Electrical stimulation systems and methods for functional rehabilitation and treatment of sexual disorders

Abstract

An implantable stimulation system having a stimulation unit coupled to a programmable controller, a stimulation circuit, and an array of electrodes disposed on a pair of flexible paddles is provided for selectively stimulating at least one pelvic (e.g., cavernous) nerve. The programmable controller is preprogrammed to activate an excitation electrode routine that selectively scans the electrode array with a sequence of directional current flow and optimizes electrode selection for use in stimulating the nerve. The implantable stimulation system can be programmed to activate a first stimulation pulse sequence for inducing a rapid erectile response corresponding to a first mode, a second nerve function restoration stimulation mode for restoring nerve conduction in the cavernous nerve, a third penile function restoration mode for reducing penile fibrosis, and / or a fourth bladder nerve function restoration mode for restoring nerve conduction in nerves controlling the lower urinary tract.

Description

[Technical field]

[0001] (CROSS REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Patent Application No. 17 / 450,392, filed October 8, 2021, U.S. Patent Application No. 17 / 174,033, filed February 11, 2021 (now U.S. Patent No. 11,141,590), and U.S. Patent Application No. 17 / 174,021, filed February 11, 2021 (now U.S. Patent No. 11,141,589), the contents of each of which are incorporated by reference in their entirety herein.

[0002] FIELD OF THEINVENTION The present disclosure relates to improved implantable electrical stimulation systems and methods for treating and preventing sexual disorders such as erectile dysfunction, erectile dysfunction following prostatectomy surgery, and erectile dysfunction associated with spinal cord injury. The systems of the present invention may also be used to restore function to the cavernous nerve, reduce penile fibrosis, or treat urinary incontinence. [Background technology]

[0003] Sexual disorders (e.g., sexual dysfunction, sexual abnormality) are complications experienced by an individual male or female or couple during any phase of normal sexual activity, including erection, physical pleasure, desire, preference, arousal, or orgasm. Sexual dysfunction generally has a significant impact on the quality of life of an individual. The most widely recognized sexual disorders are erectile dysfunction (ED) and female sexual arousal disorder (FSAD).

[0004] Penile erection is a coordinated neurocardiovascular response. See Dean RC and Lue TF, Physiology of penile erection and pathophysiology of erectile dysfunction, Urol Clin North Am. 2005 Nov;32(4):379-95. In the flaccid state, the penile smooth muscle is tonically contracted, allowing only a small amount of blood flow for trophic purposes. Penile erection occurs when sexual stimulation triggers the release of neurotransmitters (mainly nitric oxide) from the cavernous nerve endings. The neurotransmitters cause relaxation of the smooth muscle cells in the cavernous arterioles and sinuses, resulting in increased blood flow into the penis. This causes the cavernous sinuses to fill with blood and expand against the tunica albuginea, partially occluding the venous outflow, thus resulting in an erection.

[0005] ED is a multicause disease with diversified etiology and may be psychogenic, vascular, hormonal, or neurogenic. However, studies indicate that neurogenic and vascular causes are the most widely accepted. In general, the main mechanisms involved in ED are a breakdown in neuronal response (e.g., prostatectomy, cystectomy, abdominoperineal resection, spinal cord injury, or diabetes) or an increase in tone and / or contraction of smooth muscle in the corpus cavernosum and penile arteries (e.g., hypertension, atherosclerosis, and diabetes). See Sadeghi-Nejad H., Penileprosthesis surgery: a review of prosthetic devices and associated complications, Sex Med. 2007 Mar;4(2):296-309.

[0006] Prostatectomy is known to cause serious ED. Generally, this essential surgical procedure for the treatment of prostate cancer often leads to ED due to the inevitable disruption of nerve pathways for erectile function. These endometrial nerves are located around the prostate and can be damaged during surgery. Currently, surgeons are trying to perform nerve-sparing surgery. However, in a real scenario, a surprising 70% of patients who undergo prostatectomy will develop ED. See Penson DF, McLerran D, Feng Z, Li L, Albertsen PC, Gilliland FD, Hamilton A, Hoffman RM, Stephenson RA, Potosky AL, Stanford JL., 5-year urinary and sexual outcomes after radical prostatectomy: results from the Prostate Cancer Outcomes Study, J Urol. 2008 May;179(5 Suppl):S40-4.

[0007] Pharmacological treatments are currently available for ED. These drugs (e.g., sildenafil, Viagra®, tadalafil, Cialis® or vardenafil, Levitra®) are efficient for the majority of ED patients. However, they show low efficacy for ED resulting from prostatectomy or other causes associated with breakdown in neuronal response. Such drugs act by enhancing the action of the neurotransmitter nitric oxide by inhibiting the enzyme phosphodiesterase type 5 (PDE-5). See Rotella DP., Phosphodiesterase 5 inhibitors: current status and potential applications, Nat Rev Drug Discov. 2002 Sep;1(9):674-82. PDE-5 is an enzyme involved in breaking down cGMP, an intracellular second messenger generated by NO stimulation. cGMP is involved in the regulation of several protein-dependent kinases, which relax smooth muscle cells and promote erection. Thus, patients with disruption of erectile neural responses do not respond well to such drug therapy. One alternative for these patients is intrapenile injection of vasodilators, which produce an erection directly, independent of neural pathways.See Leungwattanakij S, Flynn V Jr, Hellstrom WJ, Intracavernosal injection and intraurethral therapy for erectile dysfunction, Urol Clin North Am. 2001 May;28(2):343-54 and Harding LM, Adeniyi A, Everson R, Barker S, Ralph DJ, Baranowski AP, Comparison of a needle-free high-pressure injection system with needle- tipped injection of intracavernosal alprostadil for erectile dysfunction, Int J Impot Res. 2002 Dec;14(6):498-501. Alprostadil (prostaglandin E1, PGE1) is the most common vasodilator used for ED. See Harding and Eardley I, Donatucci C, Corbin J, El-Meliegy A, Hatzimouratidis K, McVary K, Munarriz R, Lee SW, Pharmacotherapy for erectile dysfunction, J Sex Med. 2010 Jan;7(1 Pt 2):524-40. Vasodilators can be injected into the corpus cavernosum with a needle and are effective in over 80% of patients. See Harding. Common side effects of intrapenile injections are penile pain, bleeding, hematoma, priapism, and penile fibrosis, which can lead to permanent ED. See Leungwattanakij.

