Hyaluronic Acid & PEGylated Hyaluronic Acid

Hyaluronic acid (HA) is a non-branched polymer glycosaminoglycan composed of N-acetylglucosamine and D-glucuronic acid disaccharide repeat units through β-(1→4) glycosidic bonds and β-(1→3) glycosidic bonds. Hyaluronic acid has excellent water retention function and is known as an ideal natural moisturizing factor. Hyaluronic acid has applications in different fields, especially in healthcare, food manufacturing and cosmetics where it plays a unique role.

Structural units of hyaluronic acidFig. 1. Structural units of hyaluronic acid.

Hyaluronic Acid Preparation

Animal tissue extraction and microbial fermentation are the two most commonly used methods for producing hyaluronic acid. The tissue extraction method is used to extract hyaluronic acid from animal tissues. This method is often used in the early stage. The extraction process is complicated, the hyaluronic acid yield is low, and it is limited by the source of raw materials. With the advancement of science and technology, fermentation has become the mainstream method for industrial production of hyaluronic acid due to its advantages of low cost, high yield, and easy large-scale production.

Animal Tissue Extraction

The main raw materials for extracting hyaluronic acid from animal tissues are cockscombs and bovine eye vitreous. First of all, raw materials are often treated with acetone or ethanol, and the main steps are homogenization, defatting, and dehydration. After immersion filtration in distilled water, treatment with aqueous NaCl and chloroform solutions, and then incubation with an enzyme. Finally, the refined hyaluronic acid is obtained under the purification effect of ion exchanger. This method has extremely low extraction yield and complicated separation process, making hyaluronic acid expensive, thus limiting its widespread use.

Microbial Fermentation

Microbial fermentation is a process that uses microorganisms to convert reactants into products needed for human life production under suitable conditions through specific metabolic methods. The strains currently used in the fermentation method mainly include Streptococcus zooepidemicus, Streptococcus equi and Streptococcus equine-like Streptococcus. Among them, Streptococcus zooepidemicus is the main source of hyaluronic acid. Due to reasons such as its pathogenicity and endotoxins in the wild-type strain, it has become a common practice to modify the wild-type strain and produce hyaluronic acid through non-pathogenic strains in actual production. The main methods for processing bacterial strains include genetic engineering, mutation breeding, and protoplasmic breeding. At present, hyaluronic acid synthesis has been achieved through heterologous expression of hyaluronic acid synthase in different hosts such as Bacillus subtilis, Lactobacillus, and Corynebacterium glutamicum.

Regardless of tissue extraction or fermentation, the crude hyaluronic acid extracted contains some proteins, nucleic acids and other impurities, which need to be separated and purified to obtain high-quality hyaluronic acid. According to the principle of separation and purification, there are three main methods: precipitation, filtration and adsorption.

Hyaluronic Acid Modification

Hyaluronic acid obtained by tissue extraction and microbial fermentation has shortcomings such as poor stability, sensitivity to hyaluronidase and free radicals, easy degradation, short retention time in the body, and lack of mechanical strength in aqueous systems, which greatly limits its application. Therefore, modifying hyaluronic acid to improve its mechanical strength and anti-degradation properties has become a research hotspot.

HA modificationFig. 2. HA modification (International Journal of Biological Macromolecules. 2019, 125: 478-484).

Cross-linked Hyaluronic Acid

The cross-linking of hyaluronic acid refers to the intermolecular cross-linking reaction between hyaluronic acid and a cross-linking agent with relevant functional groups. Or use a cross-linking agent as a catalyst to cause an intramolecular cross-linking reaction to obtain molecular network structures with different degrees of cross-linking. Thus, the molecular chain of hyaluronic acid was increased, the average molecular weight was increased, the viscoelasticity was enhanced, the water solubility was relatively weakened, and the mechanical strength was increased. Commonly used cross-linking methods include hydrazide cross-linking, disulfide cross-linking, polyethylene glycol cross-linking, aldehyde cross-linking, carbodiimide cross-linking, etc.

