Hyaluronan Hydrogels: Three Material States in Regenerative Orthopaedics.
9 affiliations
- 1Department of Orthopedics, FC Sports Traumatology, Salvador 40296-210, BA, Brazil.
- 2Department of Orthopedics, Brazilian Institute of Regenerative Medicine (BIRM), Indaiatuba 13334-170, SP, Brazil.
- 3Regenerative Medicine, Orthoregen International Course, Indaiatuba 13334-170, SP, Brazil.
- 4Department of Engineering of Materials and Bioprocesses, School of Chemical Engineering, University of Campinas, P.O. Box 6066, Campinas 13083-852, SP, Brazil.
- 5Medical School, Tiradentes University Center, Maceió 57038-000, AL, Brazil.
- 6Department of Orthopedics and Traumatology, Federal University of Tocantins (UFT), Palmas 77001-090, TO, Brazil.
- 7Medical School, Max Planck University Center (UniMAX), Indaiatuba 13343-060, SP, Brazil.
- 8Clinical Research, Anna Vitória Lana Institute (IAVL), Indaiatuba 13334-170, SP, Brazil.
- 9Medical School, Jaguariúna University Center (UniFAJ), Jaguariúna 13911-094, SP, Brazil.
Abstract
Hyaluronan-based materials are widely described as hydrogels, yet the term is applied without distinction to preparations that differ fundamentally in structure. This review addresses that imprecision by separating three material states of hyaluronan and by stating the criteria under which each may be called a gel: native linear hyaluronan, which forms a viscoelastic solution; the hexadecylamide derivative (HYADD-4), which self-assembles into a transient physical network through hydrophobic interactions; and hyaluronan cross-linked with 1,4-butanediol diglycidyl ether (BDDE), which forms a covalent three-dimensional network. A material is treated as a gel here only where both a percolated network and a solid-like mechanical response are documented. On that basis the covalent network qualifies; the derivative is elastic-dominated across the walking-to-running frequency band of the knee but has not been subjected to a formal Winter-Chambon analysis and is therefore described as gel-like; and the linear solution does not qualify at the molecular weights and concentrations used in marketed viscosupplements. We review the chemistry of network formation, the comparative physicochemical and rheological behavior, including viscosity, the storage and loss moduli, boundary lubrication, and resistance to enzymatic and oxidative degradation, and the receptor-mediated and anti-inflammatory mechanisms of action involving CD44 and molecular-weight-dependent signaling. Clinical and regenerative applications in osteoarthritis viscosupplementation and in scaffolds and carriers for cells and growth factors are summarized for each state. The networked materials show higher viscoelasticity and greater resistance to degradation than the linear solution, which provides a rationale for longer residence; the evidence for a clinical advantage over conventional hyaluronan, however, rests largely on preclinical and rheological data. A three-state framework is proposed, pending validation, to support clearer interpretation of the literature and more rational material selection.
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BibTeX
@article{costa2026hyaluronan,
title = {{Hyaluronan Hydrogels: Three Material States in Regenerative Orthopaedics.}},
author = {Fábio Ramos Costa and Maria Helena Andrade Santana and Rubens Martins de Andrade and João Protásio Netto and Luyddy Pires and Gabriel Azzini and André Kruel and Tomas Mosaner and Lucas Furtado da Fonseca and José Fábio Lana},
journal = {Gels (Basel, Switzerland)},
year = {2026},
month = sep,
doi = {10.3390/gels12100867},
url = {https://europepmc.org/article/MED/42929902},
note = {CC BY},
}
RIS
TY - JOUR
TI - Hyaluronan Hydrogels: Three Material States in Regenerative Orthopaedics.
AU - Fábio Ramos Costa
AU - Maria Helena Andrade Santana
AU - Rubens Martins de Andrade
AU - João Protásio Netto
AU - Luyddy Pires
AU - Gabriel Azzini
AU - André Kruel
AU - Tomas Mosaner
AU - Lucas Furtado da Fonseca
AU - José Fábio Lana
PY - 2026
DA - 2026/09/25
JO - Gels (Basel, Switzerland)
DO - 10.3390/gels12100867
UR - https://europepmc.org/article/MED/42929902
AB - Hyaluronan-based materials are widely described as hydrogels, yet the term is applied without distinction to preparations that differ fundamentally in structure. This review addresses that imprecision by separating three material states of hyaluronan and by stating the criteria under which each may be called a gel: native linear hyaluronan, which forms a viscoelastic solution; the hexadecylamide derivative (HYADD-4), which self-assembles into a transient physical network through hydrophobic interactions; and hyaluronan cross-linked with 1,4-butanediol diglycidyl ether (BDDE), which forms a covalent three-dimensional network. A material is treated as a gel here only where both a percolated network and a solid-like mechanical response are documented. On that basis the covalent network qualifies; the derivative is elastic-dominated across the walking-to-running frequency band of the knee but has not been subjected to a formal Winter-Chambon analysis and is therefore described as gel-like; and the linear solution does not qualify at the molecular weights and concentrations used in marketed viscosupplements. We review the chemistry of network formation, the comparative physicochemical and rheological behavior, including viscosity, the storage and loss moduli, boundary lubrication, and resistance to enzymatic and oxidative degradation, and the receptor-mediated and anti-inflammatory mechanisms of action involving CD44 and molecular-weight-dependent signaling. Clinical and regenerative applications in osteoarthritis viscosupplementation and in scaffolds and carriers for cells and growth factors are summarized for each state. The networked materials show higher viscoelasticity and greater resistance to degradation than the linear solution, which provides a rationale for longer residence; the evidence for a clinical advantage over conventional hyaluronan, however, rests largely on preclinical and rheological data. A three-state framework is proposed, pending validation, to support clearer interpretation of the literature and more rational material selection.
SN - 2310-2861
ER -