Hyaluronic Acid Aggregation, Pain, and Manual Therapy


For manual therapists, one major challenge is understanding the mechanisms at play that reduce pain for patients after soft tissue manipulation or mobilization.

There are many common reasons given for why it works, including but not limited to:

  • Counter irritation into the nervous system
  • Novelty of sensory input
  • The breaking of fibrotic adhesions, allowing for sliding of tissues
  • Reflexive muscle relaxation via cutaneous nerve stimulation

Some of these are most justified than others, with validity and practicality debated all over the internet.

A paper was published in mid January 2020 in the International Journal of Environmental Research and Public Health, titled T1ρ-Mapping for Musculoskeletal Pain Diagnosis: Case Series of Variation of Water Bound Glycosaminoglycans Quantification before and after Fascial Manipulation® in Subjects with Elbow Pain

This blog post will attempt to summarize and explain the significance of this paper, along with implications for manual therapists.

The full text copy of the original article is herel.

Pain without Tissue Damage

Sensations, be it pain or otherwise, come down to the firing or neurons to create action potentials and then cognitive processing of those signals leading to a subjective experience.

In the case of an acute injury where there is tissue damage, pain is more than likely a result as part of the body’s natural response to an injury to get us to protect that body part during the healing process.

However, pain does not necessarily imply tissue damage. There can be pain with no tissue damage.

This leads to speculation of what causes the pain? Is it a central processing error? Is it due to peripheral sensitization?

Depending on a variety of factors, there could be reduced levels of nerve stimulation needed to fire an action potential of a free nerve ending, resulting in a painful experience with no tissue damage.

The article under examination leads to a hypothesis that aggregated hyaluronic acid (HA) in the extracellular matrix (ECM) of the deep fascia, which is densely populated with nerve endings, may be lowering the stimulation needed to fire off the nerve endings, leading to pain.

Understanding why this may be the case takes some review of concepts and examination of what was performed in the study.

Let’s take a look.

Glycosaminoglycans and Water

Glycosaminoglycans, or GAGs, are a class of molecules in the body that are essentially strings of double sugars (disaccharides) that have a strong polarity, leading to bonding with water molecules.

HA is one category of GAGs and makes up the ground substance of the extracellular matrix in connective tissue, nerve tissue, and epithelial tissue.

Interesting tidbit – a 70kg person, 154lbs, has 15 grams of HA in their body. Roughly one third is turned over daily

In the ECM, there is bound and unbound water.

Bound water is water in the ground substance that is bound to GAGs since they are strongly polar.

Unbound water is water in the ground substance that is not bound to GAGs.

Presumably, the more bound water there is, the more squishy and slippery the ground substance is and the more unbound water there is, the more viscous and less ‘slippery’ the ground substance is.

This study suggests that HA not bound with water can ‘self-aggregate’ and sort of stick together, increasing the viscosity of the tissue.

This leads us to what the study we are discussing is looking at:

Is there a correlation of bound/unbound water to pain and disability?


T1P MR, DASH Index, and Fascial Manipulation®

The study had 5 participants with elbow pain not due to tissue damage or underlying disease.

To begin, they performed a type of magnetic resonance study called T1P, which can measure bound and unbound water. They also gave the participants a DASH Questionnaire – Disabilities of the Arm, Shoulder, and Hand.

Over the next 3 weeks, therapists performed one 40 minute session of Fascial Manipulation® per week, using that specific technique system.

After the treatment sessions were finished, they followed up with another MR and another DASH.

The results demonstrated a correlation between the DASH score and the bound/unbound water.

When there was more unbound water, there was a higher DASH score. When there was more bound water, there was a lower DASH score.

After the treatments, there was more bound water and a lower DASH score, suggesting that the manual therapy performed decreased pain and improved function while also shifting the water from unbound to bound.

There is no causation implied here, but there is correlation.

(Remember, unbound water is water that is not connected to the GAGs, leading to a more viscous or stiff connective tissue ground substance. A higher amount of bound water implies a more ‘slippery’ and gelatinous ground substance.)

Speculation and Conclusion

Perhaps we can speculate that certain types of manual therapy can agitate the aggregated HA, allowing the polar ends to attract water, which is why unbound water decreased and bound water increased

Perhaps aggregated HA, since it can’t bind to water, creates a subtle shift in the charge around the nerve ending, making the nerve need less stimulation to have an action potential. This could potentially explain the improved DASH scores.

Perhaps the dissolution of aggregated HA and the subsequent decrease in viscosity is part of a person’s subjective appraisal of feeling ‘looser’ after manual therapy treatments.

Perhaps this is why the manual therapist may feel tissue as less stiff after manual therapy.

Above all, perhaps it is just part of the equation since the human biological machine is a system of systems and not so simple as to just have one cause and one effect.