[0008] Another option for these patients is the penile implant, which consists of a pair of malleable or inflatable rods surgically implanted within the erectile chambers of the penis. See Sadeghi-Nejad. Different types of penile prostheses exist (rigid, semi-rigid, or inflatable), all of which usually require irreversible and destructive surgery with associated risks of intra- and post-operative complications. Such prostheses frequently require revision surgery. Nevertheless, prosthesis implantation is a common procedure due to the lack of better treatment options. Thus, there is a clear need for better therapeutic strategies for the treatment of ED resulting from the failure of neural pathways, such as post-prostatectomy ED, that offer a painless, safer, easier, non-traumatic, and more effective alternative.

[0009] Numerous studies have shown that cavernous nerve stimulation can induce and maintain erections in animals and in men. See Lue TF, Schmidt RA, Tanagho EA, Electrostimulation and penile erection, Urol Int. 1985;40(1):60-4; Shafik A, Shafik AA, Shafik IA, El Sibai 0., Percutaneous perinea! electrostimulation induces erection: clinical significance in patients with spinal cord injury and erectile dysfunction, J Spinal Cord Med. 2008;31(1):40-3; and Shafik A, el-Sibai 0, Shafik AA, Magnetic stimulation of the cavernous nerve for the treatment of erectile dysfunction in humans, Int J Impot Res. 2000 Jun;12(3):137-41. Since then, electrical nerve stimulation for erectile response has been considered an option for patients undergoing prostatectomy. However, a barrier for the development of such technology is the complex anatomy of the human cavernous nerve. See Klotz L., Intraoperative cavernous nerve stimulation during nerve sparing radical prostatectomy: how and when? Curr Opin Urol. 2000 May;10(3):239-43 and Ponnusamy K, Sorger JM, Mohr C., Nerve mapping for prostatectomies: novel technologies under development, J Endourol. 2012 Jul;26(7):769-77. Locating the optimal site for electrical nerve stimulation is difficult because the human cavernous nerve travels through complex anastomoses from the pelvic plexus to the penis.Furthermore, there is considerable anatomical variability in the location of the cavernous nerve. The pelvic plexus is a transparent veil with microscopic nerves, and the cavernous nerve is not uniformly located in all individuals. Furthermore, each patient's anatomy, disease stage, and cancer location are unique. Collectively, these barriers make identification of cavernous nerve segments for selective stimulation extremely difficult.

[0010] In some previously known systems, the location and identification of the cavernous nerve is performed during the implantation surgery. For example, U.S. Patent No. 4,585,005 to Lue requires prior identification and isolation of the cavernous nerve. U.S. Patent No. 7,328,068 to Spinelli describes a method for stimulation of the penile nerve pathway that requires precise positioning of the implant to achieve optimal stimulation. In Spinelli, neurophysiological monitoring assessments can be used as a method to locate the optimal stimulation site prior to implantation. U.S. Patent No. 7,330,762 to Boveja discloses a system for electrical neurostimulation of the cavernous nerve that includes different types of electrodes, such as spiral electrodes, cuff electrodes, steroid-eluting electrodes, wrap-around electrodes, and hydrogel electrodes. Again, the Boveja system requires identification of the optimal site for stimulation prior to implantation. U.S. Patent No. 7,865,243 to Whitehurst describes a system and method for stimulation of the cavernous nerve. However, the anatomical identification of the pudendal nerve and / or other nerve pathways to be stimulated must be located prior to implantation.

[0011] Recently, significant progress has been made in achieving a practical nerve electrical stimulation system for the treatment of ED that allows for the location and identification of the cavernous nerve after implantation. For example, U.S. Patent Nos. 9,821,163 and 10,300,279 to Fraga da Silva et al., invented by the present inventors, describe a nerve electrical stimulation system in which electrodes are stimulated after implantation to experimentally determine a preferred electrode excitation configuration for achieving sexual arousal. Although the inventions described in those patents represent a significant advance in the use of nerve electrical stimulation to treat ED, it would be desirable to provide a method for reliably determining an electrode excitation configuration for generating an excitation in which the electrode excitation configuration can be determined by an automated process.

[0012] After bilateral nerve-sparing radical prostatectomy, some patients, especially younger patients without a history of ED or associated risk factors, may recover from erectile dysfunction.However, even if an individual regains erectile function, it is typically for a long time, which may extend to several years.During the recovery period, permanent damage to the penis occurs, some of which may lead to permanent ED.

[0013] Recent advances in understanding the pathophysiology of post-prostatectomy ED have stimulated discussion regarding the management of this condition and led to the emergence of the concept of restoration of penile function after prostatectomy. For example, Wang, R., Penile rehabilitation after radical prostatectomy: where do we stand and where are we going?, J Sex Med,2007,4(4 Pt 2):1085-97, Segal, RL et al., Current penile-rehabilitation strategies: Clinical evidence, Arab J Urol,2013. 11(3):230-6, Gandaglia, G., et al. al., Penile rehabilitation after radical prostatectomy: does it work?, Transl Androl Urol, 2015, 4(2): 110-23, Clavell-Hernandez, J. et al, Penile rehabilitation following prostate cancer treatment: review of current literature, Asian J Androl, 2015. 17(6): 916-22. The rationale for such treatment recognizes that the long-term inability to achieve an erection can lead to internal fibrosis, deterioration of penile structure, and progressive worsening of ED, leading to a permanent condition of ED.

