In the complex microscopic world of the human body, hyaluronic acid (HA) was long regarded as a simple “space filler”—an inactive polysaccharide that gives skin its plumpness and lubricates joints. However, with the vigorous development of bioengineering, scientists are re-examining this native molecule from an unprecedented perspective. Hyaluronic acid, a biological polymer synthesized by the human body itself, is being engineered into intelligent biomaterials that guide cellular behavior and promote tissue reconstruction, opening a new chapter in regenerative medicine.
The Ideal Biomaterial
Hyaluronic acid has become a star material in the field of tissue engineering due to its inherent biological advantages. It is a linear macromolecular polysaccharide composed of repeating disaccharide units of D-glucuronic acid and N-acetylglucosamine. In the human body, it is widely present in the extracellular matrix, skin, synovial fluid, and vitreous humor of the eye. Its primary appeal lies in its exceptional biocompatibility and biodegradability. As an intrinsic component of the body, HA rarely triggers immune rejection or inflammatory responses and can be naturally metabolized by hyaluronidases in vivo, eliminating the need for secondary surgical removal. Secondly, its molecular chains are rich in active groups such as hydroxyl and carboxyl groups, which act like natural “chemical handles,” facilitating various modifications and functional grafting, offering great flexibility for engineering. Furthermore, HA hydrogels can mimic many physical and biochemical characteristics of the natural extracellular matrix, providing cells with a hydrophilic, flexible three-dimensional microenvironment crucial for maintaining normal cellular function and transmitting mechanical and biochemical signals.
Engineering Transformation: From Passive Scaffold to Active Guidance
Traditional biomaterials often play only a passive physical support role. The core of the bioengineering application of hyaluronic acid lies in transforming it, through chemical modifications and advanced manufacturing techniques, into an intelligent system capable of actively “communicating” with cells and dynamically responding to changes in the microenvironment.
Precise modulation of mechanical properties is the primary challenge. Natural HA hydrogels are often weak in strength and degrade too quickly. Through crosslinking technologies—such as using divinyl sulfone, aldehydes, or more advanced “click chemistry” methods—the porosity, elastic modulus, and degradation rate of the gel can be precisely controlled. For example, by adjusting the crosslinking density, hydrogels simulating the soft properties of brain tissue for nerve repair, or scaffolds with greater load-bearing capacity for cartilage regeneration, can be manufactured. Combining HA with collagen, silk fibroin, or synthetic polymers (such as poly(lactic-co-glycolic acid), PLGA) can further synergistically optimize mechanical properties and bioactivity.
Functionalization and empowerment transform HA scaffolds from an “empty house” into a “fully furnished home.” By covalently conjugating specific cell-adhesive peptides (such as the RGD sequence), cell adhesion, spreading, and migration on the material can be significantly enhanced. More sophisticated approaches involve tethering growth factors (e.g., vascular endothelial growth factor, VEGF, for vascularization; transforming growth factor-β3 for chondrogenesis) or small-molecule drugs (e.g., anti-inflammatory drugs) to the HA network via cleavable bonds, enabling their controlled, sustained release at the lesion site, delivering the right biological signals at the right time and place.
Cutting-edge research is moving towards dynamic and responsive systems. For instance, designing HA hydrogels crosslinked with linkages sensitive to specific enzymes (overexpressed at tumor or inflammatory sites), enabling their intelligent degradation and therapeutic agent release at target locations. 4D bioprinting technology introduces the time dimension, where constructs printed using HA-based bioinks can undergo pre-programmed shape or structural transformations under physiological conditions to better match complex defect morphologies.
Application Frontiers: Regenerative Practices Across Tissues
Intelligent HA-based biomaterials have demonstrated significant potential in multiple tissue repair fields.
In skin regeneration and wound healing, HA dressings not only maintain a moist environment but their oligosaccharide fragments can actively modulate inflammation, promote the migration and proliferation of keratinocytes and fibroblasts, and accelerate the healing of chronic refractory ulcers (such as diabetic foot ulcers). Functionalized HA hydrogels can serve as delivery vehicles for growth factors (e.g., EGF, bFGF), spatiotemporally regulating the healing process.
In the field of cartilage and bone tissue engineering, HA is a natural candidate. It is an important component of the articular cartilage matrix itself. Crosslinked HA hydrogels can serve as carriers for bone marrow mesenchymal stem cells, implanted into articular cartilage defects, providing mechanical support while delivering signals that induce chondrogenic differentiation. In bone repair, although HA lacks sufficient mechanical strength, when combined with hydroxyapatite, calcium phosphate ceramics, and others, the resulting scaffolds offer good osteoconductivity, and their degradation products can promote vascular ingrowth, facilitating “creeping substitution.”
Nerve regeneration is another arena where HA demonstrates its unique advantages. Its soft properties closely match those of central nervous tissue. Filling spinal cord injury cavities with HA hydrogels can provide a permissive physical channel for nerve axon regeneration. If further loaded with neurotrophic factors (e.g., BDNF, NT-3) or seeded with Schwann cells, it can significantly promote axon extension and functional recovery.
Furthermore, in angiogenesis, adipose tissue engineering, corneal repair, and even cutting-edge models like organoid construction and drug screening, customizable HA microenvironments play irreplaceable roles.
Challenges and Future Perspectives
Despite the promising prospects, the bioengineering application of hyaluronic acid still faces challenges. How to more accurately simulate the dynamic heterogeneity of the natural extracellular matrix and achieve the ordered delivery of multiple signals remains a core difficulty in material design. Quality control in large-scale production, the impact of sterilization processes on material properties, and long-term in vivo safety and efficacy evaluations are hurdles that must be overcome for clinical translation.
In the future, research on hyaluronic acid will integrate more deeply with principles from cell biology and developmental biology. We can expect the emergence of more complex “cell-instructive” HA materials that can dynamically present differential adhesion ligands, mechanical signals, and growth factors according to different stages of repair, precisely guiding stem cell fate and orderly tissue regeneration. The concept of personalized medicine will also be incorporated. Perhaps in the future, it will be possible to use a patient’s own cells and customized HA bioinks to pre-fabricate viable transplant tissues in vitro.
From a simple moisturizing ingredient to an intelligent conductor of tissue regeneration, the journey of hyaluronic acid vividly illustrates the allure of bioengineering: deeply understanding the fundamental components of life and applying engineering wisdom to redesign and reassemble them to address major challenges in human health. On the path to unraveling the mysteries of tissue regeneration, this “transparent” matrix, originating from life itself, is outlining an increasingly clear and vibrant vision of the future for us.
