RF-powered BIONs for stimulation and sensing.

Virtually all bodily functions are controlled by electrical signals in nerves and muscles. Electrical stimulation can restore missing signals but this has been difficult to achieve practically because of limitations in the bioelectric interfaces. Wireless, injectable microdevices are versatile, robust and relatively inexpensive to implant in a variety of sites and applications. Several variants are now in clinical use or under development to perform stimulation and/or sensing functions and to operate autonomously or with continuous coordination and feedback control.

Phase I and pharmacokinetic study of the novel MDR1 and MRP1 inhibitor biricodar administered alone and in combination with doxorubicin.

PURPOSE: To evaluate the safety, tolerability, and pharmacokinetics of biricodar (VX-710), an inhibitor of P-glycoprotein (P-gp) and multidrug resistance-associated protein (MRP1), alone and with doxorubicin in patients with advanced malignancies. The effect of VX-710 on the tissue distribution of (99m)Tc-sestamibi, a P-gp and MRP1 substrate, was also evaluated. PATIENTS AND METHODS: Patients with solid malignancies refractory to standard therapy first received a 96-hour infusion of VX-710 alone at 20 to 160 mg/m(2)/h. After a 3-day washout, a second infusion of VX-710 was begun, on the second day of which doxorubicin 45 mg/m(2) was administered. Cycles were repeated every 21 to 28 days. (99m)Tc-sestamibi scans were performed before and during administration of VX-710 alone. RESULTS: Of the 28 patients who enrolled, 25 patients were eligible for analysis. No dose-limiting toxicity (DLT) was observed in the nine assessable patients who received 120 mg/m(2)/h or less. Among seven patients receiving VX-710 160 mg/m(2)/h, two DLTs were seen: reversible CNS toxicity and febrile neutropenia. All other adverse events were mild to moderate and reversible. Plasma concentrations of VX-710 in patients who received at 120 and 160 mg/m(2)/h were two- to fourfold higher than concentrations required to fully reverse drug resistance in vitro. VX-710 exhibited linear pharmacokinetics with a harmonic mean half-life of 1.1 hours. VX-710 enhanced hepatic uptake and retention of (99m)Tc-sestamibi in all patients. CONCLUSION: A 96-hour infusion of VX-710 at 120 mg/m(2)/h plus doxorubicin 45 mg/m(2) has acceptable toxicity in patients with refractory malignancies. The safety and pharmacokinetics of VX-710 plus doxorubicin warrant efficacy trials in malignancies expressing P-gp and/or MRP1.

BION system for distributed neural prosthetic interfaces.

We have developed the first in a planned series of neural prosthetic interfaces that allow multichannel systems to be assembled from single-channel micromodules called BIONs (BIOnic Neurons). Multiple BION implants can be injected directly into the sites requiring stimulating or sensing channels, where they receive power and digital commands by inductive coupling to an externally generated radio-frequency magnetic field. This article describes some of the novel technology required to achieve the required microminiaturization, hermeticity, power efficiency and clinical performance. The BION1 implants are now being used to electrically exercise paralyzed and weak muscles to prevent or reverse disuse atrophy. This modular, wireless approach to interfacing with the peripheral nervous system should facilitate the development of progressively more complex systems required to address a growing range of clinical applications, leading ultimately to synthesizing complete voluntary functions such as reach and grasp.

Phase I study in advanced cancer patients of a diversified prime-and-boost vaccination protocol using recombinant vaccinia virus and recombinant nonreplicating avipox virus to elicit anti-carcinoembryonic antigen immune responses.

PURPOSE: This trial sought to determine, for the first time, the validity in human vaccinations of using two different recombinant vaccines in diversified prime-and-boost regimens to enhance T-cell responses to a tumor antigen. PATIENTS AND METHODS: Eighteen patients with advanced tumors expressing carcinoembryonic antigen (CEA) were randomized to receive either recombinant vaccinia (rV)-CEA followed by three avipox-CEA vaccinations, or avipox-CEA (three times) followed by one rV-CEA vaccination. Subsequent vaccinations in both cohorts were with avipox-CEA. Immunologic monitoring was performed using a CEA peptide and the enzyme-linked immunospot assay for interferon gamma production. RESULTS: rV-CEA followed by avipox-CEA was superior to the reverse order in the generation of CEA-specific T-cell responses. Further increases in CEA-specific T-cell precursors were seen when local granulocyte-macrophage colony-stimulating factor (GM-CSF) and low-dose interleukin (IL)-2 were given with subsequent vaccinations. The treatment was extremely well tolerated. Limited clinical activity was seen using vaccines alone in this patient population. Antibody production against CEA was also observed in some of the treated patients. CONCLUSION: rV-CEA was more effective in its role as a primer of the immune system; avipox-CEA could be given up to eight times with continued increases in CEA T-cell precursors. Future trials should use rV-CEA first followed by avipox-CEA. Vaccines specific to CEA are able to generate CEA-specific T-cell responses in patients without significant toxicity. T-cell responses using vaccines alone may be inadequate to generate significant anticancer objective responses in patients with advanced disease. Cytokines such as GM-CSF and IL-2 may play a key role in generating such responses.

