Implant Stimulator

Abstract

The use of neurostimulation leads in the craniofacial region is associated with skin erosion and lead displacement. The cylindrical shape and associated thickness of the most advanced leads can lead to erosion through the skin or lead displacement, resulting in the electrodes no longer covering the target nerve. An implantable stimulation device (1001110) is provided, including a substrate (300, 1400) including an adaptive portion with an electrode array and a pulse generator (500). Multiple electrical interconnects (250, 1210) are disposed between the surfaces of the substrate. The adaptive portion has a thickness of 0.5 mm or less. Optionally, one or more sealing layers (1300) can be provided. Optionally, one or more adhesive layers (1500) including a ceramic material can also be provided. Providing a more easily patternable substrate allows for more complex electrode array configurations and greater flexibility to accommodate lateral and / or longitudinal displacement. Providing a relatively thin implantable electrode array can enhance user comfort. The one or more adhesive layers improve sealing performance.

Description

[Technical field]

[0001] A portion of the disclosure of this patent document contains material that is subject to copyright protection. The copyright owner has no objection to the facsimile reproduction of the patent document or disclosure of the patent, as it appears in the Patent and Trademark Office patent publication or records, but otherwise reserves all copyright rights whatsoever.

[0002] The present disclosure relates to an implantable stimulation device for providing electrical stimulation to human or animal tissue having an electrode array disposed along an applied portion of a substrate. In particular, it relates to an implantable stimulation device having a sealing layer at least partially covering a portion of the substrate. It also relates to a method of manufacturing the implantable stimulation device. [Background technology]

[0003] An implantable electrical stimulation system can be used to provide electrical stimulation therapy to a patient to treat a variety of symptoms or conditions, such as headaches, back pain, and incontinence. Summary of the Invention [Problem to be solved by the invention]

[0004] In many electrical stimulation applications, it is desirable for a stimulator device, which typically includes a therapeutic lead (a lead that includes electrodes and electrical connections), to provide electrical stimulation to one or more precise locations within the body. Often, precise alignment of the stimulating electrodes during implantation can be difficult due to the curvature of tissue and anatomical structures. Mismatches in the curvature of the electrode sections of the lead can create unexpected and / or unpredictable electrical resistance between one or more electrodes and the underlying tissue. Furthermore, repeated movement of the relevant area of ​​the body can further exacerbate the mismatch. A particular issue with subdermal implants is that even slight differences in flexibility between the implant and the surrounding tissue can affect patient comfort and cause irritation of the overlying skin. This is particularly problematic with subdermal implants.

[0005] In particular, the use of neurostimulation leads in the craniofacial region is associated with skin erosion and lead displacement: the cylindrical shape and associated thickness of the most distal lead can result in the lead eroding through the skin or the lead becoming displaced such that the electrodes no longer cover the target nerve.

[0006] More recently, plastics and polymers have been used, which have inherent flexibility or can be made in a curved shape, as described, for example, in US Patent Application Publication No. 2016 / 0166828. Although such leads can be manufactured in a curved shape or deformed by human manual manipulation during implantation, this is inconvenient. The high degree of anatomical variability found in humans and animals means that manufacturers must provide a wide range or pre-curved leads or make the leads adjustable. If they are deformable during implantation, this further complicates the implantation process.

[0007] Implanted active devices require a method of protection to protect the implanted electronics from bodily fluids present in the human or animal body. Bodily fluids typically contain ions that can cause electrochemical reactions such as corrosion in the presence of electrical current. Therefore, sealing is a critical component for medical device design. It acts as a barrier between these ionic liquids and critical electronic / electrical interfaces, reducing and / or preventing degradation of the implanted electronics.

[0008] Polyimides are popular for use as substrate materials in microfabrication of electronic devices, and attempts have been made to encapsulate polyimides with silicone rubber encapsulants such as polydimethylsiloxane rubber (PDMS). Bonding these two flexible materials remains a significant challenge, as described in "Irreversible bonding of polyimide and polydimethylsiloxane (PDMS) based on a thiol-epoxy click reaction," Hoang, Chung and Elias, Journal of Micromechanics and Microengineering,10.1088 / 0960-1317 / 26 / 10 / 105019. Some degree of delamination of the encapsulant from the substrate can reduce resistance to fluid ingress. The degree of bonding has been enhanced by functionalizing the surfaces of the PDMS and polyimide substrates with mercaptosilane and epoxysilane, respectively, to form thiol-epoxy bonds in the click reaction. It has also been enhanced by functionalizing one or both surfaces with mercaptosilane and introducing an epoxy adhesive layer between the two surfaces.

[0009] Although PDMS is substantially biocompatible and can minimize tissue reactions while having a relatively long-term biostability, it is still relatively permeable to moisture, which can lead to degradation of the implant's electronics. Many other encapsulants that have a lower degree of moisture permeability may have a lower degree of biocompatibility. Recently, LCP (Liquid Crystal Polymer) has been considered for use as a substrate for electronics, and there is also a need to improve the bonding technology between LCP and encapsulants. [Means for solving the problem]

[0010] It is to be understood that both the following summary and the detailed description are exemplary and explanatory and are intended to provide further explanation of the invention as claimed. Neither the summary nor the following description is intended to define or limit the scope of the invention to the specific features set forth in the summary or description. Rather, the scope of the invention is defined by the appended claims.

[0011] In certain embodiments, the disclosed embodiments may include one or more of the features described herein.

[0012] An implantable stimulator is provided that includes: a substrate including first and second surfaces, the substrate having a thickness defined by the first and second surfaces; a pulse generator configured to generate at least one stimulation pulse; and an electrode array including at least two electrodes disposed along an adaptive portion of the substrate. The implantable stimulator further includes a plurality of electrical interconnects electrically coupling the pulse generator to the at least two electrodes of the electrode array, the plurality of electrical interconnects being disposed between the first and second surfaces of the substrate, and a thickness of the substrate along the adaptive portion is 0.5 mm or less.

[0013] The products and methods described herein provide a high degree of conformability and a high degree of configurability. Greater conformability may result in greater user comfort. Optionally, the thickness of the conformable portion is 0.3 mm or less, or 0.2 mm or less, or 0.1 mm or less.

[0014] Optionally, if the substrate includes a further portion along which the pulse generator is disposed, the implantable stimulator further includes a sealing layer at least partially covering the further portion of the substrate.

[0015] Additionally or alternatively, the substrate and further portions of the pulse generator are at least partially embedded in one or more flexible biocompatible encapsulating layers.

[0016] The encapsulation may improve the reliability and / or lifespan of the implant substrate.

[0017] Additionally or alternatively, the implantable stimulation device further comprises an adhesion layer adjacent at least a portion of the substrate. Optionally, the substrate comprises two or more adjacent substrate layers, the adhesion layer being between the substrate layers.

[0018] The adhesive layer or layers may improve the performance of the seal, which may also improve the reliability and / or lifespan of the implant substrate. By providing multiple layers, thinner leads may be used, providing increased flexibility and therefore improved adaptability.

[0019] Optionally, the adhesion layer comprises a ceramic material, which may be advantageously included in the adhesion layer between the substrate material and the encapsulant.

[0020] Optionally, the ceramic material is selected from the group consisting of HfO2, Al2O3, Ta2O3, SiC, Si3N4, TiO2, and any combination thereof.

[0021] Additionally or alternatively, the adhesion layer includes at least one first layer including HfO2 and at least one second layer adjacent to the at least one first layer including Al2O3. Additionally or alternatively, the adhesion layer includes at least one first layer including Ta2O3 and at least one second layer adjacent to the at least one first layer including Al2O3. Additionally or alternatively, the adhesion layer includes at least one first layer including TiO2 and at least one second layer adjacent to the at least one first layer including Al2O3.

[0022] Optionally, the ceramic portion of the adhesion layer has an average thickness in the range of 25 nm to 200 nm.Optionally, the adhesion layer comprises a ceramic portion that is applied using atomic layer deposition (ALD).

[0023] Additionally or alternatively, the thickness of the stimulator along the further portion is 5mm or less, or 4mm or less, or 3mm or less.

[0024] This may further improve the flexibility of further portions of the substrate.

[0025] Additionally or alternatively, the plurality of electrical interconnects are disposed between the first and second surfaces of the substrate using a metallization method. Additionally or alternatively, the plurality of electrical interconnects are included in one or more conductive interconnect layers, the one or more conductive interconnect layers being included between two adjacent polymer substrate layers. Effect of the Invention

[0026] By providing a more easily patternable substrate, more complex electrode array configurations can be mounted, allowing a greater degree of flexibility to accommodate lateral and / or longitudinal misalignment.

[0027] A method of manufacturing an implantable stimulation device is provided, the method including: providing a substrate including first and second surfaces, the substrate having a thickness defined by the first and second surfaces; providing a pulse generator configured to generate at least one stimulation pulse; disposing an electrode array including at least two electrodes along an adaptive portion of the substrate; and depositing or electroplating a plurality of electrical interconnects on the substrate; and electrically coupling the pulse generator to the at least two electrodes of the electrode array, wherein a thickness of the substrate along the adaptive portion is 0.5 mm or less.

[0028] Optionally, a pulse generator is provided along a further portion of the substrate, the method further comprising at least partially covering the further portion of the substrate with an encapsulation layer.

[0029] Additionally or alternatively, the stimulator further includes: a sealing layer at least partially covering the substrate; and an adhesive layer between the sealing layer and the substrate in at least one location.

[0030] Additionally or alternatively, the sealing layer covers at least a portion of the applied portion of the substrate, and the adhesive layer is between the sealing layer and at least a portion of the applied portion of the substrate.

[0031] Such products and related methods described herein provide improved bonding to improve resistance to fluid ingress in implant devices that include flexible substrates. The sealant / adhesive layer can be optimized to protect the surfaces of many types of substrates. When the substrate is constructed and arranged to be substantially flexible, the substrate can have a high degree of adaptability. Due to the high degree of adhesion of the sealant / adhesive layer, the flexible sealant layer can provide a high degree of ingress protection to one or more surfaces of the flexible substrate.

[0032] One or more regions of the substrate surface may be protected by an encapsulant / adhesive layer, each of which may be optimized separately or together to a certain extent.

[0033] Optionally, the adaptive portion of the substrate comprises a liquid crystal polymer (LCP).

[0034] Additionally or alternatively, the substrate includes a further portion in which the pulse generator is disposed, the encapsulation layer at least partially covering the further portion of the substrate.

[0035] Optionally, the sealing layer comprises a polymer and / or polydimethylsiloxane (PDMS).

[0036] By providing a bilayer with an encapsulant comprising PDMS and a conformal adhesive layer comprising a ceramic material, it has been found that the adhesive layer exhibits significantly higher stability in ionic media, thereby providing longer protection against delamination or water penetration through the encapsulant. The PDMS flows between defects and gaps in the adhesive layer, which may further contribute to longer-lasting adhesion and reduced defects. In particular, the relatively low viscosity of PDMS may result in a higher degree of reduced defects.

[0037] The ceramic materials HfO2, Al2O3, Ta2O3, SiC, Si3N4, TiO2, and any combination thereof may be advantageously used as an adhesion layer for the PDMS encapsulant layer.

[0038] A method of manufacturing an implantable stimulation device is provided, the method including: providing a substrate including first and second surfaces, the substrate having a thickness defined by the first and second surfaces; providing a pulse generator configured to generate at least one stimulation pulse; disposing at least two electrodes along an adapted portion of the substrate; depositing or electroplating a plurality of electrical interconnects on the substrate electrically coupling the pulse generator to the at least two electrodes; applying an adhesive layer at least partially covering the substrate; and applying a sealing layer over the adhesive layer, wherein a thickness of the substrate along the adapted portion is 0.5 mm or less.

[0039] Optionally, the adhesion layer is applied using atomic layer deposition (ALD). Additionally or alternatively, a pulse generator is provided along the further portion of the substrate, and the adhesion layer and sealing layer are applied to at least partially cover the further portion of the substrate.

[0040] Certain illustrative embodiments, illustrating its construction and method of operation, together with objects and advantages, can be best understood by reference to the following detailed description taken in conjunction with the accompanying drawings, which are not necessarily drawn to scale.

[0041] The accompanying drawings, which are incorporated in and form a part of this specification, illustrate exemplary embodiments and, together with the description, serve to further enable a person of ordinary skill in the relevant art to make and use these embodiments, as well as other embodiments that will be apparent to one of ordinary skill in the art. [Brief description of the drawings]

[0042] [Figure 1A] FIG. 1A is a cross-sectional view of a first implementation of an implantable stimulation device consistent with certain embodiments of the present invention. [Figure 1B]FIG. 1B is a top view of a first implementation of an implantable stimulation device consistent with certain embodiments of the present invention. [Figure 1C] FIG. 1C is a bottom view of a first implementation of an implantable stimulation device consistent with certain embodiments of the present invention. [Figure 2A] FIG. 2A is a cross-sectional view of a second implementation of an implantable stimulation device consistent with certain embodiments of the present invention. [Figure 2B] FIG. 2B is a top view of a second implementation of an implantable stimulation device consistent with certain embodiments of the present invention. [Figure 2C] FIG. 2C is a bottom view of a second implementation of an implantable stimulation device consistent with certain embodiments of the present invention. [Figure 3A] FIG. 3A is a cross-sectional view of a third implementation of an implantable stimulation device consistent with certain embodiments of the present invention. [Figure 3B] FIG. 3B is a top view of a third implementation of an implantable stimulation device consistent with certain embodiments of the present invention. [Figure 3C] FIG. 3C is a bottom view of a third implementation of an implantable stimulation device consistent with certain embodiments of the present invention. [Figure 4A] FIG. 4A is a first diagram of an alternative electrode configuration of an implantable stimulator consistent with certain embodiments of the present invention. [Figure 4B] FIG. 4B is a second diagram of an alternative electrode configuration of an implanted stimulator consistent with certain embodiments of the present invention. [Figure 4C] FIG. 4C is a third diagram of an alternative electrode configuration of the implant 30 stimulator consistent with certain embodiments of the present invention. [Diagram 5] FIG. 5 illustrates nerve locations in the front of the human head that may be treated through operation of an implanted stimulator device consistent with certain embodiments of the present invention. [Figure 6] FIG. 6 illustrates nerve locations in the posterior part of the human body that may be treated through operation of an implanted stimulator device consistent with certain embodiments of the present invention. [Figure 7]FIG. 7 illustrates nerve locations in the human body that may be treated through operation of an implanted stimulator device in accordance with certain embodiments of the present invention. [Figure 8A] Figure 8A shows the Electrochemical Impedance Spectroscopy (EIS) results Bode plot. Figure 8A: Impedance magnitude. [Figure 8B] Figure 8B shows the Electrochemical Impedance Spectroscopy (EIS) results as Bode plots: Figure 8B: Phase angle of the three samples. [Figure 8C] Figure 8C shows the EIS results at 10-2 Hz for 450 days of immersion. Figure 8C: Impedance magnitude. [Figure 8D] Figure 8D shows the EIS results at 10-2 Hz for 450 days of immersion. Figure 8D: Phase angle of the four samples. [Figure 9] FIG. 9 shows measurements comparing the average tensile force of LCP coated with PDMS using different processes, when dry and after immersion. [Figure 10] FIG. 10 shows a cross section of the test sample. [Figure 11A] FIG. 11A shows a cross section of the improved implant electrical device. [Figure 11B] FIG. 11B shows a cross section of the improved implant electrical device. [Figure 11C] FIG. 11C shows a cross section of the improved implant electrical device. [Figure 12A] FIG. 12A shows a cross section of an improved implanted medical device including an improved implanted electrical device and one or more electrodes. [Figure 12B] FIG. 12B shows a cross section of an improved implanted medical device including an improved implanted electrical device and one or more electrodes. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0043] Although the present invention can be implemented in many different forms, as shown in the drawings and described in detail herein, specific embodiments are shown in the drawings and described in detail herein. It is understood that the present disclosure of such embodiments should be considered as examples of the principles, and is not intended to limit the present invention to the specific embodiments shown and described. The described embodiments and their detailed structures and elements are merely provided to aid in a comprehensive understanding of the present invention. The scope of the present invention is best defined by the appended claims. In the following description, like reference numerals are used to describe the same, similar, or corresponding parts in several or different figures of the drawings.

[0044] Thus, it is apparent that the present invention can be implemented in various ways and that none of the specific features described herein are essential. Also, well-known functions or structures have not been described in detail, as they would obscure the present invention in unnecessary detail. Signal arrows in the drawings / figures should be considered as illustrative only, and not limiting, unless otherwise specified.

[0045] In this specification, terms such as first, second, etc. may be used to describe various elements, but it is understood that these elements should not be limited by these terms. These terms are used only to distinguish one element from another element. For example, a first element may be referred to as a second element, and similarly, a second element may be referred to as a first element without departing from the scope of the exemplary embodiment. As used herein, the term "and / or" includes any and all combinations of one or more of the associated listed items. As used herein, "at least one of A, B, and C" refers to A or B or C, or any combination thereof. As used herein, the singular form of a word includes the plural form and vice versa, unless the context clearly dictates otherwise.

[0046] The terms "a" or "an," as used herein, are defined as one or more. The term "multiple," as used herein, is defined as two or more than two. The term "another," as used herein, is defined as second or more. The terms "comprising" and / or "having," as used herein, are defined as including (i.e., open terms). The term "coupled," as used herein, is defined as connected, although not necessarily directly, and not necessarily mechanically.

[0047] It should also be noted that in some alternative embodiments, the functions / acts described may occur out of the order noted in the figures, for example two figures shown in succession may in fact be executed substantially concurrently or in the reverse order, depending on the functions / acts involved.

