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Inlay arthroplasty (IA) has seen growing interest as a new primary arthroplasty intervention for patients that need to transition from biology to joint replacement. The purpose of this study was to investigate the biological response to this procedure.Patients presenting with symptomatic mono- or bicompartmental arthrosis and varus malalignment underwent IA and concurrent medial open wedge high tibial osteotomy (HTO). A subset of patients required hardware removal and consented to second-look arthroscopy without biopsy allowing for assessment of IA components and compartment-specific findings related to implant fixation, cartilage flow, propagation of lesions, and opposing tibial surfaces.In a series of 41 knees (35 patients) treated with combined IA and HTO (mean varus >7°), 26 knees (23 patients, 18 male, 5 female) with a mean age of 52 years (range = 43-67) required HTO plate removal. Concurrent second look arthroscopy was performed at a mean of 14 months (range = 12-19) following the index procedure. On probing, all arthroplasty components showed solid fixation without gap formation. On the medial femoral condyle, 15 mm implants (n = 14) showed a peripheral cartilage flow of 12% (range = 5% to 25%), 20 mm implants (n = 12) of 9% (range 5% to 15%), and trochlear implants (n = 12) of 20% (range 10% to 40%). No progressive deterioration of the index defects or progression of tibial and retropatellar grades were seen.Joint surface reconstruction using IA showed stable fixation with peripheral cartilage coverage ranging from 9% to 20% and no further chondral damage on opposing surfaces. Future clinical effectiveness studies are required to support the positive biological integration.