This study investigated the efficacy of a combination gene therapy to repress IL-1 and RANKL for the treatment of particulate debris-induced aseptic loosening, and tried to explore the molecular mechanism the exogenous gene modifications on osteoclastogenesis. RAW cells activated by titanium particles were transduced with DFG-IL-1Ra and AAV-OPG individually or in combination for 4 weeks. Pro-inflammatory cytokines in culture media were determined by ELISA, and gene expressions of RANK, IL-1β, c-Fos, TRAF6, JNK1, and CPK were examined using real-time PCR. An established knee-implant-failure mouse model was employed to evaluate the efficacy of the in vivo double-gene therapy. The surgical implantation of a titanium alloy pin into the proximal tibia was followed by monthly challenge with titanium debris. Peri-implant gene transfers of IL-1Ra and OPG (respectively or in combination) were given three weeks after surgery. The combination of OPG and IL-1Ra gene transfer exhibited strong synergetic effects in blockage of inflammation and osteoclastogenesis at 8-weeks after gene modification. The combination therapy reversed peri-implant bone resorption and restored implant stability when compared with either single gene transduction. Real-time PCR data indicated that the action of IL-1Ra gene therapy may be mediated via the JNK1 pathway, while the reduction of osteoclastogenesis by OPG gene modification may be regulated by c-Fos expression. In addition, both gene modifications resulted in significantly diminishment of TRAF6 expression.
A novel drug delivery system incorporating human serum albumin, poly(lactic-co-glycolic acid, magnetite nanoparticles, and therapeutic agent(s) was developed for potential application in the treatment of diseases such as rheumatoid arthritis and skin cancer. An oil-in-oil emulsion/solvent evaporation (O/OSE) method was modified to produce a drug delivery system with a diameter of 0.5–2 μm. The diameter was mainly controlled by adjusting the viscosity of albumin in the discontinuous phase of the O/OSE method. The drug-release study showed that the release of drug and albumin was mostly dependent on the albumin content of the drug delivery system, which is very similar to the drug occlusion-mesopore model. Cytotoxicity tests indicated that increasing the albumin content in the drug delivery system increased cell viability, possibly due to the improved biocompatibility of the system. Overall, these studies show that the proposed system could be a viable option as a drug delivery system in the treatment of many illnesses, such as rheumatoid arthritis, and skin and breast cancers.
Biomimetic composites were constructed using anorganic bone to initiate the polymerization of cyclic lactones. The resulting anorganic bone/polylactone composites preserve the inorganic structure and the mechanical properties of the original bone. Thermal conditions used to prepare the anorganic bone were shown to control the surface functionalities, surface area, and crystallinity, all of which influence the rates of subsequent polymerizations. Thermal pretreatment of anorganic bone was examined as a function of time and temperature, ranging from 400°C to 800°C. Polymerization rates of different monomers were also compared. Additionally, in vitro evaluations of anorganic bone/poly-L-lactide and anorganic bone/polyglycolide composites for osteoblast and osteoclast competence suggest that these composites are good candidates for potential in vivo use, since both composites promoted osteoblast differentiation. The anorganic bone/poly-L-lactide composite also promoted osteoclast differentiation.
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