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  • Review Article
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Interaction-driven classification of hyaluronic acid products

Nature Reviews Bioengineering volume 4, pages 269–286 (2026) Cite this article

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Abstract

Hyaluronic acid (HyA), also known as hyaluronan or hyaluronate in its salt form, is a linear glycosaminoglycan biopolymer that has been used in therapeutics and biomaterials engineering owing to its abundant distribution in biological tissues and diverse roles in biological processes. The well-established biocompatibility of HyA has facilitated its adoption in numerous medical devices, particularly in reconstructive surgery and tissue regeneration applications. The interactions of HyA with cells and their respective surface receptors across tissues throughout the body mediate the effects of the former in the context of development, wound healing, tissue repair and regeneration. In this Review, we address the impact of HyA on tissue regeneration and discuss muscle injuries as an example in which strategies for HyA-based products could enhance muscle’s intrinsic regenerative capabilities. Finally, we consider the evolving regulatory oversight of HyA-based products by the Food and Drug Administration in the context of the roles of HyA in biological processes to understand these products’ putative modes of action. Deeper understanding of the mechanism of action of HyA in the body can inform the regulatory classification of future HyA-based products.

Key points

  • Hyaluronic acid (HyA) is a glycosaminoglycan that interacts with a wide variety of cell types derived from all three germ layers in the human body, mediating its effects through seven major cell-surface receptors.

  • These HyA–cell surface interactions are crucial for modulating a range of cellular behaviours, including adhesion, migration and proliferation, underscoring HyA’s role in tissue homeostasis and repair.

  • The molecular weight and physical properties of HyA determine its function within the body. These characteristics dictate its behaviour, influencing whether HyA acts as a structural scaffold, a signalling molecule or a space-filling agent in various tissues.

  • The inherent biocompatibility of minimally modified HyA has enabled its widespread use as a device in clinical applications across ophthalmology; orthopaedics; surgery; dentistry; ear, nose and throat; neurology; gynaecology; and urology.

  • HyA plays a critical role in endogenous wound healing and skeletal muscle repair, making it an exceptionally promising material for developing advanced therapies aimed at the repair and regeneration of damaged tissues, particularly in cases of severe injury or disease.

  • The Food and Drug Administration’s notice that new HyA-based products, or new indications for HyA products for intra-articular injection for pain relief in osteoarthritis, may be classified as drugs rather than devices, based on data showing they achieved their primary intended purpose via chemical action, highlights the need for deeper mechanistic understanding of HyA products.

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Fig. 1: HyA tertiary structure, biological function and physical properties according to molecular weight.
The alternative text for this image may have been generated using AI.
Fig. 2: HyA–cell receptor binding interactions and signalling pathways.
The alternative text for this image may have been generated using AI.

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References

  1. Bukhari, S. N. A. et al. Hyaluronic acid, a promising skin rejuvenating biomedicine: a review of recent updates and pre-clinical and clinical investigations on cosmetic and nutricosmetic effects. Int. J. Biol. Macromol. 120, 1682–1695 (2018).

    Article  Google Scholar 

  2. Papakonstantinou, E., Roth, M. & Karakiulakis, G. Hyaluronic acid: a key molecule in skin aging. Dermato-Endocrinology 4, 253–258 (2012).

    Article  Google Scholar 

  3. Ucm, R. et al. Comprehensive review on biotechnological production of hyaluronic acid: status, innovation, market and applications. Bioengineered 13, 9645–9661 (2022).

    Article  Google Scholar 

  4. Gupta, R. C., Lall, R., Srivastava, A. & Sinha, A. Hyaluronic acid: molecular mechanisms and therapeutic trajectory. Front. Vet. Sci. https://doi.org/10.3389/fvets.2019.00192 (2019).

  5. Prosdocimi, M. & Bevilacqua, C. Exogenous hyaluronic acid and wound healing: an updated vision. Panminerva Med. 54, 129–135 (2012).

    Google Scholar 

  6. Marinho, A., Nunes, C. & Reis, S. Hyaluronic acid: a key ingredient in the therapy of inflammation. Biomolecules 11, 1518 (2021).

    Article  Google Scholar 

  7. Allison, D. D., Braun, K. R., Wight, T. N. & Grande-Allen, K. J. Differential effects of exogenous and endogenous hyaluronan on contraction and strength of collagen gels. Acta Biomater. 5, 1019–1026 (2009).

    Article  Google Scholar 

  8. Chao, H. & Spicer, A. P. Natural antisense mRNAs to hyaluronan synthase 2 inhibit hyaluronan biosynthesis and cell proliferation. J. Biol. Chem. 280, 27513–27522 (2005).

    Article  Google Scholar 

  9. Webber, J., Jenkins, R. H., Meran, S., Phillips, A. & Steadman, R. Modulation of TGFβ1-dependent myofibroblast differentiation by hyaluronan. Am. J. Pathol. 175, 148–160 (2009).

    Article  Google Scholar 

  10. Nishida, Y., Knudson, W., Knudson, C. B. & Ishiguro, N. Antisense inhibition of hyaluronan synthase-2 in human osteosarcoma cells inhibits hyaluronan retention and tumorigenicity. Exp. Cell Res. 307, 194–203 (2005).

    Article  Google Scholar 

  11. Valachová, K., Hassan, M. E. & Šoltés, L. Hyaluronan: sources, structure, features and applications. Molecules 29, 739 (2024).

    Article  Google Scholar 

  12. Scheibner, K. A. et al. Hyaluronan fragments act as an endogenous danger signal by engaging TLR2. J. Immunol. 177, 1272–1281 (2006).

    Article  Google Scholar 

  13. Ferreira, N. D. R., Sanz, C. K., Raybolt, A., Pereira, C. M. & DosSantos, M. F. Action of hyaluronic acid as a damage-associated molecular pattern molecule and its function on the treatment of temporomandibular disorders. Front. Pain Res. 3, 852249 (2022).

    Article  Google Scholar 

  14. Cyphert, J. M., Trempus, C. S. & Garantziotis, S. Size matters: molecular weight specificity of hyaluronan effects in cell biology. Int. J. Cell Biol. 2015, 563818 (2015).

    Article  Google Scholar 

  15. Karam, J. et al. Molecular weight of hyaluronic acid crosslinked into biomaterial scaffolds affects angiogenic potential. Acta Biomater. 169, 228–242 (2023).

    Article  Google Scholar 

  16. Powell, J. D. & Horton, M. R. Threat matrix. Immunol. Res. 31, 207–218 (2005).

    Article  Google Scholar 

  17. Taylor, K. R. et al. Recognition of hyaluronan released in sterile injury involves a unique receptor complex dependent on Toll-like receptor 4, CD44, and MD-2. J. Biol. Chem. 282, 18265–18275 (2007).

    Article  Google Scholar 

  18. Jiang, D., Liang, J. & Noble, P. W. Hyaluronan as an immune regulator in human diseases. Physiol. Rev. 91, 221–264 (2011).