[0014] As discussed in the aforementioned references, regular cycles of penile erection are essential for maintaining tissue oxygenation and penile function in healthy men. Indeed, physiological nocturnal penile tumescence during sleep and spontaneous erection play an important role in maintaining organ oxygenation and function. In contrast, long-term inability to achieve erection leads to chronic penile hypoxia and resulting profibrotic cytokine production, as described in Gandaglia;Muller, A., et al., The effect of hyperbaric oxygen therapy on erectile function recovery in a rat cavernous nerve injury model, J Sex Med, 2008. 5(3): p.562-70. This unfavorable local intrapenile environment can lead to apoptosis and increased collagen production, altering cavernous structure. See, e.g., Gandaglia; Moreland, R.B., Is there a role of hypoxemia in penile fibrosis: a viewpoint presented to the Society for the Study of Impotence, Int J Impot Res, 1998. 10(2): p. 113-20.

[0015] As further discussed in the above references, penile function restoration is defined as the use of any medical intervention or combination of interventions at or after prostatectomy, with the goal of increasing penile blood flow, improving internal oxygenation, and avoiding or reducing fibrosis until the ability to achieve natural erectile function is restored. Penile function restoration treatment should preferably be applied until nerve regeneration is achieved, which may take 12-18 months, or even up to several years, after prostatectomy. Currently, the state of the art calls for oral PDE5 inhibitors, internal injection therapy (e.g., alprostadil), vacuum erection devices, or a combination of these treatments. See Mulhall, JP, et al., Standard operating procedure for the preservation of erectile function outcomes after radical prostatectomy, J Sex Med, 2013. 10(1):195-203 and Fode, M., et al., Penile rehabilitation after radical prostatectomy: what the evidence really says, BJU Int, 2013. 112(7):p.998-1008. Collectively, clinical trials using these approaches have reported little or no improvement. See Clavell-Hern and ez; Fode.

[0016] Another complication that may occur after prostatectomy or spinal cord injury is urinary incontinence due to damage to one or more nerves that control the lower urinary tract, namely the pelvic parasympathetic nerve, the hypogastric sympathetic nerve, and the pudendal nerve. Electrical stimulation may be used to treat neurogenic bladder dysfunction. The following techniques have been used: transrectal / transvaginal electrical stimulation, transepidermal electrical nerve stimulation (TENS), and sacral neuromodulation. Electrical pelvic floor stimulation (EPFS) may improve urinary incontinence. Early EPFS was performed by external stimulation devices such as anal and / or vaginal electrodes, but these devices are associated with several side effects, including leakage of electrical current from the device into the applied mucosa, which may result in pain during stimulation or damage to the mucosa.

[0017] The primary cause of post-prostatectomy urinary incontinence has been explained as resulting from sphincter dysfunction. Currently, pelvic floor muscle training (PFMT) is the most widely recommended non-invasive method to prevent urinary incontinence following radical prostatectomy. Nevertheless, it may take several months to regain continence, and some patients may have persistent incontinence despite continuing attempts to restore function. "Electrical stimulation of the pudendal nerve and its branches can produce direct and reflex responses of the urethra and pelvic floor striated muscles" (Yamanishi, T. et al., Pelvic floor electrical stimulation in the treatment of stress incontinence: an investigational study and a placebo controlled double-blind trial, The Journal of urology vol. 158,6 (1997):2127-31). Research has shown that low-intensity electrical stimulation of the pelvic floor can help promote nerve regeneration and thus improve urinary function following radical prostatectomy.Yamanishi, Tomonori et al., Randomized, placebo controlled study of electrical stimulation with pelvic floor muscle training for severe urinary incontinence after radical prostatectomy, The Journal of urology vol. 184,5 (2010):2007-12, Mariotti, Gianna et al., Early recovery of urinary continence after radical prostatectomy using early pelvic floor electrical stimulation and 63,2 (2004):264-7.

[0018] In light of the aforementioned shortcomings of previously known systems and methods, there is a need for systems and methods that can be used to systematically identify the location of the cavernous nerve during and / or after implantation and to determine optimal parameters for different modes of activation.Furthermore, there is a need for systems and methods that can be used to increase tissue oxygenation and maintain penile function after prostatectomy, thereby reducing fibrosis and regenerating the cavernous nerve.Furthermore, there is a need for systems and methods that can be used to treat other pelvic disorders, such as urinary incontinence. [Prior art documents] [Patent documents]

[0019] [Patent Document 1] U.S. Pat. No. 4,585,005 [Patent Document 2] U.S. Pat. No. 9,821,163 Summary of the Invention [Means for solving the problem]

[0020] The present disclosure provides neuro-electrical stimulation systems and methods for treating sexual disorders, including in patients who are unable to spontaneously obtain penile erection (e.g., erectile dysfunction (ED), including ED associated with a breakdown in neuronal responses, such as post-prostatectomy ED), and in patients suffering from Female Sexual Arousal Disorder (FSAD), where optimization of electrode excitation configurations and stimulation parameters can be achieved without extensive experimental testing.

[0021] An electrical stimulation system for the treatment of sexual disorders, such as ED, in a patient may include an implantable stimulation unit, an external patient controller, and an external physician controller, as described in U.S. Patent Nos. 9,821,163 and 10,300,279, which are incorporated by reference herein in their entireties. The implantable stimulation unit includes an array of electrodes disposed on an implantable paddle and a power supply, which may be rechargeable.

[0022] In accordance with the principles of the present invention, the programmable controller of the implantable stimulation unit is pre-programmed with routines for optimizing the selection of a subset of the array of excitation electrodes and stimulation parameters to be applied to generate a rapid erectile response, restore cavernous nerve transmission function after implantation, and / or reduce penile fibrosis. The pre-programmed routines may then be activated following the implantation process, even after tissue healing, to re-optimize the selection of the subset of excitation electrodes and / or adjust the stimulation parameters employed in either the first rapid response mode, the second nerve function restoration mode, or the third penile function restoration mode.

