Composite chitosan and calcium sulfate scaffold for dual delivery of vancomycin and recombinant human bone morphogenetic protein-2

Abstract

A biodegradable, composite bone graft, composed of chitosan microspheres embedded in calcium sulfate, was evaluated in vitro for point-of-care loading and delivery of antibiotics and growth factors to prevent infection and stimulate healing in large bone injuries. Microspheres were loaded with rhBMP-2 or vancomycin prior to mixing into calcium sulfate loaded with vancomycin. Composites were evaluated for set time, drug release kinetics, and bacteriostatic/bactericidal activity of released vancomycin, induction of ALP expression by released rhBMP-2, and interaction of drugs on cells. Results showed the composite set in under 36 min and released vancomycin levels that were bactericidal to S. aureus (>MIC 8-16 μg/mL) for 18 days. Composites exhibited a 1 day-delayed release, followed by a continuous release of rhBMP-2 over 6 weeks; ranging from 0.06 to 1.49 ng/mL, and showed a dose dependent release based on initial loading. Released rhBMP-2 levels were, however, too low to induce detectable levels of ALP in W20-17 cells, due to the affinity of rhBMP-2 for calcium-based materials. With stimulating amounts of rhBMP-2 (>50 ng/mL), the ALP response from W-20-17 cells was inhibited when exposed to high vancomycin levels (1,800-3,600 μg/mL). This dual-delivery system is an attractive alternative to single delivery or preloaded systems for bone regeneration since it can simultaneously fight infection and deliver a potent growth factor. Additionally, this composite can accommodate a wide range of therapeutics and thus be customizable for specific patient needs, however, the potential interactive effects of multiple agents must be investigated to ensure that functional activity is not altered.

Novel Antibiotic-loaded Point-of-care Implant Coating Inhibits Biofilm

“…The reduction in biofilm attachment in a challenging polymicrobial in vivo model confirms the in vitro results and is consistent with release of active concentrations of antibiotic from various drug delivery vehicles [22,45,51,54,63]. Scanning electron microscopy images of biofilm formation on implants resembled images from similar retrieved infected implants [10,52] with rounded S aureus and rod-shaped P aeruginosa colonies visible in untreated groups.…”

Combination of calcium sulfate and simvastatin-controlled release microspheres enhances bone repair in critical-sized rat calvarial bone defects

“…32 In this study, we used CS (Osteoset) as a bone graft substitute because of its rapid resorption and ability to carry controlled-release SIM/PLGA for local delivery to enhance bone healing. Before clinical application, safety has to be ensured, and easy attraction of cells attaching to the scaffold surface has to be demonstrated.…”

“…A meta-analysis of studies comparing CP bone substitutes with autografts suggested that use of CP bone substitutes circumvented the need for a second incision to harvest autografts, was associated with fracture reduction, and likely improved functional outcomes. 32,33 Larsson et al have reported the effect of these substitutes in fractures of the tibia plateau, hip, and distal radius. 33 However, according to a study by Russell et still visible in most patients at one year after implantation surgery.…”

Chitosan coating to enhance the therapeutic efficacy of calcium sulfate-based antibiotic therapy in the treatment of chronic osteomyelitis

“…While chitosan coatings impede the release of the antibiotic daptomycin from a calcium-based carrier, they may increase release of some molecules such as protein growth factors like bone morphogenetic protein-2 (BMP-2) from calcium phosphate and CaSO 4 cements. 29–32 A study by Doty et al 33 demonstrated that embedding chitosan microbeads containing BMP-2 within a matrix of CaSO 4 served to slow growth factor release while maintaining active levels of released vancomycin over a period of 18 days in vitro. Composite formulations of hydroxyapatite, CaSO 4 , and chitosan have improved the release profiles of vancomycin, fosfomycin, and amphotericin B over PMMA.…”