A wireless, implantable bioelectronic system for monitoring urinary bladder function following surgical recovery

Abstract

A wireless, implantable bioelectronic system for monitoring urinary bladder function following surgical recovery is provided. Specifically, the bioelectronic system includes: a strain gauge being soft and stretchable and to be implanted on an outer wall of a bladder of the living subject for monitoring strain of the bladder; a helical coil wire connected to the strain gauge; and a wireless base station electrically connected to the strain gauge through the helical coil wire, to receive information of the strain of the bladder from the strain gauge and to transmit the information wirelessly to an external device. The strain gauge may be a permanent gauge configured to be permanently implanted on the bladder wall for chronic monitoring, or may be a temporary gauge formed by bioresorbable materials.

Description

[0001] A WIRELESS, IMPLANTABLE BIOELECTRONIC SYSTEM FOR MONITORING URINARY BLADDER FUNCTION FOLLOWING SURGICAL RECOVERY

[0002] STATEMENT AS TO RIGHTS UNDER FEDERALLY-SPONSORED RESEARCH

[0003] This invention was made with government support under grant numbers DK109539 and EB026572 awarded by the National Institutes of Health. The government has certain rights in the invention.

[0004] CROSS-REFERENCE TO RELATED APPLICATIONS

[0005] This PCT application claims priority to and the benefit of U.S. Provisional Patent Application Serial No. 63 / 568,901, which was filed March 22, 2024. The content of the aboveidentified application is incorporated herein by reference in its entirety.

[0006] FIELD OF THE INVENTION

[0007] The present invention relates generally to healthcare and vital sign monitoring, and more particularly to a wireless, implantable bioelectronic system for monitoring urinary bladder function following surgical recovery, and applications of the same.

[0008] BACKGROUND OF THE INVENTION

[0009] The background description provided herein is for the purpose of generally presenting the context of the invention. The subject matter discussed in the background of the invention section should not be assumed to be prior art merely as a result of its mention in the background of the invention section. Similarly, a problem mentioned in the background of the invention section or associated with the subject matter of the background of the invention section should not be assumed to have been previously recognized in the prior art. The subject matter in the background of the invention section merely represents different approaches, which in and of themselves may also be inventions. Work of the presently named inventors, to the extent it is described in the background of the invention section, as well as aspects of the description that may not otherwise qualify as prior art at the time of filing, are neither expressly nor impliedly admitted as prior art against the invention.

[0010] Partial cystectomy procedures for urinary bladder-related dysfunction involve long recovery periods, during which urodynamic studies (UDS) intermittently assess lower urinary tract function. However, UDS are not patient-friendly, they exhibit user-to-user variability, and they amount to snapshots in time, limiting the ability to collect continuous, longitudinal data. These procedures also pose the risk of catheter-associated urinary tract infections, which can progress to ascending pyelonephritis due to prolonged lower tract manipulation in high-risk patients.

[0011] Therefore, a heretofore unaddressed need exists in the art to address the aforementioned deficiencies and inadequacies.

[0012] SUMMARY OF THE INVENTION

[0013] In one aspect, the invention relates to a wireless, implantable bioelectronic system for monitoring urinary bladder function of a living subject. In one embodiment, the bioelectronic system includes: a strain gauge being soft and stretchable, configured to be implanted on an outer wall of a bladder of the living subject for monitoring strain of the bladder; a helical coil wire connected to the strain gauge; and a wireless base station electrically connected to the strain gauge through the helical coil wire, configured to receive information of the strain of the bladder from the strain gauge and to transmit the information wirelessly to an external device.

[0014] In one embodiment, the strain gauge is a permanent gauge configured to be permanently implanted on the bladder wall for chronic monitoring.

[0015] In one embodiment, the strain gauge is a temporary gauge formed by bioresorbable materials. In one embodiment, the bioresorbable materials include poly(octamethylenemaleate (anhydride) citrate) (POMaC) and tungsten (W) particles.

[0016] In certain embodiments, the strain gauge includes: a silicone elastomer; one or more electrodes attached to and cured on the silicone elastomer, wherein the helical coil wire is soldered on the one or more electrodes; and an encapsulating structure outside the one or more electrodes and the helical coil wire.

[0017] In one embodiment, the silicone elastomer has a sensing region containing particles of conducting carbon, and a cross-linking density of the silicone elastomer is lower than a crosslinking density of the bladder.

[0018] In one embodiment, the silicone elastomer is a carbon black doped silicone elastomer, and the electrode is a copper / polyimide (Cu / PI) electrode.

[0019] In certain embodiments, the wireless base station includes: a printed circuit board (PCB); electronic components disposed on the PCB, comprising: a strain measuring component connected to the helical coil wire, configured to measure and digitalize a resistance of the strain gauge to obtain the information of the strain; and a wireless data transmission component, configured to transmit the information wirelessly to the external device under a wireless protocol; a battery disposed on the PCB, configured to provide power to the electronic components; and an encapsulation layer coated on the PCB and encapsulating the electronic components and the battery.

[0020] In one embodiment, the wireless base station is configured to be fixed to an internal abdominal wall of the living subject.

[0021] In one embodiment, the wireless protocol is a Bluetooth protocol.

[0022] Another aspect of the invention relates to a method of monitoring bladder strain information of a living subject. In one embodiment, the method includes: implanting the wireless, implantable bioelectronic system as described above on the bladder of the living subject; and obtaining the bladder strain information from the wireless, implantable bioelectronic system.

[0023] In certain embodiments, the implanting the wireless, implantable bioelectronic system comprises: fixing the wireless base station to an abdominal wall of the living subject; and implanting the strain gauge on the bladder wall of the bladder.

[0024] In one embodiment, the implanting the strain gauge on the bladder wall of the bladder comprises: attaching the helical coil wire to a superficial portion of the bladder; connecting the strain gauge to the bladder at three points to an anterior portion of the bladder; and wrapping the strain gauge around the bladder, and securing the strain gauge at a single point on a posterior portion of the bladder.

[0025] In yet another aspect of the invention, a method of monitoring bladder recovery of a living subject is provided. In one embodiment, the method includes: implanting two bioelectronic systems on the bladder of the living subject, wherein each of the two bioelectronic systems is the wireless, implantable bioelectronic system as described above, one of the two bioelectronic systems is implanted in a scaffold area of the bladder, and the other of the two bioelectronic systems is implanted in a normal area; monitoring bladder recovery by comparing the information of the strains of the bladder received from the two bioelectronic system, wherein the bladder recovery is determined based on a difference between the strains of the bladder received from the two bioelectronic system; and in response to determining the difference between the strains of the bladder received from the two bioelectronic system being smaller than a threshold, determining a bladder tissue in the scaffold area to be fully regenerated.

[0026] In one embodiment, the two bioelectronic systems are implanted following a partial bladder cystectomy of the bladder.

[0027] Yet a further aspect of the invention relates to a strain gauge of a wireless, implantable bioelectronic system for monitoring urinary bladder function of a living subject. In one embodiment, the strain gauge includes: a silicone elastomer; one or more electrodes attached to and cured on the silicone elastomer, wherein the helical coil wire is soldered on the one or more electrodes; and an encapsulating structure encapsulated outside the one or more electrodes and the helical coil wire.

[0028] In one embodiment, the strain gauge is a permanent gauge configured to be permanently implanted on the bladder wall for chronic monitoring. In another embodiment, the strain gauge is a temporary gauge formed by bioresorbable materials comprising POMaC and W particles.

[0029] In one embodiment, the silicone elastomer has a sensing region containing particles of conducting carbon, and a cross-linking density of the silicone elastomer is lower than a crosslinking density of the bladder.

[0030] In one embodiment, the silicone elastomer is a carbon black doped silicone elastomer, and the electrode is a copper / polyimide (Cu / PI) electrode.

[0031] In yet another aspect of the invention, a method of fabricating a strain gauge of a wireless, implantable bioelectronic system for monitoring urinary bladder function of a living subject is provided. In one embodiment, the method includes: attaching a polyvinyl-alcohol (PVA) film on a glass substrate; forming a silicone elastomer on the PVA film; attaching an electrode to the silicone elastomer; soldering the helical coil wire on the electrode; forming an encapsulating structure outside the electrode and the helical coil wire; cutting an outline of the silicone elastomer; and immersing the structure in deionized (DI) water to dissolve the PVA film.

[0032] In one embodiment, the silicone elastomer is a carbon black doped silicone elastomer, and the forming the silicone elastomer includes: screen-printing the carbon black doped silicon elastomer through a polyimide (PI) mask; and curing the carbon black doped silicon elastomer on a hot plate.

[0033] In one embodiment, the method further includes: exposing a connection between the carbon black doped silicon elastomer and the electrode to a corona discharge.

[0034] In one embodiment, the silicone elastomer is formed by bioresorbable materials including POMaC and W particles.

[0035] In one embodiment, forming the silicone elastomer includes: obtaining a POMaC solution; mixing the POMaC solution and the W particles to form a POMaC -W composite; screen-printing the POMaC -W composite on a bottom POMaC film to form W-doped POMaC area; performing ultraviolet (UV) curing on the W-doped POMaC area; disposing a top POMaC film on the bottom POMaC film to overlap with the W-doped POMaC area; and bonding the top POMaC film and the bottom POMaC film by heating to form the silicone elastomer.

[0036] A further aspect of the invention relates to a method of fabricating a wireless, implantable bioelectronic system for monitoring urinary bladder function of a living subject. In one embodiment, the method includes: fabricating the strain gauge as described above, wherein the strain gauge is soft and stretchable, and is configured to be implanted on an outer wall of a bladder of the living subject for monitoring strain of the bladder; connecting a helical coil wire to the strain gauge; and electrically connecting a wireless base station to the strain gauge through the helical coil wire, wherein the wireless base station is configured to receive information of the strain of the bladder from the strain gauge and to transmit the information wirelessly to an external device.

[0037] Yet another aspect of the invention relates to a wireless, implantable bioelectronic system for monitoring urinary bladder function of a living subject, being fabricated by the method as described above.

[0038] These and other aspects of the present invention will become apparent from the following description of the preferred embodiment taken in conjunction with the following drawings, although variations and modifications therein may be affected without departing from the spirit and scope of the novel concepts of the invention.

[0039] BRIEF DESCRIPTION OF THE DRAWINGS

[0040] The accompanying drawings illustrate one or more embodiments of the invention and together with the written description, serve to explain the principles of the invention. Wherever possible, the same reference numbers are used throughout the drawings to refer to the same or like elements of an embodiment.

[0041] FIG. 1 schematically shows a wireless, implantable bioelectronic system according to certain embodiments of the present invention.

[0042] FIG. 2A shows a flowchart of a method of monitoring bladder strain information of a living subject according to certain embodiments of the present invention.

[0043] FIG. 2B shows a flowchart of steps of implanting a wireless, implantable bioelectronic system according to certain embodiments of the present invention.

[0044] FIG. 2C shows a flowchart of steps of implanting the strain gauge on the bladder wall of the bladder according to certain embodiments of the present invention.

[0045] FIG. 3 shows a flowchart of a method of monitoring bladder recovery of a living subject according to certain embodiments of the present invention.

[0046] FIG. 4A shows a flowchart of a method of fabricating a strain gauge of a wireless, implantable bioelectronic system for monitoring urinary bladder function of a living subject according to certain embodiments of the present invention.

[0047] FIG. 4B shows a flowchart of a method of forming the silicone elastomer of a strain gauge according to certain embodiments of the present invention.

