Patent Publication Number: US-2019167452-A1

Title: Physiologically active implantable biomaterials having engineered functional surfaces

Description:
CROSS-REFERENCE TO RELATED APPLICATIONS 
     The present application claims priority to the U.S. Provisional Application Ser. No. 62/594,842, filed Dec. 5, 2017, which is hereby incorporated by reference in its entirety. 
    
    
     BACKGROUND OF THE INVENTION 
     The present invention relates generally to implantable medical devices, in particular stents, and more particularly to implantable wireless medical devices having surface topographies suitable for operably coupling to and functionally interfacing with tissue, such as vascular tissue, adjacent to the implantable medical device. Implantable medical devices according to the present invention will be chronically implantable into a mammalian body and have electronic circuitry that is either embedded in the medical device or is formed as an integral part of the medical device and is configured to sense and/or stimulate tissue, such as nerves, adjacent to or in proximity to the situs of the implantable medical device. 
     As described by Chow, E., et al,  Evaluation of Cardiovascular Stents as Antennas for Implantable Wireless Applications , IEEE Transactions on Microwave Theory and Techniques, 57:10 pp. 2523-2532 (October 2009), wireless active stents act both as the package substrate and as the radiating structure. Chow, et al made a non-operational prototype by surface mounting a MEMS capacitive sensor and an application-specific integrated circuit with an onboard transmitter, wireless powering and sensor interface circuits onto a nitinol ZILVER 635 (Cook Medical) self-expanding stent. To test the configuration, an external power source wired to the integrated circuit traces was employed. The test configuration was tested both in free space and in vivo by implanting the device in a porcine chest cavity at a depth of 3.5 cm. Using an external horn antenna placed 10 cm distance away from the stent-based transmitter and the power received from the stent-based transmitter were measured, demonstrating the feasibility of using the stent as an active antenna for transmitting signals. Chow, et al. also described in U.S. Pat. No. 9,662,021 wherein a coil stent configured to be disposed in a pulmonary artery is also configured to serve as an antenna for wireless transmission of arterial pressure data. The architecture of a 700μ×700μ Application Specific Integrated Circuit (ASIC) carrying a sensor interface, wireless transmitter, voltage regulator and references, RF powering block and testing pads is also disclosed. 
     Similarly, Keikhosravy, K. et al. made a stent for monitoring in-stent restenosis in which an integrated circuit is embedded on a platform on the surface of the stent. Keikhosravy, K., et al.,  On the Use of Smart Stents for Monitoring In - Stent Restenosis,  34 th  Annual International Conference of the IEEE EMBS, San Diego, Calif. 28 Aug.-1 Sep. 2012, pp. 3231-3234. The integrated circuit includes a capacitance to frequency converter (CFC) circuit that consisting of an LC oscillator. The inductor of the CFC is integrated on-chip and the capacitance is the capacitance of a pressure sensor capacitor. The stent acts as an inductor, i.e., it acts like an antenna both to receive power and send data to an external reader. In vitro testing and simulations demonstrated that 56 μW at about 0.8 GHz frequency cold be delivered to the stent sufficient to operate the integrated circuit mounted on the stent for active monitoring of in-stent restenosis. Moreover, the simulations demonstrated that the received power was sufficient to transmit information with a power density of about 5 pW/cm 2  at the skin surface, which can be retrieved by an external reader. 
     Recently, Luo, Y, et al reported development of an RF-powered electrothermally active stent with an integrated temperature limiter for wireless hyperthermia treatment. L., Y, et. al, RF-Powered Stent With Integrated Circuit Breaker for Safeguarded Wireless Hyperthermia Treatment, J. Microelectronic Systems, 24:5, pp. 1293-1302 (October 2015). 
     Park, J., et al., developed a wireless pressure sensor that was epoxied to a polymer stent. In vitro testing validated a relationship between pressure and resonance frequency from the pressure sensor. 
