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Modern Mechanisms for Old Medicine Part 1

Leveraging Osteopathic Neuromusculoskeletal Medicine and Medical Acupuncture for Enhanced Patient Outcomes

Scott Moore, DO, DipIBLM, FACLM, PGY3 ONMM

Good morning.

I’m Scott Moore. I’m trained in Osteopathic Neuromusculoskeletal Medicine. That’s the official name.

Osteopathic. Neuro. Musculo. Skeletal. Medicine.

It’s 16 syllables long. By the time you finish saying it, the patient’s back pain has either resolved… or they’ve left the clinic.

So for everyone’s sanity — I go by Manual Medicine. It’s short and describes what I do well enough.

I don’t say that I’m the physician for every malady, but what I offer is a flavor of medicine, for those who want to avoid surgery or do not want to be on one more medication.

By holding strictly to the evidence, I recognize situations that are appropriate to give a trial of more holistic natural care; including OMT, LM, and Acupuncture, but more importantly I recognize the limitations of manual medicine which keeps my patients safe.

Manual Medicine focuses on reducing pain, and improving function and movement and today let’s talk about movement.

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Disclosures

None

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OBJECTIVES

Describe the mechanobiologic basis of manual medicine, including mechanotransduction, neuroimmune modulation, and autonomic regulation.�
Explain how osteopathic manual medicine and medical acupuncture influence pain, inflammation, and functional outcomes through identifiable physiologic mechanisms.�
Summarize the comparative effectiveness and safety profile of manual medicine relative to medications, injections, and surgical interventions for common musculoskeletal conditions.�
Identify patient populations most appropriate for referral to manual medicine within the conservative-to-interventional care spectrum.�
Recognize the “gap” in current musculoskeletal care pathways and how early referral to manual medicine may improve outcomes and reduce unnecessary procedural care.�
Apply an evidence-informed referral pathway for integrating manual medicine into surgical and primary care practice.

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What is my specialty called?

Osteopathic Neuromusculoskeletal Medicine (ONMM)

Neuromusculoskeletal Medicine (NMM)

Manual Medicine

Osteopathic Manual Medicine (OMM)

Musculoskeletal Medicine

Osteopathic Manipulative Medicine (OMM)

Osteopathy

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Modern Manual Medicine

Part 1: Mechanobiology in medicine

Part 2: How manual medicine fills the gap between conservative care and interventional care

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PART 1: THE SCIENCE

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“Motion at the tissue level.”

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“Here it is in all its glory. Fascia. Home of the interstitial space.

A living matrix of: Collagen, Lymphatics Microcirculation Interstitial Fluid Fibroblasts

Every organ, every vessel, every nerve, every muscle — is embedded in fascia. There is no structure in the body that exists outside of it.”

Cellular Layer “And within fascia, we find at least four major cell types: Fibroblasts, Fibrocytes, Myofibroblasts, and Fasciacytes. “Not fascists, but fasciacytes.”

“These are active, dynamic, mechanically responsive cells.”

The Big Thesis “One of the most important things I learned in residency is this: Everything in biology is mechanical. Yes — even emotions.

Neurochemistry has biomechanics. Synapses are force-dependent. Membranes deform. Ion channels are stretch-sensitive.

Biology is not just chemical reactions floating in space. It is chemistry constrained by physics.”

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Embryology of Fascia

Fascia formed in the mesoderm at 2-3 weeks
First to form is the mesenchyme and embryonic connective tissue
The fascia creates a body-wide communication system via transmission of mechanical forces

21 day embryo

“Where does fascia come from? Fascia originates in the mesoderm at two to three weeks of embryologic development.

At this stage, we don’t yet have differentiated organs or a fully formed musculoskeletal system.� But we already have mesenchyme — primitive connective tissue. … And that primitive connective tissue becomes fascia.

From the very beginning, fascia establishes a body-wide communication system through the transmission of mechanical force.

This is how mechanical forces become biological signals. And fascia is the medium through which those forces travel.”

“The fascia has four important universal attributes:”

It surrounds every muscle, nerve, vessel, and organ.
It forms a continuous tension–compression network.
It transmits mechanical force across regions.
It provides pathways for fluid and biochemical signaling.

Now, let’s put that in the context of the developmental timeline again. Fascia is present before organ specialization. That matters.

Because it means mechanical communication is foundational— not secondary.

Before biochemical signaling dominates, biomechanics is already shaping development.”

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Tensegrity and Mechanotransduction

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Tensegrity

ten·seg·ri·ty - ten(t)ˈsegrə̇tē: the property of a skeletal structure having continuous tension members (such as wires) and discontinuous compression members (such as metal tubes) so that each member performs efficiently in producing a rigid form

Biotensegrity

“So if fascia is present before organ differentiation…How is it organized?

It is not just wrapping tissue. It is structured as a tension–compression system.” … “This concept is called tensegrity. (CLICK)

In architecture, tensegrity describes structures where continuous tension elements and discontinuous compression elements work together to create stability.

The structure holds its shape not because it’s rigid — but because forces are balanced.” (CLICK to the biological image.)

“Biology follows the same principle. In biotensegrity:

Bones act as compression struts.
Fascia, ligaments, and muscle act as continuous tension elements.
The system distributes force across the entire network.”

“The key idea is this: Force applied in one region does not stay local. It is transmitted.” (Pause.)

“And if force is transmitted across the entire system…Then restriction in one region alters strain patterns elsewhere.

That is physics, not mysticism. - That is mechanical load redistribution.

This tensegrity structure is used to hold up both modern buildings and modern humans and is a way to transmit forces efficiently in multiple different directions.

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Mechanical Regulation of Gene Expression

Nucleus is linked to the cytoskeleton

Nucleoli undergo molecular rearrangement with external forces

Tissue stretch removes nuclear invaginations

Nuclear invaginations impact gene expression

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Epigenetic Overview of Movement in Medicine

Mechanical force applied to the nucleus tends to:

Activate

Cytoskeletal genes�
Extracellular matrix (ECM) genes�
Growth signaling�
Anti-inflammatory signaling

Silence

Pluripotency genes�
Adipogenic genes�

via chromatin repositioning and epigenetic modification.

