In vitro drug release of polymyxin B sulfate-loaded bone cement

Abstract

BACKGROUND: For diabetic foot infections, traditional vancomycin-loaded bone cement has a limited antibacterial spectrum, and there is an urgent need for novel drug carriers. OBJECTIVE: To explore the in vitro elution characteristics of polymyxin B sulfate-loaded bone cement. METHODS: Polymyxin B sulfate powder was uniformly mixed with polymethyl methacrylate bone cement and poured into molds to prepare bone cement microspheres with diameters of 5 and 7 mm. The two types of bone cement microspheres of different diameters were immersed in 1 mL of PBS, and elution samples were collected at specific time points. The concentration of polymyxin B sulfate in the eluent was determined by mass spectrometry, and the drug release pattern was analyzed. RESULTS AND CONCLUSION: (1) The drug release peaks for both types of bone cement microspheres occurred between 0 and 0.5 h, after which the release rate gradually decreased. Inter-group comparison showed that the drug release rate and cumulative release rate of the 5 mm diameter microspheres were higher than those of the 7 mm diameter microspheres. The cumulative drug release rates at 14 days for the 5 mm and 7 mm diameter microspheres were 5.08% and 3.37%, respectively. The drug release from both types of bone cement microspheres of different diameters reached 90% of the total release within 7 days, approaching the release endpoint. The in vitro drug release curves of both types of microspheres conformed to the Ritger-Peppas model (R2=0.998 56, 0.990 90), with Fickian diffusion as the dominant mechanism. (2) The polymyxin B sulfate-loaded bone cement exhibited sustained release characteristics, with drug release mainly concentrated in the first 7 days and low release thereafter. Therefore, 5-7 days after implantation is the optimal timing for secondary debridement; continued retention poses a higher risk of inducing bacterial resistance. The drug release rate is related to the size of the bone cement, and in clinical application, bone cement microspheres with a diameter of about 5 mm can be prioritized to balance rapid drug release and long-term antibacterial needs.

1. Introduction

With economic development and improved living standards, the global prevalence of diabetes has risen rapidly, currently affecting approximately 14% of adults [1]. Diabetic foot infection (DFI) is a common complication, occurring in about 25% of diabetic patients [2-3], with a mortality rate as high as 12%, and more than half of amputees may die within 5 years, posing a serious threat to patient health [4]. Current clinical guidelines for DFI primarily include debridement, negative-pressure wound therapy, revascularization, and antimicrobial therapy [5-6]. However, diabetic patients often have poor lower limb blood flow, arteriolosclerosis, or even occlusion [7], which impairs the delivery of systemic antibiotics to the wound site, compromising anti-infective efficacy.

Polymethyl methacrylate (PMMA) bone cement is a biomaterial used to fill bone gaps or cavities. Since its first application in joint arthroplasty in the 1960s, it has significantly improved surgical success rates and revolutionized orthopedic surgery. As a unique bone repair material, antibiotic-loaded bone cement can release high local drug concentrations while reducing systemic toxicity, achieving both prophylaxis and treatment of infection. Previous studies have demonstrated significant benefits of antibiotic-loaded bone cement in treating diabetic foot infections, with vancomycin being the most commonly added antibiotic [8-9]. However, current epidemiological studies indicate that Gram-negative bacteria are now more frequently isolated than Gram-positive bacteria in DFI, with multidrug-resistant organisms, especially Pseudomonas aeruginosa and Klebsiella pneumoniae, accounting for up to 36.2% of infections [10]. Moreover, in patients with Wagner grade 3-5, the incidence of extensively drug-resistant or even pan-drug-resistant bacteria is higher, making treatment more challenging [11]. Therefore, traditional vancomycin-loaded bone cement has a limited antibacterial spectrum, and there is an urgent need for novel drug carriers. Polymyxin B is effective against pan-drug-resistant Gram-negative bacteria, and foreign case reports have shown successful treatment of resistant Gram-negative osteomyelitis [12-14], but large-scale clinical studies are lacking. This study aims to explore the in vitro elution characteristics of polymyxin B sulfate-loaded bone cement, providing a basis for the treatment of diabetic foot infections caused by extensively drug-resistant Gram-negative bacteria and laying the groundwork for future clinical safety and efficacy evaluations.