Pharmacokinetics of 5-fluorouracil following different routes of intrahepatic administration in the canine model.

In an effort to achieve high concentrations of 5-fluorouracil (5-FUra) in the hepatic circulation while minimizing systemic exposure, several routes of intrahepatic administration were compared in the canine model. To ascertain these data, 5-FUra (30 mg/kg) was given as a bolus into either a systemic vein (femoral vein), hepatic artery, hepatic artery distal to its ligation after hepatic dearterialization, or through the portal vein. Three dogs were studied for each route with concomitant blood samples taken from the inferior vena cava and hepatic vein at 1, 2, 3, 5, 10, 15, 30, and 60 min after injection. 5-FUra levels were determined in plasma by high-pressure liquid chromatography. Blood flow in the portal vein and hepatic artery was measured by an electromagnetic flowmeter. The data were best described by a multicompartmental model including the measured flows. Hepatic components of the model were separate arterial and portal compartments, with elimination from each described by linear kinetics. Analysis of the results indicated that the highest hepatic levels with the least systemic exposure, as indicated by drug levels in hepatic and peripheral vein, were realized following hepatic artery administration distal to its ligation after hepatic dearterialization.

Biological and mechanical characteristics of the interface between a new swelling anchor and bone.

We recently evaluated the peak pullout loads for anchors made from our new copolymeric swelling-type material compared with anchors made of a nonswelling material. In vitro and in vivo peak pullout loads of these anchors were evaluated after different intervals of implantation in the lateral femoral condyles of New Zealand White rabbits. Scanning electron microscopy and energy dispersive x-ray analyses were additionally performed on selected retrieved samples after pullout to examine the characteristics of bone attachment to the implant. The mean peak pullout load was greater for the swelling anchors than for the nonswelling anchors after 48 hours in vitro (46.0 +/- 15.8 compared with 10.8 +/- 9.1 N, p = 0.0541). After 2 weeks in vivo, it was significantly greater for the swelling anchors than for the nonswelling controls (177.7 +/- 41.3 compared with 53.7 +/- 17.5 N, p = 0.0024). The peak pullout load was also greater for the swelling anchors after 8 weeks in vivo; however, this difference was less pronounced than at 2 weeks (101.8 +/- 35.0 compared with 58.9 +/- 9.7 N, p = 0.0508). Furthermore, the swelling implants tended to induce bone deposition at the bone-implant interface. Results from this investigation reveal that the new family of dynamic implants has potential for applications requiring fixation to cancellous or osteoporotic bone.

Role of imaging end points in atherosclerosis trials: focus on intravascular ultrasound.

Increasing attention has been focused on the appropriate role of surrogate markers in the development of novel anti-atherosclerotic therapies. Technological advances in imaging modalities allow for visualisation of the entire arterial wall. Intravascular ultrasound (IVUS) has been increasingly employed to precisely quantify the extent of coronary atherosclerosis. Use of IVUS has provided a number of important insights into the natural history of atherosclerosis and the remodelling changes of the arterial wall in response to plaque accumulation. More recently, clinical trials have employed serial evaluations of arterial segments by IVUS to assess the impact of medical therapies.

Dynamic elastic hysteretic solids and dislocations.

Recently we showed that the quasistatic response of nonlinear mesoscopic elastic solids to stress can be explained by invoking the formation of dislocation-based incipient kink bands. In this Letter, using resonant ultrasound spectroscopy, we confirm that the dynamical behavior of these nonlinear elastic systems is due to the interaction of dislocations with the ultrasound waves, thus resolving a long-standing mystery.

A numerical investigation of the mechanics of swelling-type intramedullary hip implants.

The novel concept of swelling-type intramedullary hip implants that attain self-fixation by an expansion-fit mechanism resulting from controlled swelling of the implant (by absorption of body fluids) was examined in detail using a finite element model of the implant-femur system. Some of the potential advantages of this technique over traditional techniques include enhanced fixation, lower relative micromotions, improved bony ingrowth, and elimination of acrylic cement. The finite element model created in this study incorporated: (i) the major aspects of the three-dimensional geometry of the implant and femur, (ii) the anisotropic elastic properties of bone and implant materials and the changes in orientation of the principal axes of anisotropy along the length of the implant-femur system, (iii) a layer of cancellous bone between the implant and cortical bone in the proximal femoral region, and (iv) frictional sliding between the bone and implant. The model was used to study quantitatively the parametric influence of various material design variables on the micromotions and stress fields in the bone-swelling-type implant system. The results of the finite element analyses were used to establish material behavior goals and provide targets for a material development study.