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Mechanotransduction and Cancer

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Neuroimmune and Autonomic Modulation

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Medical Acupuncture: Mechanobiology in Action

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https://biomedical-engineering-online.biomedcentral.com/articles/10.1186/1475-925X-7-19

“As the needle rotates, the mechanical engagement of fascia increases. This polarized micrograph shows white fibers at 45 degrees.

You can see the alignment area changes with needle rotation. Force is being transmitted.”

“This is also dose-dependent, if we rotate too far, we cause tissue damage as you see here in starting in image B and the damage increases as we rotate it further in images C, D, and E. Damage is NOT the intention of acupuncture.

This highlights a key difference though, between medical acupuncture and dry needling.

The intention of dry needling - tissue damage - activate the body’s natural healing mechanisms, GREAT - I do dry needling with Injections

Acupuncture does so much more - and the object is to not cause damage. But do at least 4 other things, 1. stimulate genetic change via mechanotransduction, 2. electrical energy change by the piezoelectric effect (which we will get into), 3. analgesia via the efferent nociceptive system, and 4. promote anti-inflammatory mechanisms.

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How Does Acupuncture Work?

Wang B-G, Xu L-L, Yang H-Y, Xie J, Xu G and

Tang W-C (2023) Manual acupuncture

for neuromusculoskeletal disorders:

The selection of stimulation parameters

and corresponding effects.

Front. Neurosci. 17:1096339.

doi: 10.3389/fnins.2023.1096339

https://www.frontiersin.org/journals/neuroscience/articles/10.3389/fnins.2023.1096339/full

For a little background, I understand both the Traditional Chinese Medicine and biomechanical neuroanatomical approaches to acupuncture.

but I do acupuncture like a pathologist…I need to know the anatomy that I’m influencing.

I’m basically doing an autopsy in my mind of all the organs and nerves that I’m affecting.

So, I lean heavily toward the biomechanical approach, but I still keep an open mind, because I recognize that there are lessons to be learned from a science that millions of people have used successfully for over 3,000 years.

However, we all have a duty to ourselves and to our patients to practice evidence-based medicine, when it exists. And, fortunately, it does exist here! So I’m going to use it.

In trained hands, here is the mechanism behind acupuncture:

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“The signal ascends to the CNS. And then descending inhibitory pathways activate. GABA. Serotonin. Norepinephrine. Endogenous opioids.”

“The result: Reduced nociceptive transmission. Decreased inflammation. Modulation of the HPA axis. Improved movement.”

As I said before, Acupuncture is targeted mechanotransduction…

All just by inserting a simple needle in the skin and this understanding is called the Neuroendocrine-immune network.

Acupuncture appears to function as a neuromodulatory treatment that restores regulatory balance in this network, rather than acting as a simple analgesic intervention alone.

“Again, this is not alternative medicine. This is neurophysiology that we use in medicine and novel therapeutics are influencing these same exact pathways.

My goal with this slide is to remove that “woo woo” mystical perception of acupuncture, and replace it with the scientific pathways we have discovered.

I hope that you will feel comfortable recommending anatomic medical acupuncture for standard medical care.

It’s a 3,000-year-old science, and this shows that there is biomedical credibility behind it.

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“Different mechanical inputs activate different fiber types. A-beta. A-delta. C fibers.”

“These fibers carry distinct sensory information — Touch, mechanical tension, nociception.” “The type of mechanical stimulus determines the neural response.” …. Acupuncture activates:

Aδ and C fibers, which then go on to promote: Adenosine and Endogenous opioid release, CB2 receptor modulation, TRPV1, NF-κB inhibition, and decreased inflammation with lower IL-1β, TNF-α, IL-6 and increased IL-10

Because of this, acupuncture can be seen as a primary intervention to reduce inflammation.

Meta-analyses demonstrate a reduction of inflammatory cytokines after acupuncture in:

Migraine, Knee osteoarthritis, Lumbar radiculopathy - Sciatica, Neuropathic and myofascial pain, Major Depressive Disorder, Asthma, COPD, Allergic Rhintis, Crohn's Disease, IBS, Sepsis

These have all demonstrated clinically meaningful improvement in symptoms in RCTs and Meta-analyses

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1

2

3

4

For the final slide on acupuncture, we have the Autonomic and Neuroimmune Axis

“Mechanical stimulation activates autonomic pathways.

Modern work in Nature, Neuron, and Nature Medicine has defined two autonomic anti-inflammatory circuits:

spinal-splenic circuits, illustrated at the top for high intensity stimulation from peripheral neurons to the spinal cord, then the celiac ganglion and to the spleen via the splenic nerve, decreasing inflammation by blocking the conversion of TNFa from LPS.
Discovered in 2021, the vagal-adrenal pathways. Low intensity stimulation from peripheral neurons to the spinal cord to the adrenal glands via the vagus nerve resulting in a release of adrenal catecholamines, which stimulate the B2-adrenergic receptors and inhibits the proinflammatory cytokines (IL-1B, TNF-a, and IL-6) and enhancing the andi-inflammatory IL-10.

These pathways are activated with high or low intensity physical activity or electrical stimulation and they modulate systemic cytokine production.”

“Mechanical input influences immune tone, which is how it affects the cytokines.”

This is not placebo physiology. This is bioelectronic neuromodulation.

The American Society of Pain and Neuroscience officially recognizes vagal neuromodulation as a therapeutic target.

And acupuncture has a seat at the table.

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Piezoelectric Effect

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Piezoelectric Effect in Myofascial Release

MFR treatments involve direct or indirect gliding of the fascia

Fascial glide creates a Piezoelectric effect

This effect influences other organs and structures and accelerates tissue healing

Fascial glide creates:

Local electric potentials
Ion flux
Galvanotaxis
Cytokine cascades

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Fascial Structure

Connective tissue surrounds every organ, vessel, bone, nerve, and muscle
Continuity from skin to periosteum and all organs of the body
Interstitial fluid flows through the fascia

“All of this is possible because of how fascia is built.”

“Everything we’ve discussed —� mechanical signaling,� neuroimmune modulation,� bioelectric response — they depend on structure.” (Pause.)

As A.T. Still once said, “Anatomy, Anatomy, give me more Anatomy.”

“Fascia surrounds every organ, every vessel, every nerve, every muscle.”

“It is continuous — from skin to periosteum.” (Pause.)

“It is not packaging for the muscles. It is infrastructure.” ***I like to call it the body’s magical crawl space!***

“Interstitial fluid moves through this network.