[0048] As used herein, ranges are used in shorthand form herein to avoid having to list and describe every value within the range. Any appropriate value within the range can be selected as the upper limit, lower limit, or endpoint of the range, as appropriate.

[0049] The word "comprising" should be interpreted inclusively rather than exclusively. Similarly, the terms "comprising" and "or" should be interpreted as all-inclusive unless such construction is clearly prohibited by the context. The terms "comprising" or "comprising" are intended to include embodiments that are included within the terms "consisting essentially of" and "consisting of". Similarly, the term "consisting essentially of" is intended to include embodiments that are included within the term "consisting of". Although having clear meanings, the terms "comprising", "having", and "consisting of" can be interchanged throughout the description of the present invention.

[0050] "About" means plus or minus 10% of the referenced numerical indication. For example, the term "about 4" includes a range of 3.6 to 4.4. All numerical values ​​expressing amounts of ingredients, reaction conditions, and the like used herein should be understood in all instances as being modified by the term "about". Accordingly, unless indicated to the contrary, the numerical parameters set forth herein are approximations that may vary depending on the desired properties sought to be obtained. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical parameter should be construed in light of the number of significant digits and ordinary rounding approaches.

[0051] Whenever phrases such as "for example," "such as," "including," and the like are used in this specification, they are understood to be followed by the phrase "without limitation," unless otherwise specified.

[0052] "Normally" or "optionally" means that an event or circumstance described below may or may not occur, and the description includes cases where said event or circumstance occurs or does not occur.

[0053] References throughout this document to "one embodiment," "particular embodiment," "embodiment," or similar terms mean that the particular features, structures, or characteristics described in connection with that embodiment are included in at least one embodiment of the invention. Thus, the appearances of such phrases, or in various places throughout this specification, are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner by one of ordinary skill in the art in one or more embodiments, without limitation.

[0054] In the following detailed description, numerous non-limiting specific details are given to facilitate an understanding of the disclosure.

[0055] 1A, 1B and 1C show a longitudinal section of a first embodiment 100 of an implanted stimulation device. a pulse generator 500 (shown only in FIGS. 1B and 1C) for generating at least one electrical therapy stimulation pulse; and The adaptive portion includes a foil-like substrate 300 having a longitudinal axis 600 that extends from the pulse generator 500 to a distal end of the substrate 300. The substrate 300 includes one or more adjacent polymer substrate layers and has first 310 and second 320 planar (outer) surfaces.

[0056] The implant stimulation device 100 also includes: Proximate the distal end is an electrode array 200, 400 having at least one electrode of a first 200a, 200b type and at least one electrode of a second type 400a, 400b. The electrodes 200, 400 are included on a first 310 or second 320 surface, each of which is configurable to transmit therapeutic energy during use (as a stimulating electrode) and / or (as a return electrode) to human or animal tissue. In this context, an array may be considered as a systematic arrangement of two or more electrodes 200a, 200b, 400a, 400b. 1D, 2D or 3D arrays may be provided. Optionally, they may be arranged in rows and / or columns.

[0057] The implant stimulation device 100 further comprises: The device includes one or more electrical interconnects 250 between the pulse generator 500 and the first 200a, 200b and second 400a, 400b electrodes for delivering electrical energy as one or more electrical therapy stimulation pulses to the associated first 200a, 200b and / or second 400a, 400b electrodes. The one or more electrical interconnects 250 are configured (or disposed) between the first 310 and second 320 surfaces. A plurality of electrical interconnects 250 is considered to be two or more than two electrical interconnects 250.

[0058] In the present disclosure, the adaptability of the electrode array 200, 400 is highly determined by one or more of the following: - flexibility of the part of the substrate 300 adjacent to the electrodes 200, 300; - placement and positioning of electrodes 200, 400; - the materials and dimensions (or extent) of the materials contained in the electrodes 200, 400; - the placement and location of one or more interconnects 250 in proximity to the electrodes 200, 400; and - The materials and dimensions (or extent) of the materials included in the interconnects 200, 400.

[0059] With proper configuration, arrangement and optimization, a foil-like (or film-like) and highly adaptable implant electrode array 200, 400 can be provided.

[0060] As shown, the adaptive portion of the foil-like substrate 300 is preferably elongated along a longitudinal axis 600 and has a tape-like shape, allowing the pulse generator 500 to be positioned (or be located) further away from the location of the electrodes 200, 400.

[0061] When the substrate 300 is substantially planar (by, in a non-limiting example, conforming the substrate 300 to a planar surface), the first 310 and second 320 surfaces are disposed along substantially parallel transverse planes 600, 700. As shown in FIG. 1A, the first surface 310 lies in a plane that includes a longitudinal axis 600 and a first transverse axis 700. The first transverse axis 700 is substantially perpendicular to the longitudinal axis 600. As shown in FIG. 1A, the plane of the first surface 310 is substantially perpendicular to the plane of the cross-section (substantially perpendicular to the surface of the paper).

[0062] The conforming portion of the foil-like substrate 300 has a maximum thickness of 0.5 mm or less and is adjacent to the first 200a, 200b and second 400a, 400b electrodes, the thickness being defined by the first 310 and second 320 surfaces. This may be determined by the perpendicular distance between corresponding points on the first 310 and second planar 320 surfaces. This is preferably determined when the substrate 300 conforms to the planar surface.

[0063] The foil-like substrate 300 has a thickness or extent along a second transverse axis 750. This second transverse axis 750 is substantially perpendicular to both the longitudinal axis 600 and the first transverse axis 700. As depicted, it is in the plane of the drawing (along the surface of the paper). The first surface 310 is depicted as the top surface and the second surface 320 is depicted as the bottom surface.

[0064] Thus, the thickness may be determined by the perpendicular distance along the second transverse axis 750 between corresponding points on the first 310 and second plane 320. The maximum thickness of the applicable portion of the foil-like substrate 300 proximate the first 200a, 200b and second 400a, 400b electrodes is 0.5 mm or less, preferably 0.3 mm or less, even more preferably 0.2 mm or less, and even more preferably 0.1 mm or less.

[0065] In general, the smaller the maximum thickness (i.e., the thinner the substrate), the better the fit, although a higher maximum thickness may be preferred to improve mechanical strength.

[0066] To clarify the differences between the various figures depicted, the axes are given nominal directions: - the longitudinal axis 600 extends from a proximal end on the left (not shown in FIG. 1A, but shown in FIGS. 1B and 1C) to a distal end shown on the right side of the drawing; a first horizontal axis 700 extends into the plane of the drawing; and A second horizontal axis 750 runs from the bottom to the top of the drawing.

[0067] The adaptive portion of the foil-like substrate 300 can be constructed and arranged as a multilayer. It includes two or more adjacent polymer substrate layers secured together and having a first 310 and a second 320 plane. One or more electrical interconnects 250 are also constructed (or arranged) between the first 310 and second 320 planes. However, it is not necessary that the two or more polymer substrate layers and / or interconnects have similar extents along the first transverse axis 700. In other words, within the context of the present disclosure, adjacent to a region where the polymer substrate is substantially continuous, there may be a region where the interconnect 250 is sandwiched between regions of the polymer substrate (appearing as a multilayer in a longitudinal cross section). Similarly, adjacent to a region where the substrate includes two adjacent substrate layers, there may be a region where the interconnect 250 is sandwiched between two polymer substrate layers (appearing as a multilayer in a longitudinal cross section). Similarly, a substrate including two or more polymer substrate layers may be modified (physically and / or chemically) to appear to be one layer of the polymer substrate.

[0068] These polymeric substrate layers are selected to be flexible and include one or more electrical interconnects 250. Preferably, the polymeric substrate material is also biocompatible and durable, such as a material selected from the group including: silicone rubber, siloxane polymer, polydimethylsiloxane, polyurethane, polyetherurethane, polyetherurethaneurea, polyesterurethane, polyamide, polycarbonate, polyester, polypropylene, polyethylene, polystyrene, polyvinyl chloride, polytetrafluoroethylene, polysulfone, cellulose acetate, polymethylmethacrylate, polyethylene, and polyvinyl acetate. Suitable polymeric materials, including LCP (liquid crystal polymer) films, are described in Polymers for Neural Implants, Hassler, Boretius, Stieglitz, Journal of Polymer Science: Part B Polymer Physics, 2011, 49, 18-33 (DOI 10.1002 / polb.22169). In particular, Table 1, which is incorporated herein by reference, shows the properties of polyimide (UBE U-Varnish-S), Parylene C (PCS Parylene C), PDMS (NuSil MED-1000), SU-8 (MicroChem SU-8 2000&3000 series), and LCP (Vectra MT1300).

[0069] The conformable foil substrate 300 is configured to be flexible so as to very closely follow the contours of the underlying anatomical features. Very thin foil substrates 300 have the added advantage that they have increased flexibility.

[0070] Most preferably, the polymer substrate layer comprises LCP, parylene and / or polyimide. LCP is a chemically and biologically stable thermoplastic polymer that allows for compact, hermetic sensor modules with low moisture penetration.

[0071] Advantageously, LCP can be thermoformed, allowing complex shapes to be provided. Very thin (and therefore malleable) and very flat (very planar) layers of LCP can be provided. It can also be cut using a suitable laser to fine-tune the shape.

[0072] In a non-limiting example, the LCP adaptive foil substrate 300 may have a thickness (range along the second horizontal axis 750) ranging from 50 microns (μm) to 720 microns (μm), preferably from 100 microns (μm) to 300 microns (μm). In exemplary embodiments, values ​​of 150 μm (microns), 100 μm, 50 μm, or 25 μm may be provided.

[0073] When applied to a substantially planar surface, the foil-like surface 300 is substantially configured as a plane having a lateral extent substantially perpendicular to the longitudinal axis 600, and the planar width can be determined by the perpendicular distance between corresponding points on the outer edge of the planar foil-like substrate 300 along the lateral extent. As shown, this is along the first lateral axis 700. In one embodiment, LCP can be used to provide electrodes 200, 400 with widths between 2 mm and 20 mm.

[0074] At room temperature, LCP thin films have mechanical properties similar to steel, which is important because the implant substrate 300 must be strong enough to be implanted, strong enough to be removed (explanted), and strong enough to follow the movements of adjacent anatomical features and / or structures without degradation.

[0075] LCPs belong to the group of polymeric materials with the lowest permeability to gases and water. LCPs can bond to themselves, allowing for multilayer construction with homogeneous structures.

[0076] In contrast to LCP, polyimide is a thermosetting polymer that requires adhesives to build multilayer sections with electrode arrays. Polyimide is a thermosetting polymer material that is durable at high temperatures and flexure.

[0077] In one embodiment, LCP can be used to provide the adaptive substrate 300 as a multi-layer, i.e., two or more adjacent polymer substrate layers. In a non-limiting example, these can be 25 μm (micron) thick layers.

[0078] In one embodiment, one or more electrical interconnects 250 may be provided (or disposed) between the first 310 and second 320 surfaces by metallization techniques. These may be conductors having a single polymer layer and embedded in the substrate 300, such as by applying a conductive material using suitable deposition techniques known from the semiconductor industry.

[0079] In one embodiment, when two or more adjacent polymer substrate layers are provided, the interconnect layers may be provided using suitable techniques, such as those from the semiconductor industry. Polymer substrate layers may also be considered adjacent if one or more adhesive layers are used between them. Examples of suitable adhesive materials and adhesive layers are described below in connection with Figures 8-12.

[0080] In one embodiment, lamination may also be used to provide desired physical and chemical properties and / or a convenient manufacturing method for substrate 300. In a non-limiting example, substrate 300 may include three laminated polymer layers: two high temperature thermoplastic layers with a low temperature layer (bond ply) between them, and a high temperature layer facing first surface 310 and second surface 320.

[0081] In an alternative embodiment, two layers of silicone may be provided as the polymer substrate layer: one layer of silicone is provided and metal is patterned on one of its outer surfaces; and a second layer of silicone is added on top of the metal pattern by jetting, overmolding, or spin coating.

[0082] In one embodiment, the electrical interconnects 250 may include one or more conductive materials, such as metal, optionally formed of one or more conductive elements (wires, strands, foils, lamina, plates, and / or sheets). They may be substantially continuous (one conductor). They may also include multiple conductors that are constructed and arranged to be electrically connected to each other during use. In other words, the one or more conductors are constructed and arranged to be substantially electrically continuous during use.

[0083] Alternatively, one or more electrical interconnects 250 may be included in one or more conductive interconnect layers 250 that are included (or disposed) between two adjacent polymer substrate layers. As shown in FIG. 1A, multiple interconnects may be provided at different locations (or depths or positions) between the first surface 310 and the second surface 320.

[0084] In one embodiment, interconnects 250 in the context of the present disclosure are not configured or arranged to come into contact with human or animal tissue during use. One or more interconnects 250 are embedded in (or covered by) one or more layers of a low conductive or insulating polymer, such as LCP. Additionally or alternatively, one or more encapsulation layers may be used.

[0085] The one or more interconnect layers 250 may also be provided by metallization using techniques from the PCB (printed circuit board) industry, such as metallization with biocompatible metals such as gold or platinum. Electroplating may be used. Layers including LCP films are particularly suitable for metallization. These electrical interconnects 250 and / or interconnect layers 250 are configured to transfer electrical energy from the pulse generator 500 to the coupled first electrodes 200a, 200b and / or second electrodes 400a, 400b as one or more electrical therapeutic stimulation pulses.

[0086] The use of a suitable polymer substrate material, such as an LCP film, allows the foil-like (or film-like) substrate 300 and the corresponding portions of the electrode array 200, 300 to have a high width-to-height ratio, which provides a biocompatible electronic foil (or film), or bioelectronic foil (or film).

[0087] In one embodiment, when the substrate 300 conforms to a substantially planar surface, the ratio of maximum planar width to maximum thickness adjacent the first 200a, 200b and second 400a, 400b electrodes is 7:1 or greater, preferably 10:1 or greater, more preferably 15:1 or greater, even more preferably 30:1 or greater, and even more preferably 50:1 or greater.

[0088] Ratios of 100:1 or greater may also be advantageous and may be provided using one or more mechanically strong substrate layers of LCP film approximately 20 mm wide and approximately 0.2 mm thick. This provides a high degree of flexibility and therefore a high degree of adaptability. Additional measures may be taken to increase adaptability in the first lateral direction 700, such as varying the width of the substrate, adding one or more undulations, and / or providing bending points.

[0089] In a non-limiting example, when electrodes 200, 400 and / or a single row of electrodes 200, 400 are used in narrower widths, the width may be 4 mm and the thickness may be about 0.2 mm, which is a ratio of about 20:1.

[0090] In a non-limiting example, a larger area may be required in the portion of the board adjacent to the pulse generator 500, more highly dependent on the dimensions of the electronic components used, 20 mm wide and 3 mm thick. This is a ratio of approximately 6.67:1.

[0091] As shown in FIG. 1A, the distal end (or distal portion) of the adaptive foil-like substrate 300 is A first surface 310 includes two electrodes 200a, 200b of a first type, and It includes two electrodes 400a, 400b of a second type that are also included on the first surface 310. From the proximal end to the distal end, the order shown is 200a, 400a, 200b, 400b. In other words, each electrode of the first type 200a, 200b is adjacent to an electrode of the second type 400a, 400b and is included on the same surface 310.

[0092] The foil-like substrate 300 includes electrical interconnects 250 between each of the electrodes 200a, 400a, 200b, 400b and the pulse generator. In this embodiment, each electrical interconnect 250 is constructed and arranged such that each of the electrodes 200a, 400a, 200b, 400b is substantially independently electrically connected. Thus, one of the operational modes available by appropriately configuring the pulse generator 500 is substantially independent operation. The pulse generator 500 can be configured using one or more hardware, firmware, and / or software parameters.

[0093] Although shown in FIG. 1A as individual connections 250 at different distances (or positions) between the first 310 and second 320 surfaces, those skilled in the art will also appreciate that the same interconnects may be provided by appropriately configured interconnects 250 (or interconnect layers 250) at approximately the same distances (or positions) between the first 310 and second 320 surfaces, similar to the embodiment shown in FIG. 3B described below.

[0094] By "contained" in the first 310 or second 320 surface, it is meant that the electrode 200a, 400a, 200b, 400b is relatively thin (e.g., when the substrate is arranged to conform to a substantially planar surface, it may have an extent along the second transverse axis of 20-50 microns or less). Thinner electrodes may be used to provide an even greater degree of conformability (e.g., 1 mm or less) and may be attached to (or at least partially embedded in) the surface.

[0095] The electrodes 200, 400 may comprise conductive materials such as gold, platinum, platinum black, TiN, IrO2, iridium, and / or platinum / iridium alloys and / or oxides. Conductive polymers such as Pedot can also be used. Preferably, biocompatible conductive materials are used. They can be manufactured on or in the first 310 and / or second 330 surfaces of one or more polymeric substrate layers using PCB / metallization techniques.

[0096] For electrodes 200a, 200b, 400a, 400b, thicker metal layers are generally preferred over thinner metal layers due to potential exposure to biological material that may dissolve the metal, although thicker metal layers typically result in increased stiffness (reduced compliance) near the thicker layers.

[0097] The stimulator 100 may be implanted by first creating a subcutaneous tunnel and / or by using an implant tool. However, the high degree of malleability may make successful implantation more difficult. Even with the proper insertion tool, the position of the electrodes may later prove to be incorrect due to slippage, displacement of the lead during implantation, or displacement of the lead after implantation.

[0098] At least the distal end, including the electrode array 200, 400, is implanted. However, it may be advantageous to implant the stimulator 100.