     Oxley, et al. in WO 2017/070252 describe a stent with a plurality of wired electrodes coupled to a stent. The electrodes sense and/or stimulate neurons under either wired or wireless control of an external controller unit. The stent described by Oxley, et al. employs an implanted chip that is mounted on the stent and includes circuitry for signal amplification, signal multiplexing and power and data transmission. 
     Hunter, in US 2016/0038087 describes a stent having a plurality of openings that pass either entirely through or partially into a thickness of the stent. Various sensors, such as blood flow sensor, pressure sensor, position sensor, pH sensor, are positioned within the openings. The sensors are interrogated by an external control unit and are powered by a power scavenger circuit that generates power from mechanical movement. 
     Each of the foregoing references represent the general state of the art and are hereby expressly incorporated by reference in their entirety. 
     For purposes of clarity, but without intent to be limited to a particular structure, the implantable medical device will be referred to as a stent. Stents are well known in the art as radially expandable scaffolds that are typically percutaneously delivered to a situs within a body lumen. Stents may comprise a plurality of structural support members forming a tubular structure having a luminal surface facing the body lumen and an abluminal surface facing the body tissue. The term “physiologically active medical device” is intended to encompass a type of implantable medical devices (or “physiologically active stent”) that have embedded electronic circuitry capable of receiving externally applied signals, processing the externally applied signals and responding to the externally applied signals in a predetermined manner. The response by the active stent may be to emit an electrical signal to local tissue adjacent the active stent, transmit sensor data, activate sensor functions, or any such other function to activate active stent functionality. External signals may be applied by an external device that wirelessly communicates with the electronic circuitry in the active stent. 
     The medical devices or stents of the present invention are particularly well-suited for neurovascular delivery to a situs within the brain where the stent may be in electrical communication with portions of the brain that communicate signals to different sensory or motor portions of the body. For example, the Broca&#39;s area of the brain is implicated language production, and in planning and imitating movement and understanding another&#39;s movement. It has recently been found that Broca&#39;s area appears to act as an intermediary between the temporal cortex, which organizes incoming sensory information, and the motor cortex, which carries out the movements of the mouth. It is known that the M1 horizontal segment of the middle cerebral artery supplies the Broca&#39;s area and that decreased perfusion of this vessel or proximal to it causes Broca&#39;s aphasia. Placement of the inventive active device in the M1 segment of the middle cerebral artery will allow for both signal sensing and stimulation of the Broca region. Alternatively, the primary motor cortex, which lies posterior and adjacent Broca&#39;s region, controls both motor imagery, i.e., motor cognition and motor function, is supplied by both the middle and anterior cerebral arteries, with the middle cerebral artery supplying the lateral primary motor cortex and the anterior cerebral artery supplying the medial primary motor cortex. The homunculus describes the organization of the precentral gyms of the primary motor cortex, with the lower parts of the body, e.g., legs and feet, receiving motor movement commands from the superior part of the precentral gyms. The upper parts of the body, e.g., face and arms are innervated by the inferior part of the precentral gyms. Placement of the inventive active device in the anterior cerebral artery will allow for both signal sensing and stimulation of the corresponding portions of the primary motor cortex. 
     Thus, the inventive active device has particular use in detecting neurological conditions in neuronal signaling, vascular flow or pressure or the like. The inventive active device also has particular use in neurostimulation as it is capable of delivering electrical signals through onboard electrodes to different regions of the brain accessible through the neurovasculature. 
     Those skilled in the art will appreciate that the inventive active device also has use in the coronary arteries and may be used for cardio-pacing, for monitoring coronary artery flow and pressure, or for detecting coronary or cardiac conditions and stimulating cardiac tissue. It will further be appreciated that the inventive active device may be employed in other anatomic lumens or organ systems both for detection of conditions and for nerve stimulation. 
