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Molecular Weight-Driven Tunable Hyaluronic Acid-Based Hydrogels Modulate Immune Polarization in Three-Dimensional

Jaechang Kim1, Inwoo Son2, Vesper Evereux3

  • 1Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, Kentucky 40536, United States.

ACS Biomaterials Science & Engineering
|March 19, 2026
PubMed
Summary

High-molecular-weight hyaluronic acid (HA) in 3D hydrogels promotes anti-inflammatory macrophage responses. This study reveals HA

Keywords:
3D cultureshyaluronic acidimmunomodulationinflammationregenerative medicinetunable hydrogel

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Area of Science:

  • Biomaterials Science
  • Immunology
  • Regenerative Medicine

Background:

  • Macrophage behavior is influenced by the extracellular matrix (ECM), with hyaluronic acid (HA) playing a key immunomodulatory role.
  • Previous research on HA's immunomodulatory effects often used 2D cultures, limiting physiological relevance.
  • Hyaluronic acid's effects are molecular weight (MW)-dependent, but in vivo conditions are complex to replicate.

Purpose of the Study:

  • To investigate the molecular weight-dependent immunomodulatory effects of hyaluronic acid (HA) on macrophages within a 3D hydrogel system.
  • To explore HA-based hydrogels as biomimetic scaffolds for controlling immune responses.

Main Methods:

  • Fabrication of HA-based hydrogels with distinct biophysical properties using varying HA molecular weights (MWs) and PEG-SH4 cross-linking.
  • Encapsulation of immortalized macrophages within the 3D HA hydrogels.
  • Assessment of macrophage expression of pro-inflammatory and anti-inflammatory markers.

Main Results:

  • Hydrogels incorporating high-MW HA significantly increased the expression of anti-inflammatory markers in macrophages.
  • The biophysical characteristics of the HA hydrogels influenced the immunomodulatory effects of HA.
  • Demonstrated MW-dependent immunomodulatory capacity of HA in a 3D environment.

Conclusions:

  • High-molecular-weight hyaluronic acid in 3D hydrogels can promote an anti-inflammatory macrophage phenotype.
  • HA-based hydrogels serve as effective ECM-mimetic scaffolds for modulating immune cell responses.
  • Customizable HA hydrogels show promise for applications in regenerative medicine and immunomodulation.