From formation history to intra-articular service: coupling network evolution, fatigue, degradation, and drug release...

Hydrogel microspheres intended for intra-articular delivery are commonly compared by particle size, encapsulation efficiency, equilibrium modulus, static degradation, and cumulative drug release. These endpoints do not recover the specimen's life-cycle history. Crosslinker transport, reaction kinetics, washing, storage, reconstitution, and needle passage can leave gradients in crosslink density, water content, residual functionality, cargo distribution, and relaxation. In the joint, that hidden state evolves under compression, shear, friction, and wear, while reversible adaptation competes with defect accumulation, bond loss, degradation, and erosion. Each process can alter transport pathways and local exposure. This Mini Review examines evidence linking formation history to intra-articular service, emphasizing hydrogel microspheres rather than bulk injectable gels. Direct end-to-end evidence remains sparse: only one particle-containing study identified here compared release after repeated compression, and tribology, injection, storage, release, and pharmacokinetics are usually tested separately. We integrate findings from external gelation, dynamic networks, hydrogel fatigue, mechanically modulated release, synovial-fluid interfaces, and joint pharmacokinetics. A service-aware framework follows initially matched particles through storage, reconstitution, injection, relaxation, cyclic loading, wear, degradation, release, and repeat administration. The critical design variable is the measurable network state inherited from manufacture and altered by use, not a bond label or initial modulus alone.