Antimicrobial dental composites with K18-methyl methacrylate and K18-filler.

OBJECTIVE: To determine the effects of using K18-methyl methacrylate (K18-MMA) and K18-Filler on composite cure, esthetic, mechanical, polymerization shrinkage, and antimicrobial properties. METHODS: K18-MMA (0-20% w/w) was used to replace TEGDMA in a 70:30 Bis-GMA:TEGDMA composite filled to 70% w/w with barium glass or K18-Filler. Composite degree of cure (Rockwell15T hardness and near Infrared FTIR), hydrophilicity (contact angle measurements), translucency (transparency parameter measurements, TP), mechanical (3-point bend test), polymerization shrinkage (volumetric shrinkage and shrinkage stress), and antimicrobial properties (colony counting assay) against Streptococcus mutans, Streptococcus sanguinis, and Candida albicans were determined. RESULTS: All experimental groups had comparable degrees of cure (near Infrared FTIR and Rockwell15T Hardness), TP, moduli, polymerization volumetric shrinkages and shrinkage stresses to those of controls (Bonferroni corrected p > 0.0018). Only one group (15% K18-MMA+K18-Filler) had significantly different (lower) contact angles as compared to that of controls (Bonferroni corrected p < 0.0018). Most of the K18-Filler-containing composites had significantly lower ultimate transverse strengths (UTS) than controls (Bonferroni corrected p < 0.0018). Controls had significantly greater S mutans colony counts than 15% and 20% w/w K18-MMA+K18-Filler groups, and greater S sanguinis and C albicans colony counts than K18-containing groups. Of the composites with that provided significant antimicrobial properties against S. mutans, S. sanguinis, and C. albicans, only the 20% K18-MMA+K18-Filler group had significantly lower UTS than controls. SIGNIFICANCE: Composites with K18-MMA and K18-Filler with comparable physical properties to control composites and significant antimicrobial properties have been developed. K18-MMA and K18-Filler seem to be suitable for incorporation into commercial dental resins.

A low-shrinkage, hydrophobic, degradation-resistant, antimicrobial dental composite using a fluorinated acrylate and an oxirane.

OBJECTIVE: To develop a low shrinkage, hydrophobic, degradation-resistant, antimicrobial dental composite using a fluorinated acrylate, and a difunctional oxirane. METHODS: The effects of a fluorinated acrylate (2-(perfluorooctyl)ethyl acrylate; PFOEA), a difunctional oxirane (EPALLOY™ 5001; EP5001), and a three-component initiator system (camphorquinone/ethyl 4-dimethylaminobenzoate/4-Isopropyl-4'-methyldiphenyl iodonium Tetrakis (pentafluorophenyl) borate; CQ/EDMAB/Borate) on bisphenol A glycidyl dimethacrylate: triethylene glycol dimethacrylate (BisGMA:TEGDMA) composite surface hardness, degree of monomer-to-polymer conversion, hydrophobicity, translucency, mechanical properties, polymerization shrinkage and shrinkage stress, degradation, water imbibition, and antimicrobial properties were determined. RESULTS: Overall the experimental composites had comparable mechanical properties and lower volumetric polymerization shrinkage and shrinkage stress as compared to BisGMA:TEGDMA controls. Addition of PFOEA increased composite hydrophobicity, but it decreased degree of cure, ultimate transverse strength, and translucency. It also decreased polymerization shrinkage and shrinkage stress. The use of the CQ/EDMAB/Borate initiator system was beneficial for the cure and mechanical properties of the 30% w/w PFOEA group. However, it decreased the hydrophobicity and translucency of those composites. The addition of EP5001, at the low concentration used in this work, did not contribute to reduced polymerization volumetric shrinkage or antimicrobial properties, but it did reduce shrinkage stress. CONCLUSIONS: A mechanically viable hydrophobic composite system with reduced polymerization shrinkage and shrinkage stress has been developed by adding PFOEA and EP5001. However, the addition of EP5001 did not render the composite antimicrobial due to the low concentration used. Further research is needed to determine the lowest concentration at which EP5001 provides antimicrobial activity. The composites developed here have the potential to improve longevity of traditional BisGMA:TEGDMA composite systems.

Non-toxic HSC Transplantation-Based Macrophage/Microglia-Mediated GDNF Delivery for Parkinson's Disease.

Glial cell-line-derived neurotrophic factor (GDNF) is a potent neuroprotective agent in cellular and animal models of Parkinson's disease (PD). However, CNS delivery of GDNF in clinical trials has proven challenging due to blood-brain barrier (BBB) impermeability, poor diffusion within brain tissue, and large brain size. We report that using non-toxic mobilization-enabled preconditioning, hematopoietic stem cell (HSC) transplantation-based macrophage-mediated gene delivery may provide a solution to overcome these obstacles. Syngeneic bone marrow HSCs were transduced ex vivo with a lentiviral vector expressing macrophage promoter-driven GDNF and transplanted into 14-week-old MitoPark mice exhibiting PD-like impairments. Transplant preconditioning with granulocyte colony-stimulating factor (G-CSF) and AMD3100 was used to vacate bone marrow stem cell niches. Chimerism reached ∼80% after seven transplantation cycles. Transgene-expressing macrophages infiltrated degenerating CNS regions of MitoPark mice (not wild-type littermate controls), resulting in increased GDNF levels in the midbrain. Macrophage GDNF delivery not only markedly improved motor and non-motor dysfunction, but also dramatically mitigated the loss of dopaminergic neurons in both substantia nigra and the ventral tegmental area and preserved axonal terminals in the striatum. Striatal dopamine levels were almost completely restored. Our data support further development of mobilization-enabled HSC transplantation (HSCT)-based macrophage-mediated GDNF gene delivery as a disease-modifying therapy for PD.

GDNF-expressing macrophages mitigate loss of dopamine neurons and improve Parkinsonian symptoms in MitoPark mice.

Glial cell line-derived neurotrophic factor (GDNF) is the most potent neuroprotective agent tested in cellular and animal models of Parkinson's disease (PD). However, CNS delivery of GDNF is restricted by the blood-brain barrier (BBB). Using total body irradiation as transplant preconditioning, we previously reported that hematopoietic stem cell (HSC) transplantation (HSCT)-based macrophage-mediated gene therapy could deliver GDNF to the brain to prevent degeneration of nigrostriatal dopamine (DA) neurons in an acute murine neurotoxicity model. Here, we validate this therapeutic approach in a chronic progressive PD model - the MitoPark mouse, with head shielding to avoid inducing neuroinflammation and compromising BBB integrity. Bone marrow HSCs were transduced ex vivo with a lentiviral vector expressing macrophage promoter-driven GDNF and transplanted into MitoPark mice exhibiting well developed PD-like impairments. Transgene-expressing macrophages infiltrated the midbrains of MitoPark mice, but not normal littermates, and delivered GDNF locally. Macrophage GDNF delivery markedly improved both motor and non-motor symptoms, and dramatically mitigated the loss of both DA neurons in the substantia nigra and tyrosine hydroxylase-positive axonal terminals in the striatum. Our data support further development of this HSCT-based macrophage-mediated GDNF delivery approach in order to address the unmet need for a disease-modifying therapy for PD.