     The implantable medical device is configured to have a surface topography configured to increase surface area contact with adjacent tissue such that electrical contact is made between the implantable medical device and the adjacent tissue. The surface topography may consist of raised projections that are in contact with or penetrate into the adjacent tissue. Preferably, the raised projections are formed integrally with and of the material of the implantable medical device. 
     The inventive implantable medical devices may be fabricated of polymers, pre-existing conventional wrought metallic materials, such as stainless steel or nitinol hypotubes, or may be fabricated by vacuum deposition of metallic or pseudometallic materials. In accordance with the present invention, it is preferable to fabricate the inventive implantable materials and resulting devices by vacuum deposition of either or both of the base implant material and the chemically and/or physiochemically active features. Vacuum deposition permits a high level of control over many material characteristics and properties of the resulting deposited material and formed device. Vacuum deposition allows for control over the material properties of the deposited material, including, for example, grain size, grain phase, grain material composition, bulk material composition and mechanical properties, such as transition temperatures in the case of a shape memory alloy. Vacuum deposition techniques also allow for precise sub-micron feature formation during fabrication of the resulting device. Features may be formed during deposition both within the thickness of the deposited material and/or on surfaces of the deposited material. For example, multi-layer structures, complex geometrical configurations, feature and material tolerances, such as thickness or geometry, are all advantages of vacuum deposition processing. 
     In vacuum deposition technologies, materials are formed directly in the desired geometry, e.g., planar, tubular, layered, etc. As is well known in the microelectronics fabrication field, complex layered electronic circuitry, including transistors, diodes, capacitors, amplifier circuits, oscillators, timers, counters, memory, etc. may all be fabricated by microelectronics fabrication techniques that are well known. 
     The application of microelectronic fabrication techniques to medical device or stent fabrication is still in a nascent stage. Fabrication of medical devices, such as stents, by vacuum deposition techniques has been accomplished, as represented by U.S. Pat. Nos. 6,379,383 and 6,357,310, which are hereby incorporated by reference. 
     In addition to materials and devices that are made of a single metal or metal alloy layer, the inventive devices may be comprised of a layer of biocompatible material or of a plurality of layers of biocompatible materials formed upon one another into a self-supporting multilayer structure because multilayer structures are generally known to increase the mechanical strength of sheet materials, or to provide special qualities by including layers that have special properties such as superelasticity, shape memory, radio-opacity, corrosion resistance etc. A special advantage of vacuum deposition technologies is that it is possible to deposit layered materials and thus films possessing exceptional qualities may be produced (cf., H. Holleck, V. Schier:  Multilayer PVD coatings for wear protection , Surface and Coatings Technology, Vol. 76-77 (1995) pp. 328-336). Layered materials, such as superstructures or multilayers, are commonly deposited to take advantage of some chemical, electronic, or optical property of the material as a coating; a common example is an antireflective coating on an optical lens. Multilayers are also used in the field of thin film fabrication to increase the mechanical properties of the thin film, specifically hardness and toughness. Vacuum deposition fabrication of such layered biomaterials is disclosed in U.S. Pat. No. 9,566,148, also incorporated herein by reference. 
     Finally, surface topography features, such as raised features or recessed features, may be made by photolithography as taught by U.S. Pat. No. 9,050,394, incorporated herein by reference, or by additive or subtractive vacuum deposition techniques as taught by U.S. Pat. No. 7,736,687, also incorporated herein by reference. 
     While there is a growing body of work directed toward creating physiologically active wireless medical devices, the goal of having stents with fully integrally fabricated on-board electronic circuitry, has so-far proven elusive. Nano- and microelectronic technology has been successful in creating extremely small-scale electronic components suitable for use with the present invention. The current state of the art in smart or active medical devices has relied upon coupling, such as by welding or epoxy adhesive, the electronic circuitry to a bedding surface on a stent. Medical device fabrication technology has, heretofore, not deployed manufacturing technologies well-suited to making implantable physiologically active medical devices with integrally fabricated on-board electronics. 
