What is Hyaluronic Acid

What is hyaluronic acid?

From a chemical standpoint, hyaluronic acid is a polysaccharide belonging to the family of glycosaminoglycans (GAGs), composed of repeating disaccharide units of N-acetylglucosamine and D-glucuronic acid.

It has a gelatinous consistency, and its peculiar characteristics include excellent viscoelasticity and high biocompatibility1.

HYALURONIC ACID
IN SYNOVIAL FLUID

A fundamental component of the synovial fluid and the articular cartilage matrix is hyaluronic acid (HA).

  • HA is secreted into the joints by synovial cells present in the synovial membrane2
  • The HA contained in the synovial fluid has a molecular weight of several millions of Daltons.
Where does it come from

The origin of Hyaluronic Acid

Hyaluronic Acid (HA) has two main sources of origin: extraction from animal tissues and bacterial production through biofermentation.

Traditionally, hyaluronic acid was extracted from animal tissues, such as rooster combs, but this method could introduce impurities such as endotoxins and protein residues with potential immunogenic effects3.

Today, the technology of production through microbial fermentation allows the obtainment of hyaluronic acid of high purity, with low levels of proteins and endotoxins.

The transition from traditional extraction from animal sources to biofermentative production has represented a significant advancement in the production of hyaluronic acid, ensuring products of greater purity and safety, as well as better meeting the needs of modern treatments. This change highlights not only technological evolution but also a greater respect for ethical concerns related to the use of raw materials of animal origin.

What is its role

ROLE OF HYALURONIC ACID IN
SYNOVIAL FLUID

Hyaluronic Acid provides the viscoelastic properties to the synovial fluid (4,5)

The synovial fluid, rich in hyaluronic acid, performs crucial functions of lubrication and nutrition4 of the joint cartilage and is essential for reducing friction between the joint cartilages during movement, thus protecting the joints from wear and mechanical stress.

Synovial fluid functions

The synovial fluid is the interface between the synovial membrane and the cartilage:

  • Reduces friction between joint surfaces6
  • Protects the joint from mechanical stress6

With advancing age or in the case of osteoarthritis, the synovial fluid responds less to mechanical stresses because it loses its viscoelastic properties due to a reduction in the concentration and molecular weight of hyaluronic acid, and the joint is not optimally protected (1,2).

Where is it used

Use of
Hyaluronic
Acid

In patients suffering from osteoarthritis or other degenerative joint diseases and in case of traumas, viscosupplementation with hyaluronic acid represents a valuable therapeutic strategy for restoring joint functions, offering pain relief, and improving mobility.

In cases of arthritic disease or with advancing age, the synovial fluid inside the joints loses its viscoelastic properties due to a reduction in the concentration and molecular weight of hyaluronic acid.

Under these conditions, it becomes beneficial to restore an adequate concentration of hyaluronic acid through ultrasound-guided intra-articular injections, a treatment known as VISCOSUPPLEMENTATION.

restores the viscoelasticity of the synovial fluid5

helps reduce
pain7

improves joint functionality7

The effectiveness of infiltrative therapy depends on the characteristics of the hyaluronic acid: concentration and molecular weight.

The concentration of hyaluronic acid in healthy synovial fluid varies from 1 to 4 mg/ml9, while in the synovial fluid of joints affected by osteoarthritis it varies from 0.32 to 3.61 mg/ml1.

The higher the concentration of hyaluronic acid for infiltration, the greater the probability of recovering the properties of healthy synovial fluid9.

IBSA’s experience, thanks to the search for new production solutions and new technologies, has given rise to three generations of hyaluronic acid for infiltrative therapy:

IBSA is the first and only company to have developed, through the patented NAHYCO® Hybrid Technology, hybrid formulations of hyaluronic acid that combine high and low molecular weight hyaluronic acid, achieving one of the highest hyaluronic acid concentrations on the market (3.2%) and with rheological properties like those of endogenous synovial fluid, mimicking its activity.

The same technology has allowed the development of a new formulation with one of the highest concentrations of hyaluronic acid on the market (72 mg in 3 ml), based on combined hybrid hyaluronic acid characterized by hybrid complexes made up of high weight hyaluronic acid molecules molecular and non-sulphated sodium chondroitin, a new polysaccharide of biofermentative origin.

Currently, viscosupplementation represents one of the main conservative treatments in clinical practice for mild to moderate osteoarthritis of the knee, hip, and shoulder8 as well as in small joint, like hand OA.

It is also recommended for other pathologies of the peri-articular structures such as bursitis, capsulitis, fasciitis, enthesopathies, and tendinitis, which can occur because of trauma or from wear and tear of the joints when they are intensely stressed, for example during physical activity, in competitive sports and in some work activities that require physical effort.

LINEAR
HYALURONIC
ACID

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Hybrid
HYALURONIC
ACID

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COMBINED hybrid
HYALURONIC
ACID

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How it is produced

The production process
of IBSA hyaluronic acid

IBSA Hyaluronic Acid:
Biofermentative, ultra-pure, produced in EU

IBSA’s production facilities stand out for adopting a cutting-edge production process for the manufacture of biofermentative origin hyaluronic acid (HA).

