Dopamine and beta-band oscillations differentially link to striatal value and motor control.

Parkinson's disease is characterized by decreased dopamine and increased beta-band oscillatory activity accompanying debilitating motor and mood impairments. Coordinate dopamine-beta opposition is considered a normative rule for basal ganglia function. We report a breakdown of this rule. We developed multimodal systems allowing the first simultaneous, chronic recordings of dopamine release and beta-band activity in the striatum of nonhuman primates during behavioral performance. Dopamine and beta signals were anticorrelated over seconds-long time frames, in agreement with the posited rule, but at finer time scales, we identified conditions in which these signals were modulated with the same polarity. These measurements demonstrated that task-elicited beta suppressions preceded dopamine peaks and that relative dopamine-beta timing and polarity depended on reward value, performance history, movement, and striatal domain. These findings establish a new view of coordinate dopamine and beta signaling operations, critical to guide novel strategies for diagnosing and treating Parkinson's disease and related neurodegenerative disorders.

The Feelings of Others Don't Impress Me Much - Effects of Living Group Climate on Empathy in Adolescent Male Offenders.

The present study is a replication in Germany of a study originally performed in the Netherlands regarding the association between a positive living group climate and self-reported empathy in incarcerated adolescent male offenders (n = 49). A structural equation model was fitted to the data and showed a relation between a positive living group climate and increased empathy after six months. The discussion focuses on group dynamics in youth prisons. The present results open the way to further research into the importance of group processes in residential youth care. A positive living group climate could turn out to be an important factor contributing to the effectiveness of secure institutional treatment.

Miniaturized, biopsy-implantable chemical sensor with wireless, magnetic resonance readout.

Biopsy is an important diagnostic tool for a broad range of conditions. Cancer diagnoses, for example, are confirmed using tissue explanted with biopsy. Here we demonstrate a miniaturized wireless sensor that can be implanted during a biopsy procedure and return chemical information from within the body. Power and readout are wireless via weak magnetic resonant coupling to an external reader. The sensor is filled with responsive nuclear magnetic resonance (NMR) contrast agents for chemical sensitivity, and on-board circuitry constrains the NMR measurement to the contents. This sensor enables longitudinal monitoring of the same location, and its simple readout mechanism is ideal for applications not requiring the spatial information available through imaging techniques. We demonstrated the operation of this sensor by measuring two metabolic markers, both in vitro and in vivo: pH in flowing fluid for over 25 days and in a xenograft tumor model in mice, and oxygen in flowing gas and in a rat hind-limb constriction experiment. The results suggest that this in vivo sensing platform is generalizable to other available NMR contrast agents. These sensors have potential for use in biomedicine, environmental monitoring and quality control applications.

Electro-thermally induced structural failure actuator (ETISFA) for implantable controlled drug delivery devices based on micro-electro-mechanical-systems.

A new electro-thermally induced structural failure actuator (ETISFA) is introduced as an activation mechanism for on demand controlled drug delivery from a Micro-Electro-Mechanical-System (MEMS). The device architecture is based on a reservoir that is sealed by a silicon nitride membrane. The release mechanism consists of an electrical fuse constructed on the membrane. Activation causes thermal shock of the suspended membrane allowing the drugs inside of the reservoir to diffuse out into the region of interest. The effects of fuse width and thickness were explored by observing the extent to which the membrane was ruptured and the required energy input. Device design and optimization simulations of the opening mechanism are presented, as well as experimental data showing optimal energy consumption per fuse geometry. In vitro release experiments demonstrated repeatable release curves of mannitol-C(14) that precisely follow ideal first order release kinetics. Thermally induced structural failure was demonstrated as a feasible activation mechanism that holds great promise for controlled release in biomedical microdevices.

An implantable MEMS drug delivery device for rapid delivery in ambulatory emergency care.

We introduce the first implantable drug delivery system based on MEMS (Micro-Electro-Mechanical-Systems) technology specifically designed as a platform for treatment in ambulatory emergency care. The device is named IRD(3) (implantable rapid drug delivery device) and allows rapid delivery of drugs. Vasopressin was used as a model drug for in vitro tests as it is a commonly used drug for cardiac resuscitation. Experimental results reveal that the IRD(3) provides an effective method for rapid delivery without significant drug degradation. Several medical uses and delivery modalities for IRD(3) are proposed.

Microchip technology in drug delivery.

