Metabolically Engineered Extracellular Vesicles Released From a Composite Hydrogel Delivery System Regulate the...

Area of Science:

• Biomaterials Science
• Regenerative Medicine
• Orthopedic Surgery

Background:

• Aseptic loosening of titanium (Ti) alloy implants remains a clinical challenge due to poor wear resistance and biological inertness.
• Inflammatory osteolysis and suboptimal osseointegration impede implant longevity.
• Novel cell-free therapeutic strategies are needed to address periprosthetic osteolysis.

Purpose of the Study:

• To develop engineered extracellular vesicles (EVs) for targeted delivery to combat periprosthetic osteolysis.
• To create a multifunctional scaffold for enhanced implant performance and controlled therapeutic release.
• To evaluate the therapeutic potential of DS-EVs and the integrated scaffold system in vitro and in vivo.

Main Methods:

• Metabolic glycan labelling (MGL)-mediated click chemistry was used to create dextran sulfate-tagged EVs (DS-EVs).
• Engineered stem cells produced DS-EVs for targeted macrophage reprogramming.
• A 3D titanium alloy scaffold with MXene-PVA hydrogel coating (Ti-PPM) was developed to incorporate DS-EVs.

Main Results:

• DS-EVs exhibited specific macrophage tropism, shifting phenotypes from pro-inflammatory M1 to regenerative M2.
• This reprogramming attenuated osteoclastogenesis and enhanced osseointegration via GPC6/Wnt pathway activation in vitro.
• The Ti-PPM scaffold demonstrated improved wear resistance, interfacial adhesion, and controlled DS-EV release, promoting osseointegration in vivo.

Conclusions:

• DS-EVs represent a novel cell-free therapeutic system for periprosthetic osteolysis.
• The integrated Ti-PPM scaffold system offers enhanced wear resistance and controlled EV delivery.
• This approach holds transformative potential for modulating the osseointegration microenvironment and macrophage heterogeneity.