[0099] Furthermore, during implantation, it can be difficult to pinpoint the desired location for stimulation. After implantation, the stimulation electrode should be placed close enough to the nerve to be stimulated. However, the nerve pathways are not always clearly visible to the implanting specialist, and the nature and path of the nerve pathways vary greatly from person to person.

[0100] 1, there is no substantial hardware difference between the first type 200a, 200b and the second type 400a, 400b electrodes. The functional difference is determined in this implementation primarily by the configuration (one or more hardware, firmware, and / or software parameters) of the pulse generator 500. There may be less impact on electrical characteristics due to the placement and routing of the interconnects 250.

[0101] One or more coupled electrodes of the same type 200a, 200b or 400a, 400b can be operated in substantially the same way by appropriate configuration of the pulse generator 500. In other words, the stimulation energy applied to the electrodes 200, 400 is substantially the same at the same time (usually measured as voltage, current, power, charge, or any combination thereof). This can also be used to predict and / or correct for slippage and / or lead displacement. This is advantageous since the configuration can be performed at least in part using software.

[0102] Additionally or alternatively, two or more electrodes 200, 400 may be configured and positioned using one or more parameters of the pulse generator 500 as stimulation or return electrodes. This may provide a greater degree of configurability as it only requires implanting the substrate 300 such that at least two electrodes are in proximity to desired stimulation locations.

[0103] In this embodiment 100, electrodes of a first type 200a, 200b are nominally constructed and arranged to act as stimulation electrodes.

[0104] The electrodes of the second type 400a, 400b are configured to nominally act as return electrodes. Each is configured to provide an electrical return to one or more stimulation electrodes 200a, 200b during use. In other words, the electrical return 400a, 400b closes an electrical circuit. They may also be similarly configured to provide an electrical ground to a corresponding electrical energy source.

[0105] Therefore, based on this nominal configuration, one of three configurations is offered: - the stimulation / return electrode pair 200a / 400a is adjacent to the first surface 310 at its stimulation / return position; or the stimulation / return electrode pair 200b / 400b is adjacent to the first surface 310 at its stimulation / return position; or -Any combination of them.

[0106] In one embodiment, one or more stimulation electrodes 200a, 200b may be provided in such a stimulation device 100. The number, size, and / or spacing of the stimulation electrodes 200a, 200b may be selected and optimized depending on the treatment. In one embodiment, if more than one stimulation electrode 200a, 200b is provided, each stimulation electrode 200a, 200b may provide: -Different, similar or the same stimulus effect.

[0107] To avoid slippage, a choice can be made between one or two electrodes 200a, 200b in close proximity to the tissue where the effect is to occur.

[0108] If stimulation over a larger area and / or at locations between the active stimulation electrodes 200a, 200b is required, two or more stimulation electrodes 200a, 200b can be active substantially simultaneously.

[0109] In one embodiment, the stimulation electrodes 200a, 200b measure 6-8 mm along the longitudinal axis 600 and 3-5 mm along the first transverse axis 700, thus approximately 18-40 square millimeters (mm 2 )

[0110] In one embodiment, a foil-like substrate 300 suitable for an implantable stimulation device may contain up to twelve stimulation 200a, 200b and return 400a, 400b electrodes over a length of 15 cm, allowing for compensation of misalignment or simply allowing a professional to select the most effective stimulation location.

[0111] In one embodiment, Figure IB shows a view of the second surface 320 of the implantable distal end (or portion) of the foil-like substrate 300 shown in Figure IA. In other words, the second surface 320 is drawn on the paper and lies along the longitudinal axis 600 (drawn from bottom to top) and along the first transverse axis 700 (drawn from left to right). The second transverse axis 750 extends into the paper. The first surface 310 is shown in Figure IB but is higher (into the paper) along the second transverse axis 750 and is also substantially parallel to the plane of the drawing. The foil-like substrate 300 is arranged to conform to a substantially planar surface.

[0112] The pulse generator 500 may be disposed (or located) between the second 320 surface and the first 310 surface. In Figures 1B and 1C, this is shown by a dotted line. Alternatively, the pulse generator 500 may be at least partially disposed on the first surface 310 or the second surface 320. Alternatively, the pulse generator 500 may be at least partially embedded in the first surface 310 or the second surface 320.

[0113] Depending on the degree of embedding and the electrical component or components used in the pulse generator 500, the maximum thickness can be optimized. To minimize the thickness, the components can be thinned. If the substrate 300 is constructed and arranged in a malleable and / or foil-like manner, the maximum thickness of the implant stimulator 100 in the portion of the substrate adjacent to the pulse generator 500 can be 5 mm or less, preferably 4 mm or less, and more preferably 3 mm or less. The thickness is determined by the vertical distance between corresponding points on the outer plane when the implant stimulator 100 is adapted to a substantially planar surface. Additional optional electrical components such as coils or antennas, including dipoles or fractal antennas, can also affect the thickness depending on the degree to which they are embedded in the substrate.

[0114] The stimulator 100 and the foil-like substrate 300 extend along a first transverse axis 700 (considered as the planar width of the stimulator 100 / foil-like substrate 300 when applied to a substantially planar surface). As shown, the planar width of a portion of the substrate adjacent to the pulse generator 500 may be greater than the planar width of another portion of the substrate adjacent to the electrodes 200a, 200b, 400a, 400b at the distal end (or portion) of the foil-like substrate 300. The planar width adjacent to the pulse generator 500 may depend on the hardware and components used in the pulse generator 500. Typically, it is at least the width of the integrated circuit used in the pulse generator 500. Additional optional electrical components such as antennas including coils or dipoles or fractal antennas may also affect the planar width.

[0115] In one embodiment, the planar width adjacent to the electrodes 200a, 200b, 400a, 400b may depend on the conductors used for the electrodes 200a, 200b, 400a, 400b and the interconnect(s) 250. In one embodiment, the planar width is at least the width of the first electrode 200a, 200b or the second electrode 400a, 400b.

[0116] In one embodiment, FIG. 1C shows a view of the first surface 310 of the implantable distal end (or portion) of the foil-like substrate 300 shown in FIGS. 1A and 1B. In other words, the first surface 310 is drawn in the plane of the paper along the longitudinal axis 600 (drawn from bottom to top) and along the first transverse axis 700 (drawn from right to left). The second transverse axis 750 extends out of the plane of the paper. This is the view facing the stimulated (in use) animal or human tissue. The second surface 320, not shown in FIG. 1C, is lower (into the plane of the paper) along the second transverse axis 750 and is also substantially parallel to the plane of the drawing. The foil-like substrate 300 is arranged to conform to a substantially planar surface.

[0117] As shown in Figure 1A, one or more interconnects 250 are disposed (or located) between the first 310 and second 320 surfaces. As shown in Figure 1C, they are shown as dotted lines and represent the interconnects 250 (or one or more appropriately configured interconnect layers 250) provided to each of the electrodes 200a, 200b, 400a, 400b in this embodiment. A single dotted line 250 is drawn between the pulse generator 500 and the electrodes 200, 400 to indicate that in the embodiment 100, the interconnects 250 are in approximately the same location along the first horizontal axis 700.

[0118] As shown in FIG. 1C, electrodes 200a, 200b, 400a, 400b each have a longitudinal extent (length) along a longitudinal axis 600 and a lateral extent (width) along a first lateral axis 700.

[0119] Although depicted similarly, in reality each electrode 200a, 200b, 400a, 400b may vary in shape, cross-section, orientation and / or size (or extent) depending on the intended use and / or degree of configurability desired.

[0120] After implantation of the stimulator 100, or at least a distal end (or portion) including the electrode array 200, 400, the pulse generator 500 may be configured and arranged to provide electrical energy to one or more coupled electrodes of the first type 200a, 200b, in use, with electrical return applied to one or more coupled electrodes of the second type 400a, 400b.

[0121] The configurability of the stimulation device 100 allows the operation of one or more electrodes 200a, 200b, 400a, 400b to be determined and / or adapted before, during, and / or after implantation of at least the distal end (or portion) including the electrode array 200, 400. Operation can also be reconfigured one or more times during the time the stimulation device 100 is implanted to optimize and / or extend therapy.

[0122] In one embodiment, pulse generator 500 may be initially configured to nominally operate with 200a and 400a as the stimulation / return electrode pair, respectively. After implantation of at least distal ends 200, 400, insufficient stimulation may be observed and / or measured. If this is assumed to be primarily due to longitudinal misalignment, pulse generator 500 may alternatively be configured to nominally operate with 200b and 400b as the stimulation / return electrode pair, respectively, using one or more parameters.

[0123] The stimulator 100 may be further configured and arranged to switch the pulse generator 500 between these configurations under predefined and / or controlled conditions. It may be convenient to further consider these configurations as first and second electrode modes and allow a user to select the modes as preferred and / or switching modes. Alternatively, the pulse generator 500 may switch modes under predefined and / or controlled conditions.

[0124] Additionally or alternatively, other modes may be provided to configure the pulse generator 500 to operate in: - in a first electrode mode, electrical stimulation energy is provided as one or more electrical therapy stimulation pulses to one or more coupled electrodes of a first type 200a, 200b, and one or more coupled electrodes of a second type 400a, 400b are configured to provide a corresponding electrical return to the one or more first electrodes 200a, 200b, during use; or - In a second electrode mode, energy is provided as one or more electrical therapy stimulation pulses to one or more coupled electrodes of the second type 400a, 400b, and the one or more coupled electrodes of the first type 200a, 200b are configured to provide a corresponding electrical return to the one or more second electrodes 400a, 400b, during use.

[0125] Again, the stimulator 100 may be further configured and arranged to switch the pulse generator 500 between these configurations or modes under predefined and / or controlled conditions. Additionally or alternatively, a user may select a mode as a preferred and / or switch mode.

[0126] Those skilled in the art will appreciate that the electrodes 200a, 200b, 400a, 400b may be configured to operate in more complex configurations, such as: - 400a and 200a can each be operated as a stimulation / return electrode pair (reversing the original intended operation); -400b and 200b can each be operated as a stimulation / return electrode pair; - if moderate stimulation is preferred, two or more electrodes 200a, 200b, 400a, 400b may operate substantially simultaneously as one or more stimulation electrodes; - one or more of the electrodes 200a, 200b, 400a, 400b may be operated as one or more return electrodes; - electrode 400a acts as a stimulation electrode and, in combination, electrodes 200a and 200b act as return electrodes; - Electrodes 400a and 400b act as stimulation electrodes and, in combination, electrodes 200a and 400b act as return electrodes.

[0127] Alternatively or additionally, the shape, orientation, cross-section, and / or size (or length) of one or more stimulation electrodes may be configured differently compared to one or more return electrodes.

[0128] When configuring and positioning the portion of the foil-like substrate 300 proximate the electrode array 200, 400 for compatibility, several parameters and characteristics can be considered, such as: the lateral 700 and / or longitudinal extent 600 of one or more electrodes 200a, 200b, 400a, 400b; the thickness of the foil-like substrate 300, or the vertical distance between the first surface 310 and the second surface 320 -Materials contained in the foil-like substrate 300 and their physical properties The number and extent of interconnects 250 and / or interconnect layers 250 between the first surface 310 and the second surface 320.

[0129] Attempts have been made to make conventional leads, such as cylindrical leads, much thinner to allow for subcutaneous implantation and / or to increase comfort by flattening, but the surface area of ​​the flattened electrodes can be disadvantageously small.

[0130] As a non-limiting example, a conventional 0.2 mm round lead with a 1 cm long electrode would be approximately 6 mm 2 This is estimated to result in an electrode having an electrode surface of

[0131] However, using the adaptive electrode array described herein, a thin substrate 300 having dimensions of 0.2 mm thick and 4 mm wide can be stretched to approximately 35 mm in length. 2 The electrode surface of the electrode can be constructed and arranged to provide an electrode surface area of ​​approximately 100 nm, which is estimated to reduce impedance by a factor of approximately 35 / 6 and reduce power consumption by approximately 35 / 6.

[0132] In one embodiment, Figures 2A, 2B and 2C show a longitudinal section through a second embodiment 101 of an implantable stimulation device, which is similar to the first embodiment 100 shown in Figures 1A, 1B and 1C, with the following exceptions: Instead of four electrodes included on the first surface 310, this embodiment includes two electrodes on the first surface 310 (an electrode nominally of the first type 200a and an electrode nominally of the second type 400a). From the proximal end to the distal end, the depicted order is 200a, 400a. In other words, an electrode of the first type 200a is adjacent to an electrode of the second type 400a on the first surface 310. The distal end of the stimulator 101 also comprises two electrodes on the second surface 320 (a further electrode, nominally of the first type 200b, and a further electrode, nominally of the second type 400b). From the proximal end to the distal end, the depicted order is 200b, 400b. In other words, an electrode of the first type 200b is adjacent to an electrode of the second type 400b on the second surface 320. In FIG. 2B, a view of the second surface 320 shows two electrodes 200a, 400a contained therein, with one or more interconnects 250 indicated using dotted lines. In FIG. 2C, a view of the second surface 320 shows two electrodes 200b, 400b included on that surface, with one or more interconnects 250 indicated using dotted lines.

[0133] In this embodiment 101, electrodes of a first type 200a, 200b are nominally constructed and arranged to operate as stimulation electrodes, and electrodes of a second type 400a, 400b are nominally configured to operate as return electrodes.

[0134] Thus, three main configurations are offered: the stimulation / return electrode pair 200a / 400a is adjacent to the first surface 310; or the stimulation / return electrode pair 200b / 400b is adjacent to the second surface 320; or -Any combination of them.

[0135] This can be advantageous when there is uncertainty as to whether the implantable distal end of the foil-like substrate 300 may be "above" or "below" the target tissue (e.g., "above" or "below" a nerve), which can be determined by attempting stimulation in each nominal configuration after implantation and observing and / or measuring the presence of nerve stimulation.

[0136] As discussed above with respect to FIGS. 1A, 1B and 1C, each electrode 200a, 200b, 400a, 400b can operate as one or more stimulation electrodes or as one or more return electrodes.

[0137] In one embodiment, Figures 3A, 3B and 3C show a longitudinal cross section of a third embodiment 102 of an implantable stimulation device, which is similar to the second embodiment 101 shown in Figures 2A, 2B and 2C, with the following exceptions: - the interconnects 250 are disposed in substantially the same location along the second transverse axis 750 as shown in Fig. 3A. The lines 250 are hatched to indicate that they are not drawn as being in the same longitudinal cross section. There are interconnects 250 disposed in substantially different locations along the first transverse axis 700; - the interconnects 250 are arranged in substantially different configurations along the first horizontal axis 700 as two adjacent dashed lines between the electrode array 200, 400 and the pulse generator 500, as shown in Figures 3B and 3C; - instead of the first surface 310 nominally comprising first 200 and second 400 type electrodes, the first surface 310 nominally comprises first 200a and second 200b electrodes of the first type 200; Instead of the second surface 320 nominally comprising first 200 and second 400 type electrodes, the second surface 320 nominally comprises first 400a and second 400b electrodes of the second type 400.

[0138] In this embodiment 102, electrodes of a first type 200a, 200b are nominally constructed and arranged to operate as stimulation electrodes, and electrodes of a second type 400a, 400b are nominally configured to operate as return electrodes.

[0139] Thus, three main configurations are offered: - the stimulation / return electrode pair 200a / 400a for stimulating between the first surface 310 and the second surface 320 is close to the location of this electrode pair; or - the stimulation / return electrode pair 200b / 400b for stimulating between the first surface 310 and the second surface 320 is close to the location of this electrode pair; or -Any combination of them.

[0140] This may be advantageous to correct for longitudinal misalignment or simply to allow the medical professional to select the most effective stimulation location.

[0141] As discussed above with respect to Figures 2A, 2B and 2C, each electrode 200a, 200b, 400a, 400b can operate as one or more stimulation electrodes or as one or more return electrodes.

[0142] Additionally or alternatively, one or more electrodes of the same type 200a, 200b or 400a, 400b may be electrically connected to each other by appropriately configuring one or more interconnects 250. They then operate in substantially the same way. This can be used to predict and / or correct for misalignment and / or lead migration, since longitudinal positioning is less sensitive (stimulation is provided over a larger longitudinal and / or lateral range).

[0143] 4A, 4B and 4C show alternative electrode array 200, 400 configurations suitable for inclusion in an implantable stimulation device 100, 101, 102 as described herein.

[0144] Fig. 4A shows an implantable distal end of a further embodiment 103 of the stimulation device. Similar to the distal end shown in Fig. 1C, the first surface 310 includes two electrodes 200a, 200b of a first type and two electrodes 400a, 400b of a second type. From the proximal end to the distal end, the depicted order is 200a, 400a, 200b, 400b. In other words, each electrode of the first type 200a, 200b is adjacent to an electrode of the second type 400a, 400b and is included in the same surface 310.

[0145] The distal end shown in FIG. 4A is the same as that shown in FIG. 1A with the following exceptions: The electrodes 200, 400 extend at an angle to the longitudinal axis 600. This may reduce sensitivity to longitudinal misalignment as the longitudinal positions at which tissue stimulation may be provided are increased.

[0146] Additionally or alternatively, the second surface 320 may also include two electrodes 200a, 200b of a first type and two electrodes 400a, 400b of a second type.

[0147] As noted above, each electrode 200a, 200b, 400a, 400b can operate as one or more stimulation electrodes or as one or more return electrodes.

