N. Sheppard

This paper describes a microfluidic system in which fluids are pumped by centrifugal force through microscopic channels defined in a plastic disk in order to perform complex analytical processes. The channels are created either by casting poly(dimethylsiloxane) against molds fabricated by photolithography or by conventional machining of poly(methyl methyacrylate). The channels have a wide range of diameters (5 μm−0.5 mm) and depths (16 μm−3 mm). Fluids are loaded into reservoirs near the center of the disk, the disk is rotated on the shaft of a simple motor at 60−3000 rpm, and the fluids are pumped outward by centrifugal force through microfluidic networks. The control of flow in the time domain, i.e., gating, is achieved by the use of passive valves based on capillary forces. Flow rates ranging from 5 nL/s to >0.1 mL/s have been achieved using channels of different dimensions and different rates of rotation. The method of pumping is insensitive to many physicochemical properties of the liquid, such as pH and ionic strength, so it has been possible to pump biological fluids, such as blood and urine, a buffer containing a detergent, and some organic solvents. A system that performs multiple (48) enzymatic assays simultaneously using colorimetric detection on a dedicated instrument has been demonstrated. These integrated assays have been used both to yield the Michaelis constant (Km) of an enzyme and to determine the dose response of an enzyme to a drug. The fluid pumping and control embodied in this system may be readily integrated with other analytical components (e.g., heating, detection, and informatics) to form the basis for a microscale total analysis system for use in genomics, proteomics, high-throughput screening, and molecular diagnostics.

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.