[0023] In a preferred embodiment, the implantable stimulation unit includes an array of electrodes disposed on a pair of flexible paddles sized and shaped to be implanted in the pelvic plexus to selectively stimulate at least one cavernous nerve. The array of electrodes on each of the pair of paddles is coupled to a programmable controller including a stimulation circuit, a non-volatile memory, and a microprocessor coupled to the stimulation circuit and the non-volatile memory. According to one aspect of the invention, the programmable controller is pre-programmed to initiate an excitation electrode routine that selectively scans the electrode array on the paddles with a series of directional current flows in at least two directions and in at least two regions to optimize electrode selection for use in stimulating the patient's cavernous nerve.

[0024] Upon completion of the electrode selection configuration process, the identity of a preferred subset of the array of electrodes ("excitation electrodes") is defined and stored in the non-volatile memory of the programmable controller. The stored electrode configuration is then employed with stimulation parameters optimized to stimulate one or more nerves of the pelvic plexus, e.g., at least one cavernous nerve, sufficiently to cause sexual arousal, e.g., erection. The stimulation regimen may consist of stimulation parameters including pulse duration, frequency, voltage, and current, which may be adjusted after implantation by an external physician controller and / or an external patient controller.

[0025] In a preferred embodiment, the programmable controller initiates a pre-programmed electrode configuration process that causes the stimulation circuit to selectively activate a first series of electrode pairs of the electrode array to generate a first current flow therebetween in a first direction to stimulate the cavernous nerve and elicit a first erectile response. The electrode configuration process then selectively activates a second series of electrode pairs of the electrode array to generate a second current flow therebetween in a second direction that is different from and may be oblique to the first direction to stimulate the cavernous nerve and elicit a second erectile response. The first and second erectile responses are then compared, for example, by a physician to select which of the first and second directional current flows provides the more preferred erectile response, thereby determining a preferred current flow direction, which may be stored in non-volatile memory for future stimulation. The programmed instructions may identify a preferred erectile response in response to input generated by a sensor system associated with the programmable controller or in response to input provided by an external patient controller or an external physician controller.

[0026] The programmable controller then causes the stimulation circuitry to selectively activate a subset of the electrode array to stimulate the cavernous nerve in at least a first and second region using the previously determined preferred current flow direction. Specifically, a first subset of the electrode array in the first region is stimulated to generate a first localized response, and a second subset of the electrode array in a second region different from the first region is stimulated to generate a second localized response. The first and second localized responses are compared to determine which response is more preferred, and their corresponding regions of the electrodes are selected as preferred excitation regions and stored in non-volatile memory for future stimulation.

[0027] The programmable controller then causes the stimulation circuitry to sequentially activate subsets of electrodes within the preferred excitation region using the previously determined preferred current flow direction to elicit a series of erectile responses, which are compared to determine which response is more preferred, and their corresponding subsets of electrodes are selected as preferred excitation electrodes and stored in non-volatile memory for future stimulation.

[0028] Once the preferred excitation region, including the preferred excitation electrodes with directional current flow, is determined, the programmable controller selectively activates the stimulation circuitry to define at least a first stimulation mode in which the applied electrical stimulation induces a rapid erectile response. Specifically designed, the programmable controller causes the stimulation circuitry to apply first and second stimulation regimens employing different stimulation parameters in sequence, thereby inducing first and second stimulation responses. The patient's physician or the patient then compares the first and second responses, determines which stimulation regimen produces a stronger and / or more rapid erectile response, and selects that stimulation regimen as the preferred first stimulation mode and stores it in the non-volatile memory. In a preferred embodiment, the system of the present invention may include an external controller that the patient may operate in an "on-demand" mode, for example, by pressing a button to activate the implantable stimulation unit and induce a rapid erectile response.

[0029] According to another aspect of the invention, the programmable controller may also determine a second nerve function recovery stimulation mode corresponding to a lower current intensity than the first stimulation mode. For example, the nerve function recovery stimulation mode may have a set of stimulation parameters that apply a current amplitude in the range of 0.1-2 mA with a pulse width of 0.01-1.0 ms at a frequency of 10-48 Hz, while the first stimulation mode may have a set of stimulation parameters that apply a current amplitude in the range of 0.5-25 mA with a pulse width of 0.1-1.0 ms at a frequency of 10-48 Hz. The nerve function recovery stimulation mode is designed to improve the transmission of neural activity along at least one cavernous nerve. The programmable controller may be programmed to automatically execute the nerve function recovery stimulation pulse sequence at one or more defined times, for example, immediately before the patient awakens, at least once a day.

[0030] According to another aspect of the present invention, the programmable controller may also provide a third penile function recovery stimulation mode corresponding to a higher current intensity than the second stimulation mode. For example, the penile function recovery stimulation mode may have a set of stimulation parameters that applies a current amplitude in the range of 0.5 to 25 mA with a pulse width of 0.1 to 1.0 milliseconds at a frequency of 10 to 48 Hz. The penile function recovery mode is designed to induce at least partial penile tumescence, increase tissue oxygenation, and reduce the risk of penile fibrosis. The programmable controller may be coupled to a sensor that monitors the degree of penile tumescence, and the programmed instructions may store the set of stimulation parameters that generates the highest degree of penile tumescence as the optimal set of stimulation parameters. The programmable controller may more preferably be programmed to automatically execute the penile function recovery stimulation pulse sequence at one or more defined times, for example, immediately before the patient awakens, at least once a day. Following prostatectomy, both the neural function restoration stimulation mode and the penile function restoration stimulation mode may be performed automatically and separately at least once per day.