[0048] FIG. 5 shows a wireless implantable system for real-time, quantitative monitoring of bladder function, where (A) shows schematic illustrations of the use scenario in long-term monitoring of the recovery and regeneration period after a partial cystectomy; (B) shows schematic illustrations of the bladder monitoring system; (C) shows illustrations of the use of a bioresorbable strain gauge as the basis for a temporary monitoring system; (D) shows the relative change in resistance of a bioresorbable strain gauge due to filling of a mimic bladder at three different rates (black, red and blue line for 300, 60, 30 mL / min, respectively); and (E) shows images of the accelerated dissolution of a bioresorbable strain gauge in PBS solution (pH = 7.4) at 75 °C.

[0049] FIG. 6 shows a photograph of a wireless, implantable bioelectronic system according to certain embodiments of the present invention.

[0050] FIG. 7 shows the remaining weight of the bioresorbable strain gauge as a function of time in PBS solution (pH = 7.4) at 37 °C and 75 °C.

[0051] FIG. 8 shows characterization of the strain gauge system, where (A) shows the relative change in resistance of the strain gauge as a function of strain for devices with various lengths of carbon black doped silicone elastomer; (B) shows the relative change in resistance of the strain gauge with various thicknesses of silicone elastomer coatings on the connection between the wire and the Cu / PI electrode while mechanically shaking the wire; and (C) shows the bending cyclic test of a strain gauge system fabricated with and without corona treatment.

[0052] FIG. 9 shows the bending cyclic test of strain gauge systems with various types of interconnecting wire.

[0053] FIG. 10 shows (A) schematic illustration and (B) photograph of a benchtop setup with a mimic rat bladder model.

[0054] FIG. 11 shows (A) the relative change in resistance of a strain gauge on a mimic bladder during injection of saline solution; (B) the relative change in resistance of a strain gauge at different injection rates; and (C) the cyclic test for 100 h.

[0055] FIG. 12 shows an exemplary process for fabricating the strain gauge according to certain embodiments of the present invention, where (A) shows preparation of a glass substrate; (B) shows attachment of a PVA film; (C) shows spin-coating of a silicone elastomer; (D) shows attachment of the Cu / PI electrode; (E) shows attachment of the PI mask; (F) shows screenprinting of a carbon black doped silicone elastomer; (G) shows removal of the PI mask. (H) shows corona treatment of the carbon black doped silicone elastomer and Cu / PI electrode; (I) shows attachment of a silicone elastomer mask on the Cu / PI electrode; (J) shows spin-coating of a silicone elastomer and removal of the PDMS mask; (K) shows laser cutting of the strain gauge outline; (L) shows soldering of a helical coil wire to the Cu / PI electrode; (M) shows coverage of silicone elastomer on the solder joint to the wire; (N) shows dissolution of the PVA film with DI water; and (O) shows a completed strain gauge.

[0056] FIG. 13 shows an exemplary process for fabricating the base station according to certain embodiments of the present invention, where (A) shows preparation of a PCB with a Au / Cu electrode; (B) shows soldering of circuit components; (C) shows parylene coating of the PCB; (D) shows soldering of the battery; (E) shows soldering of the helical coil wire; (F) shows covering the soldered parts with marine epoxy; (G) shows PDMS dip coating; and (H) shows silicone elastomer encapsulation with a 3D-printed mold.

[0057] FIG. 14 shows the benchtop tests and FEM simulation results for monitoring of a human bladder model at three time points after a partial cystectomy, where (A) shows schematic illustrations of the recovery process with a scaffold implanted after a partial cystectomy; (B) shows the strain-stress curves of model materials for a normal bladder, a regenerating bladder on a scaffold, and a scaffold; (C-E) show strain distributions calculated from FEM simulations for three models after partial cystectomy and scaffold implantation; and (F-K) show the benchtop setups and strain changes for three models after partial cystectomy and scaffold implantation.

[0058] FIG. 15 shows FEM simulation setups for three models after partial cystectomy and scaffold implantation, where (A) shows that the first model corresponds to the case after suturing the scaffold to the upper part of the resected bladder, with normal bladder tissue in the lower part; (B) shows that the second model corresponds to partial regeneration of bladder tissue with the scaffold; and (C) shows that the third model corresponds to fully regenerated bladder tissue and fully bioresorbed scaffold.

[0059] FIG. 16 shows a table of the FEM simulation results for human bladder model.

[0060] FIG. 17 shows (A) a schematic illustration of experiments with a rat model; (B) illustrations of the system components, the positions of the suture holes, and interface to the bladder; (C) a photograph showing the strain gauge sutured onto the outside surface on the bladder wall of a rat; (D and E) shows chronic measurements from a rat model, where relative change in resistance of the strain gauge as a function of time at 2 and 4 weeks postsurgery; (F) shows urine volume validation setup in a rat model; and (G) shows a plot of the relative change in resistance of the strain gauge as a function of time (black) and amount of urine determined using the filter paper method (red).

[0061] FIG. 18 shows detailed surgical procedure for experiments with rat models, where (A) shows opening the skin and abdominal wall for implantation of the strain gauge system; (B) and (C) show suturing the (B) first and (C) second suture holes of the base station to the abdominal wall; (D) shows placing the helical coil wire into the abdomen; (E) shows suturing the strain gauge on the front side of bladder wall; (F) shows suturing the strain gauge on the back side of bladder wall; (G) shows suturing the wire to the abdominal wall; and (H) shows closing the abdominal wall and skin with suture and surgical staples.

[0062] FIG. 19 shows (A) an image showing the strain gauge implanted on the bladder wall of rat; and (B) and (C) show X-ray images of urodynamic study after (B) 2 weeks and (C) 4 weeks post-surgery.

[0063] FIG. 20 shows an image of a smartphone for urine measurement using the filter paper method.

[0064] FIG. 21 shows the amount of urine as a function of the wetting area of a piece of filter paper.

[0065] FIG. 22 shows biocompatibility studies in a rat model, where (A-C) show images for H&E after 1, 2, and 4 weeks post-surgery; (D-F) show images for CD68 after 1, 2, and 4 weeks post-surgery; (G-I) show images for MPO after 1, 2, and 4 weeks post-surgery; and (J) shows quantitative histological evaluation of CD68 and MPO after 1, 2, and 4 weeks post-surgery.

[0066] FIG. 23 shows schematic illustrations and UDS for nonhuman primate models, where (A) shows diagrams of the location of the implanted system and BLE wireless interface to a smartphone; (B) shows illustrations of the system components, the positions of the suture holes, and interface to the bladder; (C) shows an image of a strain gauge sutured to the surface of the bladder wall of a baboon with a normal bladder; (D-F) show C-arm fluoroscopy images of UDS 6-week post-surgery; (G) shows a plot of the relative change in resistance of the strain gauge as a function of the bladder pressure determined during a urodynamic study; and (H) shows a Bland- Altman plot, showing the difference between the pressure inferred from the strain gauge and that measured directly as a function of the latter.

[0067] FIG. 24 shows preoperative urodynamics studies of normal baboon bladder, where (A) shows the bladder pressure measured by the physiological pressure transducer during saline injection; (B-D) show C-arm fluoroscopic images after instillation of 25, 50, and 95 mL of saline solution into the bladder; and (E-G) show ultrasound images for left and right kidney, and bladder.

[0068] FIG. 25 shows urodynamics studies 6 weeks post-surgery of normal baboon bladder, where (A) shows the bladder pressure measured by the physiological pressure transducer during saline injection; (B-D) show C-arm fluoroscopic images after instillation of 20, 45, and 60 mL of saline solution into the bladder; and (E-G) show ultrasound images for left and right kidney, and bladder.

[0069] FIG. 26 shows urodynamics studies 10 weeks post-surgery of normal baboon bladder.

[0070] (A) shows the bladder pressure measured by the physiological pressure transducer during saline injection; (B-D) show C-arm fluoroscopic images after instillation of 25, 60, and 81 mL of saline solution into the bladder; and (E-G) show ultrasound images for left and right kidney, and bladder.

[0071] FIG. 27 shows Uro Preoperative urodynamics studies of baboon bladder that underwent partial cystectomy, where (A) shows the bladder pressure measured by the physiological pressure transducer during saline injection; (B-D) show C-arm fluoroscopic images after instillation of 25, 50, and 142 mL of saline solution into the bladder; and (E-G) show ultrasound images for left and right kidney, and bladder.

[0072] FIG. 28 shows urodynamics studies 6 weeks post-surgery of bladder that underwent the partial cystectomy in a baboon model, where (A) shows the bladder pressure measured by the physiological pressure transducer during saline injection; (B-D) show C-arm fluoroscopic images after instillation of 5, 25, and 41 mL of saline solution into the bladder; and (E-G) show ultrasound images for left and right kidney, and bladder.

[0073] FIG. 29 shows chronic studies in nonhuman primate models, where (A) shows the relative change in the resistance of the strain gauge for the entire time period of the study; (B) shows the relative change in the resistance of the strain gauge at 1 week postsurgery; (C) shows the relative change in the resistance of the strain gauge at 4 weeks postsurgery; (D) shows the relative change in the resistance of the strain gauge at 8 weeks postsurgery; (E) shows the number of voids in 12-h periods throughout the study; (F) shows the difference in resistance before and after voiding for an animal with a normal bladder; and (G) shows the difference in resistance before and after voiding for an animal with a partial cystectomy.

[0074] FIG. 30 shows the relative change in the resistance of the strain gauge, presented as raw data without baseline correction.

[0075] FIG. 31 shows the relative change in the resistance of the strain gauge from 0 h to 120 h post-surgery.

[0076] FIG. 32 shows the relative change in the resistance of the strain gauge from 120 h to 240 h post-surgery.

[0077] FIG. 33 shows the relative change in the resistance of the strain gauge from 240 h to 360 h post-surgery.

[0078] FIG. 34 shows the relative change in the resistance of the strain gauge from 360 h to 480 h post-surgery.

[0079] FIG. 35 shows the relative change in the resistance of the strain gauge from 480 h to 600 h post-surgery.

[0080] FIG. 36 shows the relative change in the resistance of the strain gauge from 600 h to 720 h post-surgery.

[0081] FIG. 37 shows the relative change in the resistance of the strain gauge from 720 h to 840 h post-surgery.

[0082] FIG. 38 shows the relative change in the resistance of the strain gauge from 840 h to 960 h post-surgery.

[0083] FIG. 39 shows the relative change in the resistance of the strain gauge from 960 h to 1080 h post-surgery.

[0084] FIG. 40 shows the relative change in the resistance of the strain gauge from 1080 h to 1200 h post-surgery.

[0085] FIG. 41 shows chronic studies in non-human primate models, where (A) shows filling and (B) shows voiding times throughout the study.

[0086] FIG. 42 shows the results of benchtop tests of (A) a normal bladder model and (B) a bladder model after partial cystectomy.

[0087] FIG. 43 shows studies of biocompatibility of the wireless bladder monitoring system, where images for (A) H&E, (B) tri chrome, and (C) M1 / M2 inflammatory responses of bladder muscle near a strain gauge sutured onto the outer surface of a normal bladder; images for (D) H&E, (E) trichrome, and (F) M1 / M2 inflammatory responses of bladder muscle near a strain gauge sutured onto the outer surface of a bladder after a partial cystectomy; and quantitative histological evaluation of (G) collagen, (H) Ml, and (I) M2 inflammatory responses forbladder muscle near strain gauges applied to a normal bladder and one with partial cystectomy.

