9 Evidence-Based Benefits and Side Effects of Hyaluronic Acid

What is hyaluronic acid?
Hyaluronic acid (also called hyaluronan) is one of the main components of the extracellular matrix in vertebrate tissues and is a type of glycosaminoglycan. It exists in almost all body fluids and tissues, such as skin, muscle, synovial fluid, the vitreous body of the eye and cartilage, and can bind other molecules to create a scaffolding effect that gives structural elasticity.

Beyond this, hyaluronic acid is involved in several important physiological functions, such as regulating cell adhesion, cell motility, cell differentiation and proliferation, as well as providing mechanical properties to tissues.

With aging and external stressors such as sunlight, UV radiation, smoking and air pollution, the body’s hyaluronic acid reserves decline year by year, leading to phenomena such as dry skin, wrinkles and joint damage. This has given rise to various supplementation methods, including subcutaneous injection, topical application and oral intake.

What are the evidence-based benefits of hyaluronic acid?

1. Hyaluronic acid benefits the diabetic foot
Diabetic foot syndrome comprises several pathological features, mainly diabetic peripheral neuropathy and peripheral arterial disease, which lead to foot ulcers.

It is estimated that people with diabetes have a 15% to 25% lifetime risk of developing a diabetic foot ulcer, with higher prevalence among men and those over 60.

Diabetic foot ulcers can lead to amputation, especially when the wound is infected or osteomyelitis is involved, and related complications may also occur, such as nephropathy, retinopathy, ischemic heart disease and cerebrovascular disease.

A systematic review and meta-analysis (including 4 randomized controlled trials with a total of 328 diabetic foot patients) indicated that hyaluronic acid-based topical formulations can increase the rate of wound healing and help treatment of the affected area.

* Conclusion: For the diabetic foot, topical hyaluronic acid may offer positive benefits, but limited by small sample sizes, more large, long-term trials are still needed for further verification.

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2. Hyaluronic acid improves skin condition
The skin is a multifunctional organ with important defensive functions, serving both as a physical barrier against the external environment and providing immune defense against potentially pathogenic microorganisms.

However, organ aging begins from birth, and the skin is no exception. The skin is affected by intrinsic (time) and extrinsic (environmental) aging, leading to loss of function and phenomena such as wrinkles, loss of elasticity, sagging, roughness, dryness and atrophy.

Several randomized, double-blind, placebo-controlled clinical studies have indicated that for patients with dry skin, intake of hyaluronic acid can increase skin moisture.

Another double-blind, placebo-controlled study (lasting 12 weeks, with 60 adults who had crow’s feet) indicated that oral hyaluronic acid can improve wrinkles and skin condition (such as luster and softness). Note 2

In addition, topical application of hyaluronic acid can also improve skin hydration and elasticity, thereby improving wrinkle depth.

* Conclusion: Whether taken orally or applied topically, hyaluronic acid may help improve skin condition.

3. Hyaluronic acid benefits sinusitis
Rhinosinusitis is a broad term covering many diseases, including acute and chronic sinusitis and nasal polyposis. It has many subtypes and different etiologies, with wide variation in severity and clinical presentation, and lacks a simple, accurate office-based test.

Acute sinusitis is defined as inflammation of the nose and paranasal sinuses, characterized by two or more of the following symptoms: blockage, congestion, facial pain, and reduced or lost sense of smell, lasting less than 12 weeks.

Chronic sinusitis is defined as nasal congestion or blockage lasting more than 12 weeks, accompanied by one of the following three symptoms: facial pain or pressure, colorless nasal discharge or postnasal drip, and reduced or lost sense of smell.

Patients with allergies, especially those with IgE-mediated allergic rhinitis, have a higher incidence of sinusitis than the general population (approximately 25% – 50%).

A systematic review (including 5 studies) indicated that topical hyaluronic acid nebulization therapy minimizes sinusitis symptoms because it avoids systemic side effects and increases local drug activity, and prevents re-treatment by significantly improving quality of life. Note 2

* Conclusion: For acute and chronic sinusitis, topical hyaluronic acid nebulization therapy may help improve symptoms, but limited by small sample sizes, more large trials are still needed for corroboration.