Fixation strength of swellable bone anchors in low-density polyurethane foam.

This study represents a natural extension of our previous efforts in the design and development of a new class of swellable bone anchors, which absorb body fluids and achieve fixation by an expansion-fit mechanism. Specifically, this study investigates (i) correlations between the optimal swelling strain for highest fixation strength and the foam (or bone) density, and (ii) the influence of a threaded surface on the fixation strength of the swellable implant. For this purpose, the immediate and the final (after swelling) fixation strengths of two variations of the swellable bone anchor designs (a smooth anchor and a screw anchor) were measured in two different foams (used to simulate bone) with different densities. The amount of swelling was varied systematically for each foam and anchor design combinations. This study indicates that the screw swellable anchors have higher initial fixation strength than smooth swellable anchors, but the final fixation strengths of both anchors are quite similar. Further, it is observed that the optimal swelling strain decreased with increasing foam density. Both the smooth and screw swellable anchors were also found to exhibit higher fixation strengths than the metallic screws of similar geometry.

Development of self-anchoring bone implants. I. Processing and material characterization.

We recently designed and produced a family of new swelling-type materials that are potentially capable of self-fixation in bone. These materials are designed to absorb body fluids and swell by small amounts, which will allow the implants made from these materials to achieve self-fixation by an expansion-fit mechanism. The developed material system is essentially a crosslinked random copolymer based on poly (methyl methacrylate-acrylic acid). For potential structural (load-bearing) bioimplant applications, we reinforced this copolymer with AS-4 carbon and Kevlar 49 fibers. The details of processing these materials and the steps involved in optimizing their microstructures are presented in this article. A set of mechanical tests were performed on these materials in both dry and swollen conditions to measure their moduli and yield strengths. In the dry state, the copolymers were found to exhibit Young's moduli in the range of 3 to 4 GPa and yield strengths in the range of 70 to 85 MPa. The reinforced composites exhibited moduli in the range of 15 to 65 GPa and yield strengths in the range of 125 to 500 MPa. Upon controlling the volumetric swelling in these materials to be less than about 10%, the loss in mechanical properties was found to be less than about 30%. These hygromechanical properties are well suited for self-anchoring bone implant applications.

Fully reversible, dislocation-based compressive deformation of Ti3SiC2 to 1 GPa.

Dislocation-based deformation in crystalline solids is almost always plastic. Here we show that polycrystalline samples of Ti3SiC2 loaded cyclically at room temperature, in compression, to stresses up to 1 GPa, fully recover on the removal of the load, while dissipating about 25% (0.7 MJ x m(-3)) of the mechanical energy. The stress-strain curves outline fully reversible, rate-independent, closed hysteresis loops that are strongly influenced by grain size, with the energy dissipated being significantly larger in the coarse-grained material. At temperatures greater than 1,000 degrees C, the loops are open, the response is strain-rate dependent, and cyclic hardening is observed. This hitherto unreported phenomenon is attributed to the reversible formation and annihilation of incipient kink bands at room-temperature deformation. At higher temperatures, the incipient kink bands dissociate and coalesce to form regular irreversible kink bands. The loss factor for Ti3SiC2 is higher than most woods, and comparable to polypropylene and nylon. The technological implications of having a stiff, lightweight machinable ceramic that can dissipate up to 25% of the mechanical energy per cycle are discussed.

Kinking nonlinear elastic solids, nanoindentations, and geology.

The physical mechanism responsible for nonlinear elastic, hysteretic, and discrete memory response of nonlinear mesoscopic elastic solids has to date not been identified. We show, by nanoindenting mica single crystals, that this response is most likely due to the formation of dissipative and fully reversible, dislocation-based kink bands. We further claim that solids with high c/a ratios, which per force are plastically anisotropic, should deform by kinking, provided they do not twin. These kinking nonlinear elastic solids include layered ternary carbides, nitrides, oxides, and semiconductors, graphite, and the layered phases, such as mica, present in nonlinear mesoscopic elastic solids.