Non Cross-Linked Hyaluronic Acid

Esterification modification, graft modification and hydrophobic modification are common methods for the preparation of non-crosslinked hyaluronic acid. The esterification modification of hyaluronic acid includes hydroxyl modification and carboxyl modification, that is, the hydroxyl group in the structure of hyaluronic acid reacts with acids or anhydrides. Or carboxyl groups react with alcohols, phenols, epoxy substances or halogenated hydrocarbons to form esterified derivatives. The grafting reaction of hyaluronic acid is to graft small molecular substances or polymers onto the main chain of hyaluronic acid. Some scholars have grafted and copolymerized hyaluronic acid and high-density polyethylene (HDPE) to prepare a biomaterial that can be used in bone tissue repair. In addition, hyaluronic acid is highly hydrophilic, often exists in the form of sodium salt, and is insoluble in most organic solvents. Therefore, it is difficult to modify or combine many hydrophobic substances. CTA-HA with strong hydrophobicity is obtained by modifying sodium hyaluronate with cetyl ammonium bromide (CTA-Br). Then, the acyl chloride-terminated polylactic acid (COL-OLA) was grafted onto CTA-HA in dimethyl sulfoxide to obtain a degradable derivative CTA-HAOLA, which could further self-assemble in aqueous solution to form hydrogels.

What Does Hyaluronic Acid Do?

Medical Field

The application of hyaluronic acid in scientific research not only helps to understand its biological properties, but also promotes the progress of medicine and life sciences, providing new solutions for research in various fields.

1. Drug delivery and sustained-release systems: Hyaluronic acid can be used as a drug delivery carrier or a component of a sustained-release system. Due to its high absorbency and biocompatibility, hyaluronic acid can be used to encapsulate and stabilize drugs for release within the body.

2. Tissue engineering: Hyaluronic acid can be combined with other degradable materials and used in tissue engineering and regenerative medicine. It acts as a scaffold or matrix, providing an environment for cells to grow and differentiate and promoting the formation of new tissue.

3. Medical devices: Hyaluronic acid can be used in a variety of material applications in the biomedical field, such as bioglues, fillers, and adhesives. It has good plasticity and biocompatibility and can be used to alleviate tissue irritation and provide mechanical support.

4. Soft matter and nanotechnology: Hyaluronic acid is widely used in soft matter and nanotechnology research. It can be used as a basic building material for the preparation of nanoparticles, nanofilms, and nanomicelles, and plays an important role in the fields of nanomedicine delivery, imaging, and biosensing.

Cosmetics and Daily Chemicals

Hyaluronic acid is abundantly present in the human body and other biological tissues and has extremely strong moisturizing properties. It is mainly used as a moisturizer, thickener, and emulsifier in cosmetics. Currently, hyaluronic acid is included in almost all types of cosmetic formulas on the market. Hyaluronic acid easily forms a hydration film on the skin to improve skin lubrication and promotes the skin's absorption of active substances. In addition, the formation of membrane can isolate bacteria to a certain extent, which is beneficial to skin anti-inflammatory and repair, and delays skin aging. In addition, because hyaluronic acid has anti-inflammatory and repairing effects in the oral cavity, and can play a certain moisturizing and functional role when added to toothpaste, the application of hyaluronic acid in daily necessities is constantly expanding and deepening.

PEGylation of Hyaluronic Acid

PEGylated hyaluronic acid is a modified form of hyaluronic acid designed to overcome the limitations of natural hyaluronic acid in various biomedical applications. There are many methods for PEGylation of hyaluronic acid, including chemical conjugation, enzymatic modification, and physical adsorption. Chemical conjugation involves the reaction of hyaluronic acid with PEG derivatives such as PEGylated succinic anhydride or PEGylated maleimide. Enzymatic modification involves the use of enzymes such as hyaluronidase or transglutaminase to catalyze the covalent attachment of PEG chains to hyaluronic acid. Physical adsorption involves mixing hyaluronic acid and PEG in solution, where PEG molecules bind to the hyaluronic acid surface through noncovalent interactions such as hydrogen bonds or electrostatic attraction.

PEGylation of hyaluronic acid nanoparticlesFig. 3. PEGylated hyaluronic acid for nanoparticles (Biomaterials. 2011, 32: 1880-1889).

PEGylation of hyaluronic acid can improve its pharmacokinetic properties, alter its physicochemical and biological properties, and improve its therapeutic efficacy, safety, and patient compliance. PEGylated hyaluronic acid has been studied for use in drug delivery, tissue engineering, and cosmetic surgery, and has shown promising results in preclinical and clinical studies.


  1. Huang, G.L. et al. Preparation and applications of hyaluronic acid and its derivatives. International Journal of Biological Macromolecules. 2019, 125: 478-484.
  2. Choi, K.Y. et al. PEGylation of hyaluronic acid nanoparticles improves tumor targetability in vivo. Biomaterials. 2011, 32: 1880-1889.

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