    Article  Google Scholar 

  19. Snetkov, P., Zakharova, K., Morozkina, S., Olekhnovich, R. & Uspenskaya, M. Hyaluronic acid: the influence of molecular weight on structural, physical, physico-chemical, and degradable properties of biopolymer. Polymers 12, 1800 (2020). This article includes a survey of HyA literature to explore how HyA molecular weight impacts the polymer’s physico-chemical, structural, rheological and degradation properties.

    Article  Google Scholar 

  20. Nicholls, M., Manjoo, A., Shaw, P., Niazi, F. & Rosen, J. Rheological properties of commercially available hyaluronic acid products in the united states for the treatment of osteoarthritis knee pain. Clin. Med. Insights Arthritis Musculoskelet. Disord. 11, 1179544117751622 (2018).

    Article  Google Scholar 

  21. Zavan, B. et al. Hyaluronic acid induces activation of the κ-opioid receptor. PLoS One 8, e55510 (2013).

    Article  Google Scholar 

  22. Lim, J., Machin, D. R. & Donato, A. J. The role of hyaluronan in endothelial glycocalyx and potential preventative lifestyle strategy with advancing age. Curr. Top. Membr. 91, 139–156 (2023).

    Article  Google Scholar 

  23. Dogné, S. & Flamion, B. Endothelial glycocalyx impairment in disease: focus on hyaluronan shedding. Am. J. Pathol. 190, 768–780 (2020).

    Article  Google Scholar 

  24. Hardingham, T. I. M. in Chemistry and Biology of Hyaluronan (eds Garg, H. G. & Hales, C. A.) 1–19 (Elsevier, 2004).

  25. Giubertoni, G., Burla, F., Bakker, H. J. & Koenderink, G. H. Connecting the stimuli-responsive rheology of biopolymer hydrogels to underlying hydrogen-bonding interactions. Macromolecules 53, 10503–10513 (2020).

    Article  Google Scholar 

  26. Fundarò, S. P., Salti, G., Malgapo, D. M. H. & Innocenti, S. The rheology and physicochemical characteristics of hyaluronic acid fillers: their clinical implications. Int. J. Mol. Sci. 23, 10518 (2022).

    Article  Google Scholar 

  27. Svedlund, F. L., Altiok, E. I. & Healy, K. E. Branching analysis of multivalent conjugates using size exclusion chromatography–multiangle light scattering. Biomacromolecules 17, 3162–3171 (2016).

    Article  Google Scholar 

  28. Wolf, K. J. & Kumar, S. Hyaluronic acid: incorporating the bio into the material. ACS Biomater. Sci. Eng. 5, 3753–3765 (2019).

    Article  Google Scholar 

  29. Haward, S. J., Jaishankar, A., Oliveira, M. S., Alves, M. A. & McKinley, G. H. Extensional flow of hyaluronic acid solutions in an optimized microfluidic cross-slot device. Biomicrofluidics 7, 044108 (2013).

    Article  Google Scholar 

  30. Sneath, R. J. & Mangham, D. C. The normal structure and function of CD44 and its role in neoplasia. Mol. Pathol. 51, 191–200 (1998). This review by Sneath and Mangham provides an in-depth examination into the structure, isoforms and varied physiological roles of CD44, including its interactions with HyA and potential role in cancer metastasis.

    Article  Google Scholar 

  31. Harris, E. N. & Baker, E. Role of the hyaluronan receptor, stabilin-2/HARE, in health and disease. Int. J. Mol. Sci. https://doi.org/10.3390/ijms21103504 (2020). Harris and Baker review the molecular structure, clearance roles, signalling functions and ligand interactions of stabilin-2/HARE, the principal receptor for the systematic removal of HyA, and examine the influence of this removal in health and disease contexts.

  32. Misra, S., Hascall, V. C., Markwald, R. R. & Ghatak, S. Interactions between hyaluronan and its receptors (CD44, RHAMM) regulate the activities of inflammation and cancer. Front. Immunol. 6, 201 (2015). Misra et al. review the dynamic relationship between varying the molecular weight of HyAs and binding to HyA receptors CD44 and RHAMM, particularly in the context of inflammation and tumour progression.

    Article  Google Scholar 

  33. Wu, M. et al. Low molecular weight hyaluronan induces lymphangiogenesis through LYVE-1-mediated signaling pathways. PLoS One 9, e92857 (2014).

    Article  Google Scholar 

  34. Arrighi, N. et al. Characterization of adipocytes derived from fibro/adipogenic progenitors resident in human skeletal muscle. Cell Death Dis. 6, e1733 (2015).

    Article  Google Scholar 

  35. Bonet, I. J. M. et al. Mechanisms mediating high-molecular-weight hyaluronan-induced antihyperalgesia. J. Neurosci. 40, 6477–6488 (2020).

    Article  Google Scholar 

  36. Ferrari, L. F., Khomula, E. V., Araldi, D. & Levine, J. D. CD44 signaling mediates high molecular weight hyaluronan-induced antihyperalgesia. J. Neurosci. 38, 308–321 (2018).

    Article  Google Scholar 

  37. Caires, R. et al. Hyaluronan modulates TRPV1 channel opening, reducing peripheral nociceptor activity and pain. Nat. Commun. 6, 8095 (2015).

    Article  Google Scholar 

  38. Altman, R. D., Dasa, V. & Takeuchi, J. Review of the mechanism of action for Supartz FX in knee osteoarthritis. Cartilage 9, 11–20 (2018).

    Article  Google Scholar 

  39. Termeer, C. et al. Oligosaccharides of hyaluronan activate dendritic cells via Toll-like receptor 4. J. Exp. Med. 195, 99–111 (2002).

    Article  Google Scholar 

  40. Jiang, D., Liang, J. & Noble, P. W. Hyaluronan in tissue injury and repair. Annu. Rev. Cell Dev. Biol. 23, 435–461 (2007).

    Article  Google Scholar 

  41. Rudzki, Z. & Jothy, S. CD44 and the adhesion of neoplastic cells. Mol. Pathol. 50, 57–71 (1997).

    Article  Google Scholar 

  42. Underhill, C. CD44: the hyaluronan receptor. J. Cell Sci. 103, 293–298 (1992).

    Article  Google Scholar 

  43. Bhattacharya, D. et al. Impact of structurally modifying hyaluronic acid on CD44 interaction. J. Mater. Chem. B 5, 8183–8192 (2017).

    Article  Google Scholar 

  44. Ren, C. L., Carvajal, D., Shull, K. R. & Szleifer, I. Streptavidin–biotin binding in the presence of a polymer spacer. A theoretical description. Langmuir 25, 12283–12292 (2009).

    Article  Google Scholar 

  45. Underhill, C. B. Interaction of hyaluronate with the surface of simian virus 40-transformed 3t3 cells: aggregation and binding studies. J. Cell Sci. 56, 177–189 (1982).