[0088] DETAILED DESCRIPTION OF THE INVENTION

[0089] The invention will now be described more fully hereinafter with reference to the accompanying drawings, in which exemplary embodiments of the invention are shown. This invention may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Rather, these embodiments are provided so that this specification will be thorough and complete, and will fully convey the scope of the invention to those skilled in the art. Like reference numerals refer to like elements throughout.

[0090] The terms used in this specification generally have their ordinary meanings in the art, within the context of the invention, and in the specific context where each term is used. Certain terms that are used to describe the invention are discussed below, or elsewhere in the specification, to provide additional guidance to the practitioner regarding the description of the invention. For convenience, certain terms may be highlighted, for example using italics and / or quotation marks. The use of highlighting has no influence on the scope and meaning of a term; the scope and meaning of a term are the same, in the same context, whether or not it is highlighted. It will be appreciated that same thing can be said in more than one way. Consequently, alternative language and synonyms may be used for any one or more of the terms discussed herein, nor is any special significance to be placed upon whether or not a term is elaborated or discussed herein. Synonyms for certain terms are provided. A recital of one or more synonyms does not exclude the use of other synonyms. The use of examples anywhere in this specification including examples of any terms discussed herein is illustrative only, and in no way limits the scope and meaning of the invention or of any exemplified term. Likewise, the invention is not limited to various embodiments given in this specification.

[0091] It will be understood that, as used in the description herein and throughout the claims that follow, the meaning of “a”, “an”, and “the” includes plural reference unless the context clearly dictates otherwise. Also, it will be understood that when an element is referred to as being “on” another element, it can be directly on the other element or intervening elements may be present therebetween. In contrast, when an element is referred to as being “directly on” another element, there are no intervening elements present. As used herein, the term “and / or” includes any and all combinations of one or more of the associated listed items.

[0092] It will be understood that, although the terms first, second, third, etc. may be used herein to describe various elements, components, regions, layers and / or sections, these elements, components, regions, layers and / or sections should not be limited by these terms. These terms are only used to distinguish one element, component, region, layer or section from another element, component, region, layer or section. Thus, a first element, component, region, layer or section discussed below could be termed a second element, component, region, layer or section without departing from the teachings of the invention.

[0093] Furthermore, relative terms, such as “lower” or “bottom” and “upper” or “top,” may be used herein to describe one element’s relationship to another element as illustrated in the figures. It will be understood that relative terms are intended to encompass different orientations of the device in addition to the orientation depicted in the figures. For example, if the device in one of the figures, is turned over, elements described as being on the “lower” side of other elements would then be oriented on “upper” sides of the other elements. The exemplary term “lower”, can, therefore, encompasses both an orientation of “lower” and “upper,” depending on the particular orientation of the figure. Similarly, if the device in one of the figures is turned over, elements described as “below” or “beneath” other elements would then be oriented “above” the other elements. The exemplary terms “below” or “beneath” can, therefore, encompass both an orientation of above and below.

[0094] It will be further understood that the terms “comprises” and / or “comprising,” or “includes” and / or “including” or “has” and / or “having”, or “carry” and / or “carrying,” or “contain” and / or “containing,” or “involve” and / or “involving, and the like are to be open-ended, i.e., to mean including but not limited to. When used in this specification, they specify the presence of stated features, regions, integers, steps, operations, elements, and / or components, but do not preclude the presence or addition of one or more other features, regions, integers, steps, operations, elements, components, and / or groups thereof.

[0095] Unless otherwise defined, all terms (including technical and scientific terms) used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. It will be further understood that terms, such as those defined in commonly used dictionaries, should be interpreted as having a meaning that is consistent with their meaning in the context of the relevant art and this specification, and will not be interpreted in an idealized or overly formal sense unless expressly so defined herein.

[0096] As used in this specification, “around”, “about”, “approximately” or “substantially” shall generally mean within 20 percent, preferably within 10 percent, and more preferably within 5 percent of a given value or range. Numerical quantities given herein are approximate, meaning that the term “around”, “about”, “approximately” or “substantially” can be inferred if not expressly stated.

[0097] As used in this specification, the phrase “at least one of A, B, and C” should be construed to mean a logical (A or B or C), using a non-exclusive logical OR. As used herein, the term “and / or” includes any and all combinations of one or more of the associated listed items.

[0098] The description below is merely illustrative in nature and is in no way intended to limit the invention, its application, or uses. The broad teachings of the invention can be implemented in a variety of forms. Therefore, while this invention includes particular examples, the true scope of the invention should not be so limited since other modifications will become apparent upon a study of the drawings, the specification, and the following claims. For purposes of clarity, the same reference numbers will be used in the drawings to identify similar elements. It should be understood that one or more steps within a method may be executed in a different order (or concurrently) without altering the principles of the invention.

[0099] Increasing interest in personalized medical systems motivates the development of bioelectronic implants for sensing physiological functions. Such implants could potentially provide physicians with real-time information to guide treatment and management strategies regarding tissue disease or trauma. Within the context of urinary bladder dysfunction, internal pressures can be indicative of bladder recovery following surgical interventions.

[0100] As discussed above, there is a need for systems and methods for monitoring bladder function, including following surgery. In certain aspect, a fully bladder-implantable platform is provided that allows for continuous, real-time measurements of changes in mechanical strain associated with bladder filling and emptying via wireless telemetry, including a wireless bioresorbable strain gauge validated in a benchtop partial cystectomy model. The fully implantable system is usable for quantitative measurements of the temporal dynamics of bladder filling and voiding via wireless telemetry7, employing stretchable strain gauges in both permanent and bioresorbable forms. The inventors demonstrate that this system can reproducibly measure real-time changes in a rodent model up to 30 days postimplantation with minimal foreign body response. Studies in a nonhuman primate partial cystectomy model demonstrate concordance of pressure measurements up to 8 weeks compared with traditional UDS. Validation studies in rodent and nonhuman primate models demonstrate the potential for this system to provide personalized treatment and rehabilitation strategies to human counterparts. These results suggest that the system can be used as a suitable alternative to UDS for long-term postoperative bladder recovery monitoring.

[0101] Specifically, the urinary bladder is a hollow organ that expands and contracts to allow for the storage and emptying of urine during micturition under volitional control. Patients who are candidates for a bladder-sparing treatment approach for muscle-invasive bladder cancer may undergo a partial cystectomy, while those with end-stage neurogenic bladder will be offered bladder augmentation enterocystoplasty. In these patients, complete functional recovery of bladder mechanics following surgical excision of the bladder wall is typically slow and difficult to assess. Urodynamic studies (UDS) are essential in the diagnosis and management of lower urinary tract dysfunction in the pre- and postoperative settings. Abnormal or worsening urodynamic parameters, such as high bladder storage pressures and decreased bladder capacity, can be symptomatic of impending upper urinary tract deterioration and subsequent renal failure. In the clinical setting, UDS involve inserting urethral catheters and rectal electromyography electrodes, filling the bladder with saline at a set rate, and measuring changes in detrusor pressures during filling and emptying cycles. These measurements are correlated with patient symptoms to aid in diagnosis. This office-based procedure is often time consuming, expensive, and results in significant patient discomfort. Traditional urodynamics can be limited by nondiagnostic results due to patient intolerance, or poor interrater reliability and protocol inconsistency due to variations in provider training. Additionally, these studies only provide a glimpse into bladder function at a single point in time and do not reflect the characteristics of chronic urinary conditions that many patients face, particularly with ambulation and daily activities.

[0102] To improve upon the accessibility and to address the diagnostic limitations of urodynamics, there is growing interest in ambulatory urodynamic monitoring (AUM) with continuous catheter-based pressure sensing. These studies suggest that AUM could replace conventional office urodynamics with portable recording devices that have the potential to detect involuntary detrusor activity with improved specificity. The use of chronic catheterization can, however, lead to stone formation, significant patient discomfort, and risk for urinary tract infections with ascending pyelonephritis. Recent technological advances form the basis of implantable, soft, and stretchable electronic bladder pressure sensors with the ability to obtain long-term, continuous data on bladder storage and emptying parameters without the use of indwelling catheters. These devices come in the forms of intravesical, intradetrusor, or transdetrusor platforms. Many are limited by short battery lives, limited operational range, and / or requirements for explantation and disassembly to retrieve data. Majerus et al. describe the use of a wireless implantable intracavity micromanometer (WIMM), a battery-powered rechargeable device that permanently implants cystoscopically within the wall of the bladder. The data from this study demonstrate adequate wireless detection of pressure changes in real-time and a correlation coefficient of r = 0.95 with a matched reference device when used in anesthetized female canine subjects. Additionally, this study suggests potential applications in a “closed-loop system” by relaying feedback to coupled neuromodulation devices. The experimental prototype is, however, bulky, with a battery life of 1 week with need for intermittent recharge sessions, given that it is a permanently implanted device. In 2017, the same group published data on the suburothelial implantation of their piezoelectric catheter-free pressure sensor in a canine model. The results show a strong correlation (r = 0.98) between the device and reference catheter data in these animal subjects. Limitations are in the use of a wired prototype and the loss of consistent recordings due to significant erosion of the implant through the detrusor in the majority of the subjects. Frainey et al published their data using the UroMonitor™ transurethral telemetric ambulatory pressure monitoring system in 11 human subjects. This monitoring system detects intravesical bladder pressure during a single office visit, with same-day reference measurements obtained by traditional UDS. While the authors demonstrate the feasibility of this approach and moderate correlation with UDS, the absence of long-term data prevents conclusions on safety and efficacy. Additionally, as an intravesical device, static pressure accuracy at low volumes is poorly correlative. Of note, the device is not designed to provide bladder volume data, thereby limiting the accuracy of compliance and capacity assessment. Previous work describes noninvasive bladder monitoring methods based on electrical impedance and ultrasound. These techniques, however, are currently designed to monitor overall volume changes in the bladder, an averaged quantity. Detailed measurements of two or more different regions of a single bladder are difficult. Also, artifacts associated with body movements place constraints on measurement conditions. This consideration, along with the required wired hardware and external data acquisition equipment, makes long-term, real-time monitoring of volume changes impossible. Monitoring must therefore be performed episodically, in specialized facilities where equipment is installed, such as hospitals, resulting in additional medical costs and time / space constraints.

[0103] FIG. 1 schematically shows a wireless, implantable bioelectronic system according to certain embodiments of the present invention. As shown in FIG. 1, the bioelectronic system 100 includes a strain gauge 110, a helical coil wire 120 and a wireless base station 130. The strain gauge 110 is soft and stretchable, and is configured to be implanted on an outer wall of a bladder of the living subject for monitoring strain of the bladder. In certain embodiments, the strain gauge 110 may be a permanent gauge configured to be permanently implanted on the bladder wall for chronic monitoring, or may be a temporary gauge formed by bioresorbable materials. The helical coil wire 120 is used to be connected to the strain gauge 110 and the wireless base station 130. The wireless base station 130 is electrically connected to the strain gauge 110 through the helical coil wire 120, and is configured to receive information of the strain of the bladder from the strain gauge 110 and to transmit the information wirelessly to an external device 150.