[0031] Furthermore, in accordance with the principles of the present invention, the programmable controller may be programmed to reactivate the excitation electrode configuration process and optionally select the first, second, and / or third stimulation modes several weeks or months after the implantation procedure is completed. In this manner, the selection of the preferred excitation electrode and / or stimulation regimen may be reoptimized to address, for example, tissue encapsulation and take into account the healing response of the tissue surrounding the implantable stimulation unit. In addition, such reoptimization programming may enable the system of the present invention to capture improvements in neural transmission achieved by the neural function recovery stimulation mode, such as eliciting a rapid erectile response using a lower current intensity than that originally required after implantation. Such adjustments may be made under the control of the physician or patient. Alternatively, adjustments to the excitation electrode configuration and / or stimulation regimen of the first, second, and / or third stimulation modes may be made using at least one of machine learning or other forms of artificial intelligence.

[0032] The external patient controller may be configured to selectively activate the implantable stimulation unit in response to patient input, operate an excitation electrode configuration process, and / or refine the stimulation prescription plan employed in the first, second, and / or third stimulation modes, selectively activate the first stimulation mode on demand, and set parameters, e.g., activation time and duration for the functional recovery stimulation mode. The external physician controller is also configured to provide similar capabilities, including selectively activating the excitation electrode configuration process, and revising and / or reoptimizing the electrode configuration and stimulation prescription plan stored in non-volatile memory. The external physician controller preferably also provides the capability to interrogate the implantable stimulation unit and retrieve other operational data regarding the status and use of the implantable stimulation unit.

[0033] The implantable stimulation unit and the external patient controller preferably communicate wirelessly. Thus, the implantable stimulation unit may include a first transceiver and the external patient controller may include a second transceiver. The first and second transceivers may be IEEE 802.11 or Bluetooth® compatible. TM A communication scheme may be employed. The wireless communication between the first transceiver and the second transceiver may be encrypted. The external patient controller may be specifically designed for communication with the implantable stimulation unit or may comprise a smartphone, laptop, tablet, or smartwatch programmed to communicate with the implantable stimulation unit.

[0034] The implantable stimulation unit and the external physician controller also preferably communicate wirelessly, and the external physician controller may include a third transceiver. The first and third transceivers may be IEEE 802.11 or Bluetooth® compatible. TM A communication scheme may be employed and the wireless communication between the first transceiver and the third transceiver may be encrypted. The external physician controller may be specifically designed for communication with the implantable stimulation unit or may be a smartphone, laptop, tablet, or desktop computer programmed to communicate with the implantable stimulation unit.

[0035] The flexible paddles with the electrode array are preferably sized and shaped to conform to the anatomical shape of a portion of the pelvic plexus, and more preferably to be implanted laparoscopically. In one embodiment, each of the flexible paddles has a hemispherical shape that conforms to half of the pelvic plexus and provides bilateral stimulation. Each paddle includes an array of at least two rows and two columns of individually addressable electrodes. Each paddle may also include one or more features, such as suture holes or anchors, configured to hold the paddle in contact with the pelvic plexus following radical prostatectomy. The anchors may be, for example, sutures or biocompatible glue. Alternatively or in addition, each flexible paddle may include at least one opening designed to allow connective tissue growth into and / or through the paddle and anchor the paddle adjacent to the pelvic plexus.

[0036] Methods of implanting the implantable stimulation unit, programming the implantable stimulation unit and configuring preferred excitation electrodes, electrode areas, current direction, and stimulation regimens to induce rapid erectile responses, restore neural transmission, or reduce penile fibrosis, and methods of using the system are also provided herein. The implantable stimulation unit and flexible paddles can be sized and shaped for implantation using a robotic guided surgical system or laparoscopically.

[0037] According to another aspect of the invention, the system may be used to treat urinary incontinence, for example, by electrically stimulating one or more nerves of the lower urinary tract. Electrical stimulation of the pelvic floor may help promote nerve regeneration and thus improve urinary function following radical prostatectomy. In particular, low intensity stimulation may re-establish nerve function by promoting axonal regrowth and reconnection.

[0038] The programmable controller may cause the stimulation circuitry to activate a pair of electrodes of the array of electrodes to stimulate at least one nerve associated with control of the bladder sphincter, such as the pudendal nerve, the hypogastric sympathetic nerve, or the pelvic parasympathetic nerve, to promote nerve function recovery. The bladder nerve function recovery stimulation mode may have a set of stimulation parameters that apply a current amplitude in the range of 0.1-2 mA, a frequency in the range of 10-48 Hz, and a pulse width in the range of 0.01-1 milliseconds, and may be performed automatically for at least one hour per day following prostatectomy.

[0039] The flexible paddle may further include a second array of electrodes disposed on a second side opposite the first side. The programmable controller may cause the stimulation circuit to activate a pair of electrodes of the second array of electrodes to stimulate at least one nerve associated with control of the bladder sphincter.

[0040] A method of treating urinary incontinence using the system described above is also provided herein.For example, the method may include: implanting a flexible paddle having a first array of electrodes arranged on a first side and a second array of electrodes on a second side at a position adjacent to a pelvic plexus; coupling a programmable controller to the array of electrodes; and executing instructions programmed to cause a stimulation circuit stored in a memory to activate a pair of electrodes on the first and / or second array of electrodes to stimulate at least one nerve associated with the control of the bladder sphincter. [Brief description of the drawings]

[0041] These and other features, aspects, and advantages of the present disclosure will become apparent from the following description, appended claims, and the accompanying exemplary embodiments illustrated in the drawings briefly described below.

[0042] [Figure 1] FIG. 1 is a schematic diagram of an exemplary electrical stimulation system constructed in accordance with the principles of the present disclosure.

[0043] [Diagram 2] 2A and 2B are, respectively, a plan view of an exemplary flexible paddle suitable for use with the present invention and a plan view of the distal ends of two paddles positioned for positioning against a patient's pelvic plexus.

[0044] [Diagram 3] FIG. 3 is a plan view of an alternative embodiment of a flexible paddle suitable for use with the system of the present invention.

