Laser-micromachined, chip-scaled ceramic carriers for implantable neurostimulators.

Hermetic encapsulation of long-term implantable devices using ceramics has been investigated over several decades. Our studies focus on the miniaturization of ceramic encapsulations for large numbers of stimulation channels. Laser-patterning of screen printed platinum (Pt) paste on cofired ceramics has been shown to enable the construction of features comparable in size to classical screen printing. A novel technique for embedding Pt structures into the surface of Al(2)O(3) substrates is shown to produce features with a line width minimum of 20 µm and a pitch of 40 µm. Polishing the ceramic substrates enables flip-chip bonding of application specific integrated circuits (ASIC) using gold stud bumps. A new technique for fine tuning of an ASIC stimulator with stud bump bridges is described. The technique eliminates the need for wire bond loops and increases reliability and integration density of the system, which are major requirements used to construct a visual prosthesis or other implantable devices requiring miniaturization. The methods for laser-patterned Pt tracks in alumina for fine pitch structures are described. Feasibility studies for flip-chip bonding and stud bump bridges were undertaken and the results were found to be promising.

Towards a chip scale neurostimulator: system architecture of a current-driven 98 channel neurostimulator via a two-wire interface.

With more clinical trials proving viability of visual prosthesis follows the demand for higher resolution devices. As the number of electrodes increases, due to surgical difficulties, it is preferred to keep their length short by placing the implant close to the stimulation site, where there are considerable constraints on device size. On the contrary, the physical volume of the implant generally increases with increasing number of electrodes. Splitting the implant into two modules and placing only the essential circuits near the site of stimulation solves the aforementioned problem. However now the problem is redirected to the robustness and the safety of the interface joining these modules. A novel two-wire interface driving a 98 channel neurostimulator incorporating the split-architecture is presented. The stimulator is provided with both power and data by sending square current waveforms via the two-wire interface. The stimulator itself is fabricated using 0.35 µm HVCMOS technology and occupies 4.9 × 4.9 mm(2) and requires no external decoupling capacitor.

Isolation of quercetin's salts and studies of their physicochemical properties and antioxidant relationships.

Hydroxyflavones in alkaline solutions show high free radical scavenging activities. Quercetin, one of these hydroxyflavones may be submitted to chemical reactions yielding a mixture of mono-, di- and tri-sodium salts. These salts were recovered after solubilization and stepwise precipitation in methylalcohol/ethylacetate solvents. The different salts were analyzed using sodium emission spectrophotometry and nuclear magnetic resonance to determine the number of acid hydrogens at pH10 and the position of these acid hydrogens. Our study demonstrates that among the three salts of quercetin, the di-sodium compound is endowed with the more efficient scavenging properties in a phosphate buffer at physiological pH7.4. Physicochemical parameters and free hydroxyl radical scavenging activity relationships were also determined, allowing to explain the mechanisms whereby hydroxyl groups exert their radical scavenging activities.

Anti- and pro-oxidant activity of rutin and quercetin derivatives.

Some semi-synthetic flavonoids, particularly derivatives of rutin, are used as therapeutic agents in the treatment of diseases involving free radicals. Here, for the first time, a complete study has been made of the relationship between the structure of such molecules and their superoxide, hydroxyl and peroxyl radical scavenging activity. The molecules chosen for this study were rutin, its aglycone (quercetin), and their methyl ethyl and hydroxyl-ethyl derivatives. Our results are consistent with the general agreement on the structural requirements for free radical scavenging activity. Moreover, we have shown that alkylation of the hydroxyl in position 7 enhanced the scavenging, and also that in a Fenton reaction system, some quercetin derivatives with free catechol moiety or free hydroxyl in position 3 (or both) were pro-oxidant, through superoxide radical and hydrogen peroxide production. Although the structural features needed for pro-oxidant activity are not entirely clear, it appears that to avoid pro-oxidant behaviour, the hydroxyl group in position 3 should be blocked to prevent its auto-oxidation. Thus, flavonoids cannot only be considered purely as antioxidants, since under certain reaction conditions they can also display pro-oxidant activity. This unexpected behaviour could explain, in part, the observed toxicity of some flavonoids in-vivo.

In vitro inhibition of simvastatin metabolism, a HMG-CoA reductase inhibitor in human and rat liver by bergamottin, a component of grapefruit juice.

Grapefruit juice is responsible for many drug interactions but the exact components involved in this interaction are not precisely known. Flavonoids and furocoumarin derivatives such as naringenin and bergamottin, respectively, could be involved in the inhibition of drug metabolism. The objective of this paper is to investigate in vitro the possible metabolic hepatic interaction between simvastatin (SV) and bergamottin (BG) and thus to compare its effects to those of naringenin (NRG) the aglycone form of naringin (NR) (a flavonoid present in grapefruit juice). In human and rat microsomes and in rat hepatocytes, BG was found to be a mixed type inhibitor of SV metabolism. In rat liver microsomes the K(i) value of BG (K(i)=174+/-36 microM) is higher than the K(i) value of NRG (K(i)=29+/-11 microM). However, in human liver microsomes the K(i) values are similar in BG and NRG (K(i)=34+/-5 microM and 29+/-11 microM, respectively). Moreover, it seems that there is an interspecies difference between human and rat hepatic metabolism of SV involving different isoenzymes of CYP 450. In conclusion, our study shows that BG inhibits SV metabolism. BG and NRG could therefore be applied as markers in food-drug interaction studies in order to adjust posology.

Subclinical protein malnutrition is a determinant of hyperhomocysteinemia.

OBJECTIVES: Hyperhomocysteinemia is regarded as a public health problem of increasing importance likely to contribute to vascular disorders and premature mortality. Folate, cobalamin, pyridoxine, and riboflavin dietary deficiencies are currently regarded as causative factors. However, several investigations have indicated that the theory of vitamin B deprivation provides only a partial explanation for the observed abnormalities of sulfur-containing amino acids. We investigated the potential contributory role played by protein malnutrition. METHODS: For that purpose, three cohorts of 20 adult patients presenting stage I, II, and III goiter underwent careful medical history, dietary inquiry, and clinical examination. Their overall health and nutrition states were assessed with classic anthropometry, measurement of vitamin B blood parameters, visceral protein markers, essential amino acids, total homocysteine, and cystathionine. RESULTS: The concentrations of transthyretin, seven essential amino acids, and cystathionine progressively decreased as the thyroid gland increased. Methionine was the sole essential amino acid whose values did not change; total homocysteine was unique in that increased levels correlated negatively with transthyretin values. Taken together, the data point to a progressive deterioration of protein nutrition status impairing the transsulfuration pathway and is best explained by an acquired defect of cystathionine-beta-synthase activity. CONCLUSIONS: Hyperhomocysteinemia may arise from the shrinking of endogenous nitrogen pools as a result of decreased protein intake or stress-induced increased losses. Raised total homocysteine may result from the attempt of the malnourished and/or stressed body to preserve methionine homeostasis.