Journal 

Source Biomaterials

Title 

Machine learning–guided design of cooperative multi-size hydrogel microspheres for osteoarthritis therapy

Research 

Strategy To tackle the coexisting pathological cascades of osteoarthritis and the functional limitation of single-size hydrogel microspheres, three types of hyaluronic acid-based hydrogel microspheres with distinct sizes were fabricated. The size-dependent divergent biological functions were systematically deciphered. A Bayesian optimization framework based on machine learning was established to screen the optimal blending ratio of multi-sized microspheres. The synergistic performance of the optimized system was validated through in vitro cell experiments, in vivo animal models and transcriptomic analysis.

Highlights

1. Uncover the divided biological effects of hyaluronic acid microspheres with different particle sizes and establish the size–function correlation.
2. Integrate deep kernel learning Gaussian process model with Bayesian optimization for quantitative formulation design of multi-component microsphere systems.
3. Construct a cooperative multi-size microsphere system to simultaneously achieve joint lubrication, immune modulation and cartilage repair.
4. Propose a generalizable data-driven design paradigm of injectable biomaterials applicable to multiscale degenerative diseases.

Material Development Materials: Methacrylated hyaluronic acid was used as the raw material. Small, medium and large injectable hydrogel microspheres were prepared via microfluidic water-in-oil emulsion followed by UV crosslinking. The obtained materials exhibit favorable biocompatibility, swelling behavior and enzymatic degradability. Functions: Small microspheres enhance interfacial lubrication and upregulate lubricating protein expression; medium microspheres modulate macrophage polarization and mitigate synovial inflammation; large microspheres build a 3D microenvironment to facilitate chondrocyte proliferation and extracellular matrix synthesis. The combined formulation synergistically alleviates pathological joint damage in osteoarthritis.

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