Given those background results, pursuing a new set of design rules is a worthwhile goal to investigate and may provide a solution to the problem of deteriorating microelectrode effectiveness. Specifically, we are implementing several different geometries using the following design principles:

• Design the recording electrode sites separately from the large penetrating probe shank(Talwar)
• Physically displace the electrodes from the shank
• Minimize the substrate around the electrodes, thus maximizing the area of tissue to tissue confluence     
• Reduce the transfer of mechanical tethering forces by adding 2-D springs to the support arms
• Maintain adequate stiffness in the shank to pierce the pia matter and sustain a straight trajectory
• Design the probe distal end to act as a piercing blade and protective leading edge, thereby reducing the insertion forces applied to the flexible portion of the probe

These ideas have lead us to develop ‘open architecture’ probes that have smaller, more mesh-like features for improved integration and less tissue reaction. The flexibility and fabrication requirements of this probe makes silicon a problematic choice for the substrate material. A polymer-based substrate is an obvious choice given its greater elasticity and lower Young’s modulus. Our prototype of this new type of probe using a parylene substrate is described in Core Project 1 in the research plan.

Polymer neural probes are not unique (Takeuchi 2004), but to-date no one has attempted a design using the principles laid out here. One group has built a polyimide nerve cuff with perforations to allow the surgeon to suture the probe to the fascicle, but the tissue response was not investigated and only acute recordings were attempted (Gonzalez 1997).

Regardless of the probe design, the plain fact is that all probes will cause tissue damage during insertion and subsequent placement (Szarowski 2003). This leads to the second theme of biology-centered intervention strategies that is intended to reduce or interfere with the inflammatory response and/or the ongoing reactive tissue response. One approach is based on drug eluting probe coatings, with several types of drugs and coatings. An alternative approach involves sustained drug release from a fluidic channel in the probe (Shain 2003). The proof-of-concept for this type of intervention strategy has now been established through results showing decreased tissue response (Spataro 2002) or increased recording quality (Prof. D. Anderson, unpublished results), although the approaches have not been optimized. While these strategies are likely to become part of next-generation probes, they have not yet been reduced to practice and incorporated into ‘stock’ implantable probe systems.

Complementary to the probe refinements that are designed to minimize tissue responses and the intervention strategies that are intended to reduce them even further, the third theme involves adding a neurotrophic component that is intended to attract neurons or neuronal processes to the recording sites. The most notable work in this theme is the ‘neurotrophic electrode’ (or ‘cone’ electrode) developed by Dr. Kennedy and colleagues (Kennedy, P.R. 2000). This device consists of microwires inserted into a short length of a tapered micropipette that is filled with a neurotrophic substance. Several weeks after the device is permanently implanted in cortex, functional neuronal processes grow into and through the cone such that their spike activity can be recorded with the microwires. The experimental evidence in rats, monkeys, and humans suggest that this device typically results in a stable recording interface. This work is significant because it demonstrates the potential for using neurotrophic components to attract neurons to an interface, although the device itself has a number of characteristics that limit its usefulness as a neuroscience research tool (e.g., remapping of neuronal processes, limited number of channels, and limited to spike recording). The current approaches for adding neurotrophic components to conventional types of microscale probes mirror those used for intervention strategies, including direct injection using fluidic channels (W. Shain, personal communication) and drug-eluting polymer coatings that contain neutrotrophic molecules such as NGF and BDNF to attract neurons toward the probe surface. Similar to the state-of-the art for intervention strategies, neurotrophic components have not yet been reduced to practice and incorporated into ‘stock’ probe systems.

These three research themes for improving the function of implantable probes are not mutually exclusive. Considering that the field is in transition from being device-centered to biodevice-centered, there is a clear need to coordinate these themes in order to develop and optimize multi-faceted device improvements, and thus increase the rate of progress in the field. The proposed CNCT will have the focus, resources, and collaborative relationships to make progress in these directions. This involves the second objective of this proposal.