    Article  Google Scholar 

  46. Bartolazzi, A., Nocks, A., Aruffo, A., Spring, F. & Stamenkovic, I. Glycosylation of CD44 is implicated in CD44-mediated cell adhesion to hyaluronan. J. Cell Biol. 132, 1199–1208 (1996).

    Article  Google Scholar 

  47. Katoh, S., Zheng, Z., Oritani, K., Shimozato, T. & Kincade, P. W. Glycosylation of CD44 negatively regulates its recognition of hyaluronan. J. Exp. Med. 182, 419–429 (1995).

    Article  Google Scholar 

  48. Schmitt, M., Metzger, M., Gradl, D., Davidson, G. & Orian-Rousseau, V. CD44 functions in Wnt signaling by regulating LRP6 localization and activation. Cell Death Differ. 22, 677–689 (2015).

    Article  Google Scholar 

  49. Jain, M. et al. Role of CD44 in the reaction of vascular smooth muscle cells to arterial wall injury. J. Clin. Investig. 97, 596–603 (1996).

    Article  Google Scholar 

  50. Nedvetzki, S. et al. RHAMM, a receptor for hyaluronan-mediated motility, compensates for CD44 in inflamed CD44-knockout mice: a different interpretation of redundancy. Proc. Natl Acad. Sci. USA 101, 18081–18086 (2004).

    Article  Google Scholar 

  51. Politz, O. et al. Stabilin-1 and -2 constitute a novel family of fasciclin-like hyaluronan receptor homologues. Biochem. J. 362, 155–164 (2002).

    Article  Google Scholar 

  52. Zhou, B., Weigel, J. A., Fauss, L. & Weigel, P. H. Identification of the hyaluronan receptor for endocytosis (HARE). J. Biol. Chem. 275, 37733–37741 (2000).

    Article  Google Scholar 

  53. Blundell, C. D. et al. Towards a structure for a TSG-6.hyaluronan complex by modeling and NMR spectroscopy: insights into other members of the link module superfamily. J. Biol. Chem. 280, 18189–18201 (2005).

    Article  Google Scholar 

  54. Weigel, P. H. & Yik, J. H. N. Glycans as endocytosis signals: the cases of the asialoglycoprotein and hyaluronan/chondroitin sulfate receptors. Biochimic. Biophys. Acta 1572, 341–363 (2002).

    Article  Google Scholar 

  55. Hirose, Y. et al. Inhibition of Stabilin-2 elevates circulating hyaluronic acid levels and prevents tumor metastasis. Proc. Natl Acad. Sci. USA 109, 4263–4268 (2012).

    Article  Google Scholar 

  56. Fraser, J. R. E. & Laurent, T. C. in The Biology of Hyaluronan: Ciba Foundation Symposium 143 (eds Evered, D. & Whelan, J.) 41–53 (Wiley, 1989).

  57. Qian, H. et al. Stabilins are expressed in bone marrow sinusoidal endothelial cells and mediate scavenging and cell adhesive functions. Biochem. Biophys. Res. Commun. 390, 883–886 (2009).

    Article  Google Scholar 

  58. Lehka, L. & Rędowicz, M. J. Mechanisms regulating myoblast fusion: a multilevel interplay. Semin. Cell Dev. Biol. 104, 81–92 (2020).

    Article  Google Scholar 

  59. Park, S.-Y. et al. Stabilin-2 modulates the efficiency of myoblast fusion during myogenic differentiation and muscle regeneration. Nat. Commun. 7, 10871 (2016).

    Article  Google Scholar 

  60. Jackson, D. G. Hyaluronan in the lymphatics: the key role of the hyaluronan receptor LYVE-1 in leucocyte trafficking. Matrix Biol. 78-79, 219–235 (2019). This review integrates literature on the structural biology of LYVE1, immune cell migration and immune cell models to explore how HyA binding to LYVE1 mediates leukocyte trafficking in the body.

    Article  Google Scholar 

  61. Banerji, S., Hide, B. R. S., James, J. R., Noble, M. E. M. & Jackson, D. G. Distinctive properties of the hyaluronan-binding domain in the lymphatic endothelial receptor LYVE-1 and their implications for receptor function. J. Biol. Chem. 285, 10724–10735 (2010).

    Article  Google Scholar 

  62. Lawrance, W., Banerji, S., Day, A. J., Bhattacharjee, S. & Jackson, D. G. Binding of hyaluronan to the native lymphatic vessel endothelial receptor LYVE-1 is critically dependent on receptor clustering and hyaluronan organization. J. Biol. Chem. 291, 8014–8030 (2016).

    Article  Google Scholar 

  63. Bono, P., Rubin, K., Higgins, J. M. G. & Hynes, R. O. Layilin, a novel integral membrane protein, is a hyaluronan receptor. Mol. Biol. Cell 12, 891–900 (2001).

    Article  Google Scholar 

  64. Borowsky, M. L. & Hynes, R. O. Layilin, a novel talin-binding transmembrane protein homologous with C-type lectins, is localized in membrane ruffles. J. Cell Biol. 143, 429–442 (1998).

    Article  Google Scholar 

  65. Brissett, N. C. & Perkins, S. J. The protein fold of the hyaluronate-binding proteoglycan tandem repeat domain of link protein, aggrecan and CD44 is similar to that of the C-type lectin superfamily. FEBS Lett. 388, 211–216 (1996).

    Article  Google Scholar 

  66. Bono, P. et al. Layilin, a cell surface hyaluronan receptor, interacts with merlin and radixin. Exp. Cell Res. 308, 177–187 (2005).

    Article  Google Scholar 

  67. Ohashi, K., Burkart, V., Flohé, S. & Kolb, H. Cutting edge: heat shock protein 60 is a putative endogenous ligand of the toll-like receptor-4 complex. J. Immunol. 164, 558–561 (2000).

    Article  Google Scholar 

  68. Byrd-Leifer, C. A., Block, E. F., Takeda, K., Akira, S. & Ding, A. The role of MyD88 and TLR4 in the LPS-mimetic activity of Taxol. Eur. J. Immunol. 31, 2448–2457 (2001).

    Article  Google Scholar 

  69. Matzinger, P. The danger model: a renewed sense of self. Science 296, 301–305 (2002).

    Article  Google Scholar 

  70. Stenson, W. F. & Ciorba, M. A. Nonmicrobial activation of TLRs controls intestinal growth, wound repair, and radioprotection. Front. Immunol. 11, 617510 (2020).

    Article  Google Scholar 

  71. Garantziotis, S. & Savani, R. C. Hyaluronan biology: a complex balancing act of structure, function, location and context. Matrix Biol. 78-79, 1–10 (2019).

    Article  Google Scholar 

  72. Fallacara, A., Baldini, E., Manfredini, S. & Vertuani, S. Hyaluronic acid in the third millennium. Polymers 10, 701 (2018).