The realization that the therapeutic efficacy of certain drugs can be affected dramatically by the way in which they are delivered has created immense interest in controlled drug delivery systems. Much previous work in drug delivery focused on achieving sustained drug release rates over time, while a more recent trend is to make devices that allow the release rate to be varied over time. Advances in microfabrication technology have made an entirely new type of drug delivery device possible. Proof-of-principle experiments have shown that silicon microchips have the ability to store and release multiple chemicals on demand. Future integration of active control electronics, such as microprocessors, remote control units, or biosensors, could lead to the development of a 'pharmacy on a chip,' ie 'smart' microchip implants or tablets that release drugs into the body automatically when needed.

Microchips as Controlled Drug-Delivery Devices.

Controlled-release systems are common in a number of product areas, including foods, cosmetics, pesticides, and paper. Microencapsulated systems, for example, are used for the release of flavors and vitamins in foods, fragrances in perfumes, and inks in carbonless copy paper. Controlled-release systems for drug delivery first appeared in the 1960s and 1970s. In the past three decades, the number and variety of controlled release systems for drug-delivery applications has increased dramatically. Many of these use polymers having particular physical or chemical characteristics such as biodegradability, biocompatibility, or responsiveness to pH or temperature changes. However, recent advances in the field of microfabrication have created the possibility of a new class of controlled-release systems for drug delivery, namely, that of small, programmable devices. Their small size, potential for integration with microelectronics, and ability to store and release chemicals on demand could make controlled-release microchips useful in a number of areas, including medical diagnostics, analytical chemistry, chemical detection, industrial process monitoring and control, combinatorial chemistry, microbiology, and fragrance delivery. More importantly, drug-delivery microchips resulting from this convergence of controlled release and microfabrication technologies may provide new treatment options to clinicians in their fight against disease.

Oral dosage forms fabricated by three dimensional printing.

Three Dimensional Printing is a novel technique used in the fabrication of complex oral dosage delivery pharmaceuticals. It is possible to engineer devices with complicated internal geometries, varying densities and diffusivities, and multiple actives and excipients. Samples were fabricated using this technique using standard pharmaceutical materials. Erosion mechanism delayed-release tablets were constructed with varying polymer content from 8.9 to 17. 9%. Lag times varied between 25 and 50 min with a corresponding decrease in release rate as polymer content increased. Diffusion mechanism tablets were constructed with varying polymer content from 9.0 to 16.7%. The peak release rate decreased and the time to exhaustion increased with polymer content, whereas lag time was not affected. Active delivery studies with fluorescein indicated that Three Dimensional Printing is capable of accurately constructing dosage forms with active content as low as 10(-12) moles per tablet. Hardness and friability testing indicated that samples fabricated with this technique are comparable to other standard pharmaceutical products.

Multimechanism oral dosage forms fabricated by three dimensional printing.

Four types of complex oral drug delivery devices have been fabricated using the three dimensional printing process. Immediate-extended release tablets were fabricated which were composed of two drug-containing sections of different pH-based release mechanisms. Pulsed release of chlorpheniramine maleate occurred after a lag time of 10 min followed by extended release of the compound over a period of 7 h. Breakaway tablets were fabricated composed of three sections. An interior fast-eroding section separating two drug-releasing sub-units eroded in 30-45 min in simulated gastric fluid. Enteric dual pulsatory tablets were constructed of one continuous enteric excipient phase into which diclofenac sodium was printed into two separated areas. These samples showed two pulses of release during in vitro USP dissolution at 1 and 8 h with a lag time between pulses of about 4 h. Dual pulsatory tablets were also fabricated. These samples were composed of two erosion based excipient sections of opposite pH based solubility. One section eroded immediately during the acid dissolution stage releasing diclofenac during the first 30 min, and the second section began eroding 5 h later during the high pH stage.

A controlled-release microchip.

Much previous work in methods of achieving complex drug-release patterns has focused on pulsatile release from polymeric materials in response to specific stimuli, such as electric or magnetic fields, exposure to ultrasound, light or enzymes, and changes in pH or temperature. An alternative method for achieving pulsatile release involves using microfabrication technology to develop active devices that incorporate micrometre-scale pumps, valves and flow channels to deliver liquid solutions. Here we report a solid-state silicon microchip that can provide controlled release of single or multiple chemical substances on demand. The release mechanism is based on the electrochemical dissolution of thin anode membranes covering microreservoirs filled with chemicals in solid, liquid or gel form. We have conducted proof-of-principle release studies with a prototype microchip using gold and saline solution as a model electrode material and release medium, and we have demonstrated controlled, pulsatile release of chemical substances with this device.