[0148] 4B shows an implantable distal end of a further embodiment 104 of the stimulator. Similar to the distal end shown in FIG. 1C, the first surface 310 includes four electrodes. However, in this embodiment 104, the first surface 310 includes: It includes four electrodes 200a, 200b, 200c, 200d of a first type and an electrode 400 of a second type. From the proximal end to the distal end, the depicted order is 200a, 200b, 200c, 200d. Laterally adjacent to the four electrodes of the first type 200 are electrodes of the second type 400, which extend longitudinally adjacent each electrode of the first type 200.

[0149] Electrodes of the first type 200 can nominally act as one or more stimulating electrodes. Electrodes of the second type 400 can nominally act as return electrodes for one or more stimulating electrodes.

[0150] This may reduce sensitivity to longitudinal misalignment as the number of different longitudinal positions from which tissue stimulation may be provided that may be selected is increased.

[0151] Additionally or alternatively, the second surface 320 may similarly include four electrodes 200a, 200b, 200c, 2003 of a first type and one adjacent longitudinally extending electrode 400 of a second type.

[0152] As noted above, each electrode 200a, 200b, 200c, 200d, 400 can operate as one or more stimulation electrodes or as one or more return electrodes.

[0153] 4C shows an implantable distal end of a further embodiment 105 of the stimulation device. Similar to the distal end shown in FIG. 4B, the first surface 310 includes four electrodes 200a, 200b, 200c, 200d of a first type. However, in this embodiment 105, the first surface 310 further includes four adjacent electrodes 400a, 400b, 400c, 400d of a second type. From the proximal end to the distal end, the depicted order is 200a / 400a, 200b / 400b, 200c / 400c, 200d / 400d. Laterally adjacent to each of the four electrodes of the first type 200 are electrodes of the second type 400 in approximately the same arrangement along the longitudinal axis 600.

[0154] An electrode of the first type 200 can nominally act as one or more stimulating electrodes. An electrode of the second type 400 can nominally act as a return electrode for one or more stimulating electrodes. Nominally, adjacent electrodes can be considered as a stimulating / return pair 200 / 400.

[0155] In other words, a 2x4 electrode array (2 along the transverse axis and 4 along the longitudinal axis) is provided.

[0156] This may reduce sensitivity to longitudinal misalignment by providing four different stimulus / return 200 / 400 pairs at substantially different longitudinal locations, increasing the selection from which tissue stimulation may be provided.

[0157] Additionally or alternatively, the second surface 320 may also include four electrodes 200a, 200b, 200c, 200d of a first type and four adjacent electrodes 400a, 400b, 400c, 400d of a second type.

[0158] As described above, each electrode 200a, 200b, 200c, 200d, 400a, 400b, 400c, 400d can act as one or more stimulation electrodes or as one or more return electrodes, which may also reduce sensitivity to lateral displacement.

[0159] The stimulators 100, 101, 102, 103, 104, and 105 further include The pulse generator 500 may include an energy receiver configured and arranged to wirelessly receive energy from an associated energy transmitter when the associated energy transmitter is in proximity, the pulse generator 500 being further configured and arranged to receive electrical energy from the energy receiver for its operation.

[0160] 5 and 6 show neural configurations that may be stimulated using appropriately configured implantable distal ends of stimulators 100, 101, 102, 103, 104, 105 to provide neural stimulation for treating a medical condition such as a headache or primary headache.

[0161] Figure 5 shows the left supraorbital nerve 910 and the right supraorbital nerve 920, which may be electrically stimulated using appropriately configured equipment. Figure 6 shows the left greater occipital nerve 930 and the right greater occipital nerve 940, which may also be electrically stimulated using appropriately configured equipment.

[0162] Depending on the size of the area to be stimulated and the dimensions of the portion of the device to be implanted, the appropriate location for providing the electrical stimulation required for the treatment is determined. The approximate implant locations of the distal portion of the stimulators, including stimulators 100, 101, 102, 103, 104, 105, are shown as the following areas: - Position 810 for left supraorbital stimulation and position 820 for right supraorbital stimulation to treat chronic headaches such as migraines and cluster headaches. - Location 830a or 830b for left occipital stimulation and location 840a or 840b for right occipital stimulation for treating chronic headaches such as migraines, cluster headaches, occipital neuralgia, etc. Locations 830b, 840b for stimulation are located above ("above") the (external) occipital eminence inion.

[0163] In many cases, these will be the approximate locations 810, 820, 830a / b, 840a / b of the implanted stimulation devices 100, 101, 102, 103, 104, 105.

[0164] A separate stimulation system can be used for each implant location 810, 820, 830a / b, 840a / b. If the implant locations 810, 820, 830a / b, 840a / b are adjacent to one another or overlap, a single stimulation system can be configured to stimulate multiple implant locations 810, 820, 830a / b, 840a / b.

[0165] The multiple stimulators 100, 101, 102, 103, 104, 105 may be operated separately, simultaneously, sequentially, or any combination thereof to provide the required therapy.

[0166] 7 shows further configurations of nerves that may be stimulated using appropriately configured improved implant stimulators 100, 101, 102, 103, 104, 105 to provide nerve stimulation to treat other conditions. The locations (810, 820, 830, 840) shown in FIGS. 5 and 6 are also shown in FIG. 7.

[0167] Depending on the size of the area to be stimulated and the dimensions of the portion of the device to be implanted, an appropriate location for providing the electrical stimulation required for therapy is determined. The approximate implant locations of the portion of the stimulator that contains the stimulation electrodes are indicated as the following areas: - Location 810 for cortical stimulation to treat epilepsy; -Deep brain stimulation for tremor control treatment in Parkinson's patients;Treatment of dystonia, obesity, essential tremor, depression, epilepsy, obsessive-compulsive disorder, Alzheimer's disease, anxiety, bulimia, ENT, traumatic brain injury, Tourette's, sleep disorders, autism, bipolar disorder;Place 850 for stroke recovery; - Place 860 for vagus nerve stimulation to treat epilepsy, depression, anxiety, bulimia, obesity, ENT, obsessive-compulsive disorder, heart failure, Crohn's disease, rheumatoid arthritis; - Location 860 for carotid artery or carotid sinus stimulation to treat hypertension; - Location 860 for hypoglossal and phrenic nerve stimulation to treat sleep apnea; -Place 865 for cerebrospinal stimulation to treat chronic neck pain; - Location 870 for peripheral nerve stimulation to treat limb pain, migraine, limb pain; -Place 875 for spinal cord stimulation to treat chronic back pain, angina, asthma, general pain; - Place 880 for gastric stimulation for the treatment of obesity, bulimia, interstitial cystitis; -Site 885 for sacral and pudendal nerve stimulation for the treatment of interstitial cystitis; -Site 885 for sacral nerve stimulation for the treatment of urinary incontinence, fecal incontinence; - Location 890 for sacral neuromodulation for bladder control therapy; and - Location 895 for peroneal nerve stimulation to treat gait or foot drop.

[0168] Other conditions that can be treated include gastroesophageal reflux disease, autoimmune diseases, inflammatory bowel disease, and inflammatory disorders.

[0169] The adaptability and reduced thickness of the substrate 100 and electrode arrays 200, 400 make the implantable stimulation device(s) 100, 101, 102, 103, 104, 105 highly advantageous for stimulation of one or more nerves, one or more muscles, one or more organs, spinal tissue, brain tissue, one or more cortical surface regions, one or more sulci, and any combination thereof.

[0170] The implantable stimulation devices 100, 101, 102, 103, 104, 105 described above in connection with Figures 1-4 can generally be described as embodiments constructed and arranged for improved flexibility.

[0171] The stimulators 100, 101, 102, 103, 104, 105 may be further modified. Non-limiting examples include: The foil-like substrate 300 and portions of the pulse generator 500 may be embedded in one or more flexible biocompatible encapsulation layers, as described below. These layers may include liquid crystal polymers (LCP), polydimethylsiloxane (PDMS), silicone polyurethane, polyimide, parylene, biocompatible polymers, biocompatible elastomers, and any combination thereof.

[0172] The implanted electrical devices 1100, 1101, 1102 described below in connection with Figures 8-12 can be generally described as embodiments that are constructed and arranged to provide an improved seal. As described below, they can be included in implanted medical devices 1110, 1111 that are constructed and arranged to provide a degree of stimulation.

[0173] FIG. 11A shows a cross-section of an improved implantable electrical or electronic device 1100. It includes a substrate 1400 having a first surface 1410 and one or more electrical conductors 1210 .

[0174] Optionally, substrate 1400 may be substantially biocompatible. However, the use of one or more encapsulation layers 1310 may allow for the use of substrates 1400 and conductors 1210 that are biocompatible, partially biocompatible, or not significantly biocompatible.

[0175] Generally, the degree of biocompatibility of a material or layer can be determined by measuring the degree of tissue reaction and the length of time over which it is considered biostable, with a lower degree of tissue reaction and / or a longer period of biostable indicating greater biocompatibility.

[0176] The substrate 1400 is further constructed and arranged to be substantially flexible. In other words, the substrate is substantially pliable, flexible, or compliant. The degree of flexibility can be adjusted using parameters such as: - the dimensions of the device 1100 elements, and / or - the inclusion of materials and substances with desirable properties, and / or - the combination of materials and substances used, and / or - the proportions of materials and substances used, and / or -Inclusion of recesses, openings, apertures and reinforcements.

[0177] Additionally or alternatively, one skilled in the art will appreciate that the degree of flexibility may be tailored using the parameters discussed above for substrate 300 described in connection with FIGS. 1-4.

[0178] The one or more conductors 1210 are depicted very diagrammatically. They may be conductors, for example with a single polymer layer, embedded or deposited in the substrate 1400 by applying a conductive material using a suitable deposition technique known from the semiconductor industry. The one or more conductors 1210, such as metal, may be formed, for example, of one or more conductive elements (wires, strands, foils, thin layers, plates, and / or sheets) as required. Optionally, the one or more conductors may be disposed between the outer surfaces of the substrate 1400.

[0179] The device 1100 further includes: a first biocompatible sealing layer 1310 comprising polydimethylsiloxane (PDMS) rubber; and - a first adhesive layer 1510.

[0180] In the context of this disclosure, ceramics should be considered advanced ceramics and / or technical ceramics that offer a relatively high degree of thermal stability, wear resistance, and corrosion resistance.

[0181] The most suitable ceramic materials are those that have a high degree of adhesion to the encapsulant layer and / or substrate, can be applied in a relatively uniform coating, and provide a relatively low degree of permeability to moisture. Ceramic materials in this context can be inorganic, non-metallic, or metallic, often crystalline oxide, nitride, or carbide materials. Some elements, such as carbon and silicon, are also considered ceramics. Non-metallic ceramics can include both non-metallic and metallic elements.

[0182] Optionally, the first adhesive layer 1510 may be substantially biocompatible. However, the use of one or more encapsulation layers 1310 may allow for the use of one or more adhesive layers 1510 that are biocompatible, partially biocompatible, or not significantly biocompatible.

[0183] First adhesive layer 1510 and first sealing layer 1310 are constructed and arranged to resist ingress of fluid from the human or animal body to at least a portion of first surface 1410. Constructions and arrangements are described further below.

[0184] As shown in Figure 11A, the extent of the adhesive / sealing layer 1510 / 1310 in this cross section may be smaller than the extent of the substrate 1400. In general, the extent of the adhesive / sealing layer 1510 / 1310 may be larger than, equal to, or smaller than the extent of the substrate 1400. A "larger" embodiment of the adhesive and sealing layers is shown in Figure 11C. Further "smaller" embodiments of the adhesive and sealing layers are shown in Figures 11B and 12A.

[0185] Generally, the portion of the first surface 1410 that is protected from fluid ingress is below the extent of the adhesive / sealing layer 1510 / 1310.

[0186] As shown in Figure 11A, the extent of the adhesive layer 1510 in this cross section may be smaller than the extent of the encapsulation layer 1310. In some configurations, this is advantageous since the edges of the adhesive layer 1510 are at least partially encapsulated 1310. In general, the extent of the adhesive layer 1510 may be greater than, equal to, or less than the extent of the encapsulation layer 1310. Further "smaller" embodiments are shown in Figures 11C and 12A. An "equal" portion of the substrate is shown in Figure 12B.

[0187] In a preferred embodiment, the extent of the adhesive layer 1510 is equal to or greater than the extent of the encapsulation layer 1310. This can be advantageous in certain configurations as the surface area of ​​the encapsulant 1310 in direct contact with the surface 1410 of the substrate 1400 is greatly reduced. In some cases, this surface area is substantially zero, further reducing the possibility of fluid intrusion. A "substantially zero" embodiment is shown in Figure 11C, and a portion of the substrate is shown in Figure 12B.

[0188] Figure 11B shows another implanted electrical or electronic device 1101. It is the same as the implanted electrical device 1100 shown in Figure 11A, except that it further includes: - second surface 1420; - a second biocompatible sealing layer 1320 comprising polydimethylsiloxane (PDMS) rubber; and - A second adhesive layer 1520 comprising a ceramic material disposed between the second planar surface 1420 and the second encapsulation layer 1320. The second adhesive layer 1520 is further configured and arranged to conform to the second surface 1420. In other words, it is a conforming layer.

[0189] Second adhesive layer 1520 and second sealing layer 1320 are constructed and arranged to resist ingress of fluid from the human or animal body to at least a portion of second surface 1420. Constructions and arrangements are described further below.

[0190] The second encapsulation layer 1320 may be substantially identical to, highly similar to, or substantially different from, the first encapsulation layer 1310.

[0191] The second adhesive layer 1520 may be substantially identical to, highly similar to, or substantially different from, the first adhesive layer 1510.

[0192] Although the first surface 1410 and the second surface 1420 are depicted as opposing sides of a substrate in FIG. 11B, other combinations are possible, such as: - applying a first adhesive / sealing layer 1310 / 1510 and a second adhesive / sealing layer 1320 / 1520 to different areas of the first surface 1410; - applying a first adhesive / sealing layer 1310 / 1510 and a second adhesive / sealing layer 1320 / 1520 to different areas of the second surface 1420; - the first surface 1410 and the second surface 1420 are adjacent to each other; - the first surface 1410 and the second surface 1420 are opposite each other; - the first surface 1410 and the second surface 1420 are at an angle to each other; The first surface 1410 and the second surface 1420 are substantially perpendicular to each other.

[0193] Figure 11C shows a further implanted electrical or electronic device 1102, which in this cross section is the same as the implanted electrical device 1100 shown in Figure 11A, with the following exceptions: - the substrate 1400 comprises four protected surfaces, each surface being protected by a further adhesive layer 1500 and a further encapsulation layer 1300; the extent of the further adhesive layer 1500 is greater than the extent of the substrate 1400 on each protected surface; the extent of the further encapsulation layer 1300 is greater than the extent of the substrate 1400 of each protected surface; and The extent of the further adhesive layer 1500 is smaller than the extent of the sealing layer 1300 on each protected surface.

[0194] Functionally, the further encapsulation layer 1300 can also be considered to include a first 1310 and a second 1320 encapsulation layer as shown in FIG. 11B.

[0195] Functionally, the further adhesive layer 500 can also be considered to include the first 1510 and second 1520 adhesive layers shown in FIG. 11B.

[0196] Functionally, the substrate 1400 shown in Figure 11C may also be considered to include protected portions of the first 1410 and second 1420 surfaces shown in Figure 11B. However, the substrate 1400 shown in Figure 11C includes two or more further protected surfaces adjacent such protected first or second surfaces.

[0197] The additional encapsulation layer 1300 of Figure 11C may be substantially identical to, highly similar to, or substantially different from the first encapsulation layer 1310 shown in Figure 11A or 11B. The additional encapsulation layer 1300 of Figure 11C may be substantially identical to, highly similar to, or substantially different from the second encapsulation layer 1320 shown in Figure 11B.

[0198] The additional adhesive layer 1500 in Figure 11C may be substantially identical to, highly similar to, or substantially different from the first adhesive layer 1510 shown in Figure 11A or 11B. The additional adhesive layer 1500 in Figure 11C may be substantially identical to, highly similar to, or substantially different from the second adhesive layer 1520 shown in Figure 11B.

[0199] The further embodiment 1102 may be advantageous for the following reasons: the portion of the surface of the substrate 1400 that is protected from the ingress of fluids is smaller than the extent of the further sealing layer 1300; - the edges of the further adhesive layer 1500 are substantially sealed 1300; and The surface area of ​​the encapsulant 1300 in direct contact with the surface of the substrate 1400 is close to zero or substantially zero.

[0200] Experiments were performed to establish the suitability of particular adhesive layers 1510, 1520 to provide a high degree of bonding to PDMS.

[0201] A. Sample Preparation FIG. 10 shows a cross section of a test sample 1130 .

[0202] 1) IDC using Pt metallization method The encapsulation performance was evaluated using an interdigitated capacitor (IDC) 1230. Approximately 600 nm of Pt (platinum) was sputtered onto a 1 μm (1 micron) thick plasma enhanced chemical vapor deposition (CVD) SiO2 layer 1435 with an intermediate 10 nm titanium adhesive layer. Details of these IDCs 1230 can be found in "Silicone rubber encapsulation for an endoscopically implantable gastrostimulator, Lonys, Vanhoestenberghe, Julemont, Godet, Delplancke, Mathys and Nonclercq, Med. Biol. Eng. Comput. 53 319-29, 2015". The SiO2 layer 1435 was provided on a silicon substrate 1430.

[0203] 2) ALD coating Atomic layer deposition (ALD) is a coating process that can be used to create nanometer-thick adaptive coatings. The ALD coatings were applied using a PICOSUN® R-200 Advanced ALD reactor at reduced pressure (N2 atmosphere) of approximately 1 mbar (1 hPa).

