Patent Document

RELATED PATENT APPLICATIONS 
   The present application is a continuation of application Ser. No. 10/320,072 filed Dec. 16, 2002, now U.S. Pat. No. 6,719,582, which is a continuation in part of application Ser. No. 09/653,489, filed Aug. 31, 2000, now U.S. Pat. No. 6,495,020, which is, in turn, a divisional of application Ser. No. 09/518,006, filed Mar. 2, 2000, now U.S. Pat. No. 6,368,147 issued Apr. 9, 2002. 

   STATEMENT OF GOVERNMENT SUPPORT 
   This invention was made with government support under 2R44NS33427 awarded by the SBIR. The government has certain rights in the invention. 

   BACKGROUND OF THE INVENTION 
   The present invention is a method of making a flexible brain probe assembly. 
   Creating a probe that contacts the brain tissue represents a challenge to researchers. Researchers typically wish to measure electrical activity at specific sites within the brain that share a well-defined physical relationship to one another. Probes produced by photolithographic techniques, such as the probe designed by personnel at the University of Michigan that is known in the industry and research community as the “University of Michigan Probe,” permit the accurate placement of electrode sites that are sufficiently small to permit the measurement of electrical activity at a specific set of predefined sites within the brain. Unfortunately, the desire to use photolithography has prompted the use of silicon as a substrate. Because this material is quite brittle, the use of it creates a risk of breakage inside the brain, endangering the subject or patient and limiting the insertion strategies available to researchers. Moreover, the use of silicon prevents the University of Michigan probe from moving with the brain, which does move about slightly within the skull. In addition, silicon is subject to some restoring force, which tends to cause a silicon probe to migrate over time. Both of these drawbacks have the potential result of causing trauma to the brain tissue. 
   Another type of probe that is currently available includes a set of insulated wires having laser created apertures exposing electrode sites. Although this type of probe is useful for many applications, it does not yield the precision or the freedom of electrode placement that the University of Michigan probe permits. 
   A nerve cuff is a device for wrapping about a nerve to electrically stimulate and/or receive electric signals from the nerve. The production of nerve cuffs has also been problematic as the fine scale of the needed features has been difficult to produce on a flexible substrate capable of being wrapped about a nerve. 
   What is needed but not yet available is an electrode probe and method of making the same that affords unconstrained and accurate placement of the electrodes, but offers flexibility and robustness and is thereby less susceptible to breakage than currently available probes. 
   SUMMARY 
   In a first separate aspect, the present invention is a method of producing an electrode bio-probe assembly, using a flexible substrate comprising a polymeric layer bearing a conductive material coating. Photolithography and electroplating are used to form a set of contacts and conductors on the polymeric layer of the flexible substrate. Also, the flexible substrate is shaped to have a distal end and to be greater than 5 mm long, less than 5 mm wide and less than 1 mm thick. 
   In a second separate aspect, the present invention is a method of producing a nerve cuff assembly for application to a target nerve. The method includes the use of photolithography and electroplating to form a set of contacts and conductors on the polymeric layer of a flexible substrate having a polymeric layer and bearing a conductive material coating. The flexible substrate is sized and shaped to fit about the target nerve. 
   The foregoing and other objectives, features and advantages of the invention will be more readily understood upon consideration of the following detailed description of the preferred embodiment(s), taken in conjunction with the accompanying drawings. 

   
     BRIEF DESCRIPTION OF THE DRAWINGS 
       FIG. 1  is a side view of the connector of  FIG. 1 , shown attached to a skull and connected to a brain probe that is embedded in brain tissue. 
       FIG. 2  is an exploded perspective view of a connector according to the present invention. 
       FIG. 3  is a perspective view of the connector of  FIG. 1 , with the two connector halves mated. 
       FIG. 3A  is a perspective of a portion of an alternative embodiment to  FIG. 1 , showing the differing structure of the alternative embodiment. 
       FIG. 4  is a greatly expanded plan view of a connective surface of the connector of  FIG. 1 . 
       FIGS. 5   a – 5   g  is a series of greatly enlarged side cross-sectional views showing the construction of the connector flex circuit, or thin film, which may include the brain probe flex circuit of  FIG. 1  in a single unit. 
       FIG. 6  shows an expanded flexible brain probe, according to the present invention, and a tool for pushing this brain probe through brain tissue, also according to the present invention. 
       FIG. 7  shows the flexible brain probe and tool of  FIG. 6 , in a 180° rotated view. 
       FIG. 8  shows a nerve cuff produced in accordance with the present invention, wrapped about a nerve. 
       FIG. 9  shows a nerve cuff produced in accordance with the present invention. 
       FIG. 10  shows an alternative embodiment of a nerve cuff produced in accordance with the present invention. 
   

   DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT 
   Referring to  FIG. 1 , a percutaneous connector  10  is screwed into the skull  1  and is connected, by way of a multi-conductor microcable  20 , to a brain probe  24  that passes through an aperture  2  in the skull, through the dura  4  (and into the brain  6 ), for measuring brain activity at a specific set of points. 
   Referring to  FIGS. 2 ,  3  and  3 A a percutaneous connector  10  according to the present invention includes a male-half  12 , a female-half bracket  14  and a female-half flex circuit (or flexible polymer) connective assembly  16  bearing a set of contacts  17  and conductive traces  19 . A multi-conductor microcable  20  forms a portion of assembly  16  and is threaded through an aperture  22  in bracket  14 . The microcable  20  attaches to and extends traces  19  to brain probe  24 . As shown in  FIG. 3   a  in an alternative embodiment, a connective assembly  16 ′ includes a microcable  20 ′ that includes a brain probe  24 ′ as a unitary part of its construction. The male-half includes a resilient clip portion  28 , the exterior of which is covered with a flex-circuit  34  bearing a set of contacts  36  (matching the arrangement of contacts  19 ) and conductive traces  38 . 
   A first prong  40  and a second prong  42 , which is physically coincident with an op-amp housing, partially defines clip portion  28 . A user can grasp male-half  12  by the first and second prongs  40  and  42  to squeeze these prongs  40  and  42  together. The male-half  12  can then be inserted into the female-half  14 , without exerting pressure against female-half  14 , which could cause pain or tissue trauma to the patient or test subject. Finally, the user releases prongs  40  and  42  so that the resiliency of clip  28  will force each exterior side of clip  28 , and therefore contacts  36 , to touch the contacts  17  in female-half  14 . 
   Referring to  FIGS. 4 and 5   a – 5   g , contacts  17  and traces  19  are made of conductive material, such as a metal (copper, gold or sliver) or a conductive polymer that has been deposited and etched on top of a laminate having a layer of dielectric substrate  50  and a base layer silicone  70  or some other biocompatible, compliant material. Semicircular isolation cuts  48  through the layers  50  and  70  (in an alternative preferred embodiment only layer  50  is cut through by the laser) positionally decouple a first contact  17   a  from neighboring contacts  17   b ,  17   c  and  17   d , permitting contact  17   a  to be depressed into the spongy layer of silicone  70  without pulling down the neighboring contacts  17   b ,  17   c  and  17   d . This independent depressability causes the protrusional misalignment of contacts  17  and  36  to be forgiven. 
   The miniature scale that is made possible by the use of photolithography and flex circuit technology, as described above, facilitates a further advantage that may be realized as part of the present invention. This is the placement of op amps in extremely close proximity to contacts  36 . For connectors in which the contacts are spread apart from each other, it is necessary to gather together conductive paths from all the different contacts prior to sending them all to a set of op amps. Because contacts  36  are all so close together, traces  38  are routed to a set of op amps  44 , that are about 0.5 cm away and are housed in the second prong  42 , which doubles as an op amp housing. As a result, signal line noise and cross talk are minimized. 
   Referring to  FIGS. 5   a – 5   g , the photolithography process for making the brain probe  24  and the contacts of the percutaneous probe contact structure  30  are quite similar, except that different materials may be used and the percutaneous probe contact structure  30  includes a base layer of silicone  70 , that is only shown in  FIG. 5   g , for the sake of simplicity. Referring specifically to  FIG. 5   a , the photolithography process begins with a layer of dielectric substrate  50 , the composition of which is discussed below, that is coated with a base layer of conductive material  52 , such as a titanium-gold-titanium sandwich.  FIG. 5   b  shows the structure of  FIG. 5   a , which at this point has been covered with a layer of photo resist material  54 , typically applied by spin-coating.  