[0104] In certain embodiments, the strain gauge 110 may include a silicone elastomer; one or more electrodes attached to and cured on the silicone elastomer, and an encapsulating structure. The helical coil wire 120 is soldered on the one or more electrodes, and the encapsulating structure is encapsulated outside the one or more electrodes and the helical coil wire 120. In one embodiment, the silicone elastomer has a sensing region containing particles of conducting carbon, and a cross-linking density of the silicone elastomer is lower than a cross-linking density of the bladder. For example, in one embodiment, the silicone elastomer is a carbon black doped silicone elastomer, and the electrode is a copper / polyimide (Cu / PI) electrode. In another embodiment, the silicone elastomer may be formed by bioresorbable materials such as poly(octamethylenemaleate (anhydride) citrate) (POMaC) and tungsten (W) particles.

[0105] In certain embodiments, the wireless base station 130 includes: a printed circuit board (PCB); electronic components disposed on the PCB, comprising: a strain measuring component connected to the helical coil wire, configured to measure and digitalize a resistance of the strain gauge to obtain the information of the strain; and a wireless data transmission component, configured to transmit the information wirelessly to the external device under a wireless protocol; a battery disposed on the PCB, configured to provide power to the electronic components; and an encapsulation layer coated on the PCB and encapsulating the electronic components and the battery. In one embodiment, the wireless base station is configured to be fixed to an internal abdominal wall of the living subject. In one embodiment, the wireless protocol is a Bluetooth protocol.

[0106] FIG. 2A shows a flowchart of a method of monitoring bladder strain information of a living subject according to certain embodiments of the present invention. Specifically, as shown in FIG. 2A, at procedure 210, the wireless, an implantable bioelectronic system (e.g., the implantable bioelectronic system as described above) is implanted on the bladder of the living subject. At procedure 220, the bladder strain information is obtained from the wireless, implantable bioelectronic system.

[0107] FIG. 2B shows a flowchart of steps of implanting a wireless, implantable bioelectronic system according to certain embodiments of the present invention. As shown in FIG. 2B, at procedure 212, the wireless base station 130 is fixed to an abdominal wall of the living subject. Then, at procedure 214, the strain gauge 110 is implanted on the bladder wall of the bladder.

[0108] FIG. 2C shows a flowchart of steps of implanting the strain gauge on the bladder wall of the bladder according to certain embodiments of the present invention. As shown in FIG. 2C, at procedure 230, the helical coil wire 120 is attached to a superficial portion of the bladder. At procedure 240, the strain gauge 110 is connected to the bladder at three points to an anterior portion of the bladder. At procedure 250, the strain gauge 110 is wrapped around the bladder, and is secured at a single point on a posterior portion of the bladder.

[0109] The bioelectronic device as described above may be used for monitoring bladder recovery of a living subject. For example, FIG. 3 shows a flowchart of a method of monitoring bladder recovery of a living subject according to certain embodiments of the present invention. As shown in FIG. 3, at procedure 310, two bioelectronic systems are implanted on the bladder of the living subject. Specifically, the two bioelectronic systems may be implanted following a partial bladder cystectomy of the bladder, and each of the two bioelectronic systems may be an individual one of the wireless, implantable bioelectronic system as described above. For example, one of the two bioelectronic systems is implanted in a scaffold area of the bladder, and the other of the two bioelectronic systems is implanted in a normal area. At procedure 320, bladder recovery is monitored by comparing the information of the strains of the bladder received from the two bioelectronic system, where the bladder recovery is determined based on a difference between the strains of the bladder received from the two bioelectronic system. Specifically, with the progress of the bladder recovery, the performance of the scaffold area of the bladder and the normal area of the bladder becomes closer, and the difference between the strains measured in the two areas becomes smaller. At procedure 330, in response to determining the difference between the strains of the bladder received from the two bioelectronic system being smaller than a threshold, a bladder tissue in the scaffold area is determined to be fully regenerated.

[0110] As described above, the strain gauge 110 of the bioelectronic system 100 may be a permanent gauge or a temporary gauge, and may be formed by various ways. For example, FIG. 4 shows a flowchart of a method of fabricating a strain gauge of a wireless, implantable bioelectronic system for monitoring urinary bladder function of a living subject according to certain embodiments of the present invention. As shown in FIG. 4, at procedure 410, a polyvinyl-alcohol (PVA) film is attached on a glass substrate. At procedure 420, a silicone elastomer is formed on the PVA film. At procedure 430, an electrode is attached to the silicone elastomer. At procedure 440, the helical coil wire is soldered on the electrode. At procedure 450, an encapsulating structure is formed outside the electrode and the helical coil wire. At procedure 460, an outline of the silicone elastomer is cut. Finally, at procedure 470, the structure is immersed in deionized (DI) water to dissolve the PVA film, thus obtaining the strain gauge.

[0111] In one embodiment, the silicone elastomer is a carbon black doped silicone elastomer, and the forming the silicone elastomer includes: screen-printing the carbon black doped silicon elastomer through a polyimide (PI) mask; and curing the carbon black doped silicon elastomer on a hot plate. In one embodiment, the method further includes: exposing a connection between the carbon black doped silicon elastomer and the electrode to a corona discharge, thus ensuring robust adhesion and long-term operation stability.

[0112] In one embodiment, the silicone elastomer may be formed by bioresorbable materials including POMaC and W particles. For example, FIG. 4B shows a flowchart of a method of forming the silicone elastomer of a strain gauge according to certain embodiments of the present invention. As shown in FIG. 4B, at procedure 421, a POMaC solution is obtained. At procedure 423, the POMaC solution and the W particles are mixed to form a POMaC-W composite. At procedure 425, screen-printing is performed to dispose the POMaC-W composite on a bottom POMaC film to form W-doped POMaC area. At procedure 426, ultraviolet (UV) curing is performed on the W-doped POMaC area. At procedure 427, a top POMaC film is disposed on the bottom POMaC film to overlap with the W-doped POMaC area. At procedure 429, the top POMaC film and the bottom POMaC film are bonded by heating to form the silicone elastomer.

[0113] These and other aspects of the invention are further described below. Without intent to limit the scope of the invention, exemplary instruments, apparatus, methods and their related results according to the embodiments of the invention are given below. Note that titles or subtitles may be used in the examples for convenience of a reader, which in no way should limit the scope of the invention. Moreover, certain theories are proposed and disclosed herein; however, in no way they, whether they are right or wrong, should limit the scope of the invention so long as the invention is practiced according to the invention without regard for any particular theory or scheme of action.

[0114] EXAMPLES

[0115] To avoid limitations associated with previously described monitoring platforms, the inventors introduce herein an implantable system that includes a strain gauge capable of realtime bladder monitoring via telemetry, with options in permanent as well as bioresorbable forms. The work includes rigorous experimental testing and computational modeling in benchtop phantoms of bladder insult / recovery as well as studies evaluating efficacy in rodent and nonhuman primate baboon injury models. Data accrued from these studies demonstrate an ability to monitor bladder pressure as a function of strain for extended periods of time via wireless, remote data capture and analysis. Although the overall risks of surgery for strain gauge implantation and removal are higher than those associated with pacing a chronic catheter, the system provides accurate measures of bladder strain compared to catheter placed intraluminally. Additionally, the technology reduces the risk of urinary tract infection compared to chronic catheterization and offers the potential for a more comfortable solution for long-term monitoring.

[0116] Results

[0117] Bladder Function Monitoring System for Human Applications. FIG. 5 shows a wireless implantable system for real-time, quantitative monitoring of bladder function. Specifically, FIG. 5(A) shows the schematic illustrations of the technology and envisioned clinical use case. Following a partial bladder cystectomy, the system continuously monitors filling and voiding dynamics through a soft, stretchable strain gauge that encircles the bladder and a companion wireless module that streams data to an external device using standard Bluetooth Low Energy (BLE) communication protocols. The resulting information provides insights to aid in care decisions associated with postoperative recovery and healing, potential complications due to infections, and other processes. FIG. 5(B) and FIG. 6 present schematic illustrations and a photograph of the strain gauge and its helical interconnection to the wireless base station, respectively. A critical feature of the gauge is that it avoids any significant mechanical constraint on the natural processes of filling and voiding of the bladder, through the use of ultrathin, low modulus designs. The device exploits a silicone elastomer with low crosslinking density (Ecoflex 00-30), with a sensing region that contains particles of conducting carbon at loading levels slightly above the threshold for percolation electrical transport. The system can be designed as either a permanent implant for chronic monitoring or as a temporary device based on bioresorbable materials, specifically on POMaC and W particles. In this latter iteration, the strain gauge dissolves and disappears in the body to eliminate device load on the bladder after a period of clinical need, as shown in FIG. 5(C). FIG. 5(D) shows the relative change in resistance of such a bioresorbable strain gauge following injection of saline into a bladder mimic at three different rates. FIG. 5(E) and FIG. 7 illustrate the process of accelerated dissolution in phosphate-buffered saline (PBS, pH = 7.4) at 75 °C. The focus of the following description is on the permanent version of the device.

[0118] Strain Gauge Design and Assessment. A robust sensor with suitable properties follows from appropriate selection of the length of the sensing region, the thickness of the encapsulation (Ecoflex 00-30) at the interface to the helical wire, and the parameters for corona treatment of this interface to ensure robust adhesion. Increasing the length of the sensing region increases the relative change in resistance for a given strain (and thus the gauge factor), to levels that ensure high signal-to-noise ratio across a range of elongations relevant to filling and voiding of the bladder, as shown in FIG. 8(A). A thick encapsulation layer reduces the effects of artifacts due to motion of the wire relative to the gauge, as shown in FIG. 8(B). Specifically, increasing the thickness from -100 to -500 pm, decreases artifacts associated with shaking the wire from -14% to -3%. A balancing consideration is that thin encapsulation layers reduce the mechanical load on the bladder and the foreign body response. Results described in the following use a thickness of 500 pm. Finally, corona treatment of the connection area between the carbon black doped silicone elastomer and copper / polyimide (Cu / PI) electrodes ensures robust adhesion and long- term operation stability. FIG. 8(C) shows the results of cyclic bending tests to verify the longterm operation. Without corona treatment, the connection area between the carbon black doped silicone elastomer and Cu / PI electrodes breaks after 45 cycles. With corona treatment, the connection area persists even beyond 25,000 cycles. FIG. 9 shows the bending cyclic test of strain gauge systems with various types of interconnecting wire. Similar cyclic testing with different types of wires indicates that helical coils of stainless steel offer the best performance, as shown in FIG. 9.

[0119] FIG. 10 shows a benchtop setup for comprehensive testing of the strain gauge and connecting wire using a silicone (Ecoflex 00-50; 260 kPa) bladder mimic for a rat model (ellipsoid, 4.5 mm * 7.5 mm; 300 pm thickness) immersed in phosphate-buffered saline (PBS) solution at 37 °C. FIG. 11(A) and (B) highlight the relative change in resistance as a function of the volume of saline injected into the bladder at three different rates. FIG. 11(C) shows the results of cyclic testing using this setup for over 100 h.

[0120] The helical coil wire serves as a connection to the base station, which includes a printed circuit board (PCB), lithium-ion battery (60 mAh), and electronic components for measurement and digitalization of the resistance of the strain gauge and for wireless data transmission. Layers of parylene, marine epoxy and poly(dimethylsiloxane) (PDMS) encapsulate the base station to prevent penetration of biofluids and to establish a mechanically soft interface to surrounding tissues.