[0045] [Figure 4-1] Figures 4A and 4B are side cross-sectional and perspective views, respectively, of different electrode shapes for use in the flexible paddles of Figures 2 and 3, while Figures 4C-4E depict the charge distribution across the various electrode shapes depicted in Figures 4A and 4B. [Figure 4-2] Figures 4A and 4B are side cross-sectional and perspective views, respectively, of different electrode shapes for use in the flexible paddles of Figures 2 and 3, while Figures 4C-4E depict the charge distribution across the various electrode shapes depicted in Figures 4A and 4B.

[0046] [Diagram 5] FIG. 5 depicts a generalized block diagram of an exemplary programmable controller of the implantable stimulation unit of the stimulation system of FIG.

[0047] [Figure 6] FIG. 6 depicts a generalized block diagram of an exemplary external patient controller of the stimulation system of FIG.

[0048] [Figure 7] FIG. 7 is a block diagram of functional components of an exemplary software-based programming system configured to run on the external physician controller of the stimulation system of FIG.

[0049] [Figure 8]8A and 8B are perspective views with inset details showing placement of the flexible paddle of FIG. 2 positioned over the patient's prostate and pelvic plexus, respectively.

[0050] [Figure 9] 9A and 9B are plan views, respectively, showing alternative placement of the flexible paddle of the present invention relative to the patient's urethra.

[0051] [Figure 10] 10A-10C depict various directional current flows between adjacent electrode pairs disposed on the flexible paddle of FIG. 2A.

[0052] [Figure 11] 11A-11C depict illustrative regions within the electrode array of the flexible paddle of FIG. 2A.

[0053] [Figure 12] 12A-12C depict preferred electrode pair selections within various electrode regions according to the present invention.

[0054] [Figure 13] FIG. 13 depicts an exemplary method of defining preferred excitation electrodes and regions for use in electrical neurostimulation to obtain sexual arousal.

[0055] [Figure 14] FIG. 14 illustrates a method for intraoperative scanning of sequential, adjacent electrode pairs in accordance with the principles of the present invention.

[0056] [Figure 15] FIG. 15 is a flow chart illustrating steps of an exemplary method for configuring a subset of an array of electrodes for stimulation to induce optimal sexual arousal in accordance with the principles of the present invention.

[0057] [Figure 16]FIG. 16 is a flow chart illustrating steps of an exemplary method for determining an optimal location for implanting a flexible paddle in accordance with the principles of the present disclosure.

[0058] [Figure 17] FIG. 17 is a flow chart illustrating steps of an exemplary method for determining an optimal stimulation regimen for inducing an erection, a stimulation regimen for functional restoration of at least one cavernous nerve, and / or a stimulation regimen for penile function restoration to reduce penile fibrosis.

[0059] [Figure 18] FIG. 18 is a flow chart illustrating steps of an exemplary method for adjusting the optimal mode for functional recovery after a certain time interval after implantation.

[0060] [Figure 19] FIG. 19 is a schematic diagram of the local anatomy in the male pelvic region.

[0061] [Figure 20-1] 20A and 20B are cross-sectional side views of an exemplary flexible paddle.

[0062] [Figure 20-2] 20C and 20D are perspective views with inset details showing placement of the flexible paddles of FIGS. 20A and 20B positioned over the patient's pelvic plexus, respectively. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0063] The systems and methods described herein may be used to treat erectile dysfunction (ED), including ED associated with a breakdown in neuronal response (e.g., resulting from prostatectomy, cystectomy, abdominoperineal resection, spinal cord injury, and / or diabetes), and ED associated with increased tone and / or contractility of smooth muscle in the corpus cavernosum and penile arteries (e.g., resulting from hypertension, atherosclerosis, and / or diabetes), as well as sexual disorders such as female sexual arousal disorder (FSAD), as well as pelvic disorders such as urinary incontinence.

[0064] The systems and methods described herein are expected to restore function to a denervated penis, for example, by electrically stimulating the very end of the cavernous nerve. The neuronal pathway that induces the erectile response is the parasympathetic input originating from the pelvic splanchnic plexus. The pelvic splanchnic plexus is composed of branches from the second, third, and fourth sacral nerves that intertwine with the inferior hypogastric plexus and form a web of nerves in the pelvis. The cavernous nerve is derived from the pelvic splanchnic nerve and travels through and along the prostatic plexus, located approximately around the prostate, to supply parasympathetic fibers to the corpus cavernosum and corpus cavernosum of the penis. Thus, locating the optimal site for electrical nerve stimulation is difficult, as the human cavernous nerve travels through complex anastomoses from the pelvic plexus to the penis. Furthermore, there is considerable anatomical variability in the location of the cavernous nerve. Each patient's anatomy, disease stage, and / or cancer location are unique. The pelvic plexus is a transparent veil with microscopic nerves, and the cavernous nerve does not follow uniform localization in all individuals. These barriers therefore make identification of cavernous nerve segments for selective stimulation extremely difficult. Systems and methods for overcoming these barriers are provided herein.

[0065] With reference to Figure 1, an overview of an exemplary electrical stimulation system constructed in accordance with the principles of the present disclosure is provided. In Figure 1, the components of the system are not drawn to scale on either a relative or absolute basis. The electrical stimulation system 100 may include an implantable stimulation unit 200 having a programmable controller 300, an external patient controller 400, an external physician controller 500, and an external charger 600.

[0066] 2A and 2B, the implantable stimulation unit 200 includes at least one flexible paddle (illustratively a first flexible paddle 202a and a second flexible paddle 202b: each of the paddles includes an array of electrodes 204 and a suture hole 206), a cable 208, and a programmable controller 300. Each electrode 204 may be individually selected to emit electrical energy to stimulate tissue. Preferably, the electrodes 204 are selected in one or more pairs by the programmable controller of the implantable stimulation unit 200 to cause stimulation of erectile tissue when activated by a user or physician (e.g., using an external patient controller 400 or physician controller 500). The electrodes 204 may be uniformly arranged and / or arranged in different spatial configurations. For example, the electrodes 204 may be spaced apart from about 0.05 mm to about 5.0 mm, more preferably from about 0.5 mm to about 1.5 mm. By way of illustration, the electrodes 204 may be arranged in multiple rows and multiple columns, and the number of electrodes 204 may vary from about 10 to more than 50 electrodes, as desired. The electrodes 204 may apply bipolar stimulation such that current passes from one electrode to another to stimulate a nerve or group of nerves located between them. The array of electrodes 204 may have a tissue-friendly shape designed to reduce adverse tissue reactions that may lead to the formation of fibrous encapsulation. For example, the electrodes 204 may be sized and shaped such that portions of a convex, spherical, or flat shape are exposed on the flexible substrate to avoid sharp surfaces that may damage or inflame tissue. The electrodes 204 may be made of platinum, gold, or other conductive implantable materials suitable for electrical stimulation of nerves.