4. Hyaluronic acid benefits dry eye disease
Dry eye disease is a multifactorial disease caused by tears and the ocular surface. It leads to symptoms such as discomfort, visual disturbance and tear film instability, and can cause damage to the ocular surface. It is one of the most common eye diseases, with about 25% of patients visiting ophthalmology clinics reporting symptoms of dry eye.

Because the tear film of dry eye patients is unstable and cannot maintain the structure and function it requires, related discomfort symptoms include: burning sensation, stinging, gritty sensation, foreign body sensation, tearing, eye fatigue and dryness, having an adverse impact on visual function, daily activities, social and physical function, and work efficiency.

A prospective randomized controlled trial (lasting 3 months, with 54 dry eye patients) divided participants into two groups. The control group used 0.15% hyaluronic acid ophthalmic drops, while the study group used both hyaluronic acid ophthalmic drops and oral hyaluronic acid capsules (daily dose 240 mg). Note 1

The study found that the study group’s ocular surface disease index, tear break-up time and corneal fluorescein staining were significantly better than the control group.

* Conclusion: For dry eye disease, oral and topical use of hyaluronic acid may help improve corneal epithelial wound healing and related dry eye symptoms, but limited by small sample sizes, more research is still needed for corroboration.

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5. Hyaluronic acid benefits osteoarthritis
Osteoarthritis is the most common joint disease, with prevalence ranging from 33% in those over 60 to as high as 43.7% in those over 80. It is characterized by cartilage loss, subchondral bone changes, synovitis and meniscal degeneration.

Osteoarthritis easily leads to reduced quality of life and reduced participation in social activities. In addition to aging factors, common osteoarthritis risk factors include obesity, previous joint injury, genetic factors, and anatomical factors such as joint morphology and alignment. Other factors include gender, race and nutritional factors (vitamin D deficiency).

A randomized double-blind controlled study (with 60 knee osteoarthritis patients over 50) found that compared to placebo, oral hyaluronic acid (200 mg daily for 12 months) combined with quadriceps strengthening training helped improve participants’ knee osteoarthritis symptoms (such as knee pain, stiffness, quality of life and mobility, measured by the Japanese Knee Osteoarthritis Measures). Note 4

However, the same study also indicated that the improvement was only significant for patients under 70; for those over 70 there was no obvious effect, possibly related to differences in cell metabolism.

* Conclusion: Oral hyaluronic acid may offer positive benefits for improving knee osteoarthritis symptoms, but limited by small sample sizes and short study duration, more research is still needed for corroboration.

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6. Hyaluronic acid benefits gastroesophageal reflux
Gastroesophageal reflux disease is defined as the abnormal backflow of gastric contents into the esophagus or other areas, entering the mouth (including the throat) or lungs, causing symptoms or mucosal damage.

Typical symptoms include heartburn and acid regurgitation; atypical symptoms include stomach pain, indigestion, nausea, bloating and belching.

Based on the presence or absence of esophageal mucosal damage on endoscopy, gastroesophageal reflux disease can be classified as non-erosive reflux disease or erosive reflux disease.

A randomized, double-blind, placebo-controlled study (lasting 14 days, with 20 non-erosive gastroesophageal reflux patients receiving PPI treatment) indicated that a fixed combination of oral hyaluronic acid and chondroitin sulfate can significantly improve symptoms related to gastroesophageal reflux disease, such as heartburn and acid regurgitation. Note 5

In addition, the speed of action and total disappearance of symptoms data for participants taking hyaluronic acid and chondroitin sulfate were both superior to placebo.

* Conclusion: For non-erosive gastroesophageal reflux patients who respond poorly to medication control, the combined use of hyaluronic acid and chondroitin sulfate helps rapidly improve symptoms, but limited by small sample sizes, more research is still needed for corroboration.

7. Hyaluronic acid benefits periodontitis
Periodontitis is an inflammatory disease of the tooth-supporting tissues caused by specific microbial flora, leading to progressive destruction of the periodontal ligament and alveolar bone, periodontal pocket formation, gingival recession and more, affecting approximately 20% to 50% of the global population.

