Active Microelectronic Neurosensor Arrays for Implantable Brain Communication Interfaces.

We have built a wireless implantable microelectronic device for transmitting cortical signals transcutaneously. The device is aimed at interfacing a microelectrode array cortical to an external computer for neural control applications. Our implantable microsystem enables presently 16-channel broadband neural recording in a nonhuman primate brain by converting these signals to a digital stream of infrared light pulses for transmission through the skin. The implantable unit employs a flexible polymer substrate onto which we have integrated ultra-low power amplification with analog multiplexing, an analog-to-digital converter, a low power digital controller chip, and infrared telemetry. The scalable 16-channel microsystem can employ any of several modalities of power supply, including via radio frequency by induction, or infrared light via a photovoltaic converter. As of today, the implant has been tested as a sub-chronic unit in non-human primates (~ 1 month), yielding robust spike and broadband neural data on all available channels.

Active microelectronic neurosensor arrays for implantable brain communication interfaces.

We have built a wireless implantable microelectronic device for transmitting cortical signals transcutaneously. The device is aimed at interfacing a cortical microelectrode array to an external computer for neural control applications. Our implantable microsystem enables 16-channel broadband neural recording in a nonhuman primate brain by converting these signals to a digital stream of infrared light pulses for transmission through the skin. The implantable unit employs a flexible polymer substrate onto which we have integrated ultra-low power amplification with analog multiplexing, an analog-to-digital converter, a low power digital controller chip, and infrared telemetry. The scalable 16-channel microsystem can employ any of several modalities of power supply, including radio frequency by induction, or infrared light via photovoltaic conversion. As of the time of this report, the implant has been tested as a subchronic unit in nonhuman primates ( approximately 1 month), yielding robust spike and broadband neural data on all available channels.

Granulocyte colony-stimulating factor enhances bone marrow stem cell damage caused by repeated administration of cytotoxic agents.

Despite the increasing use of cytokines to circumvent the acute dose-limiting myelotoxicity of cancer treatment, little is known about the combined effects of cytotoxic agents and cytokines on the primitive stem cells responsible for long-term hematopoiesis. In an experimental model, we administered cytotoxic agents that have variable effects on primitive stem cells in C57BL/6 (B6)-mice. Mice received six every-other-week doses of cyclophosphamide (CY, 84 mg/kg), VP-16 (24 mg/kg) + cisplatinum (2.4 mg/kg), carboplatinum (50 mg/kg), chlorambucil (12 mg/kg), BCNU (13.2 mg/kg), or TBI (80 cGy). Granulocyte colony-stimulating factor (G-CSF; 250 microg/kg/day) was administered subcutaneously twice daily on days 3 to 6 after each dose of the cytotoxic agent. Comparison with animals receiving the cytotoxic agent alone was made to investigate the effects of G-CSF on long-term hematopoiesis. Hematopoiesis was measured 20 weeks after the last dose of the cytotoxic agent by assessment of peripheral blood counts, marrow cellularity, progenitor cell content (colony-forming units-spleen; CFU-S), and primitive stem cell number (long-term repopulating ability and day 28 and day 35 cobblestone area-forming cell [CAFC] frequencies). Exposure to cytotoxic agents alone resulted in a significant decrease in primitive stem cells (as measured by repopulating units [RU] and day 28 and day 35 CAFC content) in animals given carboplatinum, chlorambucil, BCNU, and TBI, but not in animals treated with cyclophosphamide or VP-16 and cisplatinum. The addition of G-CSF resulted in a significant decrease in stem cell content when compared with no G-CSF administration in animals treated with chlorambucil, BCNU, or TBI. Thus, G-CSF administered after repeated exposure to cytotoxic agents, appeared to damage the primitive stem cell compartment when used in combination with agents known to damage primitive stem cells. These results, although obtained in an experimental model, should raise concerns for the indiscriminate use of G-CSF in the clinic.

Host conditioning with 5-fluorouracil and kit-ligand to provide for long-term bone marrow engraftment.

Administration of kit-ligand (KL) before and after doses of 5-fluorouracil (5-FU) results in marrow failure in mice, presumably because of enhanced KL-induced cycling of stem cells, which makes them more susceptible to the effects of 5-FU. In attempt to capitalize on this effect on stem cells, we studied the ability of KL and 5-FU to allow stable donor engraftment of congenically marked marrow in a C57BL/6 (B6) mouse model. KL was administered subcutaneously at 50 microg/kg, 21 hours and 9 hours before and 3 hours after each of two doses of 5-FU (125 mg/kg) given 7 days apart to B6-recipients. Animals then received three injections of 10(7) congenic B6-Gpi-1a-donor bone marrow cells at 24, 48, and 72 hours after the second 5-FU dose. A separate group of animals received a single dose of either 1 x 10(7) or 3 x 10(7) donor marrow cells 24 hours after the last 5-FU dose. The level of engraftment was measured from Gpi-phenotyping at 1, 3, 6, and 8 months in red blood cells (RBCs) and at 8 months by phenotyping cells from the thymus, spleen, and marrow. Percent donor engraftment in RBCs appeared stable after 6 months. The percent donor engraftment in RBCs at 8 months was significantly higher in KL + 5-FU prepared recipients (33.0 +/- 2.7), compared with 5-FU alone (18.5 +/- 2.6, P < .0005), or saline controls (17.8 +/- 1.7, P < .0001). In an additional experiment, granulocyte colony-stimulating factor (100 microg/dose) was added to a reduced dose of KL (12.5 microg/dose); engraftment was similar to KL alone. At 8 months after transplantation the levels of engraftment in other tissues such as bone marrow, spleen, and thymus correlated well with erythroid engraftment to suggest that multipotent long-term repopulating stem cells had engrafted in these animals. There are concerns for the toxicity of total body irradiation (TBI)- or busulfan-based regimens in young recipients of syngeneic or transduced autologous marrow who are transplanted for correction of genetic disease. In these recipients complete donor engraftment may not be needed. The results with KL and 5-FU are encouraging for the further refinement of non-TBI, nonbusulfan techniques to achieve stable mixed chimerism.