That fluid movement is biologically active.” … Movement produces electrical signaling.

That electrical signaling influences: Healing, Cellular differentiation, and Immune modulation

This is not pseudoscience. This is material science applied to biology.

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Summary of Mechanobiology Mechanisms

Movement as Medicine works through:

Nuclear transcription
Inflammatory cascades
Descending pain modulation
Autonomic tone
Neuroimmune regulation
Tissue perfusion
Brain network plasticity

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PART 2:

MANUAL MEDICINE

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THE GAP

“We’ve discussed some mechanisms … Now let’s talk about application.” (Pause.)

Many of the patients you see with chronic pain fall into this GAP–they’re not surgical, but they’re not getting better.

The clinical reality you see every week: Chronic Low Back Pain … Persistent Neck Pain, Migraines, Knee OA … Adhesive capsulitis, Pregnancy-related pain

They’re not surgical … But they’re not getting better.

They’ve: Done PT. Tried NSAIDs. Maybe had an injection. Maybe seen a chiropractor. Maybe seen pain management. And they’re stuck.

They cycle through: Medications, Imaging, Specialist referrals, Opioids, Repeat injections

But they remain functionally limited…This is THE GAP. You want something effective to try BEFORE they do all these things.

Think Not surgical. Not improving. No intermediate referral option… until now,

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Manual Medicine specializes in patients:

Who are not surgical candidates

Who have persistent musculoskeletal dysfunction

Who need advanced conservative care

Who physicians don’t know what to do with

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Multimodal treatment

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Bubble Plots: Comparative effectiveness, safety, and relative cost

X-axis: representative effectiveness (negative = better)
Y-axis: adverse event / discontinuation rate
Bubble size: relative cost index
Dashed line: pragmatic MCID threshold at ≈0.5 SD

Important:

• These are cross-study visual comparisons, not direct head-to-head effect sizes.

• “Multimodal care” is a conservative modeled estimate for OMT + acupuncture + exercise.

• Surgical points reflect selected surgical candidates, not all-comer chronic pain populations.

Interpretation: treatments that land in the lower left corner on the plot provide a more favorable effectiveness–safety tradeoff; larger bubbles indicate higher relative resource intensity. These are illustrative comparative visuals and NOT precise quantitative rankings or “definitive” comparisons.

Based on systematic reviews, major trials, and practice-relevant comparative literature.

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RFA

Fusion

THE GAP

Here is our bubble plot: We see that the x axis is effectiveness, more effective on the left. It’s also measuring RMDQ score change.

As a reminder, an SMD or effect size around 0.2 is small, 0.5 is moderate, and 0.8 is large…we don’t have anything with a large effect size.

The y axis is Adverse event / discontinuation rate at 1 year. Worse at the top. The bubble size is cost. Larger = more expensive. -

Small dots - lower left corner are the treatments with highest efficacy, fewest adverse events, and lowest cost

3 very nice levels of intervention; conservative care, medications, and surgical care. You try one level before you go on to the next. You notice that we have THE GAP, that’s where I live.

The line at -0.3 on the right, is the MCID. It reflects about a drop in -2.5 points in the RMDQ, same as the forest plot before.

So, this tells us that Lumbar Spinal Fusion is arguably the single most effective intervention, but still only results in moderate benefit.

Radiofrequency Ablations (abbreviated as RFA) typically do better than OMT alone, about as well as acupuncture alone, and not as good as exercise alone. But they are for a different patient population, those who don’t respond to exercise, then RFAs are wonderful.

This shows that we sometimes miss steps, and “We are excellent at escalation…but not always at optimization.” We think, oh, this patient tried home exercise, or acupuncture, or OMT separately, so now we need to bring out the bigger guns.

We don’t always need to escalate, we can think laterally. Most physicians or patients haven’t thought to use these conservative treatments synergistically, but they have incredible power!

“This visual shows the tradeoff clearly. When we move to procedural interventions, it nearly always carries higher adverse event rates.”

“Lower-risk conservative options provide moderate benefit with minimal harm.” That is … until that moderate benefit becomes a significant benefit and we use them synergistically … The BEST patients for Manual Medicine are those who are:

Not yet surgical … Not improving … Not functioning optimally 👉 This is THE GAP

Obviously, there are still patients who will need surgery, and is still a necessary part of medicine, but there are other steps before that.

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Risk-Benefit Comparisons

Chronic Opioids: 70-80% adverse events and Dependence risk

ESI: Hyperglycemia, Dural puncture, Limited long-term benefit

Spinal Fusion: ~25% complication rate, $60k-$120k cost/surgery

Manual Medicine: Mostly transient soreness

Rare serious adverse events

Low cost relative to procedural care

“Efficacy without safety is not value though.”

“Chronic opioids carry high adverse event rates — and dependence risk.”

“Epidural steroid injections carry procedural risks and limited long-term benefit.”

“Spinal fusion carries substantial cost and complication risk.”

“Manual medicine is very effective and the most common adverse event is transient soreness.” This adverse effect not even in the same ballpark.

“Serious adverse events are rare.” for example, we’ve found that serious ones like vertebral artery dissection after visits where overly exuberant cervical manipulations occured were found to be so rare that they occurred at the same rate as they did after normal physician visits that did not include neck manipulation. So, it seems to be a misattribution of background population risk.

“Cost is also substantially lower than procedural care.”

Efficacy is better than most other interventions when used synergistically.

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Intervention	Primary Autonomic Effect	Secondary Effects
Acupuncture	Vagal tone enhancement (particularly CV-17, ST-36, PC-6)	HPA axis modulation; reduced inflammatory cytokine output
OMM (cervical/paraspinal)	Baroreflex sensitivity; reduced sympathetic skin response	Improved heart rate variability; enhanced sleep architecture
Lifestyle counseling (delivered in context)	Social engagement system activation (polyvagal ventral vagal)	Oxytocin-mediated trust and adherence

Autonomic Layering

When delivered in sequence, these effects compound synergistically: the patient leaves the encounter with restored autonomic flexibility, not merely symptom relief.

I believe that the reason why this is, is that when delivered synchronously, these interventions layer physiologic effects.

This is an amazing effect and something that I started doing in residency, with incredible outcomes! I call it Autonomic Layering or Multimodal Treatment.