[0067] The flexible paddle 202 is preferably sized and shaped to be adjacent to at least a portion of the patient's pelvic plexus. As shown in Figures 2A and 2B, the first flexible substrate 202a is configured to conform to a first half of the pelvic plexus, and the second flexible paddle 202b is configured to conform to a second half of the pelvic plexus. The flexible paddle may bend to form an arc shape that conforms to the pelvic plexus and may be implanted over the pelvic plexus (e.g., during a prostatectomy surgery). Preferably, the flexible paddle 202 conforms to the anatomical shape of a portion of the pelvic plexus and may cover a portion or the entire area of ​​the pelvic plexus so that the electrode 204 makes optimal contact with the cavernous nerve. The flexible paddle may comprise a structural matrix of silicone or other flexible, electrically non-conductive material that allows it to conform and mold to the local anatomy, optimizing placement and minimizing tissue reaction. The flexible paddles can have a flat structure designed in a suitable shape (e.g., hemispherical, rectangular, square, oval, elliptical, or trapezoidal) and dimensioned to better fit the anatomy and needs of each patient.

[0068] 1, the implantable stimulation unit 200 includes a first array of electrodes 204 disposed on a first flexible paddle 202a and a second array of electrodes 204 disposed on a second flexible paddle 202b. The programmable controller 300 is preferably programmed to activate the stimulation circuitry to simultaneously apply bilateral electrical stimulation to the patient's erectile function to one or more electrodes 204 disposed on the first flexible paddle 202a and one or more electrodes 204 disposed on the second flexible paddle 202b.

[0069] The implantable stimulation unit 200 may include at least one anchor, preferably individually coupled to the flexible paddle, to maintain the flexible paddle in contact with the pelvic plexus. The anchor may consist of a suture, a biocompatible matrix, a biocompatible glue, or some combination thereof. In one preferred embodiment, each flexible paddle includes one or more suture holes 206 through which a suture may anchor the flexible paddle to the pelvic plexus. The implantable stimulation unit 200 may be encapsulated within one or more biocompatible materials suitable for long-term implantation (e.g., titanium cage, silicone cage). In one embodiment, the flexible paddle 202 may include one or more cavities located between the electrodes 204 or within specific regions of the paddle to allow connective tissue growth within and / or through the paddle to enhance anchoring and fixation within the pelvic cavity.

[0070] A cable 208 electrically couples the electrodes 204 of the flexible paddles 202a and 202b to the programmable controller 300. The cable 208 may be an insulated multi-conductor cable with an independent wire for each electrode 204. The cable 208 may include multiple branches, as shown, to allow for connections to the flexible paddles. In one embodiment, two or more cables 208 may be coupled to each of the arrays of electrodes 204 of the first flexible paddle 202a and the second flexible paddle 202b.

[0071] The programmable controller 300 is implanted within the lower flank between the umbilical line and the iliac crest and may include circuitry configured to store stimulation routines and to cause the stimulation circuitry to deliver electrical stimulation to a selected subset of the electrodes 204 with parameters defined by a stimulation regimen. Parameters employed in such a stimulation regimen may include pulse duration, frequency of the alternating current, voltage, current, and duration of stimulation.

[0072] The programmable controller 300 may be controlled by, and optionally powered by, an external patient controller 400. The external patient controller 400 preferably includes a user interface 402 that allows a user, e.g., a patient, physician, caregiver, to adjust a limited number of operating parameters of the programmable controller 300, including starting and stopping a stimulation session. The programmable controllers 300 communicate with the external patient controllers 400 via respective communication units, each of which may include an inductive coil and / or an RF transceiver for communicating information in a bidirectional manner across the patient's skin and, optionally, transmitting power to the programmable controller 300. For example, the external patient controller 400 may selectively activate the programmable controller 300 via respective telemetry (or RF) systems within the programmable controller 300 and the external patient controller 400 in response to user input received at the user interface 402.

[0073] In a preferred embodiment, a limited number of stimulation parameters may be adjusted at the user interface 402 to reduce the chance of injury caused by poor adjustments made by a non-physician user. In an alternative embodiment, the external patient controller 400 may also send adjustments to the stimulation parameters, such as the electrodes used to apply the stimulation, the pulse duration, the frequency, voltage, current, and duration of the stimulation, to the programmable controller 300 in response to user input received at the user interface 402. In one embodiment, the external patient controller 400 may activate a pre-programmed routine stored within the programmable controller 300 to identify an optimized set of excitation electrodes and store the identification of those electrodes in non-volatile memory, as described herein below.

[0074] The external patient controller 400 may be specifically designed for use with the implantable stimulation unit 200 and the programmable controller 300. Alternatively, the external patient controller 400 may be a smartphone, laptop, tablet, smartwatch, etc., programmed to communicate with the implantable stimulation unit 200 via an application or "app" downloaded from an app store. In either case, the external patient controller 400 is programmed to interface with the implantable stimulation unit 200 and / or the external physician controller 500 and may use cellular, 802.11 Wifi, Zigbee, and / or BLUETOOTH, or other wireless technologies for communication with those devices. TM In particular, the external patient controller can be programmed to selectively activate the programmable controller 300 in response to patient input.