Micromodular implants to provide electrical stimulation of paralyzed muscles and limbs.

We describe the design, fabrication, and output capabilities of a microminiature electrical stimulator that can be injected in or near nerves and muscles. Each single-channel microstimulator consists of a cylindrical glass capsule with hermetically sealed electrodes in either end (2-mm diameter x 13-mm overall length). Power and digital control data can be transmitted to multiple implants (256 unique addresses) via a 2-MHz RF field created by an external AM oscillator and inductive coil. In vitro testing demonstrated accurate control of output pulsewidth (3-258 microseconds in 1-microseconds steps) and current (0-30 mA in two linear ranges of 16 steps each, up to 8.5 V available compliance voltage). Microstimulators were used successfully for chronic stimulation in hindlimb muscles of cats. Design and fabrication issues affecting yield and reliability of the packaging and electronics are discussed.

Cuff electrodes for chronic stimulation and recording of peripheral nerve activity.

A comparative study of 5 different designs of nerve cuff electrodes was undertaken to determine their relative merits for stimulating and recording whole-nerve activity over extended periods of chronic implantation on large and small peripheral nerves in 8 cats. Four of the designs represent novel fabrication strategies, including 2 based on flexible, thin-film substrates and 2 based on dip-coating silicone elastomer on a cylindrical mandrel. Various advantages and shortcomings of these materials and designs are discussed in the context of the biophysical factors that influence these electrophysiological interfaces, particularly the problem of recording microvolt-level neurograms in the presence of millivolt-level electromyograms from adjacent muscles in freely behaving subjects. The most effective design was one in which a thin sheath of silicone rubber was wrapped around and intra-operatively sealed to a longitudinally slit, tripolar cuff made by dip-coating silicone over stranded stainless steel leads that were prepositioned on a mandrel using polyvinyl alcohol as a temporary adhesive. When properly installed, these electrodes had stable impedances, recruitment thresholds and relatively interference-free recording properties for the duration of this study (up to 9 weeks).

Microminiature molding techniques for cochlear electrode arrays.

We provide a general method for producing a variety of small, complex electrode arrays based on injection molds produced using computer-aided drafting and machining (CAD-CAM) procedures and a novel method for connecting to the very fine electrical leads associated with the individual contacts of such arrays. Cat-sized cochlear electrode arrays with up to eight contacts were built according to these methods and their electrical contacts were characterized in vitro by impedance spectroscopy and in vivo by monitoring impedance for over 1 year of intermittent stimulation in chronically instrumented animals.

Toward the ultimate metal microelectrode.

The performance of metal microelectrodes for stimulating and recording neuronal action potentials depends on precise control of their geometrical, electrical and mechanical properties. We describe a combination of materials whose properties approach fundamental physical limitations on achievable performance and reproducible fabrication techniques that provide probes with very small dimensions. Pure iridium wire is electrolytically sharpened, vapor-coated with Parylene-C insulation and the tip exposed using an automatically steerable UV laser. Electrochemical activation of the iridium increases the capacitance of the metal-electrolyte interface so that the overall impedance in the relevant frequency band (100-10,000 Hz) is dominated by the access resistance of the surrounding tissues.

Collimator-produced energy degradation of megavoltage x rays.

Monte Carlo computer calculations have been made to assess the effects of small collimators (i.e., output field sizes less than or equal to 1 cm) on megavoltage x-ray beams. Such collimators are often used in experiments to measure beam energy, half value layers, and other beam parameters. Our calculations demonstrate, however, that such procedures can introduce significant changes in these same parameters. Under certain conditions, more than 40% of the transmitted photons exiting the collimator do so with degraded energy. Optimum collimator design, however, can greatly reduce these effects. In particular, it is shown that the thickness of material required to effect a good collimator is not only dependent upon the photon energy, but also upon the size of the collimator hole.

In vitro sublethal damage repair in tumour subpopulations from a heterogeneous human colon tumour.

The repair of sublethal radiation damage in two asynchronously growing tumour cell subpopulations (clones A and D) obtained from a single human adenocarcinoma biopsy specimen has been studied. The survival data found after generation of complete survival curves from split dose experiments in which exposures were separated by 3, 6, 12, or 24 h were examined. It was found that the method of performing irradiations (e.g., suspension cultures versus monolayer cultures) affected the shape of the single dose response curves, and as a result the interpretation of the amount of sublethal damage repair occurring after split dose irradiation.

Models in radiotherapy: volume effects.

A model for the dependence of normal tissue radiation dose response functions on volume variations and dose inhomogeneities is derived using probability theory. Power law volume correction factors and the complication probability factor are shown to be special cases arising from approximations applied to this model. Both require the assumption of small probabilities of complication. Power law volume corrections are shown to require a homogeneous dose distribution. The general model is tissue specific and can be used to calculate probabilities of complication for individual organs or isoprobability doses for radiation injury. The model is applicable to both homogeneous and inhomogeneous dose distributions and has been used in computer determination of optimal treatment parameters. Experimental data are presented which are consistent with the general model alone and which demonstrate the limits of applicability of previous models.