Interdigitating HA therapy improves multi-scale biomechanics and is retained at the defect site. A) Fortified cartilage was evaluated mechanically by macro-scale creep indentation testing (for biphasic properties), and by nanoindentation for cell-scale mechanical properties. B) Macroscale compressive modulus and C) permeability of degenerated cartilage tissue (digested in 0.01% collagenase type IV for 30 min) before (−) and after (+) HA therapy (5 min application; 15 min crosslinking, 320–400 nm, ≈5 mW cm−2). n = 7 paired samples. D) Microscale modulus measured by nanoindentation in degenerated cartilage before (−) and after (+) HA therapy. n > 400 measurements (n = 5 specimens per group). E) HA solution applied and crosslinked in trochlear defects in a Yucatan mini-pig model. F) HA therapy was retained in cartilage defects at 7 d with both 5 and 15 min of light exposure (crosslinking). White dashed line outlines defect. G) Normalized fluorescence intensity in defects, relative to empty defect controls. * and ^ depict p < 0.05 versus empty defect and +0. n = 6 defects per group, normalized to empty defect within the same knee. Horizontal line depicts mean.