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• Biphasic porous and degradable scaffolds incorporating anti-inflammatory and anabolic molecules were successfully fabricated by low-temperature rapid prototyping technology. • Using our previously established OA-OCD rabbit model, chondrogenic kartogenin and osteogenic cinnamaldehyde show that sustained release from the scaffold promotes cartilage and subchondral bone regeneration, respectively. • The anti-inflammatory effect of the scaffold alleviates sclerosis of both host and newly formed subchondral bone in papain-induced osteoarthritic joints. Osteochondral defects (OCD) are common but difficult to heal due to the low intrinsic repair capacity of cartilage and its complex hierarchical structure. In osteoarthritis (OA), OCD become more challenging to repair as both cartilage and subchondral bone regeneration are further impaired due to the arthritic environment. Numerous biomaterials have been developed and tested in osteochondral defects while ignoring the inflammatory environment. To target this challenging underlying pathophysiology, we designed and fabricated a biphasic porous and degradable scaffold incorporating anti-inflammatory and anabolic molecules by low-temperature rapid prototyping technology, and its effects on promoting osteochondral regeneration were evaluated using our well-established OA-OCD rabbit model. The biphasic porous scaffolds consisted of poly lactic-co-glycolic acid (PLGA) with kartogenin (KGN) for cartilage repair and PLGA and β-calcium phosphate (PLGA/β-TCP) with cinnamaldehyde (CIN) for subchondral bone repair. KGN is a molecule for promoting chondrogenesis and CIN is a phytomolecule for enhancing osteogenesis and alleviating inflammation. The biphasic scaffolds PLGA/KGN-PLGA/β-TCP/CIN (PK/PTC) with bio-mimic structure provided stable mechanical properties and exhibited excellent biocompatibility to support cell adhesion, proliferation, migration, and distribution. Furthermore, KGN and CIN within biphasic scaffolds could be released in a controlled and sustained mode, and the biphasic scaffold degraded slowly in vitro. Evaluating the repair of 16-weeks post-implantation into critically sized OA-OCD rabbit models revealed that the biphasic scaffold could promote subchondral bone and cartilage regeneration, as well as reverse subchondral osteosclerosis caused by inflammation in vivo. These findings support the utilization of the PK/PTC scaffold for osteochondral regeneration and provide a promising potential strategy for clinical application for the treatment of patients with OA-OCD. [Display omitted] [ABSTRACT FROM AUTHOR]

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