Shula Radin

Calcium phosphate ceramic coatings as carriers of vancomycin.

Infection in the setting of total joint arthroplasty remains a challenging problem. Attention has turned to developing methods of local delivery of antibiotics for prophylaxis. Vancomycin loaded into calcium phosphate ceramic coatings on titanium alloy substrates is a clinically relevant concept in the setting of total joint arthroplasty. Drug loading was accomplished by immersion of ceramic-coated discs in vancomycin-containing simulated physiological solution; in some experiments drug loading by immersion was followed by lipid coating in egg phosphatidylcholine solutions. The kinetics of vancomycin release and the efficacy of drug inhibition of Staphylococcus aureus were determined in vitro in comparison to the release from currently used antibiotic-laden poly(methyl methacrylate) (PMMA). The loading by immersion provided effective release and inhibition at early time points (up to 24 h); however, the lipid-coated samples demonstrated significant release and effective bacterial inhibition up to 72 h. The two-step procedure, i.e. drug loading followed by lipid coating in order to slow antibiotic elution, is more effective than the conventional one-step loading. The study indicated that the osteoconductive calcium phosphate coatings have the potential to serve as drug carriers to prevent infection in the setting of total joint arthroplasty.

Effect of calcium phosphate coating characteristics on early post-operative bone tissue ingrowth

The synthesis of model porous metal-CPC materials, and their use in one-parametric studies of bone tissue ingrowth enhancement were considered. By using the same starting calcium-deficient hydroxyapatite powder, three different coatings, CAP1, CAP2 and CAP3, were obtained of thicknesses 50 +/- 5, 75 +/- 5 and 75 +/- 5 microns, respectively. CAP1 and 2 were either the starting powder mixed in a 3:1 ratio CPC: poly(lactic acid) or the powder by itself. The CAP3 coating was the result of a thermal treatment producing a mixture of oxyhydroxyapatite, alpha- and beta-tricalcium phosphate. Orderly oriented wire mesh porous coated specimens were implanted, along with the same specimens lined with CAP 1, 2 or 3. Subsequently, the total of 156 specimens was retrieved at 2, 4 or 6 wk, and tested mechanically and processed for histomorphometry. The data produced considerable evidence for the CPC-dependent enhancement of bone tissue ingrowth in porous metals immediately after implantation. They prove that the materials processing of CPC coatings influences the resulting biological behaviour substantially. Furthermore, they support the hypothesis that ceramic dissolution is a causative factor on the bone tissue growth enhancement mechanisms.

In vitro bioactivity and degradation behavior of silica xerogels intended as controlled release materials

Room temperature-processed silica-based sol-gel, termed silica xerogel, is a novel type of controlled release material. As shown previously, these materials are porous, degradable and can release biologically functional molecules in a controlled manner. It was also demonstrated that these materials are biocompatible in vivo. Herein we report on the ability of silica-based xerogels to form a bioactive, apatite-like (AP) surface and the effect of AP surface on the xerogel stability in vitro. Formation of a crystalline, carbonated AP (c-AP) was found on all silica xerogels studied, with or without Ca- and P-oxides. Calcium and phosphate (Ca-P) free xerogels showed long times to Ca-P precipitation and to formation of a detectable AP-layer (up to 2 weeks). In contrast, the times to precipitation were reduced by 2-3 orders of magnitude, and the c-AP layer was formed within 24 h on all Ca-P containing xerogels. Mechanisms of the c-AP formation on these xerogels were similar to those typical for Ca-P based ceramics: dissolution of calcium and phosphate ions, solution oversaturation with respect to AP and subsequent precipitation of bone-like minerals. The presence of the c-AP surface film produced a remarkable surface stabilizing effect: the rates and the amounts of Si release were significantly reduced in comparison to those for xerogels without the film. This evidence of in vitro bioactivity and controlled degradation, combined with previous in vitro and in vivo reports, suggests that silica xerogel is a promising controlled release material.

The controlled release of drugs from emulsified, sol gel processed silica microspheres

Controlled release silica sol gels are room temperature processed, porous, resorbable materials with generally good compatibility. Many molecules including drugs, proteins and growth factors can be released from sol gels and the quantity and duration of the release can vary widely. Processing parameters render these release properties exquisitely versatile. The synthesis of controlled release sol gels typically includes acid catalyzed hydrolysis to form a sol with the molecules included. This is then followed by casting, aging and drying. Additional steps such as grinding and sieving are required to produce sol gel granules of a desirable size. In this study, we focus on the synthesis of sol gel microspheres by using a novel process with only two steps. The novelty is related to acid-base catalysis of the sol prior to emulsification. Sol gel microspheres containing either vancomycin (antibiotic) or bupivacaine (analgesic) were successfully synthesized using this method. Both drugs showed controlled, load dependent and time dependent release from the microspheres. The in vitro release properties of sol gel microspheres were remarkably different from those of sol gel granules produced by grinding and sieving. In contrast to a fast, short-term release from granules, the release from microspheres was slower and of longer duration. In addition, the degradation rate of microspheres was significantly slower than that of the granules. Using various mathematical models, the data reveal that the release from sol gel powder is governed by two distinct phases of release. In addition, the release from emulsified microspheres is delayed, a finding that can be attributed to differences in surface properties of the particles produced by emulsification and those produced by casting and grinding. The presented results represent an excellent data set for designing and implementing preclinical studies.