[0121] FIGS. 12 and 13 summarize the processes for fabricating the system. Specifically, FIG. 12 shows an exemplary process for fabricating the strain gauge according to certain embodiments of the present invention, where (A) shows preparation of a glass substrate; (B) shows attachment of a PVA film; (C) shows spin-coating of a silicone elastomer; (D) shows attachment of the Cu / PI electrode; (E) shows attachment of the PI mask; (F) shows screenprinting of a carbon black doped silicone elastomer; (G) shows removal of the PI mask. (H) shows corona treatment of the carbon black doped silicone elastomer and Cu / PI electrode; (I) shows attachment of a silicone elastomer mask on the Cu / PI electrode; (J) shows spin-coating of a silicone elastomer and removal of the PDMS mask; (K) shows laser cutting of the strain gauge outline; (L) shows soldering of a helical coil wire to the Cu / PI electrode; (M) shows coverage of silicone elastomer on the solder joint to the wire; (N) shows dissolution of the PVA film with DI water; and (O) shows a completed strain gauge. FIG. 13 shows an exemplary process for fabricating the base station according to certain embodiments of the present invention, where (A) shows preparation of a PCB with a Au / Cu electrode; (B) shows soldering of circuit components; (C) shows parylene coating of the PCB; (D) shows soldering of the battery; (E) shows soldering of the helical coil wire; (F) shows covering the soldered parts with marine epoxy; (G) shows PDMS dip coating; and (H) shows silicone elastomer encapsulation with a 3D-printed mold.

[0122] Benchtop Validation in an Artificial Human Bladder Model. FIG. 14 shows the benchtop tests and FEM simulation results for monitoring of a human bladder model at three time points after a partial cystectomy, where (A) shows schematic illustrations of the recovery process with a scaffold implanted after a partial cystectomy; (B) shows the strain-stress curves of model materials for a normal bladder, a regenerating bladder on a scaffold, and a scaffold; (C-E) show strain distributions calculated from FEM simulations for three models after partial cystectomy and scaffold implantation; and (F-K) show the benchtop setups and strain changes for three models after partial cystectomy and scaffold implantation. FIG. 15 shows FEM simulation setups for three models after partial cystectomy and scaffold implantation, where (A) shows that the first model corresponds to the case after suturing the scaffold to the upper part of the resected bladder, with normal bladder tissue in the lower part; (B) shows that the second model corresponds to partial regeneration of bladder tissue with the scaffold; and (C) shows that the third model corresponds to fully regenerated bladder tissue and fully bioresorbed scaffold. FIG. 16 shows a table of the FEM simulation results for human bladder model. Specifically, the ultimate goal of this system is to monitor the degree of bladder recovery after partial cystectomy in patients with bladder trauma or injury and after suturing the excised bladder area with a bioresorbable scaffold, as shown in FIG. 14(A). Benchtop studies using three models serve to verify the feasibility of this mode of use. The first model corresponds to the case after suturing the scaffold to the upper part of the resected bladder, with normal bladder tissue in the lower part. The second corresponds to partial regeneration of bladder tissue with the scaffold. The third corresponds to fully regenerated bladder tissue and complete bioresorption of the scaffold. The mimic human bladder for these studies (ellipsoid, 45 mm x 50 mm) uses silicone materials with moduli comparable to normal human bladder tissue (Ecoflex 00-50, 260 kPa), tissue undergoing regeneration with the scaffold (Dragon Skin 10, 330 kPa) and the scaffold itself (Dragon Skin 20, 400 kPa), as summarized in FIG. 14(B). Simulations based on the finite element method (FEM) include the bladder and the strain gauges, as shown in FIG. 15, for purposes of comparison to experimental results obtained with strain gauges on the upper (gauge A) and lower (gauge B) parts, for the case of injecting 300 mL of saline into the mimic bladders, as shown in the table of FIG. 16. In the first model as shown in FIG. 14(C), the lower normal bladder tissue expands more than the upper scaffold, as expected and as consistent with the responses of the strain gauges. In the second model as shown in FIG. 14(D), these differences decrease, again as expected. In the third model as shown in FIG. 14(E), the fully regenerated upper bladder tissue and the lower normal bladder tissue show similar behaviors. Benchtop experimental results appear in FIG. 14(F)-(H). Converting the measured changes in resistance to strain allows direct comparisons of experiment to simulation, as summarized in FIG. 14(I)-(K) and FIG. 8(A). In all cases, the findings are in good agreement, thereby establishing the use of the technologies introduced here for monitoring of bladder dynamics during recovery and regeneration after a cystectomy.

[0123] In Vivo Validation in a Rodent Model. Validation studies before testing in nonhuman primates involve rat models and surgical procedures for suturing the base station to the abdominal wall and the strain gauge to the bladder wall, as shown in FIG. 17(A)-(C) and FIG. 18. X-ray images at 2 and 4 weeks postsurgery indicate that these schemes ensure stable positioning, as shown in FIG. 19. As shown in FIG. 17(D) and (E), the resistance of the strain gauge gradually increases as urine fills the bladder, and then decreases sharply as voiding occurs. Even with small levels of noise caused by movements of the body or organs, the system accurately detects both large (-1,300 pL) and small (-500 pL) voiding events, as validated by using filter paper assays, as shown in FIG. 17(F) and (G) as well as FIGS. 20 and 21. FIG. 22 presents the results of bladder tissue dissections at 7 days (n = 3), 14 days (n = 3), and 30 days (n = 4) postsurgery. Gross histological examination at 7 days reveals a minor foreign body response (FBR), with inflammatory tissue surrounding the strain gauge. The FBR persists at 14 and 30 days but with no increase in severity. Histology using hematoxylin and eosin (H&E) staining confirms this inflammatory response, as shown in FIG. 22(A)-(C). FIG. 22(D)-(I) show the results of immunofluorescent staining with CD68 (macrophage marker) and MPO (myeloperoxidase, neutrophil marker) as key inflammatory markers. Initial quantification of CD68 proximal to the strain gauge at 7 days displays a positive rate of 15.6 ± 5.9%. This value decreases to 12.0 ± 2.0% at 14 days and then 6.8 ± 2.6% at 30 days. Initial quantification of MPO proximal to the strain gauge shows 5.9 ± 1.6% at 7 days, 2.6 ± 0.6% at 14 days, and 2.6 ± 1.4% at 30 days, as shown in FIG. 22(1), indicates that the FBR couples with an acute inflammatory response of both CD68 and MPO+at 7 to 14 days but slowly subsides over the 30- day period. Rodent Urine Measurements Using the Filter Paper Method. This method served to accurately and reproducibly quantify the volumes associated with urination events, as shown in FIG. 17(F) and FIG. 20, of an animal with an implanted monitoring system, placed in a transparent cage. A smartphone placed under the cage captures video of fdter wetting with urine. A calibration process used known amounts of DI water delivered to the filter paper, as shown in FIG. 21. The experiments involved continuous measurements for a period of 6 hours, as shown in FIG. 17(G), during which four large and small urinations occurred. The relative changes in resistance of the strain gauge correspond well with the volume of urine determined using this filter paper method.

[0124] UDS in a Nonhuman Primate Model. FIG. 23 shows schematic illustrations and UDS for nonhuman primate models, where (A) shows diagrams of the location of the implanted system and BLE wireless interface to a smartphone; (B) shows illustrations of the system components, the positions of the suture holes, and interface to the bladder; (C) shows an image of a strain gauge sutured to the surface of the bladder wall of a baboon with a normal bladder; (D-F) show C-arm fluoroscopy images of UDS 6-week post-surgery; (G) shows a plot of the relative change in resistance of the strain gauge as a function of the bladder pressure determined during a urodynamic study; and (H) shows a Bland-Altman plot, showing the difference between the pressure inferred from the strain gauge and that measured directly as a function of the latter. Specifically, FIG. 23(A) illustrates the placement and use of the system in a nonhuman primate model (baboon), with the strain gauge sutured to the bladder wall. Four suture holes on the base station provide fixation to the abdominal wall. FIG. 23(B) illustrates the arrangement. FIG. 23(C) shows a photograph of the gauge after implantation. UDS involves insertion of a Foley catheter into the urethra for injection of contrast solution into the bladder using an instillation pump. During this process, a physiological pressure transducer measures the bladder pressure and C-arm fluoroscopy captures images of the bladder and the strain gauge system. All urodynamics measurements use a consistent flow rate of approximately 10% of the bladder capacity, stopped at 20 cm H2O intravesical pressure to minimize the potential for perforation of the bladder. The original bladder capacity of 95 mL, as shown in FIG. 24, decreases to 60 mL (37% of original capacity) by 6 weeks postsurgery but recovers to 82 mL (85.2% of original capacity) by 10 weeks, as shown in FIGS. 25 and 26. This behavior likely follows from bladder instability during the postoperative recovery process rather than effects of the strain gauge implantation. For an animal with -50% partial cystectomy, the volume decreases from 142 mL to 41 mL (28% of original capacity) by 6 weeks postsurgery, as shown in FIG. 27 and 28. Observations reveal no signs of detrusor overactivity (DO) in either animal across all time points. Ultrasound inspection fails to detect any hydronephrosis or hydroureter, and images of the bladder show a normal morphology. The Doppler images with corresponding spectra as shown in FIGS. 24-28 show no deleterious effects on kidney parenchyma with the implementation of the strain gauge. FIG. 23(D)-(F) present C-arm fluoroscopic images for the animal with a normal bladder after injection of 20, 45, and 60 mL of contrast solution. The solution first fills the lower part of the bladder and then expands the entire bladder wall. Placement of the strain gauge on this lower part thus facilitates detection of even small amounts of urine. Calibration of the implanted strain gauge system involves measurements of changes in bladder pressure according to the volume of saline injected into the bladder through UDS, simultaneous with measurements of the relative change in resistance of the strain gauge. FIG. 23(G) presents a graph of the relative change in resistance of the strain gauge as a function of bladder pressure, showing a linear relationship as expected. The Bland-Altman plot in FIG. 23(H) indicates that the average difference and the SD of bladder pressure inferred from the strain gauge and measured directly are 8.1 * 109cmH20 and -1.2 cmHjO. Reproducible, longterm, and continuous measurements of pressure and volume changes provide aggregate data to the clinician in real-time, which can be used to determine immediate or longitudinal course of action when necessary.

[0125] Long-Term Strain Gauge Assessment in a Nonhuman Primate Model. FIG. 29 shows chronic studies in nonhuman primate models, where (A) shows the relative change in the resistance of the strain gauge for the entire time period of the study; (B) shows the relative change in the resistance of the strain gauge at 1 week postsurgery; (C) shows the relative change in the resistance of the strain gauge at 4 weeks postsurgery; (D) shows the relative change in the resistance of the strain gauge at 8 weeks postsurgery; (E) shows the number of voids in 12-h periods throughout the study; (F) shows the difference in resistance before and after voiding for an animal with a normal bladder; and (G) shows the difference in resistance before and after voiding for an animal with a partial cystectomy. Specifically, FIG. 29(A)-(D) summarize wireless measurements in the nonhuman primate model for the entire period of the study and for 1, 4, and 8 weeks postsurgery, respectively, as shown in FIGS. 30-40. The capacity of the battery in the base station (500 mAh) is the only factor that limits the duration of data collection. The relative change in resistance of the strain gauge slowly increases as urine gradually accumulates into the bladder, and then decreases rapidly as voiding occurs, with good signal-to-noise in the ambulatory animal. FIG. 29(B)-(D) show minor motion artifacts caused by movements of the body and organs. FIG. 29(E) shows the number of voids over periods of 12 h, inferred from these data. The data indicate that this number fluctuates during the first 6 weeks before subsequently stabilizing to a consistent value, consistent with expected times for full recovery. FIG. 41(A) and (B) highlight the times for filling and voiding of the bladder, respectively, as additional factors related to the degree of recovery. To compare the postoperative bladder activity between an animal with a normal bladder and one with a partial cystectomy (approximately 50%), FIG. 29(F) and (G) present differences in resistance before and after voiding for these two cases, respectively. The difference in resistance before and after voiding can be converted to the corresponding difference in bladder pressure based on the results of the urodynamics study, as shown in FIG. 23(G). Compared to the normal bladder, the bladder with partial cystectomy shows a higher difference in resistance (strain), and therefore bladder pressure, before and after voiding. This expected result follows from the reduction in overall bladder capacity and the necessity to expand to a greater degree than a normal bladder to hold the same amount of urine. FIG. 42 presents results of a confirming benchtop experiment. These findings, combined with the studies summarized in FIG. 14 strongly suggest applicability of this technology in monitoring recovery associated with a partial cystectomy.

