Hydroxyapatite microspheres induce durable pleurodesis and are rapidly cleared by pleural osteoclasts

Talc pleurodesis is highly effective for preventing recurrence of pneumothorax and pleural effusion, but it can be complicated by dissemination, acute lung injury, lead exposure, and foreign body-induced chronic inflammation and pain. Our objective is to develop a safe, biodegradable, contaminant-free particle for pleurodesis. We used mouse models of pneumothorax and malignant pleural effusion to compare the efficacy and safety of pleurodesis with talc and hydroxyapatite microspheres (HAM). Intrapleural instillation of microspheres induced pleural adhesions, fibrosis, and symphysis as effectively as talc and resulted in more durable protection from experimental pneumothorax. HAM and talc both induced an osteoclastogenic, inflammatory, and fibrotic response in pleural lavage cells. Intrapleural HAM was resorbed by osteoclast action over 3 months, whereas talc was not cleared. Deletion of the osteoclast effector, CTSK, diminished pleural adhesion formation and fibrosis by HAM, and inhibition of osteoclastogenesis with anti-RANKL antibody delayed HAM clearance. We found no difference in activity level, feeding behavior, or lung compliance between particles, but talc induced more persistent pleural inflammation. We conclude that HAM resulted in an osteoclastogenic and fibrogenic pleural response that induced pleurodesis that was more durable than talc with a superior safety profile due in part to osteoclast-mediated particle clearance.