The relationship between periodontal infection and organ systems such as the cardiovascular system, endocrine system, reproductive system and respiratory system makes it a complex multiphase disease.

A randomized trial (lasting 12 weeks, with 33 moderate-to-severe chronic periodontitis patients) indicated that using hyaluronan gel after scaling can significantly improve bleeding on probing, pocket probing depth and clinical attachment level. Note 6

* Conclusion: For chronic periodontitis patients, using hyaluronan gel after scaling helps further improve symptoms.

8. Hyaluronic acid benefits urinary tract infections
Urinary tract infections are a common infectious disease, second only to respiratory infections. It is estimated that at least one-third of women will experience a urinary tract infection requiring antibiotic treatment before age 24.

In addition, there is a 25–35% recurrence rate within 3–6 months of the first urinary tract infection, making it hard to prevent.

A double-blind controlled study (with 57 women who had recurrent urinary tract infections) found that intravesical instillation of hyaluronic acid and chondroitin sulfate helps reduce the incidence of urinary tract infections (by up to 86.6%), compared to 9.6% in the placebo group (questionnaire surveys also showed significant improvements in quality of life and overall symptoms). Note 9

In addition, there was a significant difference in average time to recurrence: about 185.2 days for the instillation treatment group, compared to 52.7 days for the placebo group.

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9. Benefits interstitial cystitis
Interstitial cystitis is a chronic inflammatory disease affecting the urinary system. The main symptoms are urgency, frequency, and bladder and pelvic pain, lasting more than 6 months. More women than men are diagnosed with this disease; the prevalence in women is about 2.71%, compared to 1.22% in men.

The pathogenic mechanism of this disease is not yet fully understood. Possible causes include autoimmune disease, occult infection, toxic substances in urine and defects in the bladder mucosal layer.

Much evidence shows that defects in the bladder mucosal layer (damage to the glycosaminoglycan layer) cause epithelial cells to come into direct contact with pathogenic bacteria or factors in the urine, triggering infection, which is the main factor in the onset of the disease.

Because hyaluronic acid and chondroitin sulfate are the main constituent molecules in the mucosal layer, they are often applied in treatment.

One study (not double-blind or controlled) found that intravesical instillation of hyaluronic acid and chondroitin sulfate helps improve various symptoms and total scores of interstitial cystitis, such as urgency score decreasing from 5.6 to 3.2, and average urine volume increasing from 129.7 ml to 162 ml. In addition, the interstitial cystitis problem index decreased from 25.7 to 20.3, and the frequency of pressure pain decreased from 14 to 11.6. Note 10

What are the side effects of hyaluronic acid (hyaluronan)?
Hyaluronic acid is generally regarded as a safe ingredient with high human tolerance, whether applied topically or taken as oral tablets. However, medical injection (instillation) requires use under a physician’s assessment.

Reported oral side effects include: stomach discomfort, gastroesophageal reflux and decreased appetite.

Hyaluronic acid sources are divided into animal-derived (chicken comb-derived) and microbial fermentation. If animal-derived, note the possibility of triggering allergies, and related products may be mixed with other ingredients, so please check the labeling before use.

Safety precautions (5 usage contraindications)

1. Pregnant women, breastfeeding mothers, children, those with abnormal liver or kidney function, or patients with major illnesses should not use it (relevant safety is unknown).
2. Those with abnormal coagulation function or taking anticoagulants should not use it (may increase bleeding risk).
3. People with cancer or a history of cancer should avoid supplementing with hyaluronic acid, as some studies suggest hyaluronic acid may promote cancer cell growth. Note 7
4. Those who have had any unusual allergic reaction to drugs, food, dyes, preservatives or animal products should use with caution.
5. Medical injections need to be performed by a qualified physician. Most common adverse reactions are injection-related and may include skin bleeding, burning, muscle pain, stiffness, headache, dizziness, nausea, itching, sensitivity, pain, swelling, redness, bruising, chills, tenderness, infection, lumps, numbness, rash, redness, tingling, tenderness, ulceration or warmth at the injection site, most of which subside on their own within a few weeks. In addition, if the raw material is animal-derived, an allergy test should be performed to reduce possible allergic reactions.