Inflammation-Induced Drug Release by using a pH-Responsive Gas-Generating Hollow-Microsphere System for the Treatment of Osteomyelitis

• Published in: Advanced healthcare materials 2014-11, Vol.3 (11), p.1854-1861
• Main Authors: Chung, Ming-Fan, Chia, Wei-Tso, Liu, Hung-Yi, Hsiao, Chun-Wen, Hsiao, Hsu-Chan, Yang, Chih-Man, Sung, Hsing-Wen
• Format: Article
• Language: English
• Subjects: Addictive behaviors; Adult and adolescent clinical studies; Animals; Anti-Bacterial Agents - chemistry; Anti-Bacterial Agents - pharmacology; anti-inflammation; Antibacterial agents; Antibiotics; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biocompatibility; Biological and medical sciences; Biomedical materials; Bone Cements - chemistry; Bone Cements - pharmacology; Bubbles; Calcium Phosphates - chemistry; Carbon Dioxide - chemistry; Cement; Cements; Delayed-Action Preparations - chemistry; Delayed-Action Preparations - pharmacology; Drug addiction; Drug Carriers - chemistry; Drug Liberation; Drugs; Gases - chemistry; Hydrogen-Ion Concentration; Inflammation - drug therapy; inflammatory diseases; Lactic Acid - chemistry; local drug delivery; Medical sciences; Microspheres; Osteomyelitis - drug therapy; Pharmacology. Drug treatments; Polyglycolic Acid - chemistry; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Rabbits; smart carriers; stimuli-responsive materials; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Technology. Biomaterials. Equipments; Thresholds; Vancomycin; Vancomycin - administration & dosage; Vancomycin - chemistry
• ISSN: 2192-2640; 2192-2659
• DOI: 10.1002/adhm.201400158

In the conventional treatment of osteomyelitis, the penetration of antibiotics into the infected bone is commonly poor. To ensure that the local antibiotic concentration is adequate, this work develops an injectable calcium phosphate (CP) cement in which is embedded pH‐responsive hollow microspheres (HMs) that can control the release of a drug according to the local pH. The HMs are fabricated using a microfluidic device, with a shell of poly(d,l‐lactic‐co‐glycolic acid) (PLGA) and an aqueous core that contains vancomycin (Van) and NaHCO3. At neutral pH, the CP/HM cement elutes a negligible concentration of the drug. In an acidic environment, the NaHCO3 that is encapsulated in the HMs reacts with the acid rapidly to generate CO2 bubbles, disrupting the PLGA shells and thereby releasing Van locally in excess of a therapeutic threshold. The feasibility of using this CP/HM cement to treat osteomyelitis is studied using a rabbit model. Analytical results reveal that the CP/HM cement provides highly effective local antibacterial activity. Histological examination further verifies the efficacy of the treatment by the CP/HM cement. The above findings suggest that the CP/HM cement is a highly efficient system for the local delivery of antibiotics in the treatment of osteomyelitis. In the inflammation‐induced acidic environment of osteomyelitis, the NaHCO3 in the hollow microspheres (HMs) that are embedded in the bone cement will react with the acid to quickly form CO2 bubbles, which create pressure inside the HMs and disrupt their walls, promptly and locally unloading an amount of encapsulated vancomycin that exceeds the therapeutic threshold for curing the disease.