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An innovative and patented manufacturing biotechnological process for the production of sodium hyaluronate has been validated in Altergon, a IBSA strategic partner company.

An Ultrapure Hyaluronic Acid with “customized” molecular weights (from 40 kDa to 3 millions Daltons) is obtained starting from the non-haemolytic cell strain Streptococcus equi, through a multi-step process that includes fermentation, filtration and ultra-purification up to the final packaging. The strain is deposited with at the Pasteur Institute in Paris.

PREPARATION OF CELL BANK TO PRE-INOCULUM

A homogeneous suspension of bacterial cells has been prepared and subdivided into vials stored frozen at ≤ -70°C. The cells taken from one of these vials are revitalized and then cultured to obtain the pre-inoculum, which is then transferred to the Fermentation area.

INOCULUM AND FERMENTATION

The bacterial cells of the preinoculum are further cultured in a seed fermenter to obtain the inoculum for the main fermentation phase. Subsequently, the inoculum is used to seed a rich growth medium in a production fermenter of approximately 5,000 liters. During fermentation, sodium hyaluronate is released in soluble form into the culture medium.

PRIMARY RECOVERY

FILTRATION AND MICROFILTRATION

Bacterial cells are removed from the harvest. The resulting solution, free of cells, is microfiltered to remove any residual fine particles.

PURIFICATION

The sodium hyaluronate solution is concentrated and diafiltrated through an ultrafiltration process during which almost all impurities are removed.
Any residual soluble impurities are removed by adsorption onto activated charcoal particles. The purified solution is further filtered using a filter press to remove the activated charcoal and then deeply microfiltered at 0.2 μm.

FINISHING AND PACKAGING

PRECIPITATION

The purified sodium hyaluronate solution is transferred to the precipitation vessel, neutralized with hydrochloric acid, and then precipitated by adding pure 96% ethanol, after several deep steps of washing in watery ethanol solution.

VACUUM DRYING

The resultant precipitated product is filtered to remove excess solvent and then dried under vacuum to obtain a fine, free-flowing powder.

The production process of IBSA hyaluronic acid begins with the selection and isolation of a highly pure bacterial strain that is an overproducer of hyaluronic acid. This is followed by bacterial fermentation using culture media containing carbon sources (such as glucose or sucrose) and nitrogen sources (yeast extract, amino acids, and vegetable peptones) for the synthesis of biofermentative hyaluronic acid.

The process continues with two purification steps:

FIRST:

aims to remove the hyaluronic acid-producing microorganism through filtration and microfiltration

SECOND:

purification step uses ultrafiltration to remove contaminants co-precipitated with HA (such as DNA, proteins, and minerals).

Finally, the finishing and packaging of the finished product involve the removal of excess water, vacuum drying of the hyaluronic acid powder, and packaging.

This innovative and efficient production process ensures the creation of ultra-pure biofermentative hyaluronic acid of Italian origin, distinguished by the absence of extraction from animal sources and its high biocompatibility, thereby contributing to meeting the therapeutic needs of doctors and patients with high-quality and safe solutions.

How is it evolved

The
evolution of hyaluronic acid

from its origins to hybrid formulations

Hyaluronic acid (HA) represents a milestone in joint health and infiltrative therapy, thanks to its exceptional viscoelastic and biomechanical properties11.

Traditionally, HA was obtained from animal tissues through an extraction method. However, this method posed the risk of containing endotoxins and protein residues with potential immunogenic effects11.

Its evolution, driven by IBSA’s constant commitment to research and development, has led to the creation of innovative therapeutic solutions capable of significantly improving the quality of life for patients.

Thanks to the introduction of new production solutions and the development of new patented technologies, it has given rise to three generations of hyaluronic acid for infiltrative therapy.

ADVANCED PRODUCTION TECHNOLOGIES

The adoption of advanced production techniques, such as biofermentation, has allowed the development of linear formulations (FIRST GENERATION) based on ultra-pure Italian biofermentative hyaluronic acid, of high quality and safety.

THE HYBRID REVOLUTION

IBSA has developed and patented the innovative NAHYCO® Hybrid Technology which, through a controlled thermal process, has made it possible to obtain hybrid complexes of hyaluronic acid with high and low molecular weight, both of biofermentative origin (SECOND GENERATION).

With the use of the same technology, it was possible to combine high molecular weight hyaluronic acid and non-sulphated sodium chondroitin, a new polysaccharide of biofermentative origin and obtain combined hybrid complexes of hyaluronic acid (THIRD GENERATION).
Hybrid innovation has given rise to the development of hybrid formulations of very high concentration hyaluronic acid with a low viscosity allowing for easy extrusion from the syringe for greater patient comfort as well as improved efficacy and long lasting of the treatment.

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Products

IBSA specialises in research and development,
production and marketing of hyaluronic acid-based products.