Injectable Chitosan-Based Thermosensitive Hydrogel/Nanoparticle-Loaded System for Local Delivery of Vancomycin in the Treatment of Osteomyelitis

Int J Nanomedicine. 2020 Aug 6:15:5855-5871. doi: 10.2147/IJN.S247088. eCollection 2020.

Abstract

Purpose: Osteomyelitis, particularly chronic osteomyelitis, remains a major challenge for orthopedic surgeons. The traditional treatment for osteomyelitis, which involves antibiotics and debridement, does not provide a complete solution for infection and bone repair. Antibiotics such as vancomycin (VCM) are commonly used to treat osteomyelitis in clinical settings. VCM use is limited by a lack of effective delivery methods that provide sustained, high doses to entirely fill irregular bone tissue to treat infections.

Methods: We engineered a chitosan (CS)-based thermosensitive hydrogel to produce a VCM-nanoparticle (NPs)/Gel local drug delivery system. The VCM-NPs were formed with quaternary ammonium chitosan and carboxylated chitosan nanoparticles (VCM-NPs) by positive and negative charge adsorption to enhance the encapsulation efficiency and drug loading of VCM, with the aim of simultaneously preventing infection and repairing broken bones. This hydrogel was evaluated in a rabbit osteomyelitis model.

Results: The VCM-NPs had high encapsulation efficiency and drug loading, with values of 60.1±2.1% and 24.1±0.84%, respectively. When embedded in CS-Gel, the VCM-NPs maintained their particle size and morphology, and the injectability and thermosensitivity of the hydrogel, which were evaluated by injectability test and rheological measurement, were retained. The VCM-NPs/Gel exhibited sustained release of VCM over 26 days. In vitro tests revealed that the VCM-NPs/Gel promoted osteoblast proliferation and activity against Staphylococcus aureus. In vivo, VCM-NPs/Gel (with 10 mg vancomycin per rabbit) was used to treat rabbits with osteomyelitis. The VCM-NPs/Gel showed excellent anti-infection properties and accelerating bone repair under osteomyelitis conditions.

Conclusion: The reported multifunctional NPs hydrogel system for local antibiotic delivery (VCM-NPs/Gel) showed bone regeneration promotion and anti-infection properties, demonstrating significant potential as a scaffold for effective treatment of osteomyelitis.

Keywords: chitosan; injectable hydrogel; nanoparticles; osteomyelitis; vancomycin.

MeSH terms

  • Animals
  • Anti-Bacterial Agents / administration & dosage*
  • Anti-Bacterial Agents / pharmacokinetics
  • Cell Proliferation / drug effects
  • Chitosan / chemistry
  • Disease Models, Animal
  • Drug Delivery Systems
  • Hydrogels / administration & dosage
  • Hydrogels / chemistry*
  • Hydrogels / pharmacology
  • Injections
  • Male
  • Nanoparticles / administration & dosage*
  • Nanoparticles / chemistry
  • Osteoblasts / drug effects
  • Osteoblasts / microbiology
  • Osteomyelitis / drug therapy*
  • Particle Size
  • Rabbits
  • Staphylococcal Infections / drug therapy
  • Staphylococcus aureus / drug effects
  • Vancomycin / administration & dosage*
  • Vancomycin / pharmacokinetics

Substances

  • Anti-Bacterial Agents
  • Hydrogels
  • Vancomycin
  • Chitosan

Grants and funding

This work was supported by the National Natural Science Foundation of China (No. 81773673 and 81803808), Zhejiang Province Public Welfare Technology Application Research Project of China (No. LGF19H300005 and LGF19H300007), Natural Science Foundation of Ningbo (No. 2018A610263), Key Laboratory of Ningbo, China (No. 2016A22002), Zhejiang University Student Science and Technology Innovation Activity Plan (No. 2017R435003), Foundation of Zhejiang educational committee (No. Y201738467) and Scientific Research Project of Zhejiang Pharmaceutical College (No. ZPCSR2017004). We thank Sarah Dodds, PhD, and Ashleigh Cooper, PhD, from Liwen Bianji, Edanz Editing China, for editing the English text of a draft of this manuscript.