Evaluating intra-articular drug delivery for the treatment of osteoarthritis in a rat model.

Osteoarthritis (OA) is a degenerative joint disease that can result in joint pain, loss of joint function, and deleterious effects on activity levels and lifestyle habits. Current therapies for OA are largely aimed at symptomatic relief and may have limited effects on the underlying cascade of joint degradation. Local drug delivery strategies may provide for the development of more successful OA treatment outcomes that have potential to reduce local joint inflammation, reduce joint destruction, offer pain relief, and restore patient activity levels and joint function. As increasing interest turns toward intra-articular drug delivery routes, parallel interest has emerged in evaluating drug biodistribution, safety, and efficacy in preclinical models. Rodent models provide major advantages for the development of drug delivery strategies, chiefly because of lower cost, successful replication of human OA-like characteristics, rapid disease development, and small joint volumes that enable use of lower total drug amounts during protocol development. These models, however, also offer the potential to investigate the therapeutic effects of local drug therapy on animal behavior, including pain sensitivity thresholds and locomotion characteristics. Herein, we describe a translational paradigm for the evaluation of an intra-articular drug delivery strategy in a rat OA model. This model, a rat interleukin-1beta overexpression model, offers the ability to evaluate anti-interleukin-1 therapeutics for drug biodistribution, activity, and safety as well as the therapeutic relief of disease symptoms. Once the action against interleukin-1 is confirmed in vivo, the newly developed anti-inflammatory drug can be evaluated for evidence of disease-modifying effects in more complex preclinical models.

Progress in intra-articular therapy.

Diarthrodial joints are well suited to intra-articular injection, and the local delivery of therapeutics in this fashion brings several potential advantages to the treatment of a wide range of arthropathies. Possible benefits over systemic delivery include increased bioavailability, reduced systemic exposure, fewer adverse events, and lower total drug costs. Nevertheless, intra-articular therapy is challenging because of the rapid egress of injected materials from the joint space; this elimination is true of both small molecules, which exit via synovial capillaries, and of macromolecules, which are cleared by the lymphatic system. In general, soluble materials have an intra-articular dwell time measured only in hours. Corticosteroids and hyaluronate preparations constitute the mainstay of FDA-approved intra-articular therapeutics. Recombinant proteins, autologous blood products and analgesics have also found clinical use via intra-articular delivery. Several alternative approaches, such as local delivery of cell and gene therapy, as well as the use of microparticles, liposomes, and modified drugs, are in various stages of preclinical development.

Amplitude noise on supercontinuum generated in microstructure fiber: Measurements and simulations

Supercontinua generated in microstructure fiber can exhibit significant excess amplitude noise. We present experimental and numerical studies of the origins of this excess noise and its dependence on the input laser pulse parameters.

Fundamental Amplitude Noise Limitations to Supercontinuum Spectra Generated in a Microstructured Fiber

Broadband supercontinuum spectra are generated in a microstructured fiber using femtosecond laser pulses. Noise properties of these spectra are studied through experiments and numerical simulations based on a generalized stochastic nonlinear Schrödinger equation. In particular, the relative intensity noise as a function of wavelength across the supercontinuum is measured over a wide range of input pulse parameters, and experimental results and simulations are shown to be in good quantitative agreement. For certain input pulse parameters, amplitude fluctuations as large as 50% are observed. The simulations clarify that the intensity noise on the supercontinuum arises from the amplification of two noise inputs during propagation - quantum-limited shot noise on the input pulse, and spontaneous Raman scattering in the fiber. The amplification factor is a sensitive function of the input pulse parameters. Short input pulses are critical for the generation of very broad supercontinua with low noise.

Fundamental Amplitude Noise Limitations to Supercontinuum Spectra Generated in a Microstructured Fiber: Erratum

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Erratum: Fundamental amplitude noise limitations to supercontinuum spectra generated in a microstructured fiber (Appl. Phys. B (2003) 77 (269-277))

SCOPUS: er.j

Particle Image Velocimetry Investigation of a finite amplitude pressure wave

Particle image velocimetry is used to study the motion of gas within a duct subject to the passage of a finite amplitude pressure wave. The wave is representative of the pressure waves found in the exhaust systems of internal combustion engines. Gas particles are accelerated from stationary to 150 m/s and then back to stationary in 8 ms. It is demonstrated that gas particles at the head of the wave travel at the same velocity across the duct cross section at a given point in time. Towards the tail of the wave viscous effects are plainly evident causing the flow profile to tend towards parabolic. However, the instantaneous mean particle velocity across the section is shown to match well with the velocity calculated from a corresponding measured pressure history using 1D gas dynamic theory. The measured pressure history at a point in the duct was acquired using a high speed pressure transducer of the type typically used for engine research in intake and exhaust systems. It is demonstrated that these are unable to follow the rapid changes in pressure accurately and that they are prone to resonate under certain circumstances.

Finite amplitude envelope solitons in pair-ion plasmas

The nonlinear coupling between finite amplitude ion thermal waves (ITWs) and quasistationary density perturbations in a pair-ion plasma is considered. A generalized nonlinear Schrödinger equation is derived for the ITW electric field envelope, accounting for large amplitude quasistationary plasma slow motion describing the ITW ponderomotive force. The present theory accounts for the trapping of ITWs in a large amplitude ion density hole. The small amplitude limit is considered and exact analytical solutions are obtained. Finite amplitude solutions are obtained numerically and their characteristics are discussed.