Development of a nanocement platform for site-specific antibiotic delivery in skeletal tuberculosis

Osteoarticular tuberculosis infection in spine, hip, and knee is the most common bone and joint extrapulmonary tuberculosis (EPTB), accounting for 10-15% of all EPTB cases. The urgent need for new treatment strategies arises from the severe clinical consequences of delayed or misdiagnosed osteoarticular TB infections, compounded by the inadequacies of current antibiotic therapies. Local antibiotic delivery approaches using advanced biomimetic biomaterials as a carrier system provide an efficient alternative. Herein, we develop an injectable, biocompatible nanohydroxyapatite-based carrier system (Nanocement; NC), compositionally similar to natural bone mineral, to deliver two first-line anti-tuberculosis antibiotics, isoniazid and rifampicin locally. The NC carrier was characterised for physicochemical properties, in vitro biocompatibility and anti-mycobacterial activities using a virulent H37Rv strain of Mycobacterium tuberculosis. The antibiotic-loaded NC was finally implanted in the spine and tibia TB infection model developed in guinea pigs for 8 weeks, using oral antibiotic therapy as a control. The results showed that the antibiotic carrier system has enormous potential to provide an promising alternative to oral antibiotic therapy or could be more beneficial if combined with an oral regime. During the surgical debridement, an irregular dead space is created that require local infection control and support for early bone healing, rather than immediate structural restoration. As an injectable cement, NC is optimized to conform to these cavities, deliver sustained local anti-tubercular therapy, and provide an osteoconductive microenvironment that supports gradual bone regeneration. While its intrinsic mechanical properties may limit its use in large, critical defects requiring structural support, NC can be effectively applied in combination with fixation devices or secondary grafting strategies. STATEMENT OF SIGNIFICANCE: Osteoarticular tuberculosis remains a debilitating global health challenge, where delayed diagnosis and limited efficacy of systemic antibiotics often result in irreversible skeletal damage. This study explores the potential of an indigenously developed injectable nanohydroxyapatite-based "Nanocement" that locally co-delivers isoniazid and rifampicin while simultaneously acting as an osteoconductive bone filler. By directly targeting infectious bone lesions, this biomimetic carrier achieves potent and sustained anti-mycobacterial activity against virulent M. tuberculosis in vivo, while promoting bone healing in infectious lesions. This dual-action strategy offers a transformative alternative to conventional oral regimens and highlights a clinically translatable approach for treating complex bone infections.