“Acupuncture enhances vagal tone and modulates inflammatory signaling.”

“Cervical and paraspinal OMT especially influence baroreflex sensitivity and sympathetic output.”

“Lifestyle counseling reinforces social engagement and promotes autonomic flexibility.” (Pause.)

Do you see where I’m going with this multimodal approach? This is setting the stage for success…

There’s actually a brief physiologic window after multimodal treatment where the nervous system is more flexible—more receptive.

In that state, patients aren’t just feeling better… they’re also more capable of change.

That’s when lifestyle interventions land. I also wait until I have a good relationship with the patient, after they trust me more like the 3rd or 4th visit.

So instead of just treating symptoms, we’re restoring autonomic balance and improving long-term behavior change sustainably—all in the same visit.”

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Is Manual Medicine Placebo?

Many procedures in manual medicine show little benefit over sham treatment

So how do we determine what actually works for patients with chronic pain?

Let’s address this head-on—because I hear it all the time:� ‘Isn’t manual medicine just placebo?’

It’s a fair question. I’ve wrestled with it myself.

In drug trials, placebo is easy—a sugar pill. No physiologic effect.

In manual medicine, there’s no true placebo. Even ‘sham’ involves touch, interaction, and mechanical input—those are all biologically active. We just went over some of the mechanisms.

So what happens? The sham performs really well. The bar gets raised.

When sham or placebo group outperforms the control, it doesn’t mean the treatment doesn’t work—� it means the ‘placebo’ is partially doing the treatment.

So yes—there’s a strong placebo effect.� But that just means the research has to be stronger to show separation…

It’s not a new problem either:

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Sham vs Knee Arthroscopy and Pain

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Vertebroplasty vs Sham over 6 months

N Engl J Med 2009;361:557-68

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Triamcinolone vs Saline in Knee OA

N Engl J Med 2009;361:557-68

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Why This Matters

Modern medicine sometimes overuses:

surgery
injections
medications

While underutilizing conservative musculoskeletal care.

These interventions have lower costs and lower adverse events

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Cervical Fusion

Chronic Neck Pain.

We use the neck disability index on the X axis measuring Standard Mean Difference, aka effect size.

And we see again, multimodal treatment - for the win!

Radiofrequency Ablations and injections are our next steps they’re more expensive, and remember that these

numbers are over 1 year. And after 1 year, RFA typically has lower pain benefits, because of nerve regrowth.

Likely, they will also come in for another manual medicine visit too, but that’s a lot cheaper with better safety.

Let me just read you the numbers for the Cervical fusion, because yes, the efficacy is arguably the same or slightly lower than multimodal treatment, but the cost and complication rates are both much higher.

The average cost is about $90k for surgery compared to about $1,000 for a 3-5 visit course of multimodal treatment, which includes OMT, Acupuncture, and Exercise.

Adverse events occurred in about 1 in 5 patients with surgery, and they are more serious.

Whereas for multimodal treatment, 1 in 25 had an adverse event which consisted of post treatment soreness for a day or two.

So, again, they’re not really even comparable and we should be starting with multimodal treatment.

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“In migraine prevention, we see similar tradeoffs.”

“Highly effective pharmacologic therapies carry higher discontinuation rates and cost.”

“Conservative therapies demonstrate moderate effect with low harm.” … until we combine them.

“Different condition. Same pattern.”

So…why aren’t we hearing more about it?

Well, again let’s follow the money,

Thin needles aren’t very expensive

Those companies don’t advertise for us like GLP-1 companies do.

Notice here that even acupuncture alone is more effective with fewer adverse effects than CGRP inhibitors.

The big thing to notice here is that multimodal treatment wins in effectiveness, cost, and adverse event profile. Then, if that doesn’t work, let’s move up the bubble plot to more expensive drugs, but not before we’ve tried our more conservative and more effective options first.

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Arthroplasty

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Key takeaways

Across all four conditions, lower-cost conservative options generally cluster more favorably than medications or procedures with high adverse-event burden.

The multimodal bubbles are modeled to visualize a clinic strategy: stacking exercise + acupuncture + OMT can move leftward without a proportional increase in harm or cost.

All modeled combination estimates are explicitly conservative and intended for visual framing.

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I mean, not we as a group have anxiety, but here is the bubble plot demonstrating that the efficacy of multimodal care extends beyond musculoskeletal pain.

We see that anxiolytics do work better for anxiety than each of my interventions alone, but are a far cry from the effectiveness of both CBT and multimodal treatment.

“In anxiety, multimodal conservative interventions demonstrate meaningful effect with low adverse burden.”

“CBT, Acupuncture, OMT, exercise, dietary modulation, autonomic regulation — these influence inflammatory tone and autonomic balance.”

(Pause.)

“Manual medicine participates in that autonomic treatment.”

I’ll put a plug in for the WFPBD which sits there right next to acupuncture, and multimodal treatment is nearly double the efficacy of each intervention individually. Talk about a synergistic effect!

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Why is Manual Medicine Underutilized?

Minimal training exposure in medical school/residency
Procedure-weighted reimbursement models
Lack of local specialists
Fragmented conservative care

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Manual Medicine Optimal Patient Populations

Chronic low back pain
Persistent neck pain
Migraine
Fibromyalgia
Pregnancy-related pain
Adhesive capsulitis
Nearly any other non-surgical musculoskeletal dysfunction

It is conservative care at a specialist level

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Evidence‑Based Referral Pathway

YES

NO

YES

NO

Where Manual Medicine Fits in:

Here

↪

Or Here

↩

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Health System Implications

Benefits to primary care:

Reduced opioid reliance
Reduced unnecessary imaging
Improved patient satisfaction
Reduced specialist bounce-back
A defined intermediate care layer

Manual medicine does not replace primary care.

It extends your conservative toolbox.

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Conclusion

Manual medicine is not alternative medicine

It is mechanobiology applied clinically by licensed, board-certified physicians

When integrated with primary care, it expands the conservative care toolbox for patients in THE GAP

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Questions?

Scott Moore, DO, FACLM, DipIBLM, ONMM-3

Please send patient referrals for Manual Medicine to

TANNER CLINIC SCHEDULING DEPARTMENT

801-773-4840

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READ ON FOR MORE DATA

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MANUAL MEDICINE UTILIZATION CHALLENGES

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Why Manual Medicine Is Underutilized

Training Gaps� Most physicians receive minimal education in biomechanics, fascia, and manual therapies.