[0126] In Vivo Biocompatibility in a Nonhuman Primate Model. Initial gross histological observations for the implanted strain gauge system at 10 weeks postsurgery confirm an expected FBR surrounding the base station, most prominently at the suture locations and the wire leading to the strain gauge. A modest FBR appears around the strain gauge integrated onto the bladder surface. Histological analysis reveals biocompatibility on H&E, trichrome, proinflammatory marker (Ml macrophage, CD86), and anti-inflammatory marker (M2 macrophage, CD206) inflammatory responses in bladder muscles near the strain gauge.

[0127] FIG. 43 shows studies of biocompatibility of the wireless bladder monitoring system, where images for (A) H&E, (B) tri chrome, and (C) M1 / M2 inflammatory responses of bladder muscle near a strain gauge sutured onto the outer surface of a normal bladder; images for (D) H&E, (E) trichrome, and (F) M1 / M2 inflammatory responses of bladder muscle near a strain gauge sutured onto the outer surface of a bladder after a partial cystectomy; and quantitative histological evaluation of (G) collagen, (H) Ml, and (I) M2 inflammatory responses forbladder muscle near strain gauges applied to a normal bladder and one with partial cystectomy. Specifically, FIG. 43(A)-(F) show the results for the normal bladder and the bladder with partial cystectomy, respectively. FIG. 43(G) indicates the collagen levels (a percentage of the collective total of collagen and muscle) to determine potential smooth muscle loss and excessive collagen formation after 10 weeks postsurgery. In the case of the smooth muscle area that is distal to the strain gauge (native), the collagen levels for the normal bladder and the bladder with partial cystectomy are 31.0 ± 6.0% and 33.0 ± 6.0%, respectively. In the case of the smooth muscle area proximal to the strain gauge, the collagen levels for the normal bladder and the bladder with partial cystectomy are 34.0 ± 9.0% and 35.0 ± 9.0%, respectively. Observations indicate no apparent differences in collagen levels in the muscle layer distal and proximal to the strain gauge (P < 0.5). The only apparent difference is the collagen level (56.0 ± 9.0%) in the smooth muscle area of the incised / reapproximated tissue in the baboon with partial cystectomy, as might be expected due to the cystectomy procedure and ensuing response. FIG. 43(H) and (I) show the results of immunofluorescence staining to monitor the presence of Ml and M2 macrophages, respectively, to statistically analyze the normal and partially cystectomized bladder. Native muscle areas of both baboons (normal bladder and bladder with partial cystectomy) have an Ml level of less than 1.1% and an M2 level of less than 0.5%. In contrast, the Ml levels in the muscle areas proximal to the strain gauge are 6 ± 1% and 5 ± 1% for the normal bladder and the bladder with partial cystectomy, respectively. The M2 levels for both cases are under 2%. The muscle area of the incised / re-approximated tissue in the baboon with partial cystectomy has an Ml level of 2.5 ± 0.6% and an M2 level of 0.3 ± 0.2%. Overall, Ml and M2 levels are relatively low in the muscle area proximal to the strain gauge for both baboons. These results demonstrate that the inflammatory response to the strain gauge is low.

[0128] Discussion

[0129] This study introduces a wireless, implantable system for remote and real-time bladder monitoring, with examples that integrate at single or multiple locations on the outer wall of the bladder. The data confirm negligible effect on natural bladder activity due to the thin geometries and low mechanical moduli of the strain gauges, available in both permanent and bioresorbable forms. The technology thus has characteristics for envisioned uses in diagnosing and managing long-term recovery of bladder function for patients who have undergone partial cystectomies as treatment for bladder-related dysfunction. The application of multiple gauges can provide data corroboration from unique bladder locales where bladder tissue homogeneity may be in question due to insult or during a regenerative phase. As a specific example, one strain gauge can be applied to monitor the degree of recovery of a normal bladder or a bladder that has undergone partial cystectomy. Alternatively, when suturing the scaffold for bladder regeneration after partial cystectomy, two strain gauges can be applied to the scaffold and the normal bladder respectively, allowing the degree of bladder recovery to be monitored by comparing normal and regenerated bladder tissue on the scaffold. Compared to traditional urodynamics, which only provide a glimpse into bladder function at a single point in time, this bladder monitoring system can inform physicians or patients of indications of bladder dysfunction or other side effects, in a remote fashion to enable early intervention. Experimental studies and computational modeling of bladder function in phantom constructs and in rat and nonhuman primate models that simulate injury / recovery verify the capabilities and highlight key engineering design features. Specific results validate the accuracy of the measurements in vivo and illustrate the ability to track bladder pressure for up to 8 weeks in nonhuman primate models with both normal and partially cystectomized bladders, without adverse effects or detrimental inflammatory responses. To avoid the need for a secondary surgery to remove the device after monitoring for a required period, the PCB, electronic components, and battery for data measurement and wireless data transmission must be converted to bioresorbable formats using previously reported schemes in bioresorbable electronics. The technologies introduced here may have broader applications as permanent or temporary implants to monitor recovery processes after invasive surgeries, for improved patient care and optimized procedures and rehabilitation strategies.

[0130] Materials and Methods

[0131] Fabrication of the Bladder Monitoring System. The fabrication process for the strain gauge involved attaching a polyvinyl-alcohol (PVA) film (50 pm, Ruimao) on a glass substrate (1 mm, Fisher brand) with PI tape (KPT-1 / 4, Bertech), spin-coating a silicone elastomer (Ecoflex 00-30, Smooth-On) at 2,000 rpm for 30 s, attaching a Cu / PI (9 pm / 12 pm) electrode, and annealing on a hot plate at 110 °C for 60 s. After screen-printing a carbon black (Vulcan XC 72R, Fuel Cell Store) doped silicone elastomer (22.5 wt%) through a PI mask (75 pm, American Durafilm) and curing on a hot plate at 110 °C for 5 h, the connection between the carbon black doped silicone elastomer and Cu / PI electrode was exposed to a corona discharge (1.5 kVa, MultiDyne M1000-261, 3DT). A mask of PDMS (thickness ~1 mm) covered the Cu / PI electrode in preparation for spin-coating a silicone elastomer at 2,000 rpm for 30 s and curing on a hot plate at 110 °C for 60 s. An ultraviolet laser prototyping system (LPKF Laser & Electronics) cut the outline of the strain gauge. Helical coil wires (SCL-0.7, Open Source Instruments) connected the strain gauge and base station by soldering to the Cu / PI electrode and the PCB, respectively. Casting a layer of silicone elastomer on the soldered regions and curing on a hot plate at 110 °C for 60 s formed an encapsulating structure. As a final step, immersion in deionized (DI) water dissolved the PVA film.

[0132] The base station used a PCB (PCBWay) populated with electronic components, including a lithium-ion battery (LP501218, 1578, DigiKey) and an interconnecting wire, using a low- temperature reflow process with soldering paste (TS391LT, Chip Quik) and heat gun (AOYUE Int866). The encapsulation process involved coating parylene, marine epoxy (1919324, Loctite), and PDMS (Sylgard 184, Dow Corning) three times. To prevent disconnection of the helical coil wire, a mold with a design that forms a conical-shaped encapsulation at the connection between the base station and the helical coil wire was used. After placing the base station in the mold, silicone elastomer was poured and annealed at 75 °C for 1 h. An ethylene oxide (EtO) sterilization process disinfected the entire system prior to implantation.

[0133] Fabrication of the Bioresorbable Strain Gauge. The process of synthesizing the POMaC involved mixing 4.08 g maleic anhydride (800408, Sigma-Aldrich), 12 g citric acid (251275, Sigma-Aldrich), and 15.22 g 1,8-octanediol (A1540214, Alfa Aesar) in a three-necked round-bottom flask, stirring under a nitrogen atmosphere, and annealing at an initial temperature of 160 °C. After the mixture melted and became a clear liquid solution, the temperature was set to 140 °C, and the mixture was continuously stirred for 2 h. Dissolving the resulting viscous prepolymer in 80 mL ethanol (07-678-007, Fisher Scientific) with 5 wt% photoinitiator (Irgacure 2959, Sigma- Aldrich) allowed for UV curing in a PTFE dish (S29215, Fisher Scientific) for 5 h. Mixing the PoMaC solution and W particles with 100 wt%. After mixing the W (GF40843245, Sigma- Aldrich) particles and POMaC solution at 100 wt% and screen-printing this composite on a film of POMaC through a PI mask, prepared this material for UV curing for 2 h. An ultraviolet laser prototyping system defines the outline of the POMaC film with the W doped POMaC. W wires (50 pm) inserted into the W doped POMaC served as an electrical interconnect. The top POMaC layer overlapped the bottom POMaC film with the W doped POMaC, with bonding by heating at 200 °C for 30 s.

[0134] Strain Gauge Implantation for the Rodent Model. Athymic nude rats (females weighing -200 g; 9 to 10 weeks of age; Charles River Laboratories) were anesthetized with inhalation of 2% isoflurane. A 3.0 cm midline incision was made, and the abdominal wall musculature was exposed with subsequent identification of the urinary bladder. The base station of the device was sutured to the internal abdominal wall at two points using a 4-0 polydioxanone suture. At this point, the bladder was filled to approximately 50% capacity with sterile saline, and the device’s wire was attached to the superficial portion of the bladder with a 7-0 polydioxanone suture at two points to stabilize the wire to the bladder. The strain gauge was then connected to the bladder at three points to the anterior portion of the bladder. Finally, the strain gauge was wrapped around the bladder and secured at a single point on the posterior portion of the bladder.

[0135] Rodent Tissue Processing. Bladder tissue was processed by dissecting the whole bladder and kidneys, fixed in 4% paraformaldehyde, and fully processed into paraffin wax molds, with tissue sections cut to 5 pm and placed on glass slides as previously described.

[0136] Rodent Histological Analysis and Immunostaining. H&E staining was completed as previously described. Tissue sections underwent further evaluation through immunohistochemistry staining. With the use of inflammatory markers CD68 and MPO with a concentration of 3 to 4 pg / mL (Abeam). Secondary antibodies ranged from 2 to 4 pg / mL (Invitrogen) with DAPI nuclei staining.

[0137] Quantitative Histological Evaluation for the Rodent Model. H&E tissue evaluation was performed with 10x magnification of the strain gauge implanted area. Immunofluorescent quantification involved assessing n = 5, 10x images of the implanted strain gauge area per animal and utilizing the same ImageJ function as previously described.

