First-in-human implantation of a mid-field powered neurostimulator at the sacral nerve: Results from an acute study.

INTRODUCTION: Commercially approved implantable systems for sacral neuromodulation require the implantation of a multipolar lead subcutaneously connected to an implantable pulse generator (IPG). Eliminating the need for an IPG would eliminate the need for tunneling of the lead, reduce procedure time, infection risk, and the need for IPG replacement. The objective was to demonstrate the feasibility of implanting the AHLeveeS System in the S3 Foramen to stimulate the S3 sacral nerve. MATERIALS AND METHODS: A first-in-human, prospective, single center, nonrandomized, acute feasibility clinical investigation at the Maastricht University Medical Center+. Patients with refractory overactive bladder underwent acute implantation of the AHLeveeS neurostimulator before the InterStim procedure. Outcome measurements included motor responses, procedural time and a scoring of the difficulty of the implant and explant procedure. Retrospectively, qualitative responses to the stimulation protocol were assessed by video motion analyses. Only descriptive statistics were used. RESULTS: During the stimulation a motor response to stimulation was seen in four of the five subjects. In all implantations the AHLeveeS was correctly placed. The median time for complete procedure was 24 minutes. The implant and explant procedures were successfully performed and no device or procedure related adverse events occurred. CONCLUSIONS: The results from this acute first-in-human study demonstrate the feasibility of implantation and acute stimulation of the sacral nerve with this mid-field powered system. Future clinical studies will focus on safety and efficacy of a chronically implanted device.

Origins of Stereoselectivity of Chiral Vicinal Diamine-Catalyzed Aldol Reactions.

The sources of asymmetric induction in aldol reactions catalyzed by cinchona alkaloid-derived amines, and chiral vicinal diamines in general, have been determined by density functional theory calculations. Four vicinal diamine-catalyzed aldol reactions were examined. The cyclic transition states of these reactions involve nine-membered hydrogen-bonded rings in distinct conformations. Using nomenclature from eight-membered cycloalkanes, the heavy atoms of the low-energy transition states are in crown (chair-chair) and chair-boat conformations. The factors that control which of these are favored have been identified.

Wirelessly powered, fully internal optogenetics for brain, spinal and peripheral circuits in mice.

To enable sophisticated optogenetic manipulation of neural circuits throughout the nervous system with limited disruption of animal behavior, light-delivery systems beyond fiber optic tethering and large, head-mounted wireless receivers are desirable. We report the development of an easy-to-construct, implantable wireless optogenetic device. Our smallest version (20 mg, 10 mm(3)) is two orders of magnitude smaller than previously reported wireless optogenetic systems, allowing the entire device to be implanted subcutaneously. With a radio-frequency (RF) power source and controller, this implant produces sufficient light power for optogenetic stimulation with minimal tissue heating (<1 °C). We show how three adaptations of the implant allow for untethered optogenetic control throughout the nervous system (brain, spinal cord and peripheral nerve endings) of behaving mice. This technology opens the door for optogenetic experiments in which animals are able to behave naturally with optogenetic manipulation of both central and peripheral targets.

Wireless power transfer to deep-tissue microimplants.

The ability to implant electronic systems in the human body has led to many medical advances. Progress in semiconductor technology paved the way for devices at the scale of a millimeter or less ("microimplants"), but the miniaturization of the power source remains challenging. Although wireless powering has been demonstrated, energy transfer beyond superficial depths in tissue has so far been limited by large coils (at least a centimeter in diameter) unsuitable for a microimplant. Here, we show that this limitation can be overcome by a method, termed midfield powering, to create a high-energy density region deep in tissue inside of which the power-harvesting structure can be made extremely small. Unlike conventional near-field (inductively coupled) coils, for which coupling is limited by exponential field decay, a patterned metal plate is used to induce spatially confined and adaptive energy transport through propagating modes in tissue. We use this method to power a microimplant (2 mm, 70 mg) capable of closed-chest wireless control of the heart that is orders of magnitude smaller than conventional pacemakers. With exposure levels below human safety thresholds, milliwatt levels of power can be transferred to a deep-tissue (>5 cm) microimplant for both complex electronic function and physiological stimulation. The approach developed here should enable new generations of implantable systems that can be integrated into the body at minimal cost and risk.

Accessible gold clusters using calix[4]arene N-heterocyclic carbene and phosphine ligands.

We investigate the synthesis of accessible calix[4]arene-bound gold clusters consisting of open "coordinatively unsaturated" active sites, using a comparative approach that relies on calix[4]arene ligands with various upper- and lower-rim substituents. In contrast with a reported Au(I)-tert-butyl-calixarene phosphine complex, which exhibits a single cone conformer in solution, the H upper-rim analog exhibits multiple conformers in solution. This contrasts with observations of the tert-butyl upper-rim analog, which exhibits a single cone conformer in solution under similar conditions. In the solid state, as determined by single-crystal X-ray diffraction, both H and tert-butyl upper-rim analogs exhibit exclusively cone conformer. A detailed structural analysis of these two solid-state structures highlights a CH-π interaction involving a methoxy lower-rim substituent and phenyl substituent on P as the key feature that enforces a tight configuration of Au(I) atoms on the same side of the calix[4]arene lower-rim plane. We hypothesize that such a configuration promotes chelation of the ligand to a gold surface and facilitates the synthesis of small Au11-sized clusters after reduction of both complexes. The new cluster, like the one reported with the tert-butyl analog, has an extraordinary 25% of surface atoms that are open and accessible to a 2-NT (2-naphthalenethiol) probe in solution. We also investigated the effect of calix[4]arene lower-rim substituents that coordinate to the metal, by using N-heterocyclic carbene (NHC) functional groups rather than phosphines. Four small (<1.6 nm diameter) calix[4]arene NHC-bound gold clusters were synthesized, including three using novel calix[4]arene NHC ligands. The smallest calix[4]arene NHC-bound Au cluster consisted of a 1.2 nm gold core, and its number density of accessible and open surface sites was measured. This required development of a new titration method for open sites on gold clusters, using a SAMSA fluorescein dye molecule, which excites and emits at lower energy relative to the previously used 2-NT probe. The number density of open sites on the new calix[4]arene NHC-bound gold cluster measured by the SAMSA fluorescein probe strongly supports the generality of a mechanical model of accessibility, which does not depend on the functional group involved in binding to the gold surface and rather depends on the relative radii of curvature of bound ligands and the gold cluster core.