[0204] The R-200 Advanced from Picosun Oy of Finland offers very high quality ALD film deposition, and the manufacturer suggests it is suitable for depositions including Al2O3, TiO2, SiO2, Ta2O5, HfO2, ZnO, ZrO2, AlN, TiN, and metals such as Pt and Ir.

[0205] It consists of a remote microwave plasma generator with adjustable 300-3000 W power, 2.45 GHz frequency, mounted on a loading chamber and connected to the reaction chamber. Up to 12 sources with 6 separate inlets can be used; 7 if the plasma option is selected. Precursor sources may include liquid, gaseous, and / or solid chemicals. Precursors may also include ozone and / or plasma. The remote plasma option allows deposition of metals with a significantly reduced risk of short circuits and / or plasma damage. Processing temperatures are typically 50-500 °C. Plasma can typically be used up to about 450 °C, or up to about 650 °C with a heated sample holder.

[0206] It consists of inlets and equipment substantially isolated from the hot wall, providing relatively low particle (or substantially particle free) processing that can be adapted on a variety of materials for wafers, 3D objects, and nanoscale features. It uses a proprietary Picoflow™ diffusion enhancer to provide a high degree of uniformity even in porous, through-porous, high aspect ratio (up to 1:2500), and nanoparticle samples. This enhancer provides a protective gas flow in the intermediate space to significantly reduce back diffusion of plasma species.

[0207] A suitable ALD process for forming a monolayer comprising a first and a second element may include: - Loading the substrate as a sample into the reaction space; - introducing into the reaction space an amount of first molecules comprising a first element, whereby at least a first portion of the first molecules adsorb onto the surface of the substrate; and - introducing an amount of second molecules comprising a second element into the reaction space, whereby at least a second portion of the second molecules reacts with the first portion on the surface of the substrate to form a monolayer of a compound comprising the first and second elements.

[0208] The Picohot™ source system (PH-300) with the PicoSolution option of the R-200Advanced was used to vaporize precursors from stainless steel precursor bottles at elevated temperatures and at room temperature. The Picohot™ 300 source system allows source heating up to 300 °C and the manufacturer suggests that it is suitable for source chemicals with a vapor pressure of at least 2 mbar at the source temperature. The Picosolution™ 600 source system allows the use of liquid precursors. The manufacturer suggests that it is suitable for source chemicals with a vapor pressure of at least 10 mbar at the source temperature.

[0209] A 200° C. thermal ALD process was used in a layer-by-layer deposition fashion using two different precursor materials (separated by a N2 purge to remove excess molecules from the reaction space) to build up a HfO2 (hafnium dioxide) coating 1530, shown as coating 1530 in FIG. 10, which substantially covers the outer surfaces of the substrates 1430, 1435 and the IDC sensor 1230.

[0210] An optional stabilization time of about 90 minutes was used at 200° C. Ten layers of about 5 nm were applied to provide an ALD layer of about 50 nm.

[0211] ALD is believed to be advantageous for creating ultra-thin, adaptive coatings with fewer defects and / or fewer pinholes, and ALD deposition temperatures can be kept below 200° C., which is advantageous for devices incorporating sensitive metallization and / or polymers.

[0212] 3) PDMS encapsulation The sample was encapsulated with a layer 1330 comprising substantially biocompatible PDMS (MED2-6215, NuSil Carpinteria, USA).

[0213] From nusil.com / product / med-6215_optically-clear-low-consistency-silicone-elastomer: MED-6215 is an optically clear, low density silicone elastomer. It is supplied as a two-part, solvent-free, relatively low viscosity product. It cures thermally with addition cure chemistry. The mix ratio is 10:1 (Part A:Part B).

[0214] MED-6215 is believed to be substantially biocompatible, and the manufacturer suggests that it can be used for human implantation for periods in excess of 29 days.

[0215] [Table 1]

[0216] [Table 2]

[0217] [Table 3]

[0218] The manufacturer suggests the silicone primer Nu-Sil MED1-161 as a primer to further improve adhesion of MED-6215 to a variety of substrates, including: metals (stainless steel, steel, copper, aluminum, etc.), ceramic materials, hard plastics, and other silicone materials.

[0219] MED-6215 is available in medical grade, i.e., substantially biocompatible and suitable for use in medical implantable devices. This is achieved by ensuring that all raw materials, intermediates, and finished products (for medical grade) are manufactured to applicable GMP and / or appropriate regulatory standards (cGMP 21CFR §820 (devices), cGMP 21CFR §210-211 (drugs / APIs) and ISO 9001).

[0220] A dip-coating process was used for encapsulation. It was determined that the average relatively low viscosity, e.g., 4000-7000 cP (mPas), allowed the PDMS to flow more easily over the sample. The thickness of the PDMS 1330 was estimated to be 50-200 μm (microns).

[0221] B. Experimental Setup The reliability of the lifetime of ALD coatings can depend on factors such as the layer's conformality and adhesion, as well as its stability in ionic media, which was measured using the impedance of the IDC after long-term soak tests.

[0222] For long-term immersion, phosphate buffered saline (PBS) was used at about room temperature (approximately 23°C).

[0223] Electrochemical impedance spectrometry (EIS) was performed to evaluate the performance of the ALD and ALD-PDMS coatings as described in “Apparatus to investigate the insulation impedance and accelerated life-testing of neural interfaces, Donaldson, Lamont, Shah Idil, Mentink, Perkins, J. Neural Eng, 2018, 10.1088 / 1741 -2552 / aadeac.”

[0224] The measurements were performed using a Solartron Modulab equipped with a potentiostat in combination with a frequency response analyzer. Measurements were performed in a two-cell electrode configuration between the combs of an IDC structure. A Faraday cage was also used.

[0225] III. Results and Discussion A. Measurement results After sample preparation and immersion in saline, EIS measurements were performed.

[0226] 8A and 8B show the EIS results 1700, 1710 for the three samples.

[0227] FIG. 8A shows a Bode plot 1700 with the magnitude of impedance along the vertical (Y) axis being 10 1 ~10 11 |Z|Ω, and the frequency along the horizontal (X) axis is 10 -2 ~10 5 In Hz: A bare IDC with exposed Pt metal 1701 is -2 , 5×10 6 From 10 4 , 10 2 It forms a nearly straight line up to 10 5 , 10 2 Further straight lines continue until; -HfO2ALD1702 coated IDC was -2 , 10 9 From 10 5 , 10 3 form an approximately straight line; and -ALD-PDMS bilayer 1703 coated IDCs, 10 -2 , 10 11 From 10 5 , 10 5 forms an almost straight line.

[0228] FIG. 8B shows a Bode plot 1710, where the phase along the vertical (Y) axis is 0 to -90° and the frequency along the horizontal (X) axis is 10 -2 ~10 5 In Hz: A bare IDC with exposed Pt metal 1711 is 10 -2 , -20 to 10 0 , -70 to 10 2 , -80 to 10 -4 , -20 to 10 -5 , form a curve that passes through 0; -HfO2ALD1712 coated IDC is 10 -2 , -60 to 10 0 , -80 to 10 2 , -90 to 10 -4 , -80 to 10 -5 , forming a curve that passes through -70; and -ALD-PDMS bilayer 1713 coated IDCs were -2 , -80 to 10 0 , -90 to 10 2 , -90 to 10 -4 , -80 to 10 -5 , forming a curve that passes through -90.

[0229] For bare IDC1701, 1711, mid-frequency band (10 0 Hz~10 3 Hz), the phase 1711 appears to be relatively constant at about -80°. -2 Hz), the polarization resistance appears to dominate, resulting in a phase of approximately -20°, which may indicate that the metal is fully exposed to the electrolyte.

[0230] The ALD coated IDCs 1702, 1712 appeared to exhibit relatively high impedance values, indicating a more capacitive behavior across the frequency range. This capacitance is believed to be caused by the Pt metal and electrolyte separated by the ALD layer acting as a dielectric. A fully conformal coating on the metal, or a high resistance to fluid ingress, is believed to result in a substantially capacitive behavior in the EIS results 1700, 1710.

[0231] For the ALD-PDMS bilayer 1703, 1713, the impedance 1703 and phase 1713 results show substantially capacitive behavior over substantially the entire frequency range, with the phase result 1713 being close to approximately -90°.

[0232] Delamination or cracking of the ALD layer can expose more metal to the electrolyte, resulting in <10 -1 8A and 8B, a comparison between the ALD 1702, 1712 and the ALD-PDMS bilayer 1703, 1713 shows impedance values ​​1703 that are about two orders of magnitude higher for the bilayer encapsulated IDC 1703, 1713. Furthermore, the phase results 1713 show a substantially more capacitive behavior.

[0233] In addition, the metal areas exposed by ALD defects are also reduced by approximately 10 15 The combs are sealed with PDMS, which has a resistivity of Ω·cm. Significant delamination of the PDMS from the ALD is believed to allow water condensation, resulting in one or more conductive paths between the combs. This can result in low impedance and phase angles, ca. <10 -1 This is more evident in the low frequency range of Hz.

[0234] Monthly EIS measurements were taken on all samples to track changes in sealing and adhesion performance. A baseline of approximately 10 -2 The impedance and phase angle of Hz were selected.

[0235] 8C and 8D show adhesion evaluation results 1720, 1730 for two ALD samples and two ALD-PDMS samples over 450 days of immersion. The results shown in FIGS. 8A and 8B were taken as values ​​measured at T=0 days.

[0236] Figure 8C shows the range from 0 to 10 11Adhesion assessment 1720 in impedance magnitude along the vertical (Y) axis up to |Z|Ω, and time from 0 to 16 months along the horizontal (X) axis: -HfO2ALD1722a and 1722b coated IDCs were 9 From 16, 10 9 Both samples give virtually identical results, with the lines virtually overlapping except for small deviations at 0–1 month and 15–16 months; and Two IDCs coated with -ALD-PDMS bilayers 1723a, 1723b were 11 From 16, 10 11 Both samples give substantially the same results, with the lines essentially overlapping.

[0237] FIG. 8D shows adhesive evaluation 1730 with phase along the vertical (Y) axis from -30° to -90°, and time from 0 to 16 months along the horizontal (X) axis: - The first IDC1732a coated with HfO2ALD formed an almost linear relationship from 0,-70 to 16,-65; - The second IDC1732b coated with HfO2ALD formed an almost linear line from 0, -75 to 2, -63 to 4, -65 to 16, 60; - The first IDC1733a coated with an ALD-PDMS bilayer formed an almost linear line from 0, -83 to 2, -78 to 6, -80 to 16, -80; and The second IDC1733b, coated with an -ALD-PDMS bilayer, forms nearly straight lines from 0, -80 to 2, -78 to 6, -77 to 10, and -80 to 16, -78.

[0238] For the ALD-only samples 1722, 1732, a drop in phase angle 1732a, 1732b was measured after the first month of immersion, suggesting that fluid contacted the metal through one or more defects in the ALD layer. Substantially stable results were observed during extended immersion. This would indicate a substantially higher stability of the HfO2 adhesion layer in ionic media and a substantially higher degree of adhesion of HfO2 to the Pt over time. Significant degradation of the HfO2 layer would be expected to indicate relatively more capacitive behavior, such as a significant drop in impedance magnitude 1720, but this was not observed. Additionally, significant delamination of the ALD layer from the Pt would be expected to result in a substantially more resistive behavior due to the metal being exposed to salt water, but this was also not observed.

[0239] Optical examination of ALD samples 1722 and 1732 supported these conclusions, as no significant layer discoloration or degradation was observed.

[0240] Thus, for the ALD-PDMS bilayer samples 1723, 1733, substantially stable results were recorded over time, suggesting a relatively high degree of adhesion between the two layers and a substantially high resistance to fluid intrusion.

[0241] B. Conclusion Pt is widely used for the conductor and / or electrode regions due to its high biocompatibility and stability, however, the relatively poor adhesion of encapsulants such as PDMS, Parylene, and epoxy to Pt can reduce long-term stability in conventional systems.

[0242] The results suggest that it may be advantageous to add an adhesion layer comprising one or more ceramic materials. In particular, a HfO2 ALD layer with an average thickness of about 25 nm to 100 nm, preferably about 50 nm, may provide a substantially stable intermediate adhesion layer between Pt and PDMS. Furthermore, a relatively high degree of adhesion was measured between the HfO2 layer and the SiO2 substrate, especially between the Pt fork.

[0243] Thus, if desired, substrates comprising other materials can be provided with layers of SiO2 and / or Pt to improve adhesion to the HfO2 ALD layer.

[0244] The ALD-PDMS bilayer of sealing layer 1330 and adhesion layer 1530 appears to be particularly advantageous: The -HfO2 ALD adhesion layer appears to exhibit remarkably high stability in ionic media, thereby providing longer resistance to delamination or water penetration in the PDMS encapsulation. - PDMS with a relatively low average viscosity, e.g., 4000-7000 cP (mPas), for a significant period during encapsulation may contribute to even longer-lasting adhesion and reduced defects due to flow of PDMS between defects and openings in the ALD layer. -PDMS type materials are generally well suited for implants due to their relatively high biocompatibility. With proper selection and processing, many PDMS type materials can be constructed and arranged to be substantially biocompatible.

[0245] The polymeric material included in the substrate 1400 is preferably flexible and selected for its adaptability to include one or more electrical conductors 1210. Preferably, the polymeric substrate material has a high degree of biocompatibility and durability. Polymeric materials suitable for inclusion in the substrate 1400 include those discussed above for the adaptable substrate in connection with Figures 1-4. In particular, polyimide, parylene C, SU-8, LCP, polyurethane, or any combination thereof may be used.

[0246] Preferably, the first and / or second surfaces 1410, 1420 include a significant amount of one or more liquid crystal polymers (LCPs). Optionally, the first and / or second surfaces 1410, 1420 can consist substantially of one or more LCPs. Optionally, the first and / or second surfaces 1410, 1420 can consist essentially of one or more LCPs.

[0247] The following table compares some physical and chemical properties of common polyimides and common LCPs.

[0248] [Table 4]

[0249] Advantageously, the substrate 1400, comprising for example LCP, has a Young's modulus in the range of 2500-3600 MPa (2.5-3.6 GPa).

[0250] Optionally, the substrate 1400 may further include one or more electrical or electronic components configured to receive energy when electrical energy is applied to the one or more electrical conductors 1210. For example, it may be inductively coupled, capacitively coupled, or directly connected. This is particularly advantageous for substrates that contain large amounts of one or more LCPs, as PCB technology may be used. Preferably, a biocompatible metal such as gold or platinum is used.

[0251] Preferably, the one or more sealing layers 1310, 1320 and the one or more adhesive layers 1510, 1520 are constructed and arranged to resist ingress of fluid to at least a portion of the one or more surfaces 1410, 1420 adjacent to the one or more components.

[0252] For example, the one or more components can be: an active component, a passive component, an electronic component, an integrated circuit (IC), an application specific integrated circuit (ASIC), a field programmable gate array (FPGA), an analog component, a digital component, a surface mounted device (SMD), a through-hole package, a chip carrier, a pin grid array, a fat package, a small outline package, a chip scale package, a ball grid array, a small pin count package, a flexible silicon device, a thin film transistor (TFT), and any combination thereof.

[0253] The one or more electrical components may be configured and arranged to: resist, store charge, induce, sense, stimulate, amplify, process data, detect, measure, compare, switch, time, store data, count, vibrate, execute logic, add, generate stimulation pulses, and any combination thereof.

[0254] Substrates 1400 may further be constructed and arranged to have a degree of flexibility as described above. They are foil-like (or film-like) and, by being flexible, can very closely follow the contours of the underlying anatomical features. Very thin foil-like substrates 1400 have the added advantage that they have increased flexibility.

[0255] The implanted electrical devices 1100, 1101 described herein may be included in an implanted medical device 1110, 1111. For example, such medical devices 110, 1111 may be constructed and arranged to provide some degree of sensing, stimulation, data processing, detection or measurement, data storage, vibration, logic performance, stimulation pulse generation, or any combination thereof.

[0256] The embodiments described above in relation to FIGS. 1-4, in particular the implanted stimulation devices 101, 102, 103, 104, 105, may include implanted electrical devices 1100, 1101, 1102.

[0257] As shown in Figure 12A, an improved implanted medical device 1110 can be provided by modifying the implanted device 1100 shown in Figure 11A, which in this cross-section is the same as the implanted electrical device 1100 shown in Figure 11A, with the following exceptions: - the substrate 1400 comprises three protected surfaces, each surface being protected by a further adhesive layer 1500 and a further sealing layer 1300. The three protected surfaces comprise two opposing protected surfaces and a further adjacent surface; the extent of the further adhesive layer 1500 is smaller than the extent of the substrate 1400 of the two opposing protected surfaces; the extent of the further adhesive layer 1500 is larger than the extent of the substrate 1400 of the third adjacent protected surface; the extent of the further encapsulation layer 1300 is smaller than the extent of the substrate 1400 of the two opposing protected surfaces; the extent of the further encapsulation layer 1300 is larger than the extent of the substrate 1400 of the third adjacent protected surface; and The extent of the further adhesive layer 1500 is smaller than the extent of the further sealing layer 1300 on each protected surface.

[0258] Functionally, the further encapsulation layer 1300 can also be considered to include a first 1310 and a second 1320 encapsulation layer as shown in FIG. 11B.

[0259] Functionally, the further adhesive layer 1500 can also be considered to include the first 1510 and second 1520 adhesive layers shown in FIG. 11B.

[0260] However, the substrate 1400 shown in FIG. 12A includes a further protected surface adjacent such a protected first or second surface.