[0138] Strain Gauge Implantation and Urodynamics for the Nonhuman Primate Model. Anesthesia of baboons (Pcipio anubis,' female; 7 to 10 kg; 2 to 4 y in age) consisted of ketamine (10 mg / kg, IM) for sedation and propofol (2 to 4 mg / kg, IV to effect) for endotracheal intubation. Hydromorphine (0.1 mg / kg, IV), extended-release meloxicam (0.6 mg / kg, SQ, once), and cefazolin (25 mg / kg, IV) were given preoperatively for analgesia and antibiotic prophylaxis. General anesthesia was maintained using inhalational isoflurane (0.5 to 1%), with continuous cardiopulmonary monitoring performed by veterinary staff. Extended-release buprenorphine (0.2 mg / kg, SQ, once) was given for postoperative analgesia. A 10-French foley catheter was placed using a sterile technique. Following adequate anesthesia, the bladder was fully drained. After initial bladder and renal ultrasound imaging (Sonosite M Turbo FUJIFILM SonoSite), images of the kidney were taken in a transverse and longitudinal fashion in gray scale and with Doppler. For UDS, the foley catheter was connected to a physiological pressure transducer (SP844, MEMSCAP) and an instillation pump (11 Elite Syringe Pump-Harvard Apparatus). A 25 / 75 CystoConray contrast solution and sterile saline filled the bladder at a rate of 10% projected bladder capacity per minute. The foley catheter connected to a transducer and bridge amplifier (Model FE221; AD Instruments) recorded continuous tracings of the transvesical pressures using LabChart 7.3 Software (AD Instruments). C-arm fluoroscopy was used to obtain images intermittently throughout filling. Instillation of contrast solution was halted, and capacity was recorded when 20 cm H2O intravesical pressure was achieved. A postfill set of ultrasound images and observations were completed evaluating the bladder, ureter, and kidneys. Subsequently, instilled sterile saline fills the bladder to 50% urodynamic capacity, and then, the foley catheter was capped. The abdomen was prepared with Betadine scrub and alcohol washed and draped. A vertical midline incision was made sharply, and dissection was carried through the fascia to the bladder. The base station of strain gauge system was implanted into the internal abdominal wall utilizing the four suture holes fabricated on the base station device using four nonabsorbable monofilament sutures (4-0 prolene). The implantation process of the strain gauge involved suturing the elastic portion of the strain gauge to the superficial portion of the bladder at five connection points and suturing the wire to the bladder at two points to add extra support. One other baboon underwent an approximate 50% partial cystectomy using electrocautery, followed by the closure of the bladder with 4-0 Vicryl as described. To confirm the functionality of the strain gauge system, the inserted foley catheter infused the bladder with sterile saline prior to abdominal closure. The fascia was then closed in a running fashion using a 2-0 polydioxanone suture. 0.25% Bupivacaine was injected directly into the subcutaneous tissue. The abdominal wall was closed in layers, with Scarpa’s fascia closed using 4-0 interrupted Vicryl, and 4-0 Vicryl as a subcuticular running skin closure. The strain gauge system monitored the postoperative bladder function postsurgery. Prior to killing, baboons were sedated with a treatment of ketamine and xylazine (10 mg / kg and 1 mg / kg, IM, respectively) to perform ultrasound, urodynamic study, and C-arm fluoroscopy as previously described. Killing was completed using pentobarbital IV overdose. The strain gauge device was then removed, followed by bladder, kidney, and ureter explantation. All animal procedures were completed in accordance with guidelines set forth and approved by the University of Illinois at Chicago Animal Care Committee (ACC) and the Northwestern University Institutional Animal Care and Use Committee (IACUC). Nonhuman Primate Tissue Processing. Resected tissues were fixed in 4% paraformaldehyde for 24 h and then subjected to a tissue processing protocol utilizing an increasing percentage of ethanol solutions and finished with xylenes and paraffin washes. Following paraffin washes, paraffin wax molds were made, and samples were cut using an RM2125 RT microtome (Leica) to a 5 pm thickness and placed on glass slides.

[0139] Nonhuman Primate Tissue Histological Analysis and Immunostaining. Glass slides of sectioned tissue underwent Masson’s trichrome staining (Sigma-Aldrich) to identify trilayer bladder architecture, followed by H&E to identify any inflammatory infiltration. Additional tissue sections underwent immunofluorescence staining with the following inflammatory markers to determine an inflammatory response to the strain gauge; Ml (CD86), M2 (CD206) with concentrations ranging from 2 to 4 pg / mL (Abeam). Secondary antibodies ranged from 2 to 4 pg / mL (Invitrogen). Immunohistochemistry was completed with DAPI to visualize nuclei and completed with Vectashield (Vector Laboratories) to prolong fluorescence.

[0140] Nonhuman Primate Tissue Quantitative Histological Analysis. Collagen and muscle levels were determined through microscopic imaging with a Nikon Eclipse 50i Microscope (Nikon Inc.) equipped with Spot Advanced Imaging Software (Diagnostic Instruments). Images were taken at 10* magnification with n = 10 images per animal of the respective tissue area (native, proximal to strain gauge, incised / re-approximated tissue) of each animal. Collagen and muscle percentages were evaluated utilizing (Adobe Systems Inc.). To amplify the difference between collagen (blue) and muscle (red) pixels, the magenta levels were increased twofold and cyan in the red / magenta spectra were reduced twofold. The histogram tool was then adjusted to 115% fuzziness and channels of red and blue pixels were selected individually per image. The collagen and muscle ratio were then calculated from these values. Inflammatory cell quantification was performed by evaluating n = 5, 10* images per appropriate tissue area and then manually counting positively stained inflammatory cells (through immunofluorescence methods) by utilizing the ImageJ cell counter plugin function (NIH). Total cell counts were performed by also using Imagel software by adjusting the images to binary mode and then separating cells using the watershed function. The total cell count was then automatically counted with the analysis particle function.

[0141] FEM Simulations. The commercial software ABAQUS was used for FEM simulation of the strains during the expansion of the bladder following cystectomy, during recovery, and after complete recovery. The simulation involved two strain gauges attached to a hollow ellipsoid with eight-node 3D solid elements (C3D8RH). Refined mesh ensured accuracy, especially in the regions around the strain gauges. With the hydraulic fluid cavity, FEM simulation captured the process of fluid injection inside the bladder with a fluid density of 1,000 kg / m3and bulk modulus of 2 GPa. With a zero predefined temperature field, the relative volume change due to thermal expansion was 3 aAT, where a was the thermal expansion coefficient and AT was the temperature change. Temperature expansion simulated the volume change. AT was a virtual temperature change with no unit, so it just reflected the volume change. To realize a five times fluid volume increase in experiments (50 mb to 300 mL), the settings of a and AT were 1 and 5 / 3, respectively. All materials use the Mooney-Rivlin hyperelastic model with a hardening coefficient of 0.25 and D I = 0. The initial modulus of Ecoflex 00-50 (bladder), Ecoflex 00-30 (strain gauge), Dragon skin 10 (bladder undergoing the regeneration on the scaffold), and Dragon skin 20 (scaffold) was 260 kPa, 160 kPa, 330 kPa, and 400 kPa, respectively.

[0142] In sum, the wireless, implantable bioelectronic system for monitoring urinary bladder function utilizes sensors (such as super soft, ultrathin, stretchable strain gauges) to measure strain. As the bladder fills, it expands, and the fuller the bladder becomes, the more it stretches, where the stretching pulls on the device to signal strain. Likewise, when the bladder empties, it contracts, which then relieves strain. The strain gauge may gently wrap the outside surface of the bladder, without imposing any mechanical constraints on the natural filling and voiding behaviors.

[0143] As described, in small animal studies, the system successfully delivered real-time measurements of bladder filling and emptying for 30 days. Then, in a study using non-human primates, the system successfully delivered information for eight weeks. The inventors also demonstrated that the strain gauges may be sensitive enough to detect strain from very low volumes of urine.

[0144] While the system may be unnecessary for the average person, it could be a game-changer for people with paralysis, spina bifida, bladder cancer or end-stage bladder disease, where bladder function is often compromised, and bladder reconstruction surgery may be required. The system may also enable clinicians to monitor their patients remotely and continuously to make more informed and faster treatment decisions.

[0145] In addition, the bioelectronic system may be used as one component of a fully integrated system for bladder function restoration. Specifically, in a biodegradable synthetic, flexible “bladder patch,” seeded with the patient’s own stem cells, the citrate-based “patch,” which is referred to as a pro-regenerative scaffold (PRS), enables the surgeon to reconstruct or rebuild the bladder without the need to harvest intestinal tissue, the current clinical standard for this surgery. The “patch,” which expands and contracts with the native bladder tissue, supports the migration and growth of bladder cells. Then it slowly dissolves, leaving behind new bladder tissue. In certain embodiments, it is possible to integrate the bladder regeneration technology with the wireless bioelectronic system for bladder monitoring to restore bladder function and monitor the recovery process after surgery. The integrated system may be a smart regenerative system, which includes implantable pro-regenerative devices capable of probing their microenvironment, wirelessly reporting those findings outside the body (to the patient, caregiver or manufacturer) and enabling on-demand or programmed responses to change course and improve device performance or safety.

[0146] The foregoing description of the exemplary embodiments of the invention has been presented only for the purposes of illustration and description and is not intended to be exhaustive or to limit the invention to the precise forms disclosed. Many modifications and variations are possible in light of the above teaching.

[0147] The embodiments were chosen and described in order to explain the principles of the invention and their practical application so as to enable others skilled in the art to utilize the invention and various embodiments and with various modifications as are suited to the particular use contemplated. Alternative embodiments will become apparent to those skilled in the art to which the invention pertains without departing from its spirit and scope. Accordingly, the scope of the invention is defined by the appended claims rather than the foregoing description and the exemplary embodiments described therein.

[0148] Some references, which may include patents, patent applications, and various publications, are cited and discussed in the description of this invention. The citation and / or discussion of such references is provided merely to clarify the description of the invention and is not an admission that any such reference is “prior art” to the invention described herein. All references cited and discussed in this specification are incorporated herein by reference in their entireties and to the same extent as if each reference was individually incorporated by reference.

[0149] Reference List

[0150] [1], K.-E. Andersson, A. Amer, Urinary bladder contraction and relaxation: Physiology and pathophysiology. Physiol. Rev. 84, 935-986 (2004).

[0151] [2], N. Yoshimura, W. C. de Groat, Neural control of the lower urinary tract. Int. J. Urol. 4,

[0152] 111-125 (1997).

[0153] [3], C. J. Fowler, D. Griffiths, W. C. de Groat, The neural control of micturition. Nat. Rev.

[0154] Neurosci. 9, 453-466 (2008).

[0155] [4], J. M. Holzbeierlein et al., Partial cystectomy: A contemporary review of the memorial

[0156] Sloan Kettering cancer center experience and recommendations for patient selection. J. Urol. 172, 878-881 (2004).

[0157] [5], B. K. Hollenbeck, D. A. Taub, R. L. Dunn, J. T. Wei, Quality of care: Partial cystectomy for bladder cancer-a case of inappropriate use? J. Urol. 174, 1050-1054 (2005).

[0158] [6], S. S. Chang et al., Treatment of non-metastatic muscle-invasive bladder cancer:

[0159] AUA / ASCO / ASTRO / SUO guideline. J. Urol. 198, 552-559 (2017).

[0160] [7], W. Kassouf et al., Partial cystectomy for muscle invasive urothelial carcinoma of the bladder: A contemporary review of the M. D. Anderson Cancer Center experience. J. Urol. 175, 2058-2062 (2006).