Procedure-Focused Healthcare System� Reimbursement structures often favor procedures and imaging over conservative care.

Time Constraints in Primary Care� Short visits make detailed musculoskeletal evaluation difficult.

Limited Awareness of Evidence� Many clinicians are unfamiliar with research supporting exercise and manual medicine.

Patient Expectations� Patients often expect medications, injections, or surgery rather than movement-based care.

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CLINICAL MECHANISM FOR LYMPHATIC PUMP TECHNIQUES

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Rats were infected with S. pneumoniae and sacrificed at 8 days post-infection.

CFU/lung decreased substantially with LPT.

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GENES INFLUENCED BY MECHANOTRANSDUCTION

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Key Mechanoresponsive Pathway summary

Mechanosensor	Pathway	Genes activated
Piezo1	Ca²⁺ signaling	NFAT, IL6
Integrins	FAK/Src	CTGF, CYR61
Nuclear deformation	YAP/TAZ	ANKRD1, CTGF
Actin tension	MRTF/SRF	ACTA2
Chromatin stretch	RNA Pol II recruitment	ECM genes

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Genes Activated by Nuclear Mechanical Force

Cytoskeletal / contractility genes

Activated via YAP/TAZ and SRF

Examples:

ACTA2 – α-smooth muscle actin�
MYH9 / MYH10 – myosin heavy chains�
VCL – vinculin�
TAGLN – transgelin

Extracellular matrix genes

Activated in response to matrix stiffness.

Examples:

COL1A1�
COL3A1�
FN1 (fibronectin)�
CTGF (connective tissue growth factor)�

Mechanosensitive growth genes

Often activated through YAP/TAZ nuclear translocation.

Examples:

CYR61�
CTGF�
ANKRD1�
BIRC5

These are classic YAP target genes.

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Genes Activated by Nuclear Mechanical Force

Osteogenic differentiation genes

Activated in mechanically stimulated stem cells.

Examples:

RUNX2�
SP7 (Osterix)�
ALPL�
COL1A1

Inflammatory mechanotransduction genes

Activated through NF-κB.

Examples:

IL6�
TNF�
ICAM1�
VCAM1

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Genes Silenced by Nuclear Compression

When chromatin is compressed or tethered to the nuclear lamina, genes may become heterochromatic and transcriptionally inactive.

Genes often suppressed include:

Pluripotency genes

OCT4 (POU5F1)�
SOX2�
NANOG�

These move toward lamina-associated domains (LADs) during differentiation or mechanical stress.

Cell cycle inhibitory genes

In stiff environments some suppressors are reduced.

Examples:

CDKN1A (p21)�
CDKN2A (p16)

Adipogenic genes

Mechanical stiffness suppresses adipogenesis.

Examples:

PPARG�
CEBPA

Neural lineage genes

When mesenchymal stem cells experience stiffness, neural genes decrease:

MAP2�
TUBB3�
NEUROD1

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REFERENCES

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References for Chronic Low Back Pain

Cochrane Database Syst Rev. 2021;9:CD009790.

Cochrane Database Syst Rev. 2014;9:CD000963.

Ann Intern Med. 2017;166(7):514–530.

JAMA. 2016;315(12):1240–1249.

Ann Fam Med. 2013;11(2):122–129.

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Hayden JA, van Tulder MW, Malmivaara A, Koes BW. Exercise therapy for treatment of non-specific low back pain. Cochrane Database of Systematic Reviews. 2021;9:CD009790.

Licciardone JC, Gatchel RJ, Aryal S. Recovery from chronic low back pain after osteopathic manipulative treatment: a randomized controlled trial. Journal of the American Osteopathic Association. 2016.

Licciardone JC, Brimhall AK, King LN. Osteopathic manipulative treatment for low back pain: a systematic review and meta-analysis. BMC Musculoskeletal Disorders. 2005.

Vickers AJ, Cronin AM, Maschino AC, et al.� Acupuncture for chronic pain: individual patient data meta-analysis. Archives of Internal Medicine. 2012;172(19):1444-1453.

Linde K, Allais G, Brinkhaus B, et al. Acupuncture for chronic pain. Cochrane Database of Systematic Reviews. 2016.

Chou R, Hashimoto R, Friedly J, et al. Pain management injection therapies for low back pain.� Annals of Internal Medicine. 2015.

Manchikanti L, et al. Epidural steroid injections for lumbar spinal pain. Pain Physician. 2013.

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Leggett LE, Soril LJJ, Lorenzetti DL, et al. Radiofrequency ablation for chronic low back pain: systematic review of randomized controlled trials. Pain Research and Management. 2014.

Fritzell P, Hägg O, Wessberg P, Nordwall A. Lumbar fusion versus nonsurgical treatment for chronic low back pain. Spine. 2001.

Försth P, Ólafsson G, Carlsson T, et al. A randomized trial of fusion surgery for lumbar spinal stenosis.� New England Journal of Medicine. 2016.

Hidalgo B, Hall T, Bossert J, Dugeny A, Cagnie B, Pitance L. Multimodal manual therapy and exercise for chronic neck and back pain: systematic review and meta-analysis. Journal of Orthopaedic & Sports Physical Therapy. 2017.

Qaseem A, Wilt TJ, McLean RM, Forciea MA. Noninvasive treatments for acute, subacute, and chronic low back pain. Annals of Internal Medicine. 2017.

Enthoven WTM, Roelofs PD, Koes BW. NSAIDs for chronic low back pain. Cochrane Database of Systematic Reviews. 2016. Dieleman JL et al.� US health care spending by procedure and condition.� JAMA. 2020. Healthcare Cost and Utilization Project (HCUP). Agency for Healthcare Research and Quality. Centers for Medicare & Medicaid Services.� Physician Fee Schedule and procedure cost estimates.

GoodRx Healthcare Cost Data (2024).

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References for Acute Low Back Pain

ACP Clinical Practice Guideline: Noninvasive Treatments for Acute/Subacute Low Back Pain. Ann Intern Med. 2017.

Licciardone JC et al. OMT for Low Back Pain: Meta-analysis. J Am Osteopath Assoc.

Vickers AJ et al. Acupuncture for Chronic Pain: Individual Patient Data Meta-analysis. Arch Intern Med.

