# Microalgae-Derived Extracellular Vesicle-Loaded 3D Alginate Hydrogels Promote In Vitro Skin and Bone Repair through Dual Fibroblast and Mesenchymal Stem Cell Modulation

## TL;DR

A new biomaterial using microalgae-derived vesicles in 3D hydrogels promotes skin and bone healing by guiding different cell responses.

## Contribution

MdEVs in alginate hydrogels modulate fibroblasts and stem cells differently for dual tissue repair.

## Key findings

- MdEV-loaded SA scaffolds enhance fibroblast viability and ECM remodeling for skin repair.
- MdEV-loaded SA/HAP scaffolds induce angiogenic and osteoinductive responses in stem cells.
- Material composition directs cell-specific regenerative outcomes using a single bioactive cue.

## Abstract

Chronic skin wounds with underlying bone exposure represent
a major
clinical challenge, characterized by impaired healing and limited
tissue regeneration. Sustainable, biologically active biomaterials
capable of addressing both cutaneous and bone repair remain highly
desirable. Here, we developed three-dimensional (3D) printed sodium
alginate (SA) and alginate/hydroxyapatite (SA/HAP) hydrogels incorporating
microalgae-derived extracellular vesicles (MdEVs) obtained fromEttlia oleoabundans. The constructs were characterized
for their mechanical, structural, and biological properties, and evaluated
in vitro using human dermal fibroblasts (hDFs) and mesenchymal stem
cells (hMSCs). The printed hydrogels exhibited a well-defined architecture,
mechanical stability, and high biocompatibility. Notably, the same
bioactive agent, MdEVs, elicited distinct cell-type-specific regenerative
programs depending on the material niche in which it was presented.
MdEV-loaded SA scaffolds enhanced cell viability and activated AKT/mTOR
signaling and extracellular matrix (ECM)-remodeling pathways in hDFs,
supporting cutaneous repair. In contrast, MdEV-loaded SA/HAP scaffolds
stimulated pro-angiogenic and osteoinductive gene expression in hMSCs,
indicative of bone-regenerative potential. This differential bioactivity
underscores the sophistication of the platform beyond simply promoting
repair, demonstrating how material composition can direct context-dependent
cellular responses by using a single, sustainable biological cue.
Overall, this in vitro study demonstrates that MdEV-enriched alginate-based
scaffolds can differentially guide fibroblast and stem cell responses
relevant to skin and bone regeneration. These findings highlight the
potential of algae-derived extracellular vesicles as versatile bioactive
components in next-generation regenerative biomaterials for complex
wounds involving multiple tissue types.