3D-Connected drug molecular network equipped low-porosity bone implant with high-accumulative release rate and burst-free profile: For osteomyelitis postoperative long-term treatment and bone regeneration

Despite antibiotic-loaded PMMA bone implant have long been the standard therapy in post-surgical osteomyelitis treatment, however their low cumulative drug release rate is a major cause of the increased risk of post-operative drug-resistant bacteria. A common approach to enhance release rate is to introduce numerous pores but severely compromises the mechanical properties and exacerbates the drug explosive release. Acquiring high-strength bone implant that possess high cumulative release rate devoid of burst release presents a formidable challenge. Herein, an innovative strategy which is to construct 3D interconnected drug molecule network on the pore walls of low-porosity bone implant through self-polymerization synchronous instantaneous dynamic chemical foaming reaction was proposed to address this challenge. Drug-modified foaming agent was prepared by freeze-drying technology. Foaming prompts drug molecules to redistribute from foaming agent to bubble-nucleus surface under the synergistic effect of concentration gradient, surface energy, and electrostatic adsorption potential, subsequently through the joint migration of bubble expansion force and pore wall, ultimately stabilizing adsorbed on the wall surface through hydrogen bonds, forming a non-dissociative 3D interconnected drug molecular network after bubbles ruptured. This augments the contact area between the drug and the release medium, elevates the binding energy between drug and PMMA matrix, and ensured the connection integrity of the polymer network. Prepared bone implant achieved high cumulative drug release rate of 74.79 % at a porosity of only 18.74 %, with stable release process that avoided severe explosive release, the compressive strength reached 104.3 MPa. Furthermore, the porous PMMA antibiotic-loaded bone implant showed long-term potent antibacterial activity against MRSA, superior bone regeneration in a rat bone defect model. Innovatively, an in-depth analysis was conducted on the forces exerted on drug molecule networks during formation, and the drug migration kinetics theory in a system with dual changes in viscosity and temperature was deduced. Collectively, this study underscores the multiple-advantages of 3D interconnected drug molecular network, and the low-porosity bone implant equipped with this network show great potential for long-term post-surgical osteomyelitis treatment.