     SUMMARY OF THE INVENTION 
     It is an objective of the present invention to provide an implantable physiologically active medical device that, once implanted to a situs within a mammalian body, is configured to wirelessly communicate with an external telemetry device. 
     It is another objective of the present invention to provide an implantable physiologically active stent having integrally formed on-board electronic circuitry configured to communicate with tissue adjacent the physiologically active stent to sense or detect a condition or conditions within the body and/or to issue a stimulating signal to nerves or other tissue proximate to the situs of the implanted physiologically active stent. 
     It is still another objective of the present invention that the on-board integrated electronic circuitry be fabricated as an integral part of the stent structure during fabrication of the stent structure and not formed as a separate component added to a pre-formed stent-structure. 
     It is yet another objective of the present invention that the on-board integrated electronics include an LC circuit configured to wirelessly communicate with an external control device outside the body. The external control device will periodically energize the capacitive element in the LC circuit in the implanted physiologically active device. 
     It is a further objective of the present invention that the on-board integrated electronics in the physiologically active stent include an LC circuit, a transmitter, a power supply, and an analog-digital converter. 
     It is yet another objective of the present invention to provide a method for making an implantable medical device with on-board integrated electronics configured to wireless communicate with an external control unit to detect a condition in the body and/or stimulate tissue in the region of the implanted medical device. 
     The methods, systems, and apparatuses are set forth in part in the description which follows, and in part will be obvious from the description, or can be learned by practice of the methods, apparatuses, and systems. The advantages of the methods, apparatuses, and systems will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the methods, apparatuses, and systems, as claimed. 
    
    
     
       BRIEF DESCRIPTION OF THE FIGURES 
       In the accompanying figures, like elements are identified by like reference numerals among the several preferred embodiments of the present invention. 
         FIG. 1  is partial cross-sectional diagrammatic view of a stent or medical device illustrating integrally formed electronic circuitry in accordance with the present invention. 
         FIG. 2  is a process flow chart outlining the method of making the inventive physiologically active stent or medical device. 
     
    
    
     DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS 
     The foregoing and other features and advantages of the invention are apparent from the following detailed description of exemplary embodiments, read in conjunction with the accompanying drawings. The detailed description and drawings are merely illustrative of the invention rather than limiting, the scope of the invention being defined by the appended claims and equivalents thereof. 
     The wireless physiologically active implantable medical device  10  of the present invention integrally and substantially monolithically combines a stent  12  with microelectronic components  14  and electrodes  26 . The stent  12  is preferably formed by vacuum depositing a stent forming material onto a substrate. The stent-forming material is preferably a metal suitable for use as an antenna capable of transmitting and receiving radiofrequency or other electromagnetic signals across body tissue. Of course, because it is implantable, stent  12  must also be biocompatible. A shape memory metal, such as Nitinol, is well suited both as a stent material and as an antenna. Binary, ternary, quaternary or other metal alloys may be employed as the stent-forming (or device-forming) material. Non-limiting examples include NiTi, NiTiCo, NiTiPt, NiTiPd, NiTiHf, NiTiZr, NiTiAu, NiTiCr, NiTiW, NiTiCoZr, or NiTiCuPd. 
     Stent  12  is formed having a plurality of structural members and preferably formed with at least one recess in at least one structural member of the plurality structural members. The recess may be formed during the vacuum deposition of the stent material or formed by post-processing techniques, such as photolithography. The microelectronic components  14  and electrodes  26  are then formed in situ within the recesses by known microelectronic fabrication techniques used to manufacture such devices, including, for example, physical vapor deposition of the individual sub-layers and sub-components of the microelectronic components and patterning by photolithography and etching the sub-layers and sub-components of the microelectronic components  14  or electrodes  26 . 
     For exemplary purposes only,  FIG. 1  depicts microelectronic component  14  as an LC circuit comprising a plurality of inductors  16 , capacitor layers  18 ,  20  and dielectric layers  22  that isolate the LC circuit. 
