Tailored sequential drug release from bilayered calcium sulfate composites

Abstract

The current standard for treating infected bony defects, such as those caused by periodontal disease, requires multiple time-consuming steps and often multiple procedures to fight the infection and recover lost tissue. Releasing an antibiotic followed by an osteogenic agent from a synthetic bone graft substitute could allow for a streamlined treatment, reducing the need for multiple surgeries and thereby shortening recovery time. Tailorable bilayered calcium sulfate (CS) bone graft substitutes were developed with the ability to sequentially release multiple therapeutic agents. Bilayered composite samples having a shell and core geometry were fabricated with varying amounts (1 or 10 wt%) of metronidazole-loaded poly poly(lactic-co-glycolic acid) (PLGA) particles embedded in the shell and simvastatin directly loaded into either the shell, core, or both. Microcomputed tomography (MicroCT) images showed the overall layered geometry as well as homogenous distribution of PLGA within the shells. Dissolution studies demonstrated that the amount of PLGA particles (i.e., 1 vs. 10 wt%) had a small but significant effect on the erosion rate (3% vs. 3.4% per day). Mechanical testing determined that introducing a layered geometry had a significant effect on the compressive strength, with an average reduction of 35%, but properties were comparable to mandibular trabecular bone. Sustained release of simvastatin directly loaded into CS demonstrated that changing the shell to core volume ratio dictates the duration of drug release from each layer. When loaded together in the shell or in separate layers, sequential release of metronidazole and simvastatin was achieved. By introducing a tunable layered geometry capable of releasing multiple drugs, CS-based bone graft substitutes could be tailored in order to help streamline multiple steps needed to regenerate tissue in infected defects.

Self-Setting Calcium Phosphate Cements with Tunable Antibiotic Release Rates for Advanced Antimicrobial Applications

“…Still, different inorganic powder properties have been previously modified in an attempt to control the drug release kinetics, though mostly in a robust, unsystematic way, allowing for no truly tunable controlled release to be achieved. These intrinsic parameters have included the powder composition, particle size, crystallinity, porosity, − concentration of dopants, polymorphic transitions, particle shell-to-core volume ratio, rotation speed of nanoparticles in a nanomotor, and so on. In this study, we demonstrate for the first time that the kinetics of the mechanism of formation of a solid compound can be controlled to produce tunable and numerically fittable drug release profiles.…”

Mechanism of formation governs the mechanism of release of antibiotics from calcium phosphate nanopowders and cements in a drug-dependent manner

“…The physical parameters used before with limited success include the particle size, 7 crystallinity, 8 porosity, 9 the dopant concentration 10 and the particle shell-to-core volume ratio. 11 An earlier study demonstrated that the kinetics of the formation of a material can be controlled to produce drug release profiles tunable in situ to anywhere between 1 hour and 2 weeks of total release. 12 Specifically, mixing two differently synthesized hydroxyapatite (HAp) powders with a seemingly identical crystallinity and microstructure in different ratios allowed for the in situ adjustment of the rate of release of different antibiotics.…”

Scaffold-mediated sequential drug/gene delivery to promote nerve regeneration and remyelination following traumatic nerve injuries

“…A more intuitive sequential delivery release profile is one with immediate release of the first molecule and a delayed release of the second molecule (Figure 3, Profile 2 [199,200]). This pattern of delivery may be more suitable for applications with antagonistic effects between early and late stage molecules.…”

“…L-b-L architecture has helped to sequentially deliver growth factors [13,239,248,270,278,279], low Mw drugs [280][281][282] and oligonucleotides [283]. Surprisingly, this physical entrapment was shown highly effective in delaying the release of small molecules (low mw drugs and oligonucleotides).…”