    Article  Google Scholar 

  73. Liesegang, T. J. Viscoelastic substances in ophthalmology. Surv. Ophthalmol. 34, 268–293 (1990).

    Article  Google Scholar 

  74. Yasin, A. et al. Advances in hyaluronic acid for biomedical applications. Front. Bioeng. Biotechnol. https://doi.org/10.3389/fbioe.2022.910290 (2022).

  75. Goa, K. L. & Benfield, P. Hyaluronic acid. Drugs 47, 536–566 (1994).

    Article  Google Scholar 

  76. Pape, L. G. & Balazs, E. A. The use of sodium hyaluronate (Healon®) in human anterior segment surgey. Ophthalmology 87, 699–705 (1980).

    Article  Google Scholar 

  77. Abatangelo, G., Vindigni, V., Avruscio, G., Pandis, L. & Brun, P. Hyaluronic acid: redefining its role. Cells 9, 1743 (2020).

    Article  Google Scholar 

  78. Zhang, X., Wei, D., Xu, Y. & Zhu, Q. Hyaluronic acid in ocular drug delivery. Carbohydr. Polym. 264, 118006 (2021).

    Article  Google Scholar 

  79. Ishijima, M. et al. Intra-articular hyaluronic acid injection versus oral non-steroidal anti-inflammatory drug for the treatment of knee osteoarthritis: a multi-center, randomized, open-label, non-inferiority trial. Arthritis Res. Ther. 16, R18 (2014).

    Article  Google Scholar 

  80. Cooper, C. et al. Use of intraarticular hyaluronic acid in the management of knee osteoarthritis in clinical practice. Arthritis Care Res. 69, 1287–1296 (2017).

    Article  Google Scholar 

  81. Hermans, J. et al. The effectiveness of high molecular weight hyaluronic acid for knee osteoarthritis in patients in the working age: a randomised controlled trial. BMC Musculoskelet. Disord. 20, 196 (2019).

    Article  Google Scholar 

  82. Sprott, H. & Fleck, C. Hyaluronic acid in rheumatology. Pharmaceutics 15, 2247 (2023).

    Article  Google Scholar 

  83. Recommendations for the medical management of osteoarthritis of the hip and knee: 2000 update. American college of rheumatology subcommittee on osteoarthritis guidelines. Arthritis Rheumatol. 43, 1905–1915 (2000).

  84. Vincent, P. Intra-articular hyaluronic acid in knee osteoarthritis: clinical data for a product family (ARTHRUM), with comparative meta-analyses. Curr. Ther. Res. 95, 100637 (2021).

    Article  Google Scholar 

  85. Badylak, S. F. The integrity™ implant: healing response to a hyaluronic acid-based synthetic scaffold for tendon augmentation (ANIKA, 2022).

  86. Becker, J. M. et al. Prevention of postoperative abdominal adhesions by a sodium hyaluronate-based bioresorbable membrane: a prospective, randomized, double-blind multicenter study. J. Am. Coll. Surg. 183, 297–306 (1996).

    Google Scholar 

  87. Diamond, M. P. Reduction of adhesions after uterine myomectomy by Seprafilm membrane (HAL-F): a blinded, prospective, randomized, multicenter clinical study. Seprafilm Adhesion Study. Fertil. Steril. 66, 904–910 (1996).

    Article  Google Scholar 

  88. Longinotti, C. The use of hyaluronic acid based dressings to treat burns: A review. Burns Trauma 2, 162–168 (2014).

    Article  Google Scholar 

  89. Roehrs, H. et al. Dressings and topical agents containing hyaluronic acid for chronic wound healing. Cochrane Database Syst. Rev. https://doi.org/10.1002/14651858.CD012215.pub2 (2023).

    Article  Google Scholar 

  90. Graça, M. F. P., Miguel, S. P., Cabral, C. S. D. & Correia, I. J. Hyaluronic acid—based wound dressings: a review. Carbohydr. Polym. 241, 116364 (2020).

    Article  Google Scholar 

  91. Gravante, G. et al. The use of hyalomatrix PA in the treatment of deep partial-thickness burns. J. Burn Care Res. 28, 269–274 (2007).

    Article  Google Scholar 

  92. Bogdan Allemann, I. & Baumann, L. Hyaluronic acid gel (Juvéderm) preparations in the treatment of facial wrinkles and folds. Clin. Interv. Aging 3, 629–634 (2008).

    Article  Google Scholar 

  93. Choi, M. S. Basic rheology of dermal filler. Arch. Plast. Surg. 47, 301–304 (2020).

    Article  Google Scholar 

  94. Rohrich, R. J., Bartlett, E. L. & Dayan, E. Practical approach and safety of hyaluronic acid fillers. Plast. Reconstr. Surg. Glob. Open. 7, e2172 (2019).

    Article  Google Scholar 

  95. Casale, M. et al. Hyaluronic acid: perspectives in dentistry. A systematic review. Int. J. Immunopathol. Pharmacol. 29, 572–582 (2016).

    Article  Google Scholar 

  96. Miglani, A., Vishnani, R., Reche, A., Buldeo, J. & Wadher, B. Hyaluronic acid: exploring its versatile applications in dentistry. Cureus https://doi.org/10.7759/cureus.46349 (2023).

    Article  Google Scholar 

  97. Ballini, A., Cantore, S., Capodiferro, S. & Grassi, F. R. Esterified hyaluronic acid and autologous bone in the surgical correction of the infra-bone defects. Int. J. Med. Sci. 6, 65–71 (2009).

    Article  Google Scholar 

  98. Ostos-Aguilar, B. I., Pinheiro Furquim, C., Muniz, F. W. M. G., Faveri, M. & Meza-Mauricio, J. Clinical efficacy of hyaluronic acid in the treatment of periodontal intrabony defect: a systematic review and meta-analysis. Clin. Oral Investig. 27, 1923–1935 (2023).

    Article  Google Scholar 

  99. Hashem, A. S., Issrani, R., Elsayed, T. E. E. & Prabhu, N. Topical hyaluronic acid in the management of oral lichen planus: a comparative study. J. Investig. Clin. Dent. 10, e12385 (2019).

    Article  Google Scholar 

  100. Lee, J., Jung, J. & Bang, D. The efficacy of topical 0.2% hyaluronic acid gel on recurrent oral ulcers: comparison between recurrent aphthous ulcers and the oral ulcers of Behçet’s disease. J. Eur. Acad. Dermatol. Venereol. 22, 590–595 (2008).

    Article  Google Scholar 

  101. Kumar, R. et al. Efficacy of hyaluronic acid (hyaluronan) in root coverage procedures as an adjunct to coronally advanced flap in Millers Class I recession: a clinical study. J. Indian. Soc. Periodontol. 18, 746–750 (2014).

    Article  Google Scholar 

  102. Cervino, G. et al. Surface treatment of the dental implant with hyaluronic acid: an overview of recent data. J. Environ. Res. Public Health 18, 4670 (2021).