[0161] [8], B. Abelson et al., Ambulatory urodynamic monitoring: State of the art and future directions. Nat. Rev. Urol. 16, 291-301 (2019).

[0162] [9], R. A. Schmidt, Urodynamics simplified. Urology 37, 449-454 (1991).

[0163]

[0010] , M. N. Dakurah, C. Koo, W. Choi, Y.-H. Joung, Implantable bladder sensors: A methodological review. Int. Neurourol. J. 19, 133-141 (2015).

[0164]

[0011] , S. J. A. Majerus, S. L. Garverick, M. A. Suster, P. C. Fletter, M. S. Damaser, Wireless, ultra-low-power implantable sensor for chronic bladder pressure monitoring. ACM J. Emerg. Technol. Comput. Syst. 8, 11 (2012).

[0165]

[0012] , S. J. A. Majerus et al., Suburothelial bladder contraction detection with implanted pressure sensor. PLoS One 12, e0168375 (2017).

[0166]

[0013] , B. T. Frainey et al., First in human subjects testing of the uromonitor: A catheter-free wireless ambulatory bladder pressure monitor. J. Urol. 210, 186-195 (2023).

[0167]

[0014] , Q. Wang, H.-B. Wang, H. Xu, W. Zhou, G.-Z. Liu, Noninvasive urination-desire sensing method based on bladder bioimpedance spectrum analysis. J. Med. Biol. Eng. 36, 191— 196 (2016).

[0168]

[0015] , L. Zhang et al., A conformable phased-array ultrasound patch for bladder volume monitoring. Nat. Electron. 7, 77-90 (2024).

[0016] , D. Mickle et al., A wireless closed-loop system for optogenetic peripheral neuromodulation. Nature 565, 361-365 (2019).

[0169]

[0017] , A. Gutierrez, E. Meng, Low-cost carbon thick-fdm strain sensors for implantable applications. J. Micromech. Microeng. 20, 095028 (2010).

[0170]

[0018] , N. Lu, C. Lu, S. Yang, J. Rogers, Highly sensitive skin-mountable strain gauges based entirely on elastomers. Adv. Funct. Mater. 22, 4044-4050 (2012).

[0171]

[0019] , M. Montgomery et al., Method for the fabrication of elastomeric polyester scaffolds for tissue engineering and minimally invasive delivery. ACS Biomater. Sci. Eng. 4, 3691- 3703 (2018).

[0172]

[0020] , B. L. Turner et al., Biodegradable elastomeric circuit boards from citric acid-based polyesters. NPJ Flex. Electron. 7, 25 (2023).

[0173]

[0021] , Y. Wu et al., A sewing approach to the fabrication of eco / bioresorbable electronics. Small

[0174] 19, 2305017 (2023).

[0175]

[0022] , C. Fernades, I. Taurino, Biodegradable molybdenum (Mo) and tungsten (W) devices: One step closer towards fully-transient biomedical implants. Sensors 22, 3062 (2022).

[0176]

[0023] , S. Roccabianca, T. R. Bush, Understanding the mechanics of the bladder through experiments and theoretical models: Where we started and where we are heading. Technology 4, 30-41 (2016).

[0177]

[0024] , J. Yang, A. R. Webb, G. A. Ameer, Novel citric acid-based biodegradable elastomers for tissue engineering. Adv. Mater. 16, 511-516 (2004).

[0178]

[0025] , K. Sharma et al., A nonhuman primate model for urinary bladder regeneration using autologous sources of bone marrow-derived mesenchymal stem cells. Stem Cells 29, 241-250 (2011).

[0179]

[0026] , K. Sharma et al., Cotransplantation with specific populations of spina bifida bone marrow stem / progenitor cells enhances urinary bladder regeneration. Proc. Natl. Acad. Sci.

[0180] U.S.A. 110, 4003-4008 (2013).

[0181]

[0027] , M. I. Bury et al., The effects of bone marrow stem and progenitor cell seeding on urinary bladder tissue regeneration. Sci. Rep. 11, 2322 (2021).

[0182]

[0028] , M. I. Bury et al., Multipotent bone marrow cell-seeded polymeric composites drive longterm, definitive urinary bladder tissue regeneration. Proc. Natl. Acad. Sci. U.S.A. Nexus 3, page 038 (2024), https: / / doi.org / 10.1093 / pnasnexus / pgae038.

Claims

CLAIMSWhat is claimed is:

1. A wireless, implantable bioelectronic system for monitoring urinary bladder function of a living subject, comprising: a strain gauge being soft and stretchable, configured to be implanted on an outer wall of a bladder of the living subject for monitoring strain of the bladder; a helical coil wire connected to the strain gauge; and a wireless base station electrically connected to the strain gauge through the helical coil wire, configured to receive information of the strain of the bladder from the strain gauge and to transmit the information wirelessly to an external device.

2. The bioelectronic system of claim 1, wherein the strain gauge is a permanent gauge configured to be permanently implanted on the bladder wall for chronic monitoring.

3. The bioelectronic system of claim 1, wherein the strain gauge is a temporary gauge formed by bioresorbable materials.

4. The bioelectronic system of claim 3, wherein the bioresorbable materials comprise poly(octamethylenemaleate (anhydride) citrate) (POMaC) and tungsten (W) particles.

5. The bioelectronic system of claim 1, wherein the strain gauge comprises: a silicone elastomer; one or more electrodes attached to and cured on the silicone elastomer, wherein the helical coil wire is soldered on the one or more electrodes; and an encapsulating structure encapsulated outside the one or more electrodes and the helical coil wire.

6. The bioelectronic system of claim 5, wherein the silicone elastomer has a sensing region containing particles of conducting carbon, and a cross-linking density of the silicone elastomer is lower than a cross-linking density of the bladder.

7. The bioelectronic system of claim 5, wherein the silicone elastomer is a carbon black doped silicone elastomer, and the electrode is a copper / polyimide (Cu / PI) electrode.

8. The bioelectronic system of claim 1, wherein the wireless base station comprises: a printed circuit board (PCB); electronic components disposed on the PCB, comprising: a strain measuring component connected to the helical coil wire, configured to measure and digitalize a resistance of the strain gauge to obtain the information of the strain; and a wireless data transmission component, configured to transmit the information wirelessly to the external device under a wireless protocol; a battery disposed on the PCB, configured to provide power to the electronic components; and an encapsulation layer coated on the PCB and encapsulating the electronic components and the battery.

9. The bioelectronic system of claim 8, wherein the wireless base station is configured to be fixed to an internal abdominal wall of the living subject.

10. The bioelectronic system of claim 8, wherein the wireless protocol is a Bluetooth protocol.

11. A method of monitoring bladder strain information of a living subject, comprising: implanting the wireless, implantable bioelectronic system of claim 1 on the bladder of the living subject; and obtaining the bladder strain information from the wireless, implantable bioelectronic system.

12. The method of claim 11, wherein the implanting the wireless, implantable bioelectronic system comprises:fixing the wireless base station to an abdominal wall of the living subject; and implanting the strain gauge on the bladder wall of the bladder.

13. The method of claim 12, wherein the implanting the strain gauge on the bladder wall of the bladder comprises: attaching the helical coil wire to a superficial portion of the bladder; connecting the strain gauge to the bladder at three points to an anterior portion of the bladder; and wrapping the strain gauge around the bladder, and securing the strain gauge at a single point on a posterior portion of the bladder.

14. A method of monitoring bladder recovery of a living subject, comprising: implanting two bioelectronic systems on the bladder of the living subject, wherein each of the two bioelectronic systems is the wireless, implantable bioelectronic system of claim 1, one of the two bioelectronic systems is implanted in a scaffold area of the bladder, and the other of the two bioelectronic systems is implanted in a normal area; monitoring bladder recovery by comparing the information of the strains of the bladder received from the two bioelectronic system, wherein the bladder recovery is determined based on a difference between the strains of the bladder received from the two bioelectronic system; and in response to determining the difference between the strains of the bladder received from the two bioelectronic system being smaller than a threshold, determining a bladder tissue in the scaffold area to be fully regenerated.

15. The method of claim 13, wherein the two bioelectronic systems are implanted following a partial bladder cystectomy of the bladder.

16. A strain gauge of a wireless, implantable bioelectronic system for monitoring urinary bladder function of a living subject, comprising: a silicone elastomer; one or more electrodes attached to and cured on the silicone elastomer, whereinthe helical coil wire is soldered on the one or more electrodes; and an encapsulating structure outside the one or more electrodes and the helical coil wire.

17. The strain gauge of claim 16, being a permanent gauge configured to be permanently implanted on the bladder wall for chronic monitoring.

18. The strain gauge of claim 16, being a temporary gauge formed by bioresorbable materials comprising poly(octamethylenemaleate (anhydride) citrate) (POMaC) and tungsten (W) particles.

19. The strain gauge of claim 16, wherein the silicone elastomer has a sensing region containing particles of conducting carbon, and a cross-linking density of the silicone elastomer is lower than a cross-linking density of the bladder.

20. The strain gauge of claim 16, wherein the silicone elastomer is a carbon black doped silicone elastomer, and the electrode is a copper / polyimide (Cu / PI) electrode.

21. A method of fabricating a strain gauge of a wireless, implantable bioelectronic system for monitoring urinary bladder function of a living subject, comprising: attaching a polyvinyl-alcohol (PVA) film on a glass substrate; forming a silicone elastomer on the PVA film; attaching an electrode to the silicone elastomer; soldering the helical coil wire on the electrode; forming an encapsulating structure outside the electrode and the helical coil wire; cutting an outline of the silicone elastomer; and immersing the structure in deionized (DI) water to dissolve the PVA film.

22. The method of claim 21, wherein the silicone elastomer is a carbon black doped silicone elastomer, and the forming the silicone elastomer comprises: screen-printing the carbon black doped silicon elastomer through a polyimide (PI)mask; and curing the carbon black doped silicon elastomer on a hot plate.

23. The method of claim 22, further comprising: exposing a connection between the carbon black doped silicon elastomer and the electrode to a corona discharge.

24. The method of claim 21, wherein the silicone elastomer is formed by bioresorbable materials comprising poly(octamethylenemaleate (anhydride) citrate) (POMaC) and tungsten (W) particles.

25. The method of claim 24, wherein the forming the silicone elastomer comprises: obtaining a POMaC solution; mixing the POMaC solution and the W particles to form a POMaC-W composite; screen-printing the POMaC-W composite on a bottom POMaC film to form W- doped POMaC area; performing ultraviolet (UV) curing on the W-doped POMaC area; disposing a top POMaC film on the bottom POMaC film to overlap with the W- doped POMaC area; and bonding the top POMaC film and the bottom POMaC film by heating to form the silicone elastomer.

26. A method of fabricating a wireless, implantable bioelectronic system for monitoring urinary bladder function of a living subject, comprising: fabricating the strain gauge of claim 16, wherein the strain gauge is soft and stretchable, and is configured to be implanted on an outer wall of a bladder of the living subject for monitoring strain of the bladder; connecting a helical coil wire to the strain gauge; and electrically connecting a wireless base station to the strain gauge through the helical coil wire, wherein the wireless base station is configured to receive information of the strain of the bladder from the strain gauge and to transmit the information wirelesslyto an external device.

27. A wireless, implantable bioelectronic system for monitoring urinary bladder function of a living subject, being fabricated by the method of claim 27.

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