Controlled release of vancomycin from thin sol-gel films on implant surfaces successfully controls osteomyelitis.

Peri‐prosthetic infection remains a serious complication of joint replacement surgery. Herein, we demonstrate that a vancomycin‐containing sol‐gel film on Ti alloy rods can successfully treat bacterial infections in an animal model. The vancomycin‐containing sol‐gel films exhibited predictable release kinetics, while significantly inhibiting S. aureus adhesion. When evaluated in a rat osteomyelitis model, microbiological analysis indicated that the vancomycin‐containing sol‐gel film caused a profound decrease in S. aureus number. Radiologically, while the control side showed extensive bone degradation, including abscesses and an extensive periosteal reaction, rods coated with the vancomycin‐containing sol‐gel film resulted in minimal signs of infection. µCT analysis confirmed the radiological results, while demonstrating that the vancomycin‐containing sol‐gel film significantly protected dense bone from resorption and minimized remodeling. These results clearly demonstrate that this novel thin sol‐gel technology can be used for the targeted delivery of antibiotics for the treatment of periprosthetic as well as other bone infections.

Nanostructural Control of Implantable Xerogels for the Controlled Release of Biomolecules

Based on the in vitro and the in vivo analyses, silica xerogels can be characterized as resordable and biocompatible materials for the controlled release of drugs and larger biologically active molecules.

Bactericidal micron-thin sol-gel films prevent pin tract and periprosthetic infection.

Orthopedic injuries constitute the majority of wounds sustained by U.S. soldiers in recent conflicts. The risk of infection is considerable with fracture fixation devices. In this pilot study, we examined the use of unique bactericidal micron-thin sol-gel films on fracture fixation devices and their ability to prevent and eradicate infections. External fixation was studied with micron-thin sol-gel coated percutaneous pins releasing triclosan and inserted medially into rabbit tibiae. A total of 11 rabbits received percutaneous pins that were either uncoated or sol-gel/triclosan coated. Internal fracture fixation was also studied using sol-gel coated intramedullary (IM) nails releasing vancomycin in the intramedullary tibiae. Six sheep received IM nails that were coated with a sol-gel film that either contained vancomycin or did not contain vancomycin. All animals were challenged with Staphylococcus aureus around the implant. Animals were euthanized at 1 month postoperative. Rabbits receiving triclosan/sol-gel coated percutaneous pins did not show signs of infection. Uncoated percutaneous pins had a significantly higher infection rate. In the sheep study, there were no radiographic signs of osteomyelitis with vancomycin/sol-gel coated IM nails, in contrast to the observations in the control cohort. Hence, the nanostructured sol-gel controlled release technology offers the promise of a reliable and continuous delivery system of bactericidals from orthopedic devices to prevent and treat infection.

Solution Mediated Effect of Bioactive Glass in Poly (Lactic-Co-Glycolic Acid)- Bioactive Glass Composites on Osteogenesis of Marrow Stromal Cells

A previous study demonstrated that the incorporation of bioactive glass (BG) into poly (lactic-co-glycolic acid) (PLGA) can promote the osteoblastic differentiation of marrow stromal cells (MSC) on PLGA by forming a calcium phosphate rich layer on its surface. To further understand the mechanisms underlying the osteogenic effect of PLGA-BG composite scaffolds, we tested whether solution-mediated factors derived from composite scaffolds/hybrids can promote osteogenesis of marrow stromal cells. The dissolution product from PLGA-30%BG scaffold stimulated osteogenesis of MSC, as was confirmed by increased mRNA expression of osteoblastic markers such as osteocalcin (OCN), alkaline phosphatase (ALP), and bone sialoprotein (BSP). The three-dimensional structure of the scaffolds may contribute to the production of cell derived factors which promoted distant MSC differentiation. Thus PLGA-BG composites demonstrates significant potential as a bone replacement material.

In Vitro and In Vivo Bactericidal Effect of Sol-Gel/Antibiotic Thin Films on Fixation Devices

Beneficial properties of room temperature processed silica sol-gels as resorbable and biocompatible materials for the controlled release of drugs and macromolecules have been described before. Recently, it was shown that a thin sol-gel film can be used for the controlled delivery of antibiotics such as vancomycin. It was also demonstrated that the release and degradation properties of the sol-gel films can be tailored via processing parameters. In this work, we evaluated the in vitro and in vivo bactericidal effects of vancomycin-containing thin sol-gel films applied on Ti-alloy intramedullary nails. Both the in vitro and the in vivo results demonstrate a pronounced bactericidal effect of the sol-gel/antibiotic films. This study suggests that thin antibiotic-containing sol-gel film holds great promise for the prevention and treatment of bone infections.

Thin Sol-Gel Films on Fracture Fixation Material for the Controlled Release of Antibiotics

Previously, the properties of room temperature processed silica sol gel (also called xerogels) as resorbable and biocompatible controlled release systems were described. It was demonstrated that drugs and macromolecules with a variety of properties and characteristics could be released in a controlled manner. In this study, we focus on the synthesis of antibacterial thin solgel films on intramedullary nails and fracture fixation materials. We determine the effect of processing parameters on the in vitro properties and demonstrated a time- and load- dependent release of vancomycin from the film. This study suggests that thin sol-gel films hold great promise for the prevention and treatment of bone infections.