Survival and function of hepatocytes on a novel three-dimensional synthetic biodegradable polymer scaffold with an intrinsic network of channels.

OBJECTIVE: To evaluate the survival and function of hepatocytes (HCs) on a novel three-dimensional (3D) synthetic biodegradable polymer scaffold with an intrinsic network of interconnected channels under continuous flow conditions. SUMMARY BACKGROUND DATA: The authors' laboratory has investigated HC transplantation using 3D biodegradable polymers as scaffolding as an alternative approach to treatment of end-stage liver disease. Previous studies have demonstrated survival of HCs transplanted on polymer discs in peripheral tissue sites and partial correction of single enzyme liver defects. One of the major limitations has been the insufficient survival of an adequate mass of transplanted cells; this is thought to be caused by inadequate oxygen diffusion. METHODS: HCs and nonparenchymal liver cells from Lewis rats were seeded onto 3D biodegradable polymer scaffolds. Microporous 3D polymers were created using 3D printing on copolymers of polylactide-coglycolide. The cell/polymer constructs were placed in static culture or continuous flow conditions. The devices were retrieved after 2 days and examined by scanning electron microscopy and histology. Culture medium was analyzed for albumin by enzyme-linked immunosorbent assay (ELISA). Differences in culture parameters including pH, PCO2, PO2, glucose, lactate, and HCO3 were examined. RESULTS: Scanning electron microscopy revealed successful attachment of HCs on the 3D polymer in both static and flow conditions. Histology demonstrated viable HCs in both conditions. ELISA demonstrated a significantly higher mean concentration of albumin in flow conditions than in static conditions. Culture parameter analysis revealed a significantly higher PO2 and glucose level, and a more physiologic pH in flow conditions than in static conditions. CONCLUSIONS: HCs cocultured with nonparenchymal cells can attach to and survive on the 3D polymer scaffolds in both static and flow conditions in the size and configuration used in this study. Flow conditions may provide a more conducive environment for HC metabolism and albumin synthesis than static conditions. The authors hypothesize that flow through directed channels will be necessary for the transfer of large masses of cells when implantation studies are initiated.

In vitro organogenesis of liver tissue.

The high metabolic rate of hepatocytes severely limits the mass of cells which can be transplanted without a vascular supply. We are developing an alternative approach in which vascularized tissue is grown ex vivo for anastamosis into the portal vein. Here, we discuss the key design issues for in vitro organogenesis of vascularized hepatic tissue, describe a fabrication approach for making complex degradable polymer scaffolds to organize cells in three dimensions on the scale of hundreds of microns, and demonstrate the feasibility of using these scaffolds for in vitro tissue organization in mixed-cell cultures.

Mechanical properties of dense polylactic acid structures fabricated by three dimensional printing.

Polylactic acid (PLA) is a bioresorbable polymer that is used in a number of clinical situations. Complex shapes of PLA are commonly machined for bone fixation and reconstruction. Solid free from fabrication methods, such as 3D printing, can produce complex-shaped articles directly from a CAD model. This study reports on the mechanical properties of 3D-printed PLLA parts. 3D printing is a solid free-form fabrication process which produces components by ink-jet printing a binder into sequential powder layers. Test bars were fabricated from low and high molecular weight PLA powders with chloroform used as a binder. The binder printed per unit line length of the powder was varied to analyze the effects of printing conditions on mechanical and physical properties of the PLA bars. Furthermore, cold isostatic pressing was performed after printing to improve the mechanical properties of the printed bars. The maximum measured tensile strength for the low molecular weight PLLA (53 000) is 17.40 +/- 0.71 MPa and for high molecular weight PLLA (312 000) is 15.94 +/- 1.50 MPa.

Fracture surface analysis of dental ceramics: clinically failed restorations.

Fractography was used to study all-ceramic restorations that had failed clinically. Some basic tenets of fracture mechanics and fractography are reviewed and related to the examination of clinically failed all-ceramic restorations. Dicor and Cerestore restorations that had failed either at trial placement or 17 to 36 months postcementation were evaluated. Failed Dicor restorations were studied to determine the origin of failure and calculate the intraoral stress at failure. Descriptive information regarding crack origin and crack path were obtained from failed restorations constructed of first-generation Cerestore. A majority of the crowns apparently failed from the internal surface, indicating this as the highest tensile surface and/or the location of the largest flaws. Flaws were identified as being related to fabrication or inherent in the ceramic microstructure.