First-in-human testing of a wirelessly controlled drug delivery microchip.

The first clinical trial of an implantable microchip-based drug delivery device is discussed. Human parathyroid hormone fragment (1-34) [hPTH(1-34)] was delivered from the device in vivo. hPTH(1-34) is the only approved anabolic osteoporosis treatment, but requires daily injections, making patient compliance an obstacle to effective treatment. Furthermore, a net increase in bone mineral density requires intermittent or pulsatile hPTH(1-34) delivery, a challenge for implantable drug delivery products. The microchip-based devices, containing discrete doses of lyophilized hPTH(1-34), were implanted in eight osteoporotic postmenopausal women for 4 months and wirelessly programmed to release doses from the device once daily for up to 20 days. A computer-based programmer, operating in the Medical Implant Communications Service band, established a bidirectional wireless communication link with the implant to program the dosing schedule and receive implant status confirming proper operation. Each woman subsequently received hPTH(1-34) injections in escalating doses. The pharmacokinetics, safety, tolerability, and bioequivalence of hPTH(1-34) were assessed. Device dosing produced similar pharmacokinetics to multiple injections and had lower coefficients of variation. Bone marker evaluation indicated that daily release from the device increased bone formation. There were no toxic or adverse events due to the device or drug, and patients stated that the implant did not affect quality of life.

Use of subcutaneous interstitial fluid glucose to estimate blood glucose: revisiting delay and sensor offset.

BACKGROUND: Estimates for delays in the interstitial fluid (ISF) glucose response to changes in blood glucose (BG) differ substantially among research groups. We review these findings along with arguments that continuous glucose monitoring (CGM) devices used to measure ISF delay contribute to the variability. We consider the impact of the ISF delay and review approaches to correct for it, including strategies pursued by the manufacturers of these devices. The focus on how the manufacturers have approached the problem is motivated by the observation that clinicians and researchers are often unaware of how the existing CGM devices process the ISF glucose signal. METHODS: Numerous models and simulations were used to illustrate problems related to measurement and correction of ISF glucose delay. RESULTS: We find that (1) there is no evidence that the true physiologic ISF glucose delay is longer than 5-10 min and that the values longer than this can be explained by delays in CGM filtering routines; (2) the primary impact of the true ISF delay is on sensor calibration algorithms, making it difficult to estimate calibration factors and offset (OS) currents; (3) inaccurate estimates of the sensor OS current result in overestimation of sensor glucose at low values, making it difficult to detect hypoglycemia; (4) many device companies introduce nonlinear components into their filters, which can be expected to confound attempts by investigators to reconstruct BG using linear deconvolution; and (5) algorithms advocated by academic groups are seldom compared to algorithms pursued by industry, making it difficult to ascertain their value. CONCLUSIONS: The absence of any direct comparisons between existing and new algorithms for correcting ISF delay and sensor OS current is, in part, due to the difficulty in extracting relevant details from industry patents and/or extracting unfiltered sensor signals from industry products. The model simulation environment, where all aspects of the signal can be derived, may be more appropriate for developing new filtering and calibration strategies. Nevertheless, clinicians, academic researchers, and the industry would benefit from collaborating when evaluating those strategies.

Chronic, programmed polypeptide delivery from an implanted, multireservoir microchip device.

Implanted drug delivery systems are being increasingly used to realize the therapeutic potential of peptides and proteins. Here we describe the controlled pulsatile release of the polypeptide leuprolide from microchip implants over 6 months in dogs. Each microchip contains an array of discrete reservoirs from which dose delivery can be controlled by telemetry.

Electrothermally activated microchips for implantable drug delivery and biosensing.

Novel drug delivery and biosensing devices have the potential to increase the efficacy of drug therapy by providing physicians and patients the ability to precisely control key therapy parameters. Such "intelligent" systems can enable control of dose amount and the time, rate, and location of drug delivery. We have developed and demonstrated the operation of an electrothermal mechanism to precisely control the delivery of drugs and exposure of biosensors. These microchip devices contain an array of individually sealed and actuated reservoirs, each capped by a thin metal membrane comprised of either gold or multiple layers of titanium and platinum. The passage of a threshold level of electric current through the membrane causes it to disintegrate, thereby exposing the protected contents (drugs or biosensors) of the reservoir to the surrounding environment. This paper describes the theory and experimental characterization of the electrothermal method and includes in vitro release results for a model compound.