Cochrane Reviews: NSAIDs and Muscle Relaxants for Acute LBP.

AHRQ Noninvasive Treatments for Low Back Pain Review.

Chou R et al. Interventional Therapies for LBP. Spine.

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Rehman Y, Kirsch J, Wang MYF, et al. Osteopathic manipulative treatment in the management of headaches: a systematic review and meta-analysis. J Osteopath Med. 2025;125(1):XX-XX. doi:10.1515/jom-2024-XXXX.
Linde K, Allais G, Brinkhaus B, et al. Acupuncture for the prevention of episodic migraine. Cochrane Database Syst Rev. 2016;(6):CD001218. doi:10.1002/14651858.CD001218.pub3.
Xu S, Yu L, Luo X, et al. Manual acupuncture versus sham acupuncture and usual care for prophylaxis of episodic migraine: a randomized clinical trial. JAMA Intern Med. 2020;180(6):839-847. doi:10.1001/jamainternmed.2020.0996.
Goadsby PJ, Dodick DW, Ailani J, et al. Safety, tolerability, and efficacy of atogepant for preventive treatment of migraine: a randomized clinical trial. N Engl J Med. 2020;385:695-706. doi:10.1056/NEJMoa2035908.
Ailani J, Lipton RB, Goadsby PJ, et al. Atogepant for the preventive treatment of migraine. Lancet Neurol. 2021;20(9):727-737. doi:10.1016/S1474-4422(21)00250-0.
Linde M, Mulleners WM, Chronicle EP, McCrory DC. Topiramate for the prophylaxis of episodic migraine in adults. Cochrane Database Syst Rev. 2013;(6):CD010610. doi:10.1002/14651858.CD010610.
Brandes JL, Saper JR, Diamond M, et al. Topiramate for migraine prevention: a randomized controlled trial. JAMA. 2004;291(8):965-973. doi:10.1001/jama.291.8.965.
Dodick DW, Ashina M, Brandes JL, et al. ARISE: A phase 3 randomized trial of erenumab for episodic migraine. Lancet Neurol. 2018;17(5):391-400. doi:10.1016/S1474-4422(18)30091-1.
Goadsby PJ, Reuter U, Hallström Y, et al. A controlled trial of erenumab for episodic migraine. N Engl J Med. 2017;377:2123-2132. doi:10.1056/NEJMoa1705848.
Sacco S, Braschinsky M, Ducros A, et al. European Headache Federation guideline on the use of monoclonal antibodies targeting the CGRP pathway. J Headache Pain. 2019;20:6. doi:10.1186/s10194-018-0955-y.

Migraine/Headache References

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Neck Pain References

Gross A, et al. Manipulation and mobilisation for neck pain. Cochrane Database of Systematic Reviews. 2015;(9):CD004249.
Linde K, et al. Acupuncture for chronic neck pain. Cochrane Database of Systematic Reviews. 2016;(4):CD004870.
Kay TM, et al. Exercise for mechanical neck disorders. Cochrane Database of Systematic Reviews. 2012;(8):CD004250.
Hidalgo B, et al. Multimodal manual therapy and exercise for chronic neck pain: systematic review and meta-analysis. J Orthop Sports Phys Ther. 2017;47(7):453-463.
van der Velde G, et al. Noninvasive management of neck pain and associated disorders. Eur Spine J. 2016;25(7):2008-2018.
Toward Optimized Practice. Evidence-informed primary care management of neck pain. 2017 guideline.
Enthoven xWTM, et al. NSAIDs for spinal pain: systematic review. Eur Spine J. 2016;25(2):321-332.

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References for Manual Medicine and Nausea/Vomiting

Apfel CC, et al. Postoperative nausea and vomiting. N Engl J Med. 2010;363:1023-1034.

Hesketh PJ, et al. Antiemetics: ASCO guideline update. J Clin Oncol. 2020;38(24):2782-2797.

Navari RM. Management of chemotherapy-induced nausea and vomiting. Lancet Oncol. 2016;17(2):e47-e58.

Ezzo J, et al. Acupuncture-point stimulation for chemotherapy-induced nausea or vomiting. Cochrane Database Syst Rev. 2014.

Lee A, Done ML. Stimulation of the wrist acupuncture point PC6 for preventing postoperative nausea and vomiting. Cochrane Database Syst Rev. 2015.

Licciardone JC, et al. Osteopathic manipulative treatment for postoperative recovery: systematic review evidence. J Am Osteopath Assoc.

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References for Hip Osteoarthritis

1. da Costa BR, Pereira TV, Saadat P, et al. Effectiveness and safety of non-steroidal anti-inflammatory drugs and opioid treatment for knee and hip osteoarthritis: network meta-analysis. BMJ. 2021;375:n2321.

2. Fransen M, McConnell S, Harmer AR, et al. Exercise for osteoarthritis of the hip. Cochrane Database Syst Rev. 2014;(4):CD007912.

3. Manheimer E, Cheng K, Linde K, et al. Acupuncture for peripheral joint osteoarthritis. Cochrane Database Syst Rev. 2010;(1):CD001977.

4. Bannuru RR, Osani MC, Vaysbrot EE, et al. OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis. Osteoarthritis Cartilage. 2019;27(11):1578–1589.

5. Ferreira GE, McLachlan AJ, Lin CWC, et al. Defining the minimal clinically important difference for pain and function in osteoarthritis: systematic review and meta-analysis. Br J Sports Med. 2023;57(12):742–749.

6. Learmonth ID, Young C, Rorabeck C. The operation of the century: total hip replacement. Lancet. 2007;370(9597):1508–1519.

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Moore RA, Derry S, Aldington D, Wiffen PJ. Single dose oral analgesics for acute postoperative pain in adults - an overview of Cochrane reviews. Cochrane Database Syst Rev. 2015 Sep 28;2015(9):CD008659. doi: 10.1002/14651858.CD008659.pub3. PMID: 26414123; PMCID: PMC6485441.

Zhao Y, Zhang S, Liu B, Li J, Hong H. Clinical efficacy of enhanced recovery after surgery (ERAS) program in patients undergoing radical prostatectomy: a systematic review and meta-analysis. World J Surg Oncol. 2020 Jun 17;18(1):131. doi: 10.1186/s12957-020-01897-6. PMID: 32552894; PMCID: PMC7301489.