[0261] The additional encapsulation layer 1300 of Figure 12A may be substantially identical to, highly similar to, or substantially different from the first encapsulation layer 1310 shown in Figure 11A or 11B. The additional encapsulation layer 1300 of Figure 12A may be substantially identical to, highly similar to, or substantially different from the second encapsulation layer 1320 shown in Figure 11B.

[0262] The additional adhesive layer 1500 of Figure 12A may be substantially identical to, highly similar to, or substantially different from the first adhesive layer 1510 shown in Figure 11A or 11B. The additional adhesive layer 1500 of Figure 12A may be substantially identical to, highly similar to, or substantially different from the second adhesive layer 1520 shown in Figure 11B.

[0263] The medical device 1110 further includes: The neurostimulation device includes one or more stimulation electrodes 1220 configured and arranged to transfer energy to human or animal tissue when electrical energy is applied to the one or more electrical conductors 1210. For example, the stimulation electrodes 1220 may be inductively coupled, capacitively coupled, or directly connected. In the illustrated example, the one or more stimulation electrodes 1220 are directly connected to the one or more electrical conductors 1210. In many neurostimulation applications, multiple electrodes 1220 may be required. These may be the same as, similar to, or different from the electrodes 200, 400 described above in connection with FIGS. 1-4.

[0264] Optionally or additionally, one or more sensors 1230 may be provided as well. Such sensors 1230 are configured to provide electrical signals and / or data to one or more electrical conductors 1210. For example, they may be inductively coupled, capacitively coupled, or directly connected. If electrically interconnected multi-layer boards are provided, a high degree of customization is possible. For example, parameters related to operation may be measured directly, such as humidity, temperature, electrical resistance, electrical activity, etc.

[0265] Typically, in a neural stimulation electrode, one or more electrodes 1220 are constructed and arranged to act as a ground or return electrode, which may be one of the existing electrodes or one or more additional electrodes described above for the first 200a, 200b and second 400a, 400b electrodes described above in relation to Figures 1-4.

[0266] Those skilled in the art will appreciate that such stimulating electrodes 1220 and / or tissue sensors are preferably not completely covered by the sealing layer 1300 and / or adhesive layer 1500 because their functionality requires a sufficiently high degree of electrical connection or exposure to the implant environment. For example, at least a portion of the stimulating electrodes 1220 and / or tissue sensors are masked during the sealing process to provide a conductive surface towards the tissue. Additionally or alternatively, portions of the device may not be sealed.

[0267] 12A shows the device 1110 with substantially all of the stimulating electrodes 1220 substantially uncovered. Furthermore, in this cross section, a portion of the substrate 1400 is substantially uncovered, providing the device 1100 with a substantially sealed portion and a substantially unsealed portion with one or more electrodes 1220. The extent of the further adhesive layer 1500 in this cross section on two opposing surfaces is smaller than the extent of the further sealing layer 1300 on these surfaces. This may be advantageous as the edges of the further adhesive layer 1500 are at least partially sealed 1300.

[0268] Applying this sealing to the implantable stimulation device described above in relation to Figures 1-4 generally provides a substantially unsealed portion comprising one or more electrodes 200, 400 and a substantially sealed portion comprising the pulse generator 500.

[0269] 12B illustrates a further embodiment of a medical device 1111. More specifically, it illustrates a cross-section through a portion of a substrate 1400 that includes one or more electrodes 1220. The further medical device 1111 is generally the same in this cross-section as the device 1110 illustrated in FIG. 12A, with the following exceptions: - the substrate 1400 comprises four protected surfaces, each surface being protected by a further adhesive layer 1500 and a further encapsulation layer 1300; the extent of the further adhesive layer 1500 is greater than the extent of the substrate 1400 on each protected surface; the extent of the further encapsulation layer 1300 is greater than the extent of the substrate 1400 of each protected surface; and The extent of the further adhesive layer 1500 is smaller than the extent of the sealing layer 1300 on each protected surface.

[0270] In this cross section, "portions" of the stimulation electrode(s) 1220 are not completely covered to allow for electrical connection or exposure to the implant environment after implantation. Thus, in the regions close to the stimulation electrodes 1220, all of the general statements above do not fully apply. In particular, in this cross section: a further adhesive layer 1500 is applied to the surface of the substrate 1400 adjacent to the stimulating electrode 1220 and also to the edge portions of the surface of the electrode 1220, which may provide additional protection against intrusion at any interface between the electrode 1220 and the substrate 1400; and A further sealing layer 1300 is applied to the surface of the substrate 1400 adjacent to the stimulation electrode 1220, but not significantly to the edge portions of the surface of the electrode 1220.

[0271] In other words, in this cross section at the edge portion of the surface of the electrode 1220 , the extent of the further adhesive layer 1500 is approximately the same as the extent of the further encapsulation layer 1300 .

[0272] This may be advantageous in certain configurations as the surface area of ​​the further encapsulation layer 1300 in direct contact with the surface of the electrode 1220 is greatly reduced. In some cases, this surface area may be substantially zero.

[0273] Applying this sealing to the implant stimulation device described above in relation to Figures 1-4 generally provides a substantially sealed portion including "a portion" of one or more electrodes 200, 400, and a substantially sealed portion including the pulse generator 500.

[0274] Optionally, it may be advantageous if the extent of the further sealing layer 1300 in this cross section at the edge portion of the one or more electrodes 1220 is greater than the extent of the further adhesive layer 1500. In some configurations, this may be advantageous as the edges of the further adhesive layer 1500 are at least partially sealed 1300.

[0275] Thus, one or more stimulation electrodes 1220 and / or sensors are preferably included on the surface, constructed and arranged to provide a tissue interface.

[0276] As noted above, "contained within the surface" means that the electrode 1220 is relatively thin (e.g., approximately perpendicular to the longitudinal axis of the substrate, 20-50 μm or less, when the substrate conforms to a substantially planar surface and has an extent along the transverse axis. Thinner electrodes (e.g., 1 μm or less) can be used to further increase the degree of conformability) and attached to (or at least partially embedded in) the surface.

[0277] This is particularly advantageous for substrates containing a large amount of one or more LCPs, since PCB / metallization techniques can be used to provide conductive areas, which can be configured and arranged to be electrodes 1220 and / or sensors 1230. As noted above, conductive materials such as gold, platinum, platinum black, TiN, IrO2, iridium, and / or platinum / iridium alloys and / or oxides are preferably used. Conductive polymers such as Pedot can also be used. Preferably, a biocompatible conductive material is used.

[0278] As noted above, thicker metal layers are generally preferred over thinner metal layers because the electrode 1220 may be exposed to biological material that may dissolve the metal, although thicker metal layers typically result in increased stiffness (reduced compliance) near the thicker layer.

[0279] In the second set of experiments, the adhesion of PDMS MED2-4213 from NuSil to LCP substrates was investigated using two different substrates and two different PDMS casting processes.

[0280] To evaluate the adhesion, different methods were used: adhesion evaluation by peel test (dry) after immersion in PBS at 60°C, and peel test according to ASTM D1876.

[0281] From nusil.com / product / med2-4213_fast-cure-silicone-adhesive: MED2-4213 is a two-part, translucent, thixotropic, relatively high extrusion rate, relatively high tear resistance, relatively fast curing silicone adhesive. It is also substantially free of tin (Sn), which reduces the need for atmospheric moisture to cure. It also does not contain significant amounts of cure by-products such as acetic acid and methyl alcohol.

[0282] MED2-4213 is believed to be substantially biocompatible. The manufacturer suggests that it can be used for implantation in humans for periods in excess of 29 days. Typical chemical and physical properties include:

[0283] [Table 5]

[0284] [Table 6]

[0285] [Table 7]

[0286] It may be advantageous if the first (1310) and / or second (1320) sealing layers have a tensile strength in the range of 6-8 MPa.

[0287] NuSil suggests that in many bonding applications (for substrates including aluminum, glass, PMMA and silicone) it is not necessary to use a silicone primer to promote adequate adhesion.

[0288] When bonding to substrates including polyetherimide, PEEK, plastic, polycarbonate, polyimide, polysulfone, polyurethane, and stainless steel, the use of a primer is suggested by the manufacturer.

[0289] To study the adhesion properties of PDMS on LCP using different processing methods and adhesive layers, two different test substrates were used: -Type 1: 3-layer LCP substrate with ALD coating on one side -Type 2: LCP 2-layer laminate substrate with ALD coating on one side.

[0290] In general, it is advantageous to perform as few steps as possible when manufacturing an implantable electrical device, as this reduces the risk of contamination or transportation-related issues and may reduce one or more costs.

[0291] A relatively few-step process can be based on overmolding of electronics directly attached to a substrate (here LCP). Depending on the hardware configuration, the PDMS used may need to adhere well to surfaces such as: - ASIC passivation layer for wire bonding -Si substrate in case of ASIC flip chip or ACF mount. Si substrate is one of the relevant interfaces when using bare die parts. Bare die integrated circuits are often made from a wafer or substrate, which is a thin slice of crystalline silicon semiconductor. To create the bare die parts, this material goes through many microfabrication processes to become an integrated circuit, but one side is always the raw material used, which is most often crystalline silicon. The relevant interfaces are: -ASIC Interconnect - Gold from wire bonds or stud bumps -ACF (Anisotropic Conductive Film), often epoxy based, coated with gold particles, for application of bare die components to bond pads. - A substrate, in this case a substrate containing significant amounts of LCP.

[0292] Type 1 LCP substrates were prepared using one or more of the following process steps: a) Provision of a substrate: These substrates were substantially planar LCP sheets with an average thickness of about 0.150 mm. The substrates consisted of three layers: two 0.050 mm layers of ULTRALAM® 3908 separated by one 0.050 mm layer of ULTRALAM 3850.

[0293] ULTRALAM® 3908LCP is available from Rogers Corporation (www.rogerscorp.com) and can be used as a bonding medium (adhesive layer) between copper, other LCP materials, and / or dielectric materials. It is characterized by a low and stable dielectric constant, a relatively low elastic modulus, easier bending in flex applications, and relatively low moisture absorption.

[0294] It can be used with one or more layers of ULTRALAM® 3850 LCP to create virtually any LCP multi-layer substrate that is substantially adhesive-free.

[0295] Typical values ​​for the physical and chemical properties of ULTRALAM® 3908LCP are as follows:

[0296] [Table 8]

[0297] [Table 9]

[0298] [Table 10]

[0299] [Table 11]

[0300] ULTRALAM® 3850, available from Rogers Corporation (www.rogerscorp.com), is a relatively high temperature resistant LCP. It can be provided as a dual copper clad laminate for use as a laminate circuit material. The manufacturer suggests using these products as single or multilayer substrates. ULTRALAM 3850 circuit material is characterized by a relatively low and stable dielectric constant and dielectric loss. It has a relatively low elastic modulus, making it easier to bend in flex applications and has relatively low moisture absorption.

[0301] Can be used with one or more layers of ULTRALAM® 3908 LCP to create virtually any LCP multi-layer substrate that is substantially adhesive free.

[0302] Typical values ​​for the physical and chemical properties of ULTRALAM® 3850LCP are as follows:

[0303] [Table 12]

[0304] [Table 13]

[0305] [Table 14]

[0306] [Table 15]

[0307] The Type 1 LCP substrate was further prepared using one or more of the following process steps: b1) Optional pre-cleaning of at least a portion of the substrate with IPA, followed by drying. Another suitable alcohol can also be used. b2) Application of Adhesion Coating: ALD was used to apply a coating to the outer surface of the substrate (in this case the surface containing ULTRALAM® 3908 LCP). Ten alternating layers of about 5 nm Al2O3 and about 5 nm HfO2 resulted in a multilayer of about 100 nm. The coverage of the ALD coating was approximately the same as that of the substrate. The ALD coating was applied using the PICOSUN® R-200 Advanced ALD reactor described above. It was applied at a temperature substantially below the melting temperature of the LCP. For these Type 1 LCP substrates, it was applied at about 125° C. after an optional stabilization period of about 90 minutes.

[0308] For comparison, this step was omitted in some samples (i.e., PDMS was applied directly to the LCP).

[0309] c) Cleaning of at least a portion of the adhesion coating: An optional 10 min ozone (O3) plasma treatment was performed to clean the ALD surfaces in preparation for the PDMS coating. The PDMS was applied within 15 min of the ozone clean. For comparison, some samples were not cleaned before the PDMS coating was applied.

[0310] UV O3 (ozone) plasma cleaning is suitable for dry, non-destructive atomic cleaning and removal of organic contaminants. It uses powerful ultraviolet light at 185nm and 254nm. In the presence of oxygen, the 185 line produces ozone and the 254 line excites organic molecules on the surface. This combination promotes the rapid destruction and thinning of organic contaminants.

[0311] d) Application of encapsulant coating: A PDMS coating of approximately 500um to 1000um of MED2-4213 was applied on top of the ALD coating. A syringe was filled with MED2-4213 and mixed and degassed for 3 minutes at a relatively high speed (2500 rpm). It was cured at 150°C for 10 minutes and post cured at 80°C for 24 hours. The extent of the PDMS coating was smaller than that of the ALD coating, which left the ALD coating exposed (not covered by encapsulant) near the edge of the substrate. After applying the PDMS to the substrate, the substrate was placed on a preheated plate coated with PTFE (polytetrafluoroethylene) and a weight was pressed onto it.

[0312] Therefore, six samples of type 1 LCP were prepared.

[0313] [Table 16]

[0314] Pass / Fail tests were manually defined for a Type 1 LCP board: -After the PDMS was cured, a dry peel test was performed (no immersion) and the extent of delamination was recorded. After the dry peel test, the samples were immersed in PBS solution at 60°C for 1 day, 1 week, and 4 weeks, and the peel test was repeated to measure the second delamination.

[0315] Three degrees of delamination were defined: -Delamination: PDMS was relatively easy to remove from the substrate. -Partial delamination: PDMS was relatively easy to remove in some areas but adhered relatively well in other areas -Adhesion: PDMS did not peel off substantially

[0316] Phosphate buffered saline (abbreviated PBS) is a buffer solution commonly used in biological research. It is an aqueous salt solution containing disodium hydrogen phosphate, sodium chloride, and in some preparations potassium chloride and potassium dihydrogen phosphate. Buffers help maintain a constant pH. The osmolarity and ionic concentration of the solution are chosen to match those of the human body (isotonic).

[0317] [Table 17]

[0318] Sample 1.1: Overall, PDMS showed poor adhesion to LCP.

[0319] Sample 1.2: The PDMS could not be peeled off from the surface in dry conditions. After 24 h of immersion, no moisture-filled voids were observed, but some of the PDMS could be peeled off from the substrate. After peeling off part of the PDMS, the remainder adhered very well to the substrate and could not be peeled off further, even after another 1-2 weeks of immersion. It was speculated that the initial delamination was due to localized contamination during PDMS processing or processing issues.

[0320] Sample 1.3: These samples showed good adhesion, both dry and wet, with no delamination occurring by the end of the two week test.

[0321] Conclusion: -Overall, PDMS showed poor adhesion to LCP without an adhesive layer (sample 1.1). - In sample 1.2 (coated with ALD and sealed with PDMS without O3 cleaning), the PDMS could not be peeled off from the surface in dry conditions. After 24 h of immersion, no moisture-filled voids were observed, but parts of the PDMS could be peeled off from the substrate. After peeling off part of the PDMS, the remainder adhered so well to the substrate that it could not be peeled off any further, even after an additional 2 weeks of immersion. The sample with the more compliant ALD multilayer showed good adhesion even after 2 weeks of immersion. - Sample 1.3 (coated with ALD and sealed with PDMS after an O3 cleaning step) showed the best adhesion, with no substantial delamination in dry or wet conditions (after 2 weeks of immersion). -Al2O3 / HfO2 multi-layer ALD layers with a total average thickness of about 50 nm to 200 nm, preferably about 100 nm, can provide an advantageous intermediate adhesion layer between the LCP and PDMS polymers.

[0322] A Type 2 LCP laminate substrate is prepared using one or more of the following process steps: a) Provision of the substrate: These substrates were laminated sheets of LCP with an average thickness of about 0.110 mm. The substrates were composed of four layers: one outer layer of connection pads, one 0.050 mm layer of ULTRALAM® 3850, one inner layer of one or more copper conductors, and one 0.025 mm layer of ULTRALAM 3908. a1) A first surface was covered with a first copper layer, e.g., by masking and etching, of an approximately 50 um thick sheet of LCPULTRALAM® 3850. The first copper layer was approximately 18 um thick. The first copper layer was constructed and arranged to form copper connection pads, e.g., by masking and etching, which may be considered to be included on the outer surface of the laminate substrate. a2) The ULTRALAM® 3850 was further covered with a copper layer. This second layer was about 18um thick. Optionally, it may be constructed and arranged to form one or more conductors, for example by masking and etching, which may be considered to be included on the inner surface of the laminate substrate. If no internal conductors are required, further copper layers may be omitted or removed entirely. a3) A sheet of LCPULTRALAM® 3908 approximately 25um thick, adhered to the inner surface of the ULTRALAM® 3850 layer and further adhered to one or more conductors.

[0323] Optionally, the laminate sheet may be substantially planar.

