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Abstract Macrophages are a predominant immune cell population that drive inflammatory responses and exhibit transitions in phenotype and function during tissue remodeling in disease and repair. Thus, engineering an immunomodulatory biomaterial has significant implications for resolving inflammation. Here, a biomimetic and photoresponsive hyaluronan (HA) hydrogel nanocomposite with tunable 3D extracellular matrix (ECM) adhesion sites for dynamic macrophage immunomodulation is engineered. Photodegradative alkoxylphenacyl‐based polycarbonate (APP) nanocomposites are exploited to permit user‐controlled Arg–Gly–Asp (RGD) adhesive peptide release and conjugation to a HA‐based ECM for real‐time integrin activation of macrophages encapsulated in 3D HA–APP nanocomposite hydrogels. It is demonstrated that photocontrolled 3D ECM–RGD peptide conjugation can activate αvβ3 integrin of macrophages, and periodic αvβ3 integrin activation can enhance anti‐inflammatory M2 macrophage polarization. Altogether, an emerging use of biomimetic, photoresponsive, and bioactive HA–APP nanocomposite hydrogel is highlighted to command 3D cell–ECM interactions for modulating macrophage polarization, which may shed light on cell–ECM interactions in innate immunity and inspire new biomaterial‐based immunomodulatory therapies.
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Effects of Cell-Adhesive Ligand Presentation on Pentapeptide Supramolecular Assembly and Gelation: Simulations and Experiments
The extracellular matrix (ECM) is a complex, hierarchical material containing structural and bioactive components. This complexity makes decoupling the effects of biomechanical properties and cell-matrix interactions difficult, especially when studying cellular processes in a 3D environment. Matrix mechanics and cell adhesion are both known regulators of specific cellular processes such as stem cell proliferation and differentiation. However, more information is required about how such variables impact various neural lineages that could, upon transplantation, therapeutically improve neural function after a central nervous system injury or disease. Rapidly Assembling Pentapeptides for Injectable Delivery (RAPID) hydrogels are one biomaterial approach to meet these goals, consisting of a family of peptide sequences that assemble into physical hydrogels in physiological media. In this study, we studied our previously reported supramolecularly-assembling RAPID hydrogels functionalized with the ECM-derived cell-adhesive peptide ligands RGD, IKVAV, and YIGSR. Using molecular dynamics simulations and experimental rheology, we demonstrated that these integrin-binding ligands at physiological concentrations (3–12 mm) did not impact the assembly of the KYFIL peptide system. In simulations, molecular measures of assembly such as hydrogen bonding and pi-pi interactions appeared unaffected by cell-adhesion sequence or concentration. Visualizations of clustering and analysis of solvent-accessible surface area indicated that the integrin-binding domains remained exposed. KYFIL or AYFIL hydrogels containing 3 mm of integrin-binding domains resulted in mechanical properties consistent with their non-functionalized equivalents. This strategy of doping RAPID gels with cell-adhesion sequences allows for the precise tuning of peptide ligand concentration, independent of the rheological properties. The controllability of the RAPID hydrogel system provides an opportunity to investigate the effect of integrin-binding interactions on encapsulated neural cells to discern how hydrogel microenvironment impacts growth, maturation, or differentiation.
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- Award ID(s):
- 2104723
- PAR ID:
- 10474429
- Publisher / Repository:
- Cells Tissues Organs
- Date Published:
- Journal Name:
- Cells Tissues Organs
- ISSN:
- 1422-6405
- Page Range / eLocation ID:
- 1 to 16
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1159/000534280