Yang JW, Shao JK, Wang Y, Liu Q, Liang JW, Yan SY, Zhou SC, Yang NN, Wang LQ, Shi GX, Pei W, Liu CZ. Effect of acupuncture on postoperative ileus after laparoscopic elective colorectal surgery: A prospective, randomised, controlled trial. EClinicalMedicine. 2022 May 27;49:101472. doi: 10.1016/j.eclinm.2022.101472. PMID: 35747183; PMCID: PMC9156985.

Racca V, Bordoni B, Castiglioni P, Modica M, Ferratini M. Osteopathic Manipulative Treatment Improves Heart Surgery Outcomes: A Randomized Controlled Trial. Ann Thorac Surg. 2017 Jul;104(1):145-152. doi: 10.1016/j.athoracsur.2016.09.110. Epub 2017 Jan 18. PMID: 28109570.

Postsurgical Recovery References

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Myles PS, et al. Minimal Clinically Important Difference for Three Quality of Recovery Scales. Anesthesiology. 2016. (QoR-40 MCID 6.3; QoR-15 MCID 8).�

Zhang M, et al. Effect of transcutaneous electrical acupoint stimulation on the quality of postoperative recovery: a meta-analysis. BMC Anesthesiology. 2024.�

Mihara T, et al. Effects of Steroids on Quality of Recovery and Adverse Events after General Anesthesia. PLOS ONE. 2016. (QoR-40 POD1 MD 14.2).�

Racca V, et al. Osteopathic Manipulative Treatment Improves Heart Surgery Outcomes: A Randomized Controlled Trial. Ann Thorac Surg. 2017. (shorter LOS; improved pain/respiratory function).�

Chen et al. Application of QoR-40 to evaluate ERAS protocols in gastric cancer. (Prospective controlled QoR-40 time-course; ERAS higher QoR-40 POD3/6/30).�

Carnes D, et al. Adverse events and manual therapy: a systematic review. 2010. (minor AEs common; serious rare).�

Chan MWC, et al. Safety of Acupuncture: Overview of Systematic Reviews. Sci Rep. 2017.�

Zhang J, et al. Acupuncture-related adverse events: a systematic review. 2010.�

Xu S, et al. Adverse Events of Acupuncture: A Systematic Review of Case Reports. 2013.�

Hanada M, et al. Incidence of orthostatic hypotension during early mobilization after surgery. 2017.�

Cochrane Review: Adverse side effects of dexamethasone in surgical patients. 2018.�

Peter V, et al. Single intraoperative dose dexamethasone causes significant postoperative hyperglycemia. 2022.

Postsurgical Recovery References

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Myles PS, Myles DB, Galagher W, et al. Minimal Clinically Important Difference for Three Quality of Recovery Scales. Anesthesiology. 2016;125(1):39-45.

Zhang M, et al. Effect of transcutaneous electrical acupoint stimulation on the quality of postoperative recovery: a meta-analysis. BMC Anesthesiology. 2024.

Mihara T, et al. Effects of Steroids on Quality of Recovery and Adverse Events after General Anesthesia: Meta-analysis. PLOS ONE. 2016.

Chen et al. Application of the Quality of Recovery-40 to evaluate enhanced recovery after surgery protocols. BMC Surgery. 2024.

Ljungqvist O, Scott M, Fearon KC. Enhanced Recovery After Surgery: A Review. JAMA Surgery. 2017;152(3):292-298.

Racca V, et al. Osteopathic Manipulative Treatment Improves Heart Surgery Outcomes: A Randomized Controlled Trial. Annals of Thoracic Surgery. 2017;104(1):145-152.

Carnes D, et al. Adverse events and manual therapy: a systematic review. Manual Therapy. 2010;15(4):355-363.

Chan MWC, et al. Safety of Acupuncture: An Overview of Systematic Reviews. Scientific Reports. 2017;7:3369.

Cochrane Database of Systematic Reviews. Adverse side effects of dexamethasone in surgical patients. 2018.

Postsurgical Recovery References

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References for Pregnancy

Acupuncture for labor pain: Cochrane 2020 1.
Exercise and relaxation for labor pain: Cochrane 2011 6.
Epidural analgesia: Cochrane 2018 3.
Remifentanil PCA: Cochrane 2017 7.
Labor pain overview: Cochrane 2012 2.
Acupuncture and exercise for labor pain: overview of systematic reviews 2

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1. Kelley MJ, Shaffer MA, Kuhn JE, et al. Shoulder pain and mobility deficits: adhesive capsulitis. J Orthop Sports Phys Ther. 2013;43(5):A1–A31.

2. Page MJ, Green S, Kramer S, et al. Manual therapy and exercise for adhesive capsulitis (frozen shoulder). Cochrane Database Syst Rev. 2014;(8):CD011275.

3. Challoumas D, Biddle M, McLean M, Millar NL. Comparison of treatments for frozen shoulder: a systematic review and meta-analysis. JAMA Netw Open. 2020;3(12):e2029581.

4. Litscher G, Ofner M, He W, et al. Immediate pain relief in adhesive capsulitis by acupuncture: a randomized controlled double-blinded study. Pain Med. 2017;18(2):223–231.

5. Sun Y, Lu S, Zhang P, et al. Steroid injection versus physiotherapy for adhesive capsulitis: systematic review and meta-analysis. JAMA Netw Open. 2020;3(12):e2029581.�(Note: This is part of the same JAMA Network Open systematic review dataset.)

6. Kietrys DM, Palombaro KM, Azzaretto E, et al. Trigger point dry needling for shoulder pain: systematic review and meta-analysis. J Orthop Sports Phys Ther. 2013;43(9):620–634.

7. Clewley D, Flynn T, Koppenhaver S. Trigger point dry needling as an adjunct treatment for a patient with adhesive capsulitis of the shoulder: a case report. J Orthop Sports Phys Ther. 2014;44(2):92–101.

8. Grant JA, Schroeder N, Miller BS, Carpenter JE. Comparison of manipulation and arthroscopic capsular release for adhesive capsulitis: a systematic review. Arthroscopy. 2013;29(2):347–353.