[0324] b) Application of adhesive coating: b1) Optional pre-cleaning of at least a portion of the substrate with IPA, followed by drying. Another suitable alcohol can also be used. b2) ALD is used to apply a coating to the outer surface of the substrate (in this case the surface containing ULTRALAM® 3908 LCP). This was not the outer surface of the substrate containing one or more connection pads. Ten alternating layers of about 5 nm Al2O3 and about 5 nm HfO2 resulted in a multilayer of about 100 nm. The ALD coating was applied using the PICOSUN® R-200 Advanced ALD reactor described above. It was applied at a temperature substantially below the melting temperature of the LCP. In the case of these Type 1 LCP substrates, it was applied at about 125° C. after an optional stabilization period of about 90 minutes. The coverage of the ALD coating was approximately the same as that of the substrate. b3) Application of an adhesion enhancer: NuSil's MED-166 is a specially formulated primer suggested by the manufacturer to improve adhesion of PDMS to a variety of substrates, including rigid plastics and other silicone materials. The manufacturer suggests it is suitable for use on human implants for periods greater than 29 days.

[0325] c) cleaning at least a portion of the adhesive coating prior to sealing: c1) Option 1: Wash with ethanol, then dry at 70° C. for 4 hours. Another suitable alcohol can also be used. c2) Option 2: Exposing the ALD surface to a plasma containing O2.

[0326] O2 (oxygen) plasma is a plasma treatment that is performed by actively introducing oxygen gas into the plasma chamber. Oxygen plasma is generated using an oxygen source in the plasma system.

[0327] Additionally or alternatively, ozone (O3) can be used.

[0328] d) Application of sealing coating: d1) Application of a sealing mask to simplify testing: A strip of Kapton tape (10 mm wide) was applied to one end to mask a small section where the pull tester would be clamped during the peel test. d2) Application of sealing coating: A PDMS coating of about 500 μm to 1000 μm of MED2-4213 was applied on top of the ALD coating. Vacuum stretch casting at a relatively low vacuum, e.g. 800-900 Pa (8-9 mbar), at 100 °C was used with the PTFE coated mold. Vacuum centrifugal casting was used to reduce the risk of air inclusion in the PDMS. In general, applying a vacuum can be advantageous to improve the application of the PDMS sealing adhesive coating, which has an average viscosity in the range of 55000-100000 cP (mPas) for a significant period of time.

[0329] The coverage of the PDMS coating was approximately the same as that of the ALD coating. After peeling off the Kapton tape, a strip of approximately 10 mm width was provided where the PDMS was not attached to the ALD coating.

[0330] e) Further processing carried out: For the peel test, the coated substrate with an area of ​​about 100 x 75 mm was cut into 7 pieces of about 100 x 10 mm, each piece with an area of ​​about 10 x 10 mm, and the Kapton tape was removed so that there was no PDMS coating on the edges.

[0331] Therefore, 15 samples of type (2) were prepared.

[0332] [Table 18]

[0333] The peel test according to ASTM D1876 was applied to the test of TYPE2LCP or laminated substrate. A peel tester was used to measure the peel force.

[0334] 4. Peel test results Figure 9 shows a graph 1750 of the average tensile force under dry (unimmersed) conditions compared to the average tensile force after immersion in PBS for 24 hours at 60° C. Samples of LCP were coated with PDMS using various processes.

[0335] The average peel force is plotted along the vertical (Y) axis from 0 to 18 N, and results are shown for the various samples along the horizontal (X) axis. For ease of interpretation, the order of the selected samples is, from left to right, samples 2.2, 2.2, 2.3, 2.4, and 2.5.

[0336] The vertical length of each bar for each sample indicates the average peel force in Newtons (N). For each bar, an "I" shaped line is also shown to indicate the measured variation in tensile force values ​​used to determine the average. For each sample, an unfilled bar is shown on the left, indicating the average tensile force in the dry state, and the hatched bar on the right indicates the average tensile force after immersion in PBS at 60°C for 24 hours.

[0337] For sample 2.1, the degree of variation is relatively small with the unfilled bar 1761a plotted at approximately 4 N. Post-immersion values ​​are not shown.

[0338] For sample 2.2, the unfilled bar 1762a is drawn at approximately 13 N, which is an average degree of variation, and the hatched bar 1762b is drawn at approximately 14 N, which is a relatively high degree of variation.

[0339] For sample 2.3, the unfilled bar 1763a is drawn at approximately 5 N, a relatively small degree of variation, and the hatched bar 1763b is drawn at approximately 7 N, an average degree of variation.

[0340] For sample 2.4, the unfilled bar 1764a is drawn at approximately 7 N, a relatively small degree of variation, and the hatched bar 1764b is drawn at approximately 7.5 N, an average degree of variation.

[0341] For sample 2.5, the unfilled bar 1765a is drawn at approximately 8 N, a relatively small degree of variation, and the hatched bar 1765b is drawn at approximately 8 N, an average degree of variation.

[0342] The average peel forces measured were as follows:

[0343] [Table 19]

[0344] A stable overmolding sealing process appears to have been achieved, showing that there are virtually no or very few air bubbles in the PDMS. Substantial delamination of the LCP / PDMS interface was observed in three out of seven samples immediately after overmolding. For this reason, a peel test was applied to obtain a more qualitative measure of the adhesive strength.

[0345] Sample 2.1: Without additional priming or cleaning, adhesion of PDMS to LCP was very poor (approximately 4N~1761a).

[0346] Sample 2.2: The substrate with primer appeared to have a relatively high degree of adhesion (approximately 13 N (1762a) compared to approximately 4 N (1761a)). During testing, some areas had high adhesion and the PDMS ruptured before the sample could be completely peeled off. The average tensile force after the immersion test appeared to be high at approximately 14 N (1762b), but a relatively high deviation was also observed.

[0347] Sample 2.3: The degree of dry adhesion appeared to be improved by adding the ALD multilayers, especially the HfO2-Al2O3 multilayer terminating in HfO2 (from about 4 N (1761a) to about 5 N (1763a)). The results in the dry state (1763a) appear to have a very low degree of deviation. The average tensile force after the immersion test appeared to be higher at about 7 N (1763b).

[0348] Sample 2.4: O2 plasma activation also appeared to increase adhesion (approximately 7 N (1764a) compared to approximately 4 N (1761a)). The average tensile force after immersion testing appeared to be slightly higher at approximately 7.5 N (1764b).

[0349] Sample 2.5: Plasma activation appeared to further improve the degree of adhesion (approximately 8 N (1765a) compared to approximately 4 N (1761a)). The average tensile force after the immersion test appeared to be about the same at 8 N (1765b). A slight increase in deviation (1765b) was observed after immersion.

[0350] Conclusion: -A relatively high degree of adhesion has been observed with the use of primers. For example, MED-166 from NuSil can be used. However, this may not be preferred for some applications. In particular, for implant devices, it is advantageous to use materials that are significantly biocompatible, and more preferably substantially biocompatible (having a high degree of biocompatibility). Although the manufacturer of MED-166 suggests that it is suitable for implants of 29 days or more, primers are often epoxy adhesives that use volatile solvents. This may increase the risk of contamination due to insufficient evaporation and / or require additional process steps to ensure sufficient solvent removal.

[0351] Furthermore, implantable devices often require a high degree of quality control to limit the risk of defects. Primers typically need to be applied using a spray coating process, which can be difficult to perform reliably. Such reliability issues are likely the cause of the observed partial delamination.

[0352] -Al2O3 / HfO2 multi-layer ALD layers with a total average thickness of about 50 nm to 200 nm, preferably about 100 nm, can provide an advantageous intermediate adhesion layer between the LCP and PDMS polymers. In general, ceramic layers with thicknesses of: -The ALD coating used improved the adhesion of PDMS to LCP, with a material suitable for use in implantable electrical devices. The ALD multi-layer deposition not only improved adhesion but also improved barrier properties to protect the surface area from moisture ingress. This is preferable over primers, as primers are usually highly permeable to moisture.

[0353] Based on the improved adhesion between PDMS and surfaces containing significant amounts of Pt, SiO2, and LCP, adhesion layers containing ceramic materials can be advantageously used with a wide range of substrate materials. In particular, adhesion of PDMS can be improved when the first surface 1410 and / or the second surface 1420 contain significant amounts of a material selected from the group including liquid crystal polymer (LCP), polyimide, parylene-C, SU-8, polyurethane, or any combination thereof. These materials may also be included in flexible substrates.

[0354] Thus, where appropriate, substrates comprising other materials may be provided with layers of such materials to improve adhesion to the HfO2 ALD layer.

[0355] Those skilled in the art will also appreciate that a conformal coating may be optionally or additionally applied to such substrates, for example using an ALD process, to improve adhesion by applying a layer of SiO2 (silicon dioxide).

[0356] PDMS is generally a silicone rubber that uses siloxane as the basic repeating unit. The methyl groups are replaced with various other groups, such as phenyl, vinyl, or trifluoropropyl groups, depending on the type of PDMS, allowing for the attachment of organic groups to the inorganic backbone.

[0357] Based on the improved adhesion to PDMS using one or more adhesion layers comprising HfO2 and / or Al2O3, adhesion layers comprising suitable ceramic materials can be advantageously used with a wide range of substrate materials.

[0358] Suitable ceramic surfaces are relatively rich in hydroxyl groups. It is believed that the high degree of adhesion is due to the ability of oxygen in the suitable PDMS type to form strong bonds with the hydroxyl groups of the suitable ceramic surface. This may be chemical bonds, hydrogen bonds, or some combination.

[0359] Suitable ceramics include: -Carbides such as silicon carbide (SiC); -Oxides such as aluminum oxide (Al2O3); those containing silicon (SixNy or SiNxOy), in particular nitrides such as silicon nitride (Si3N4); and Many other materials, including mixed oxide ceramics, can function as superconductors.

[0360] In particular, the adhesion of PDMS can be improved when the ceramic material is selected from the group including HfO2, Al2O3, Ta2O3, TiO2, and any combination thereof.

[0361] It is also expected that diamond-like carbon can be advantageously used to improve adhesion.

[0362] Adhesion can be further improved by activating the surface of the ceramic layer (e.g., by applying an alcohol, especially ethanol; by using an O3 (ozone)-containing and / or O2-containing plasma; by treating with silane; or any combination thereof).

[0363] The adhesive layer may be bi-layered or multi-layered, with one or more layers constructed and arranged for a relatively high degree of adhesion and one or more layers constructed and arranged for a relatively high degree of corrosion resistance (impermeability).

[0364] For example, a layer containing Al2O3 is believed to provide a relatively high degree of adhesion. For example, a layer containing HfO2 is believed to provide a relatively high degree of corrosion resistance.

[0365] 5 and 6 also show examples of nerves that may be stimulated using one or more appropriately configured improved medical devices 1110, 1111 configured to provide neurostimulation for treating, for example, headaches, chronic headaches or primary headaches. In particular, if the substrate is substantially flexible (or malleable), it can better adapt to the curved surface of the head and / or skull. This means that the comfort for the user of the implanted medical device 1110, 1111 can be improved by applying one or more of the above features to improve the adaptability.

[0366] In many cases, these will be the approximate locations 810, 820, 830, 840 of one or more implanted medical devices 110, 111.

[0367] A separate stimulator 110, 111 can be used for each implant location 810, 820, 830a / b, 840a / b. A single stimulator 110, 111 can be configured to stimulate at two or more implant locations 810, 820, 830a / b, 840a / b, even if the implant locations 810, 820, 830a / b, 840a / b are close to or overlap each other.

[0368] The multiple implanted medical devices 110, 111 may be operated separately, simultaneously, sequentially, or any combination thereof to provide the required treatment.

[0369] FIG. 7 shows further examples of nerves that may be stimulated using one or more appropriately configured improved implanted medical devices 110, 111 to provide nerve stimulation to treat other medical conditions.

[0370] The description herein should not be understood as prescribing a fixed order of performing the method steps described therein. Rather, the method steps can be performed in any order that is feasible. Similarly, the examples used to explain the algorithms are presented as non-limiting examples and are not intended to represent the only embodiment of these algorithms. Those skilled in the art can devise many different ways to achieve the same functionality provided by the embodiments described herein.

[0371] For example, one or more features that improve pliability may be applied to an embodiment constructed and arranged to improve sealing, In some embodiments, it may be advantageous to apply a feature that improves sealing but reduces pliability.

[0372] For example, one or more features that improve sealing may be applied to an embodiment that is constructed and arranged for improved flexibility. In some embodiments, it may be advantageous to apply features that improve flexibility but reduce sealing.

[0373] Many types of implantable distal ends of stimulators are depicted, however this does not exclude the remainder of the device being implanted, which should be interpreted to mean that at least the electrode portion of the distal end is preferably constructed and arranged to be implanted.

[0374] Although the present invention has been described in connection with specific exemplary embodiments, it should be understood that various changes, substitutions, and alterations apparent to those skilled in the art could be made to the disclosed embodiments without departing from the spirit and scope of the invention as set forth in the appended claims.

[0375] In one non-limiting example, one or more electrodes of a first type 200a, 200b, 1220 are included on the first surface 310, 1410 and one or more electrodes of a second type 400a, 400b, 1220 are included on the second surface 320, 1420; or - one or more electrodes of a first type 200a, 200b, 1220 are included on the first surface 310, 1410 and one or more electrodes of a second type 400a, 400b, 1220 are also included on the first surface 310, 1410; or one or more electrodes of a first type 200a, 200b, 1220 are included on the second surface 320, 1420 and one or more electrodes of a second type 400a, 400b, 1220 are included on the first surface 310, 1410; or - one or more electrodes of a first type 200a, 200b, 1220 are included on the second surface 320, 1420 and one or more electrodes of a second type 400a, 400b, 1220 are also included on the second surface 320, 1420; or -Any combination of them.

[0376] By providing a relatively large and taller electrode 200, 400, 1220 surface, the stimulator 100, 101, 102, 103, 104, 105, 1100, 1101, 1102 can be operated at lower energy / lower power, which can be advantageous in applications where high frequency and / or burst stimulation is used.

[0377] High frequency operation may require more energy than is provided by the pulse generator 500. In non-limiting examples, in applications where energy / power is at a premium, such as where extended operating life from the power source of the pulse generator 500 is desired, any reduction in required power may be advantageous. High frequency operation may be considered to generate electrical stimulation pulses at frequencies of 1000 Hz or greater, preferably 1500 Hz or greater, more preferably 2000 Hz or greater, and even more preferably 2500 Hz or greater.

[0378] In one embodiment, experiments with burst stimulation have been performed as described in "Burst Occipital Nerve Stimulation for Chronic Migraine and Chronic Cluster Headache by Garcia-Ortega et al, Neuromodulation 2019; 22: 638-644, DOI: 10.1111 / ner.12977."

[0379] For burst operation, the pulse generator 500 is further constructed and arranged to generate the electrical stimulation pulses in groups of stimulation pulses.

[0380] In a non-limiting example, a group (or burst) of stimulation pulses may include 2-10 pulses, more preferably 2-5 stimulation pulses. The stimulation pulses in a group may have a repetition frequency of greater than 500 Hz, typically 1000 Hz or greater. A group may repeat at 5 Hz or greater, typically 40 Hz or greater.

[0381] As with high frequency operation, burst operation may require more energy than can be provided by the pulse generator 500, and any reduction in required power may be advantageous.

[0382] Additionally, the rate of charge balance restoration may also be increased with lower impedance. By using a relatively thin foil substrate 300, 1400 and stimulation between electrodes of a first type 200, 1220 included on one surface 310, 1410, 320, 1420 and electrodes of a second type 400, 1220 included on the other surface 310, 1410, 320, 1420, the current path in the tissue is relatively short, lowering the impedance.

[0383] Similarly, the use of the substrate 300, 1400 and stimulation between an electrode of a first type 200, 1220 included on one surface 310, 1410, 320, 1420 and an adjacent electrode of a second type 400, 1220 included on the same surface 310, 1410, 320, 1420 provides a relatively short path through the tissue.

[0384] While certain exemplary embodiments have been described, it will be apparent that many alternatives, modifications, permutations and variations will become apparent to those skilled in the art in light of the foregoing description without departing from the spirit and scope of the invention as set forth in the following claims.

[0385] The present invention encompasses all possible combinations of the various features of each disclosed embodiment. One or more elements described herein with respect to the various embodiments may be implemented in a more separate or integrated manner than explicitly described, or removed or rendered inoperable in certain cases, as may be useful according to a particular application.

[0386] Particularly advantageous combinations of features include the following non-limiting examples:

[0387] (i) an implantable stimulation device 100, 101, 102, 103, 104, 105, 1110, 1111, a pulse generator 500 for generating one or more electrical therapy stimulation pulses; a flexible foil-like substrate 300, 1400 having a longitudinal axis 600 extending from said pulse generator 500 to a distal end of the substrate 300, 1400, the substrate comprising one or more adjacent polymeric substrate layers and having first 310, 1410 and second 310, 1420 planar surfaces; an electrode array 200, 400, 1220 proximate said distal end, having first 200a, 200b, 1220 and second 400a, 400b, 1220 electrodes included on said first 310, 1410 or second 320, 1420 surface, said electrode array 200, 400, 1220 being configurable for transferring therapeutic energy from and / or to human or animal tissue during use; Including, The implantable stimulation device 100, 101, 102, 103, 104, 105, 1110, 1111 further comprises: one or more electrical interconnects 250, 1210 between the pulse generator 500 and the first 200a, 200b, 1220 and second 400a, 400b, 1220 electrodes for delivering electrical energy as one or more electrical therapy stimulation pulses to the first electrode 200a, 200b, 1220 and / or the second electrode 400a, 400b, 1220; Including, the one or more electrical interconnects 250, 1210 are configured (or disposed) between the first 310, 1410 and second 320, 1420 surfaces, and the flexible foil-like substrate 30, 1400 has a maximum thickness of 0.5 mm or less adjacent the first 200a, 200b, 1220 and second 400a, 400b, 1220 electrodes, the thickness being determined by the perpendicular distance between corresponding points on the first 310, 1410 and second 320, 1420 planes; Implant stimulator.