     Microelectronic component  14  may be configured as an LC circuit, an amplifier, a transmitter, filter, tuner, power supply, an analog-digital converter, memory, computer, sensor or any such other microelectronic component  14  as is capable of being formed integrally and substantially monolithically within the plurality of recesses in stent  12 . Those skilled in the art of microelectronic fabrication will understand that the plurality of recesses function as packaging for the microelectronic component  14 . 
     Similarly, electrode  26  is preferably formed by vacuum depositing metal capable of acting as an electrode into electrode recesses in the stent, and depositing onto stent  12  an electrically conductive layer  24  electrically coupling microelectronic component  14  to electrode  26 . In this arrangement, electrical energy transmitted by microelectronic component  14  will be discharged by electrode  26  to tissue adjacent the stent  12 . 
     To further facilitate electrically coupling of the stent  12 , namely electrodes  26 , to the tissue adjacent the stent  12 , raised surface topographical features  28  may be provided on the surface of the electrodes  26  which will act as micro-needles and engage the tissue allowing for better electrical contact between the electrodes  26  and the tissue. In some embodiments, each micro-needle has a height of less than or equal to about 10.0 microns. 
       FIG. 2  is a process flow diagram depicting a method for fabricating the inventive physiologically active medical device  12  in accordance with the present invention. 
     A substrate is provided  100  and a device forming material, preferably metal, is vacuum deposited onto the substrate  102 . Once the device forming material is deposited, it is patterned  104  with a pattern corresponding to the recesses to be formed in a surface of the device forming material. As is well known in photolithography, a photoresist is applied to the surface of the device forming material, and a positive or negative mask is applied to the photoresist and the photoresist is exposed to light through the mask. Alternatively, a positive or negative photoresist may be employed. The exposed photoresist is then developed to remove the exposed photoresist thereby uncovering patterned regions of the device forming material to be removed. Subsequent removal  106  of portions of the patterned regions of the device forming material defines the plurality of recesses in the surface of the device forming material. Removal may be by wet or dry etching, ablation, or laser cutting, or other equivalent processes that yield high resolution recess features in the surface of the device forming material. 
     With the plurality of recesses formed in the surface of the device, conventional microelectronic fabrication techniques may be followed to deposit and form electrical component layers  108  or traces within the recess along with forming the electrodes in the electrode recesses. The electrical component layers  108 , traces and/or the electrodes may be also be formed by 3D printing into the plurality of recesses. Once the microelectronic circuitry and electrodes are formed, desired surface features on the electrodes, such as the tissue contact projections, may be formed  110  by deposition, photolithography and/or 3D printing or other processes adapted to form high resolution features on the surface of the device forming material. 
     Once the device is fully formed, it is released  112  from the substrate and any post-processing steps, such as validation, quality control, quality assurance, or the like may be undertaken on the device. 
     Finally, it will be understood that the wireless physiologically active medical device of the present invention may be formed as tubular cylinder, as with conventional radially expandable stents, or may be formed as a planar material that is capable of being coiled or folded for delivery and implantation into the body in its final device shape. The final device shape may cover all or a portion of the circumference of the body lumen at the situs of implantation. 
     Vacuum deposition onto both cylindrical and planar substrates is known in the art, as exemplified by U.S. Pat. Nos. 6,379,383 and 6,357,310, which are hereby incorporated by reference. Similarly, 3D printing onto cylindrical surfaces is also known in the art, as exemplified by WO 2011/011818, also incorporated by reference. 3D printing onto planar substrates is well known. 
     While the invention has been described in connection with various embodiments, it will be understood that the invention is capable of further modifications. This application is intended to cover any variations, uses or adaptations of the invention following, in general, the principles of the invention, and including such departures from the present disclosure as, within the known and customary practice within the art to which the invention pertains.