have a study purporting to deliver evidence about how a non-existent miracle works. Is it possible that they have “explained” a phenomenon that exists in humans, and we just didn’t know about it? Only in an “anything’s possible” sense, but it’s highly unlikely. While massage research is generally weak and incomplete, there are a many relevant clues about this in the literature.

For instance, one of the best studied sub-topics is the effect of massage on soreness after intense exercise — slightly injured muscles. This seems highly relevant. And that research shows no sign whatsoever of a robust effect on muscle recovery. (I have reviewed that evidence thoroughly.) If massage cannot treat soreness, I doubt it’s going to do much better with more seriously injured tissue.

So this is cart-before-horse research in a big way. Here’s what we really need to know: Does any kind of massage have meaningful effects on recovery? Do treated humans have less pain? Are they stronger sooner? Can they return to play earlier, with less risk of re-injury?

If massage can do that… then by all means go rooting about in cellular biology looking for how it might work. Only then do you start sacrificing mice.

Anti-inflammatory hype déjà vu

Back in 2012, a similar-in-spirit study got a lot of press. It supposedly showed that massage had an anti-inflammatory effect (see Massage Does Not Reduce Inflammation). That claim was a strained extrapolation from a biomarker of dubious relevance to anything… but it was a high-tech study with results that sounded good. It got the researchers a lot of attention, and it was probably fabulous for their careers.

And it was also great free advertising for massage therapists, who gleefully and naively cited it for years, just exactly as if had something had been proven. It didn’t. And it hasn’t been replicated, certainly not by this new study — they are thoroughly different. It probably never will be replicated.

This time around, the science is delivering free advertising for massage guns. Just imagine what this paper is worth to that industry. Millions? At least. Any follow-the-money cynic would be fully justified in wondering who has shares in what.

Interesting stuff, but way too indirect and preliminary

“Regeneration” is a foundational concept on PainScience.com. It’s part of my brand, the reason for my salamander mascot-logo. I have read and written a lot about regeneration biology; I take it seriously as a topic.

But this research does not excite me.

Wake me up when someone directly detects a clinically significant anti-inflammatory or regenerative effect of massage. In vivo. In homo sapiens.

I do not entirely dismiss the possibility that mechanical stimulation does something subtle but clinically useful to muscle. I have had too many profound-feeling experiences with massage to be simplistically skeptical about its medical value. But I do not confuse my anecdotes with evidence — they are a reason to keep studying.

They are not a reason to study mice, though. Study the clinical outcomes of massage in humans until we have confirmed an actual treatment benefit, proof that massaged humans recover faster than un-massaged humans.

Once we have that, I could perhaps endorse the sacrifice of animals to figure out how it works. Until then, animal studies like this — and all the hyperbolically optimistic extrapolations from their results — are of extremely limited value. And that’s the most polite possible version of my opinion.