Hyaluronic acid (HA) is a natural linear macromolecular acidic mucopolysaccharide. Its molecular chain is composed of repeated disaccharide units of D-glucuronic acid and N-acetylglucosamine. It was first isolated from the vitreous of bovine eyes in 1934 by Carl Mayer, Professor of Ophthalmology at Columbia University, USA. The molecular chain of HA contains a large number of carboxyl, hydroxyl and acetylamino groups, giving it a strong hydrophilic character. It can absorb water up to 1,000 times its own weight and is called a "biological macromolecular moisturiser". At the same time, the HA molecular chain is easily modified and can be combined with various functional molecules through covalent or non-covalent effects. It has a wide range of biomedical applications. Micro-nano gels are nano- or micron-sized cross-linked polymer particles with a three-dimensional network structure inside that can absorb water and swell. Compared to bulk gels, micro-nano gels have more diverse designs and broader applications. As one of the natural extracellular matrix components, HA has good biocompatibility, non-immunogenicity and biodegradability, so HA-based micro-nanogels have been widely studied in the fields of drug sustained release carriers, tissue engineering scaffolds, medical diagnosis, medical cosmetology, etc.
Application of Hyaluronic Acid-Based Micro-Nano Gel in the Biomedical Field
Hyaluronic acid-based micro-nano gel has the advantage of flexible and adjustable size, and can load various functional molecules through weak interactions such as hydrogen bonds or electrostatic interactions and covalent bonding. Compared with nanoparticles such as micelles, vesicles, and liposomes, micro-nano gel has a higher drug loading rate. Due to its high-water content, micro-nano gel can deform when subjected to external force, and due to the existence of internal cross-linked structure, it has a certain mechanical strength and can maintain the integrity of the structure. Therefore, hyaluronic acid-based micro-nano gel has a wide range of applications in the biomedical field.
Figure 1. Potential applications of HA nanogels. (Myint SS, et al.; 2023)
1. Facial Fillers
As the second largest non-surgical medical cosmetic injection after botulinum toxin, cross-linked sodium hyaluronate gel for injection is widely used around the world. It can repair and compensate for facial skin ageing and loss of elasticity caused by ageing. Cross-linked HA gel for injection is usually in the form of microgel, because microgel has good injectability and plasticity, which can better adapt to the face and make the treatment effect more natural and smoother. 1,4-Butanediol diglycidyl ether (BDDE) is a common cross-linking agent for this type of HA microgel. The cross-linked HA microgel can be obtained by reacting the hydroxyl groups on the HA molecular chain with the epoxy groups of the BDDE molecule. The degree of cross-linking, the concentration of the compound, etc. will affect the maintenance time of the filler. As HA is gradually degraded and absorbed in the human body over time, and with the continuous advancement of technology and people's increasing demands for products, the status of HA microgel fillers, which only play a physical filling role, has gradually been affected by some regenerative fillers, such as filler products encapsulated with left-handed polylactic acid microspheres or polycaprolactone microspheres. In both types of fillers, however, HA plays an indispensable role in immediate filling.
2. Drug Delivery
Hyaluronic acid-based micro-nano gels have been widely studied as drug sustained-release carriers. Micro-nano gels can protect drug molecules and release them locally slowly, which is beneficial to maintaining drug activity, reducing drug dosage, and avoiding side effects. Drug release can be achieved by changing the microenvironment of the lesion site to weaken the interaction between drug molecules and carrier materials, or by degradation of the micro-nano gel itself. According to the type of drug molecules, it can be divided into small molecule drug delivery and peptide drug delivery].
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Small molecule drug delivery
Since HA can specifically bind to CD44 receptors overexpressed on the surface of various tumor cells and increase the enrichment of drugs in tumor sites, HA nanogels are often used for targeted delivery of tumor drugs. However, it is very important to balance the stability of HA nanogels when circulating in the body and the release of drugs in the lesion site.
Peptide drugs have a short half-life and are easily degraded and inactivated. In order to achieve the ideal therapeutic effect, frequent administration is often required. On the one hand, HA-based micro-nanogels can bind to positively charged peptides through electrostatic interaction, and on the other hand, they can protect the activity of peptides in vivo. Therefore, they can be used as carriers for peptide drugs.
3. Cell encapsulation
Hyaluronic acid, as one of the components of the natural extracellular matrix, has good biocompatibility. Preparation methods such as emulsion method, microfluidic method, and template method are compatible with cell encapsulation. Cells can be directly encapsulated inside microgels during the preparation process to achieve cell delivery. Microgels can be further accumulated in three-dimensional space to form scaffolds. The existing microporous structure is conducive to cell extension and the delivery of nutrients. Therefore, microgel scaffolds have good application prospects in three-dimensional cell culture and the study of cell behavior. The particle size, porosity, and mechanical properties of microgels will affect cell migration and growth.
4. 3D Printing Bio-ink
The injectability of HA microgel makes it a good material for 3D printing bio-ink, which can be applied to research such as drug sustained release and tissue regeneration. The inherent properties and printing characteristics of microgels, such as extrusion continuity, shape fidelity, and mechanical stability, are important factors affecting subsequent applications.
5. Developer Loading
Microgels have a relatively regular shape and can be used for in vivo tumor diagnosis in combination with developer. How to load molecules or particles with developer functions into HA micro-nanogels is the key to such applications.
References
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Myint SS, et al.; Hyaluronic Acid Nanogels: A Promising Platform for Therapeutic and Theranostic Applications. Pharmaceutics. 2023, 15(12):2671.
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Giannitelli SM, et al.; Droplet-based microfluidic synthesis of nanogels for controlled drug delivery: tailoring nanomaterial properties via pneumatically actuated flow-focusing junction. Nanoscale. 2022, 14(31):11415-11428.