    Article  Google Scholar 

  103. Silva, C. R. et al. Injectable and tunable hyaluronic acid hydrogels releasing chemotactic and angiogenic growth factors for endodontic regeneration. Acta Biomater. 77, 155–171 (2018).

    Article  Google Scholar 

  104. Alhowaish, N. A., Alsudani, D. I. & Almuraikhi, N. A. Evaluation of a hyaluronic acid hydrogel (Restylane Lyft) as a scaffold for dental pulp regeneration in a regenerative endodontic organotype model. Odontology 110, 726–734 (2022).

    Article  Google Scholar 

  105. Tremolati, M. et al. Clinical performance evaluation of a hyaluronic acid dental gel for the treatment of traumatic ulcers in patients with fixed orthodontic appliances: a randomized controlled trial. Bioengineering 9, 761 (2022).

    Article  Google Scholar 

  106. Lin, J. C. March 22, 2023 — Food and Drug Administration. Food and Drug Administration 510(k) Premarket Database https://www.accessdata.fda.gov/cdrh_docs/pdf23/K230142.pdf (2023).

  107. Dwyer, C. D. et al. Silk-hyaluronic acid for vocal fold augmentation: safety profile and long-term voice outcomes. J. Voice https://doi.org/10.1016/j.jvoice.2024.02.025 (2024).

    Article  Google Scholar 

  108. Švejdová, A. et al. Injection laryngoplasty with hyaluronic acid for glottal insufficiency in unilateral vocal fold paralysis: a systematic review of the literature. Eur. Arch. Otorhinolaryngol. 279, 5071–5079 (2022).

    Article  Google Scholar 

  109. Yilmaz, M. S. et al. Histological study of the healing of traumatic tympanic membrane perforation after vivosorb and epifilm application. Ear Nose Throat J. 100, 90–96 (2021).

    Article  Google Scholar 

  110. Sayin, I., Kaya, K. H., Ekizoğlu, O., Erdim, I. & Kayhan, F. T. A prospective controlled trial comparing spontaneous closure and Epifilm® patching in traumatic tympanic membrane perforations. Eur. Arch. Otorhinolaryngol. 270, 2857–2863 (2013).

    Article  Google Scholar 

  111. Hones, K. M. et al. Outcomes following use of versawrap nerve protector in treatment of patients with recurrent compressive neuropathies. Front. Surg. 10, 1123375 (2023).

    Article  Google Scholar 

  112. Martens, M. G. INTERGEL® adhesion prevention solution reduces reformed and de novo adhesions as well as adhesions to the surgical site in women undergoing conservative surgery. Fertil. Steril. 74, S199 (2000).

    Article  Google Scholar 

  113. Johns, D. B., Keyport, G. M., Hoehler, F. & diZerega, G. S. Reduction of postsurgical adhesions with intergel® adhesion prevention solution: a multicenter study of safety and efficacy after conservative gynecologic surgery. Fertil. Steril. 76, 595–604 (2001).

    Article  Google Scholar 

  114. Oguz, F. et al. Efficacy and safety of hyadex for treatment of vesicoureteral reflux: a multicenter experience. J. Int. Med. Res. https://doi.org/10.1177/03000605231195165 (2023).

  115. Stenbäck, A. et al. Proprietary non-animal stabilized hyaluronic acid/dextranomer gel (NASHA/Dx) for endoscopic treatment of grade IV vesicoureteral reflux: long-term observational study. J. Pediatr. Urol. 16, 328.e1–328.e9 (2020).

    Article  Google Scholar 

  116. Kirsch, A. J., Perez-Brayfield, M., Smith, E. A. & Scherz, H. C. The modified sting procedure to correct vesicoureteral reflux: improved results with submucosal implantation within the intramural ureter. J. Urol. 171, 2413–2416 (2004).

    Article  Google Scholar 

  117. Garcia-Aparicio, L. et al. Randomized clinical trial comparing endoscopic treatment with dextranomer hyaluronic acid copolymer and Cohen’s ureteral reimplantation for vesicoureteral reflux: long-term results. J. Pediatr. Urol. 9, 483–487 (2013).

    Article  Google Scholar 

  118. Dienes, J. et al. Semisynthetic hyaluronic acid-based hydrogel promotes recovery of the injured tibialis anterior skeletal muscle form and function. ACS Biomater. Sci. Eng. 7, 1587–1599 (2021).

    Article  Google Scholar 

  119. Rohrer, L. et al. Acrylated hyaluronic-acid based hydrogel for the treatment of craniofacial volumetric muscle loss. Tissue Eng. Part. A 30, 704–711 (2024).

    Article  Google Scholar 

  120. Basurto, I. M. et al. Photoreactive hydrogel stiffness influences volumetric muscle loss repair. Tissue Eng. Part. A 28, 312–329 (2022).

    Article  Google Scholar 

  121. Narayanan, N. et al. Biomimetic glycosaminoglycan-based scaffolds improve skeletal muscle regeneration in a murine volumetric muscle loss model. Bioact. Mater. 6, 1201–1213 (2021).

    Google Scholar 

  122. Pfaff, M. R. et al. Viscoelastic HyA hydrogel promotes recovery of muscle quality and vascularization in a murine model of delayed rotator cuff repair. Adv. Healthc. Mater. 14, e2403962 (2025).

    Article  Google Scholar 

  123. Järvinen, T. A., Järvinen, T. L., Kääriäinen, M., Kalimo, H. & Järvinen, M. Muscle injuries: biology and treatment. Am. J. Sports Med. 33, 745–764 (2005).

    Article  Google Scholar 

  124. Grogan, B. F., Hsu, J. R. & Consortium, S. T. R. Volumetric muscle loss. J. Am. Acad. Orthop. Surg. 19, S35–S37 (2011).

    Article  Google Scholar 

  125. Kulwatno, J., Goldman, S. M. & Dearth, C. L. Volumetric muscle loss: a bibliometric analysis of a decade of progress. Tissue Eng. Part. B Rev. 29, 299–309 (2023).

    Article  Google Scholar 

  126. Garg, K. et al. Volumetric muscle loss: persistent functional deficits beyond frank loss of tissue. J. Orthop. Res. 33, 40–46 (2015).

    Article  Google Scholar 

  127. Weir, S. et al. One-year treatment costs of trauma care in the USA. Expert Rev. Pharmacoeconomics Outcomes Res. 10, 187–197 (2010).

    Article  Google Scholar 

  128. Jha, A. K. et al. Enhanced survival and engraftment of transplanted stem cells using growth factor sequestering hydrogels. Biomaterials 47, 1–12 (2015).

    Article  Google Scholar 

  129. Jha, A. K. et al. Matrix metalloproteinase-13 mediated degradation of hyaluronic acid-based matrices orchestrates stem cell engraftment through vascular integration. Biomaterials 89, 136–147 (2016).