References for Adhesive Capsulitis

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Important References for Mechanobiology

If you want the highest-quality mechanobiology literature, these are foundational:

Elosegui-Artola et al., Nature Cell Biology 2017 — Force triggers YAP nuclear entry�
Lammerding et al., JCB 2004 — Nuclear mechanics and lamin A/C�
Kirby & Lammerding, Nat Rev Mol Cell Biol 2018 — Nuclear mechanotransduction�
Guilluy et al., Nat Cell Biol 2014 — Force activates nuclear transcription�
Nava et al., Cell 2020 — Heterochromatin protects genome under mechanical stress

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Key References for Acupuncture and Mechanobiology

Langevin HM et al.� Mechanical signaling through connective tissue: a mechanism for the therapeutic effect of acupuncture.� FASEB Journal. 2001.

Langevin HM et al.� Connective tissue fibroblast response to acupuncture: dose-dependent effect of needle manipulation.� Journal of Cellular Physiology. 2006.

Langevin HM et al.� Tissue stretch induces cytoskeletal remodeling in fibroblasts.� American Journal of Physiology. 2005.

Ulloa L. Bioelectronic neuro-immunology: Neuronal networks for sympathetic-splenic and vagal-adrenal control. Neuron. 2023 Jan 4;111(1):10-14. doi: 10.1016/j.neuron.2022.09.015. Epub 2022 Oct 5. PMID: 36202096.

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Key References for Safety of Osteopathic Manipulation

Osteopathic manipulation in the management of chronic pain: current perspectives

Journal of Pain Research, 2020

Effect of osteopathic manipulative treatment vs sham treatment on activity limitations in patients with nonspecific subacute and chronic low back pain: a randomized clinical trial

JAMA Internal Medicine, 2021

Pediatric osteopathic manipulative medicine: a scoping review

Pediatrics, 2021

Manipulative therapies: what works

American Family Physician, 2019

Spinal manipulative therapy for adults with chronic low back pain

The Cochrane Database of Systematic Reviews, 2026

108 of 110

Selected references (1/2)

Vickers AJ, et al. Arch Intern Med/J Pain individual patient data meta-analyses on acupuncture for chronic pain (2012, 2018).
Licciardone JC, et al. Ann Fam Med 2013; and meta-analysis on OMT for low back pain (effect size about -0.30).
Hayden JA, et al. Br J Sports Med 2021; and related reviews on exercise for CLBP.
Petzke F, et al. Eur J Pain 2020; AHRQ surveillance report on opioids for chronic pain (small benefit, meaningful AE burden).
Leggett LE, et al. Pain Res Manag 2014; Li H, et al. Front Surg 2022 on radiofrequency denervation for CLBP.
AAFP FPIN 2022 / Cochrane-linked evidence summary: epidural steroid injections provide minimal or non-clinically meaningful benefit for chronic low back pain.
Browning R, et al. Arch Intern Med 2001 meta-analysis: cyclobenzaprine offers modest back-pain benefit with greater adverse effects.
Bydon M, et al. J Neurosurg Spine 2014 and later meta-analyses on lumbar fusion vs nonoperative care for selected discogenic pathology.
Rasmussen-Barr E, et al. 2023 review of reviews on exercise for chronic neck pain.
Liu Z, et al. J Bodyw Mov Ther 2023 meta-analysis of manipulative therapy for chronic neck pain (pain SMD -0.83).

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Selected references (2/2)

Fransen M, et al. Cochrane-style meta-analysis (exercise for knee OA; pain SMD about 0.40).
Manheimer E, et al. Meta-analysis on acupuncture for knee OA (clinically relevant vs usual care; WOMAC pain SMD about 0.39).
Xu Q, et al. J Back Musculoskelet Rehabil 2017; Zhu B, et al. Syst Rev 2024 on manual therapy for knee OA (pain SMD about -0.61).
Saltychev M, et al. 2020 meta-analysis on intra-articular corticosteroid injection for knee OA (mild-to-moderate short-term benefit).
Recent OARSI/Open studies on TKA showing large WOMAC/KOOS pain improvement beyond MCID in surgical candidates.
Ou MQ, et al. 2020 and ACP Journal Club 2016 summaries on acupuncture for migraine/chronic headache (usual-care SMD about -0.56).
Lemmens J, et al. 2019 and Varangot-Reille C, et al. 2022 on exercise for migraine (small-to-moderate benefit).
Reuter U, et al. Cephalalgia 2021 head-to-head erenumab vs topiramate (better tolerability and responder rate for erenumab).
Tassorelli C, et al. Lancet Neurol 2024; and 2025 meta-analysis on atogepant (SMD about -0.39; constipation notable).
OMT for migraine: systematic/scoping reviews (Cerritelli 2017; Cureus 2022).

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Acupuncture Anti-Inflammatory Effects

Bao, C., Wu, L., Wu, H., & et al. (2022). The effect of acupuncture on modulating inflammatory cytokines in rodent animal models of respiratory disease: A systematic review and meta-analysis. Frontiers in Immunology, 13. https://doi.org/10.3389/fimmu.2022.9241441 Cited by: 12

Chen, L., Wang, Y., & et al. (2026). The anti-inflammatory effect of acupuncture on peripheral inflammatory cytokines in patients with major depressive disorder: A systematic review and meta-analysis. Journal of Affective Disorders. Cited by: 2

Li, J., Zhang, Y., & et al. (2022). The anti-inflammatory actions and mechanisms of acupuncture from acupoint to target organs via neuro-immune regulation. Evidence-Based Complementary and Alternative Medicine. https://doi.org/10.1155/2022/8710088 Cited by: 45

Li, X., Liu, H., & et al. (2026). Usage, anti-inflammatory effect and safety of adjunctive acupuncture for cerebral infarction: An apriori algorithm-based data mining and meta-analysis. Journal of Stroke and Cerebrovascular Diseases. Cited by: 1

Vickers, A. J., Vertosick, E. A., Lewith, G., & et al. (2018). Acupuncture for chronic pain: Update of an individual patient data meta-analysis. The Journal of Pain, 19(5), 455-474. https://doi.org/10.1016/j.jpain.2017.11.005 Cited by: 1200

Zhao, J., Yang, J., & et al. (2023). Anti-inflammatory effects of acupuncture in inflammatory bowel disease: A systematic review and meta-analysis. Frontiers in Immunology, 14. https://doi.org/10.3389/fimmu.2023.1123876 Cited by: 8