[0388] (ii) an implantable stimulation device 100, 101, 102, 103, 104, 105, 1110, 1111, A substrate 300, 1400 including a top surface 310, 1410 and a bottom surface 320, 1420; a pulse generator 500 disposed along a first portion of the substrate 300, 1400, the pulse generator 500 configured to generate at least one stimulation pulse; an electrode array 200, 400, 1220 including at least two electrodes 200, 400, 1220 disposed along a second adaptive portion of the substrate 300, 1400; a plurality of electrical interconnects 250, 1210 electrically coupling the pulse generator 500 to at least two electrodes of the electrode array 200, 400, 1220, the plurality of electrical interconnects 250, 1210 being disposed between the top surface 310, 1410 and the bottom surface 320, 1420 of the substrate 300, 1400; and an encapsulation layer covering at least a portion of the first portion of the substrate 300, 1400; Including, The maximum thickness of the second portion of the substrate 300, 1400 is 0.5 mm or less; Implant stimulator.

[0389] (iii) an implant electrical device 100, 101, 102, 103, 104, 105, 1100, 1101, 1102, A substrate 300, 1400 having a first surface 310, 1410 and one or more electrical conductors 250, 1210; First biocompatible sealing layer 1300, 1310, 1320, A first adhesive layer 1500, 1510, 1520 disposed between the first surface 310, 1410 and the first encapsulation layer 1300, 1310, 1320. Including, The substrate 300, 1400 is constructed and arranged to be substantially flexible; the first adhesive layer 1500, 1510, 1520 is constructed and arranged to conform to the first surface 310, 1410 and comprises a ceramic material; the first encapsulation layer 1300, 1310, 1320 comprises polydimethylsiloxane (PDMS) rubber; and the first adhesive layer 1500, 1510, 1520 and the first sealing layer 1300, 1310, 1320 are constructed and arranged to resist ingress of fluid from a human or animal body to at least a portion of the first surface 300, 1410; Implant stimulator.

[0390] (iv) a process for applying an encapsulation layer 1300, 1310, 1320 to a surface 310, 1410, 320, 1420 of a substantially flexible substrate 300, 1400, comprising: providing a substrate 300, 1400 having a first surface 310, 1410 and one or more electrical conductors 250, 1210; applying a first conformal adhesive layer 1500, 1510, 1520 comprising a ceramic material to at least a portion of the first surface 310, 1410; applying a first biocompatible encapsulation layer 1300, 1310, 1320 comprising polydimethylsiloxane (PDMS) rubber to at least a portion of the first adhesive layer 1500, 1510, 1520; Including, the first adhesive layer 1500, 1510, 1520 and the first sealing layer 1300, 1310, 1320 are constructed and arranged to resist ingress of fluid from a human or animal body to at least a portion of the first surface 310, 1410; process.

[0391] (v) an implantable stimulation device 100, 101, 102, 103, 104, 105, 1110, 1111, a substrate 300, 1400 comprising a first surface 310, 1410 and a second surface 320, 1420, the thickness of the substrate being defined by the first 310, 1410 and second 320, 1420 surfaces; a pulse generator 500 configured to generate at least one stimulation pulse; At least two electrodes 200, 400, 1220 disposed along an applied portion of said substrate 300, 1400; a plurality of electrical interconnects 250, 1210 electrically coupling the pulse generator 500 to the at least two electrodes 200, 400, 1220; an encapsulation layer 1300, 1310, 1320 at least partially covering the substrate (300, 1400); and Adhesion layer 1500, 1510, 1520 between said encapsulation layer 1300, 1310, 1320 and said substrate 300, 1400 in at least one location Including, the thickness of the substrate 300, 1400 along the applied portion is less than or equal to 0.5 mm; Implant stimulator.

[0392] (vi) an implantable stimulation device 100, 101, 102, 103, 104, 105, 1110, 1111, A substrate 300, 1400, including a top surface 310, 1410 and a bottom surface 320, 1420; a pulse generator 500 disposed along a first portion of the substrate 300, 1400, the pulse generator 500 configured to generate at least one stimulation pulse; at least two electrodes 200, 400, 1220 disposed along a second application portion of the substrate 300, 1400; a plurality of electrical interconnects 250, 1210 electrically coupling the pulse generator to the at least two electrodes 200, 400, 1220, the plurality of electrical interconnects 250, 1210 being disposed between the upper 310, 1410 and lower 320, 1420 surfaces of the substrate 300, 1400; an encapsulation layer 1300, 1310, 1320 covering at least a portion of the first portion of the substrate 300, 1400; and Adhesion layer 1500, 1510, 1520 between said encapsulation layer 1300, 1310, 1320 and said substrate 300, 1400 in at least one location Including, The maximum thickness of the substrate 300, 1400 in the second portion is 0.5 mm or less; Implant stimulator.

[0393] (vii) An implant stimulation device 100, 101, 102, 103, 104, 105, 1110, 1111 according to any disclosed example, wherein a maximum thickness of the implant stimulation device 100, 101, 102, 103, 104, 105, 1110, 1111 adjacent to the pulse generator 500 is 5 mm or less, or 4 mm or less, or 3 mm or less, the thickness being determined by the perpendicular distance between corresponding points on an outer planar surface.

[0394] (viii) an implantable stimulation device according to any of the disclosed examples, The pulse generator 500 is disposed along a first portion of the substrate 300, 1400; The electrode array 200, 400, 1220 is disposed along a second adaptive liquid crystal polymer (LCP) portion of the substrate 300, 1400; the plurality of electrical interconnects 250, 1210 are disposed on a first adaptable LCP layer of the substrate 300, 1400 using electroplating and / or semiconductor deposition techniques, and at least one second adaptable LCP layer of the substrate 300, 1400 is secured to the first layer to cover the plurality of electrical interconnects 250, 1210; the sealing layer 1300, 1310, 1320 is biocompatible and covers at least a portion of the first portion and the second portion of the substrate 300, 1400, the sealing layer 1300, 1310, 1320 includes polydimethylsiloxane (PDMS) and has a tensile strength in the range of 6 to 8 MPa; One or more biocompatible adhesion layers 1500, 1510, 1520 adapted to the substrate 300, 1400 are disposed between the sealing layer 1300, 1310, 1320 and the substrate 300, 1400, the one or more adhesion layers 1500, 1510, 1520 comprising a ceramic portion having an average thickness in the range of 25 nm to 200 nm applied using atomic layer deposition (ALD), at least one first layer comprising TiO2, and at least one second layer adjacent to the at least one first layer and comprising Al2O3; the Young's modulus of the second portion of the substrate is in the range of 2500 to 3600 MPa; the one or more adhesive layers 1500, 1510, 1520 and the sealing layer 1300, 1310, 1320 are configured to resist ingress of fluids into the substrate 300, 1400; the thickness of the substrate 300, 1400 along the second portion is less than or equal to 0.2 mm; the thickness of said stimulator 100, 101, 102, 103, 104, 105, 1110, 1111 along said first portion is less than or equal to 4 mm; The pulse generator 500 includes an energy receiver configured to wirelessly receive energy from an energy transmitter. Implant stimulator. [Explanation of symbols]

[0395] Reference Number: 100, 101, 102 Implant stimulator 103, 104, 105 Further embodiments of the implanted stimulation device 200a, 200b one or more stimulation electrodes 250 one or more stimulating electrical interconnect layers 300 Flexible foil substrate 400a, 400b one or more return electrodes 500 Pulse Generator 600 Longitudinal axis 700 First horizontal axis 750 Second horizontal axis 810 Location of left supraorbital nerve or cortical stimulation 820 Location of right supraorbital stimulation 830a / b Left occipital nerve stimulation location 840a / b Right occipital nerve stimulation location 850 Deep Brain Stimulation Therapy Locations 860 Location of vagus nerve, carotid artery, carotid sinus, phrenic nerve or sublingual stimulation 865 Brain and Spinal Cord Stimulation Site 870 Peripheral Nerve Stimulation Site 875 Spinal Cord Stimulation Site 880 Location of gastric irritation 885 Sacral and pudendal nerve stimulation sites 890 Location of Sacral Nerve Regulation 895 Peroneal nerve stimulation location 910 Left supraorbital nerve 920 Right supraorbital nerve 930 Left greater occipital nerve 940 Right greater occipital nerve 1100, 1101, 1102 Improved implanted electrical or electronic devices 1110, 1111 Improved implantable medical devices 1130 Test Board 1210 One or more conductors 1220 one or more stimulation electrodes 1230 One or more sensors 1300 Additional biocompatible sealing layer 1310 First biocompatible sealing layer 1320 Second biocompatible sealing layer 1330 Third biocompatible sealing layer 1400 Board 1430 Silicon Substrate 1435 SiO2 (silicon dioxide) layer 1410 First Surface 1420 Second Surface 1500 Extra adhesive layer 1510 First adhesive layer 1520 Second adhesive layer 1530 Third adhesive layer 1700 Bode plot expressed as impedance magnitude 1701 Impedance magnitude of bare IDC with exposed Pt metal 1702 Impedance magnitude of IDC coated with HfO2ALD 1703 Impedance magnitude of IDCs coated with ALD-PDMS bilayer 1710 Bode plot expressed as phase angles 1711 Phase angle of bare IDC with exposed Pt metal 1712 Phase angle of HfO2ALD coated IDC 1713 Phase angle of IDC coated with ALD-PDMS bilayer 1720 Adhesion monthly performance expressed as impedance magnitude 1722a, 1722b Impedance magnitude of IDC coated with HfO2ALD 1723a, 1723b Impedance magnitude of IDCs coated with ALD-PDMS bilayers 1730 Bonding monthly performance expressed as phase angle 1732a, 1732b Phase angle of HfO2ALD coated IDC 1733a, 1733b Phase angle of IDC coated with ALD-PDMS bilayer 810 position for left supraorbital nerve or cortical stimulation 1750 Graph comparing average tensile strength in dry and after immersion 1761 Average peel force of sample 2.1 1762 Average peel force of sample 2.2 1763 Average peel force of sample 2.3 1764 Average peel force of sample 2.4 1765 Average peel force of sample 2.5

Claims

1. An implantable stimulation device (100, 101, 102, 103, 104, 105, 1110, 1111), comprising: A pulse generator (500) configured to generate at least one stimulation pulse; a flexible foil-like substrate (300, 1400) having a longitudinal axis (600) extending from the pulse generator (500) to a distal end of the substrate (300, 1400), the substrate (300, 1400) including one or more adjacent polymeric substrate layers and including first (310, 1410) and second (320, 1420) substantially planar surfaces; an electrode array (200, 400, 1220) adjacent said distal end (300, 1400), said electrode array (200, 400, 1220) being included on said first (310, 1410) or second (320, 1420) surface and having first (200, 1220) and second (400, 1220) electrodes, said electrode array (200, 400, 1220) being disposed along an adaptive portion of said substrate (300, 1420), each operative electrode (200, 400, 1220) being configurable for transferring therapeutic energy from and / or to human or animal tissue during use; The implant stimulation device (100, 101, 102, 103, 104, 105, 1110, 1111) further comprises: one or more electrical interconnects (250, 1210) between the pulse generator (500) and the first (200, 1220) and second (400, 1220) electrodes, the electrical interconnects (250, 1210) transmitting electrical energy as one or more electrical therapy stimulation pulses to the coupled first electrode (200) and / or second electrode (400); Including, the one or more electrical interconnects (250, 1210) are disposed between the first (310, 1410) and second (320, 1420) surfaces of the substrate (300, 1400); said flexible foil-like substrate (300, 1400) having a maximum thickness adjacent said first and second electrodes (200, 400, 1220) of 0.5 mm or less, said thickness being determined by the perpendicular distance between corresponding points on said first (310, 1410) and said second outer planar surfaces (320, 1420); The implantable stimulation device, wherein the substrate (300, 1400) and the pulse generator (500) are embedded in one or more flexible, biocompatible encapsulating layers comprising polydimethylsiloxane (PDMS).

2. 2. The implant stimulation device of claim 1, wherein the implant stimulation device further comprises an adhesion layer adjacent at least a portion of the substrate, the adhesion layer comprising a ceramic material.

3. The implantable stimulation device of claim 2 , wherein the substrate (300, 1400) comprises two or more adjacent substrate layers, and the adhesive layer (1500, 1510, 1520) is between the substrate layers.

4. The implant stimulation device of claim 2 or 3, wherein the implant stimulation device (100, 101, 102, 103, 104, 105, 1110, 1111) further comprises one or more additional adhesive layers (1500, 1510, 1520), the one or more adhesive layers (1500, 1510, 1520) comprising a ceramic material.

5. The implantable stimulation device of claim 4 , wherein the one or more additional adhesive layers (1500, 1510, 1520) are between substrate layers.

6. The implantable stimulation device of any one of claims 1 to 5, wherein the flexible foil-like substrate (300, 1400) has a maximum thickness adjacent to the electrode array (200, 400, 1220) of 0.3 mm, or 0.2 mm, or 0.1 mm.

7. The implantable stimulation device of any one of claims 1 to 6, wherein the stimulation device (100, 101, 102, 103, 104, 105, 1110, 1111) has a maximum thickness adjacent to the pulse generator (500) of 5 mm, or 4 mm, or 3 mm.

8. the substrate (300, 1400) has a surface contained in a plane having a lateral extent substantially perpendicular to a longitudinal axis (600); the adaptive portion of the substrate (300, 1400) has a maximum planar width, the width being determined by the perpendicular distance between corresponding points on an outer surface edge of the substrate (300, 1400) along the lateral extent; An implantable stimulation device as described in any one of claims 1 to 7, wherein the ratio of maximum planar width to maximum thickness adjacent to the at least two electrodes (200, 400) is 7:1 or more, or 10:1 or more, or 15:1 or more, or 30:1 or more, or 50:1 or more.

9. The implantable stimulation device of any one of claims 1 to 8, wherein the adaptive portion of the substrate (300, 1400) comprises one or more layers of liquid crystal polymer (LCP).

10. The implantable stimulation device of claim 1 , wherein the sealing layer (1300, 1310, 1320) comprises polydimethylsiloxane (PDMS), silicone polyurethane, polyimide, parylene, a biocompatible polymer, a biocompatible elastomer, and any combination thereof.

11. the pulse generator (500) is disposed along a first portion of the substrate (300, 1400); the electrode array (200, 400, 1220) is disposed along a second adaptive liquid crystal polymer (LCP) portion of the substrate (300, 1400); the plurality of electrical interconnects (250, 1210) are disposed on a first conformal LCP layer of the substrate (300, 1400) using electroplating and / or semiconductor deposition techniques, and at least one second conformal LCP layer of the substrate (300, 1400) is secured to the first layer to cover the plurality of electrical interconnects (250, 1210); The implant stimulation device (100, 101, 102, 103, 104, 105, 1110, 1111) further comprises: one or more adhesive layers (1500, 1510, 1520) adjacent to said substrate (300, 1400); and a sealing layer (1300, 1310, 1320) comprising polydimethylsiloxane (PDMS) covering the first portion of the substrate (300, 1400); Including, the thickness of the substrate (300, 1400) along the second portion is less than or equal to 0.2 mm; a thickness of the stimulator along the first portion is 3 mm or less; The implantable stimulation device of any one of claims 1 to 10, wherein the pulse generator (500) includes an energy receiver configured to wirelessly receive energy from an energy transmitter.

12. The stimulation device (100, 101, 102, 103, 104, 105, 1110, 1111) further comprises: an encapsulation layer (1300, 1310, 1320) at least partially covering the substrate (300, 1400); and The implantable stimulation device of any one of claims 1 to 11, comprising a biocompatible adhesive layer (1500, 1510, 1520) at least at one location between the sealing layer (1300, 1310, 1320) and the substrate (300, 1400).

13. 13. The implant stimulation device of claim 12, wherein the sealing layer (1300, 1310, 1320) covers at least a portion of the adaptive portion of the substrate (300, 1400), and the adhesive layer (1500, 1510, 1520) is between the sealing layer (1300, 1310, 1320) and at least a portion of the adaptive portion of the substrate (300, 1400).

14. 14. The implant stimulation device of claim 12 or 13, wherein the adhesion layer (1500, 1510, 1520) comprises a ceramic material, the ceramic material being selected from the group consisting of HfO2, Al2O3, Ta2O3, Si3N4, TiO2, or any combination thereof.

15. An implantable stimulation device according to any one of claims 12 to 14, wherein the Young's modulus of the adaptive portion of the substrate (300, 1400) is in the range of 2500 to 3600 MPa.

16. An implant stimulation device according to any one of claims 12 to 15, wherein the tensile strength of the sealing layer (1300, 1310, 1320) is in the range of 6 to 8 MPa.

17. An implantable stimulation device according to any one of claims 12 to 16, wherein the average thickness of the ceramic part (1500, 1510, 1520) of the adhesion layer is in the range of 25 nm to 200 nm.

18. 18. An implantable stimulation device according to any one of claims 1 to 17, configurable to stimulate one or more nerves, one or more muscles, one or more organs, spinal tissue, brain tissue, one or more cortical surface regions, one or more sulci, and any combination thereof.

19. 18. The implantable stimulation device of any one of claims 1 to 17, configurable to treat headaches, chronic headaches, primary headaches, incontinence, occipital neuralgia, sleep apnea, high blood pressure, gastroesophageal reflux disease, inflammatory diseases, limb pain, leg pain, back pain, lower back pain, phantom limb pain, chronic pain, epilepsy, overactive bladder, post-stroke pain, obesity, autoimmune disorders, rheumatoid arthritis, inflammatory bowel disease, Crohn's disease, and any combination thereof.

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