    Article  Google Scholar 

  130. Kotla, N. G. et al. Hyaluronic acid-based bioconjugate systems, scaffolds, and their therapeutic potential. Adv. Healthc. Mater. 12, e2203104 (2023).

    Article  Google Scholar 

  131. Department of Health and Human Services. Intent to consider the appropriate classification of hyaluronic acid intra-articular products intended for the treatment of pain in osteoarthritis of the knee based on scientific evidence. Fed. Regist. 83, 64844–64845 (2018).

    Google Scholar 

  132. Altman, R. D., Manjoo, A., Fierlinger, A., Niazi, F. & Nicholls, M. The mechanism of action for hyaluronic acid treatment in the osteoarthritic knee: a systematic review. BMC Musculoskelet. Disord. 16, 321 (2015).

    Article  Google Scholar 

  133. Strauss, E. J., Hart, J. A., Miller, M. D., Altman, R. D. & Rosen, J. E. Hyaluronic acid viscosupplementation and osteoarthritis: current uses and future directions. Am. J. Sports Med. 37, 1636–1644 (2009).

    Article  Google Scholar 

  134. Leahey, M. Re: Docket No. FDA-2021-N-0843-0001; Genus Medical Technologies LLC versus Food and Drug Administration; request for information and comments. Medical Device Manufacturers Association https://downloads.regulations.gov/FDA-2021-N-0843-0045/attachment_1.pdf (2021).

  135. Department of Health and Human Services. Genus Medical Technologies LLC versus Food and Drug Administration; request for information and comments. Fed. Regist. 86, 43553–43555 (2021).

    Google Scholar 

  136. Cui, Y. et al. Evaluating glioblastoma tumour sphere growth and migration in interaction with astrocytes using 3D collagen-hyaluronic acid hydrogels. J. Mater. Chem. B 11, 5442–5459 (2023).

    Article  Google Scholar 

  137. Verkhratsky, A. & Nedergaard, M. Physiology of astroglia. Physiol. Rev. 98, 239–389 (2018).

    Article  Google Scholar 

  138. Jensen, G., Holloway, J. L. & Stabenfeldt, S. E. Hyaluronic Acid biomaterials for central nervous system regenerative medicine. Cells 9, 2113 (2020).

    Article  Google Scholar 

  139. Hughes, M. W. & Chuong, C. M. A mouthful of epithelial–mesenchymal interactions. J. Investig. Dermatol. 121, vii–viii (2003).

    Article  Google Scholar 

  140. Tian, Y. B. et al. Hyaluronic acid ameliorates the proliferative ability of human amniotic epithelial cells through activation of TGF-β/BMP signaling. PeerJ 8, e10104 (2020).

    Article  Google Scholar 

  141. Lowdon, R. F. et al. Regulatory network decoded from epigenomes of surface ectoderm-derived cell types. Nat. Commun. 5, 5442 (2014).

    Article  Google Scholar 

  142. Bourguignon, L. Y. W. et al. Hyaluronan–CD44 interaction stimulates keratinocyte differentiation, lamellar body formation/secretion, and permeability barrier homeostasis. J. Investig. Dermatol. 126, 1356–1365 (2006).

    Article  Google Scholar 

  143. Rost, M. S. & Sumanas, S. Hyaluronic acid receptor Stabilin-2 regulates Erk phosphorylation and arterial—venous differentiation in zebrafish. PLoS One 9, e88614 (2014).

    Article  Google Scholar 

  144. Plouhinec, J. L. et al. A molecular atlas of the developing ectoderm defines neural, neural crest, placode, and nonneural progenitor identity in vertebrates. PLoS Biol. 15, e2004045 (2017).

    Article  Google Scholar 

  145. Senbanjo, L. T. & Chellaiah, M. A. CD44: a multifunctional cell surface adhesion receptor is a regulator of progression and metastasis of cancer cells. Front. Cell Dev. Biol. 5, 18 (2017). This review explores the diverse isoforms of CD44, a HyA receptor, as a multifunctional adhesion molecule with varied roles and well-defined regulation of molecular pathways.

    Article  Google Scholar 

  146. Xin, L. in Prostate Cancer: Cellular and Genetic Mechanisms of Disease Development and Progression (eds Dehm, S. M. & Tindall, D. J.) 67–86 (Springer, 2019).

  147. Damodarasamy, M. et al. Hyaluronan in aged collagen matrix increases prostate epithelial cell proliferation. In Vitro Cell. Dev. Biol. Animal 51, 50–58 (2014).

    Article  Google Scholar 

  148. Wollina, U. Midfacial rejuvenation by hyaluronic acid fillers and subcutaneous adipose tissue — a new concept. Med. Hypotheses 84, 327–330 (2015).

    Article  Google Scholar 

  149. Berry, D. C., Stenesen, D., Zeve, D. & Graff, J. M. The developmental origins of adipose tissue. Development 140, 3939–3949 (2013).

    Article  Google Scholar 

  150. Zhu, Y., Kruglikov, I. L., Akgul, Y. & Scherer, P. E. Hyaluronan in adipogenesis, adipose tissue physiology and systemic metabolism. Matrix Biol. 78-79, 284–291 (2019).

    Article  Google Scholar 

  151. Högerkorp, C. M., Bilke, S., Breslin, T., Ingvarsson, S. & Borrebaeck, C. A. CD44-stimulated human b cells express transcripts specifically involved in immunomodulation and inflammation as analyzed by DNA microarrays. Blood 101, 2307–2313 (2003).

    Article  Google Scholar 

  152. Rafi, A., Nagarkatti, M. & Nagarkatti, P. S. Hyaluronate-CD44 interactions can induce murine B-cell activation. Blood 89, 2901–2908 (1997).

    Article  Google Scholar 

  153. Ishida, O., Tanaka, Y., Morimoto, I., Takigawa, M. & Eto, S. Chondrocytes are regulated by cellular adhesion through CD44 and hyaluronic acid pathway. J. Bone Miner. Res. 12, 1657–1663 (2009).

    Article  Google Scholar 

  154. Shum, L. & Nuckolls, G. The life cycle of chondrocytes in the developing skeleton. Arthritis Res. 4, 94–106 (2002).

    Article  Google Scholar 

  155. Patti, A. M., Gabriele, A., Vulcano, A., Ramieri, M. T. & Della Rocca, C. Effect of hyaluronic acid on human chondrocyte cell lines from articular cartilage. Tissue Cell 33, 294–300 (2001).

    Article  Google Scholar 

  156. Litwiniuk, M., Krejner, A., Speyrer, M. S., Gauto, A. R. & Grzela, T. Hyaluronic acid in inflammation and tissue regeneration. Wounds 28, 78–88 (2016).

    Google Scholar 

  157. Aquino, J. B., Sierra, R. & Montaldo, L. A. Diverse cellular origins of adult blood vascular endothelial cells. Dev. Biol. 477, 117–132 (2021).