FIG. 5   c  shows the effect of exposing the photo resist material to a pattern of light and washing off the exposed (or not exposed if a negative process is used) material with a developing agent. Next, as shown in  FIG. 5   d , additional conductive material (typically copper) is built up on the exposed base layer  52 , typically through electrolysis. As shown in  FIG. 5   e , the remaining photo resist material  54  is washed off with a solvent and a layer of dielectric (and permanent) photo resist  58  is applied and patterned, via exposure to a pattern of light and subsequent washing with a developing agent or solvent. Then, additional electrolytic plating is performed ( FIG. 5   f ) to create a contact  60  and the substrate is cut with an nd:YAG laser to form a kerf or cut  62 . When the process shown in  FIGS. 5   a – 5   g  is for producing connector  10 , cut  62  is the same as isolation cut  48 . When the process shown in  FIGS. 5   a – 5   g  is for producing a brain probe  24 , cut  62  separates a first brain probe  24  from a wafer or thin plastic film upon which several brain probes have been etched. In contrast to the situation with respect to silicon, which may be separated by etching, it appears that no etching process has been developed for cutting the materials used for substrate  50 , which are discussed below. 
   The dielectric substrate  50  that is used for the brain probe  24  is preferably a polymer material having a high glass transition temperature, high tensile strength and low elasticity. More specifically, substrate  50  may be made of polyether sulfone, polyimide or other material having the desired characteristics. If polyimide is used, it should be coated or treated so that it does not dissolve in the body&#39;s interstitial fluid, or used for a probe that is not to be implanted for long enough for the polyimide to dissolve. Photo resist material  54  may be a photosensitive acrylate, polyether or polyurethane, preferably having a high molecular weight. Permanent photo resist  58  may be a permanent polyimide, a type of material that is widely available from well-known photo resist companies. These companies typically sell a wet etch agent specifically designed to etch each permanent polyimide photo resist that they sell. 
   Brain probe  24  includes three prongs  72 . Each prong  72  is on the order of 15 mm long, 3 mm wide and 0.3 mm thick. During the manufacturing process each prong  72  is sharpened so that it may more easily be driven through the brain tissue. It is desirable that a brain probe, if it is to be implanted for a period of time on the order of weeks, be very pliable, so that it may conform to the brain tissue surrounding it and not cause further damage by pressing against the delicate brain tissue. If the brain probe is to be installed by being driven through brain tissue, however, it must be fairly rigid, requiring a strength layer, such as layer of steel or some other resilient material, laminated beneath layer  70 , typically before the production process begins. 
   Referring to  FIGS. 6 and 7 , in one preferred embodiment a brain probe  80  is constructed to be very pliable. In brain probe  80  only a single point  90  is provided, in order to facilitate the placement process, which is complicated by the three-pointed (or pronged) embodiment shown in  FIG. 3 .  FIG. 6  shows brain probe  80  in tandem with a placement tool  84 , which engages brain probe  80  at aperture  86 . Placement tool  84  is used to push the point of probe  80  through brain tissue  6  ( FIG. 1 ), to the point at which contact with brain tissue  6  is desired. For chronically implanted brain probes, the quality of being pliable may be very important, to avoid the damage that a rigid brain probe could inflict with patient movement. The brain moves about in the skull with patient head movement, and colliding with a rigid probe could easily damage the soft brain tissue. 
   In the embodiment of  FIG. 6 , electrodes  17  are from 12.56 square microns to 300 microns in surface area. In one preferred embodiment electrodes  17  are 176 have a surface area of 176 square microns. The probe  80 , itself is at least 5 mm long, and no more than 5 mm wide and 1 mm thick. In the preferred embodiment shown, cuts  48  are through-cuts and permit tissue ingrowth, which along with the tissue ingrowth at aperture  86  helps to anchor brain probe  90 , in the brain tissue. In an alternative preferred embodiment, cuts  48  are not present. 
   Referring to  FIGS. 8 ,  9  and  10 , the method of construction shown in  FIGS. 5   a – 5   g  is used for the production of nerve cuffs  100 ,  110  and  120 . A nerve cuff is a device that is adapted to be wrapped around a nerve  130  and used to electrically stimulate the nerve  130 . In nerve cuff  110  a set of twelve contacts  112  have been created through photolithography. In nerve cuff  120  four complex contacts  122 , designed for circumferentially contacting a nerve have been created by way of photolithography. 
   The terms and expressions which have been employed in the foregoing specification are used as terms of description and not of limitation, and there is no intention, in the use of such terms and expressions, of excluding equivalents of the features shown and described or portions thereof, it being recognized that the scope of the invention is defined and limited only by the claims which follow.

Technology Category: 1