    Article  Google Scholar 

  158. Lokeshwar, V. B. & Selzer, M. G. Differences in hyaluronic acid-mediated functions and signaling in arterial, microvessel, and vein-derived human endothelial cells. J. Biol. Chem. 275, 27641–27649 (2000).

    Article  Google Scholar 

  159. Fiore, D. et al. Pharmacological blockage of fibro/adipogenic progenitor expansion and suppression of regenerative fibrogenesis is associated with impaired skeletal muscle regeneration. Stem Cell Res. 17, 161–169 (2016).

    Article  Google Scholar 

  160. Hogarth, M. W. et al. Fibroadipogenic progenitors are responsible for muscle loss in limb girdle muscular dystrophy 2B. Nat. Commun. 10, 2430 (2019).

    Article  Google Scholar 

  161. Lim, W. F., Inoue-Yokoo, T., Tan, K. S., Lai, M. I. & Sugiyama, D. Hematopoietic cell differentiation from embryonic and induced pluripotent stem cells. Stem Cell Res. Ther. 4, 71 (2013).

    Article  Google Scholar 

  162. Haylock, D. N. & Nilsson, S. K. The role of hyaluronic acid in hemopoietic stem cell biology. Regen. Med. 1, 437–445 (2006).

    Article  Google Scholar 

  163. Naor, D. Editorial: interaction between hyaluronic acid and its receptors (CD44, RHAMM) regulates the activity of inflammation and cancer. Front. Immunol. https://doi.org/10.3389/fimmu.2016.00039 (2016).

  164. Monga, I., Kaur, K. & Dhanda, S. K. Revisiting hematopoiesis: applications of the bulk and single-cell transcriptomics dissecting transcriptional heterogeneity in hematopoietic stem cells. Brief. Funct. Genom. 21, 159–176 (2022).

    Article  Google Scholar 

  165. McDonald, B. & Kubes, P. Interactions between CD44 and hyaluronan in leukocyte trafficking. Front. Immunol. 6, 68 (2015).

    Article  Google Scholar 

  166. Goldman, O. et al. Endoderm generates endothelial cells during liver development. Stem Cell Rep. 3, 556–565 (2014).

    Article  Google Scholar 

  167. Weigel, J. A., Raymond, R. C. & Weigel, P. H. The hyaluronan receptor for endocytosis (HARE) is not CD44 or CD54 (ICAM-1). Biochem. Biophys. Res. Commun. 294, 918–922 (2002).

    Article  Google Scholar 

  168. Ghose, S., Biswas, S., Datta, K. & Tyagi, R. K. Dynamic hyaluronan drives liver endothelial cells towards angiogenesis. BMC Cancer 18, 648 (2018).

    Article  Google Scholar 

  169. Zheng, M., Kimura, S., Nio-Kobayashi, J. & Iwanaga, T. The selective distribution of LYVE-1-expressing endothelial cells and reticular cells in the reticulo-endothelial system (RES). Biomed. Res. 37, 187–198 (2016).

    Article  Google Scholar 

  170. Stone, O. A. & Stainier, D. Y. R. Paraxial mesoderm is the major source of lymphatic endothelium. Dev. Cell 50, 247–255.e3 (2019).

    Article  Google Scholar 

  171. Anastassova-Kristeva, M. The origin and development of the immune system with a view to stem cell therapy. J. Hematother. Stem Cell Res. 12, 137–154 (2003).

    Article  Google Scholar 

  172. Kim, S.-S. et al. Coexpression of myofibroblast and macrophage markers: novel evidence for an in vivo plasticity of chorioamniotic mesodermal cells of the human placenta. Lab. Investig. 88, 365–374 (2008).

    Article  Google Scholar 

  173. Kim, H., Cha, J., Jang, M. & Kim, P. Hyaluronic acid-based extracellular matrix triggers spontaneous M2-like polarity of monocyte/macrophage. Biomater. Sci. 7, 2264–2271 (2019).

    Article  Google Scholar 

  174. Chal, J. & Pourquié, O. Making muscle: skeletal myogenesis in vivo and in vitro. Development 144, 2104–2122 (2017).

    Article  Google Scholar 

  175. Leng, Y., Abdullah, A., Wendt, M. K. & Calve, S. Hyaluronic acid, CD44 and RHAMM regulate myoblast behavior during embryogenesis. Matrix Biol. 78-79, 236–254 (2019).

    Article  Google Scholar 

  176. Leiding, J. W. Neutrophil evolution and their diseases in humans. Front. Immunol. 8, 1009 (2017).

    Article  Google Scholar 

  177. Neunzehn, J., Alt, F., Wiesmann, H. P. & Kruppke, B. Osteogenic stimulation of osteoprogenitors by putamen ovi peptides and hyaluronic acid. Head Face Med. 19, 34 (2023).

    Article  Google Scholar 

  178. Rutkovskiy, A., Stensløkken, K. O. & Vaage, I. J. Osteoblast differentiation at a glance. Med. Sci. Monit. Basic Res. 22, 95–106 (2016).

    Article  Google Scholar 

  179. Asparuhova, M. B., Chappuis, V., Stähli, A., Buser, D. & Sculean, A. Role of hyaluronan in regulating self-renewal and osteogenic differentiation of mesenchymal stromal cells and pre-osteoblasts. Clin. Oral Investig. 24, 3923–3937 (2020).

    Article  Google Scholar 

  180. Svensson Holm, A. C., Bengtsson, T., Grenegård, M. & Lindström, E. G. Hyaluronic acid influence on platelet-induced airway smooth muscle cell proliferation. Exp. Cell Res. 318, 632–640 (2012).

    Article  Google Scholar 

  181. Boscher, J., Guinard, I., Lanza, F. & Léon, C. Blood platelet formation at a glance. J. Cell Sci. 133, jcs244731 (2020).

    Article  Google Scholar 

  182. Almeida, C. F., Fernandes, S. A., Ribeiro Junior, A. F., Keith Okamoto, O. & Vainzof, M. Muscle satellite cells: exploring the basic biology to rule them. Stem Cells Int. 2016, 1078686 (2016).

    Article  Google Scholar 

  183. Silva Garcia, J. M., Panitch, A. & Calve, S. Functionalization of hyaluronic acid hydrogels with ECM-derived peptides to control myoblast behavior. Acta Biomater. 84, 169–179 (2019).

    Article  Google Scholar 

  184. Zuo, X. et al. Spheroids of endothelial cells and vascular smooth muscle cells promote cell migration in hyaluronic acid and fibrinogen composite hydrogels. Research 2020, 8970480 (2020).

    Article  Google Scholar 

  185. Bargehr, J. et al. Embryological origin of human smooth muscle cells influences their ability to support endothelial network formation. Stem Cells Transl. Med. 5, 946–959 (2016).

    Article  Google Scholar 

  186. Wang, C. T., Lin, Y. T., Chiang, B. L., Lin, Y. H. & Hou, S. M. High molecular weight hyaluronic acid down-regulates the gene expression of osteoarthritis-associated cytokines and enzymes in fibroblast-like synoviocytes from patients with early osteoarthritis. Osteoarthr. Cartil. 14, 1237–1247 (2006).

    Article  Google Scholar 

  187. O’Connell, J. X. Pathology of the synovium. Am. J. Clin. Pathol. 114, 773–784 (2000).

    Article  Google Scholar 

  188. Scanzello, C. R. in Synovial Fluid Analysis and The Evaluation of Patients With Arthritis (ed. Mandell, B. F.) 5–19 (Springer, 2022).

  189. Ariel, A. et al. Induction of interactions between CD44 and hyaluronic acid by a short exposure of human T cells to diverse pro-inflammatory mediators. Immunology 100, 345–351 (2000).

    Article  Google Scholar 

  190. Carvalho, A. M., Reis, R. L. & Pashkuleva, I. Hyaluronan receptors as mediators and modulators of the tumor microenvironment. Adv. Healthc. Mater. 12, e2202118 (2023).

    Article  Google Scholar 

  191. Amano, M., Nakayama, M. & Kaibuchi, K. Rho-kinase/ROCK: a key regulator of the cytoskeleton and cell polarity. Cytoskeleton 67, 545–554 (2010).

    Article  Google Scholar 

  192. Berdiaki, A. et al. Hyaluronan and reactive oxygen species signaling-novel cues from the matrix? Antioxidants 12, 824 (2023).

    Article  Google Scholar 

  193. Roskoski, R. Jr. ERK1/2 MAP kinases: structure, function, and regulation. Pharmacol. Res. 66, 105–143 (2012).

    Article  Google Scholar 

  194. Pandey, M. S. & Weigel, P. H. Hyaluronic acid receptor for endocytosis (HARE)-mediated endocytosis of hyaluronan, heparin, dermatan sulfate, and acetylated low density lipoprotein (AcLDL), but not chondroitin sulfate types A, C, D, or E, activates NF-κB-regulated gene expression. J. Biol. Chem. 289, 1756–1767 (2014).

    Article  Google Scholar 

  195. Jho, E.-h. et al. Wnt/β-Catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway. Mol. Cell. Biol. 22, 1172–1183 (2002).

    Article  Google Scholar 

  196. Roca, X. et al. CD44 isoform expression follows two alternative splicing pathways in breast tissue. Am. J. Pathol. 153, 183–190 (1998).

    Article  Google Scholar 

  197. Fonseca, I., Moura Nunes, J. F. & Soares, J. Expression of CD44 isoforms in normal salivary gland tissue: an immunohistochemical and ultrastructural study. Histochem. Cell Biol. 114, 483–488 (2000).

    Article  Google Scholar 

  198. Shimabukuro, K. et al. The expression patterns of standard and variant CD44 molecules in normal uterine cervix and cervical cancer. Gynecol. Oncol. 64, 26–34 (1997).

    Article  Google Scholar 

  199. Zeilstra, J. et al. Stem cell CD44v isoforms promote intestinal cancer formation in Apc(min) mice downstream of Wnt signaling. Oncogene 33, 665–670 (2014).

    Article  Google Scholar 

  200. Mackay, C. R. et al. Expression and modulation of CD44 variant isoforms in humans. J. Cell Biol. 124, 71–82 (1994).

    Article  Google Scholar 

  201. Bloor, B. K., Jelvagharan, M., White, K. N. & Odell, E. W. Characterization of CD44 splicing patterns in normal keratinocytes, dysplastic and squamous carcinoma cell lines. Int. J. Oncol. 18, 1053–1059 (2001).

    Google Scholar 

  202. Herold-Mende, C. et al. Expression of CD44 splice variants in squamous epithelia and squamous cell carcinomas of the head and neck. J. Pathol. 179, 66–73 (1996).

    Article  Google Scholar 

  203. Department of Health and Human Services. Assignment of agency component for review of premarket applications. Fed. Regist. 56, 58754–58758 (1991).

    Google Scholar 

  204. Department of Health and Human Services. Assignment of agency component for review of premarket applications. Fed. Regist. 68, 37075–37077 (2003).

    Google Scholar 

  205. Department of Health and Human Services. Current good manufacturing practice requirements for combination products. Fed. Regist. 78, 4307–4323 (2013).

    Google Scholar 

  206. US Food and Drug Administration. Classification of products as drugs and devices and additional product classification issues: guidance for industry and FDA staff. FDA-2011-D-0429 (FDA, 2017).

  207. Frenkel, J. S. The role of hyaluronan in wound healing. Int. Wound J. 11, 159–163 (2014).

    Article  Google Scholar 

  208. Amir, A., Kim, S., Stecco, A., Jankowski, M. P. & Raghavan, P. Hyaluronan homeostasis and its role in pain and muscle stiffness. PM R 14, 1490–1496 (2022).

    Article  Google Scholar 

  209. Piehl-Aulin, K., Laurent, C., Engström-Laurent, A., Hellström, S. & Henriksson, J. Hyaluronan in human skeletal muscle of lower extremity: concentration, distribution, and effect of exercise. J. Appl. Physiol. 71, 2493–2498 (1991).

    Article  Google Scholar 

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  1. These authors contributed equally: Ryan Granché, Kavita Parekh.

Authors and Affiliations

  1. Department of Bioengineering, University of California, Berkeley, CA, USA

    Ryan Granché, Kavita Parekh, Ehsan Farjood, Howard Ying, Manasi Kumar, Pranav Addepalli & Kevin E. Healy

  2. Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, CA, USA

    Ryan Granché, Ehsan Farjood, Howard Ying, Manasi Kumar & Pranav Addepalli

  3. Department of Biomedical Engineering, University of Virginia, Charlottesville, VA, USA

    Sydney Shriver & George J. Christ

  4. Advanced Regenerative Manufacturing Institute, Manchester, NH, USA

    Richard McFarland

  5. Department of Orthopaedic Surgery, University of Virginia, Charlottesville, VA, USA

    George J. Christ

  6. Department of Materials Science and Engineering, University of California, Berkeley, CA, USA

    Kevin E. Healy

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R.G., K.P., E.F., S.S., H.Y. and M.K. researched data for the article, including literature searching, and contributed to figures, tables, discussion of content, writing and editing. G.J.C., K.E.H., R.G., K.P., S.S. and P.A. contributed to the Box items. G.J.C., R.M. and K.E.H. contributed to writing and editing of this manuscript. G.J.C. and K.E.H. had substantial contribution to discussion of content.

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Granché, R., Parekh, K., Farjood, E. et al. Interaction-driven classification of hyaluronic acid products. Nat Rev Bioeng 4, 269–286 (2026). https://doi.org/10.1038/s44222-025-00376-5

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