[0075] The external physician controller 500 is programmed to communicate with the programmable controller 300, either directly or via the external patient controller 400. As shown in FIG. 1, the external physician controller 500 may illustratively be a computer having a non-transitory computer-readable medium programmed with instructions that, when activated on the computer, cause the computer to provide programming to the programmable controller 300. The external physician controller 500 may be wirelessly coupled to the programmable controller 300 and / or the external patient controller 400 such that the external physician controller 500 may download data stored on the programmable controller 300 and / or the external patient controller 400 for review. The external physician controller 500 may transfer programming data to the programmable controller 300 to reprogram stimulation parameters programmed into the programmable controller 300. For example, the external physician controller 500 may be used to program and adjust parameters such as the electrode pairs to be used for stimulation, pulse duration, frequency of the alternating current, voltage, current, and duration of stimulation. The external physician controller 500 may be programmed to upload and store data retrieved from the programmable controller 300 on a remote server for later access by a physician. In one embodiment, the external physician controller 500 may selectively activate a desired subset of electrodes 204 and store in the non-volatile memory of the programmable controller 300 the identity of those electrodes and a stimulation routine sufficient to induce sexual arousal or neural or penile function restoration, as described further below.

[0076] The external physician controller 500 may selectively activate the programmable controller 300 to execute scanning protocols stored in non-volatile memory which, when activated, determine preferred electrode pairs, current flow directions, and electrode regions that will cause a rapid erectile response, enable neural function recovery, and / or reduce penile fibrosis, and store the identities of those electrodes in the non-volatile memory of the programmable controller 300. More specifically, the scanning protocols may cause the microprocessor of the programmable controller 300 to selectively activate the electrodes 204 of the array in a predetermined manner, and to deliver electrical stimulation via the stimulation circuitry by determining preferred directions of current flow, preferred regions of the electrodes when stimulated in the preferred directions of current flow, preferred electrode pairs within the preferred regions of the electrodes, and preferred stimulation parameters to be applied to those preferred electrodes, as described herein below. The scanning protocol may be used to determine a stimulation pulse sequence corresponding to an erectile mode of activation; optionally, a nerve functional recovery stimulation pulse sequence corresponding to a functional recovery mode of activation for functional recovery of at least one cavernous nerve; and / or a penile functional recovery stimulation pulse sequence corresponding to a functional recovery mode of activation for inducing at least partial penile tumescence and reducing penile fibrosis.

[0077] In one embodiment, the external physician controller 500 may be used to determine preferred electrode pairs and preferred stimulation parameters that will result in a preferred rapid erectile response (or for nerve or penile function restoration) in a post-operative (e.g., prostatectomy) period. The external physician controller 500 may be used to store in the non-volatile memory of the programmable controller 300 a first stimulation regimen that induces a rapid erectile response when activated on demand by the external patient controller 400, and a second stimulation regimen that provides a lower current intensity and restores nerve transmission through at least one cavernous nerve when activated at a pre-set time via the external patient controller 400 or automatically by the programmable controller 300. The stimulation regimen is stored in the memory of the programmable controller 300, so that an erection may be achieved using those parameters at a later time (e.g., in response to user input at the external patient controller 400).

[0078] The external physician controller 500 may be specifically designed for use with the implantable stimulation unit 200. Alternatively, the external physician controller 500 may be a smartphone, laptop, tablet, desktop computer, etc., programmed to communicate with the implantable stimulation unit 200. Thus, the external physician controller 500 may interface with the implantable stimulation unit 200 and / or the external patient controller 400 using software, such as applications or "apps" downloaded from an app store, and may use cellular, 802.11 Wifi, Zigbee, and / or Bluetooth® protocols for communication with those devices. TM The external physician controller 500 may communicate with the implantable stimulation unit 200 directly or via the external patient controller 400.

[0079] An external charger 600 may be in electrical communication with the programmable controller 300 and transepidermally charge the programmable controller 300 via a respective inductive coil. The external charger 600 may generate an alert via an indicator LED, an audible alarm, or a vibration motor when the power level of the programmable controller 300 falls below a threshold power level.

[0080] 2A, 2B, and 3, an exemplary paddle design for an implantable stimulation unit is illustrated. The implantable stimulation unit 200 may include at least one flexible paddle 202 having an array of electrodes 204 and suture holes 206. The flexible paddle 202 may be operably coupled to a programmable controller 300 via a cable 208 having leads 210. The cable 208 may be an insulated multi-conductor cable having an independent wire for each electrode 204. FIG. 2A depicts an embodiment in which a single cable 208 couples the flexible paddle 202 to the programmable controller 300. Alternatively, as shown in FIG. 3, two or more cables 208 may be provided to couple the flexible paddle 202 to the programmable controller 300. 3, one of the cables 208 may electrically couple a first subset of the array of electrodes 204, e.g., six electrodes, to the programmable controller 300, and the other cable 208 may electrically couple a second subset of the array of electrodes 204, e.g., the remaining six electrodes, to the programmable controller 300. Thus, the programmable controller 300 may include multiple ports for receiving the cables 208.

[0081] The flexible paddle 202 may bend, for example, take an arc shape, and may be implanted to contact the pelvic plexus (e.g., during a prostatectomy surgery). Preferably, the flexible paddle 202 may be shape-conform to the anatomical shape of a portion of the pelvic plexus. The flexible paddle 202 may comprise at least two electrode rows and at least two electrode columns 204. In a preferred embodiment depicted in FIG. 2B, the array of electrodes 204 may include 12 electrodes on each of the first flexible paddle 202a and the second flexible paddle 202b. The flexible paddle 202 may have a substantially hemispherical shape including a protruding portion 203, which extends from the corner of the flexible paddle furthest from the cable 208. The hemispherical shape is selected to avoid damaging soft tissue, minimize injury, and reduce fibrous encapsulation that may impede the transmission of stimulation pulses from the electrode to the nerve. The protruding portion 203 also allows a flexible paddle to be placed adjacent to the cavernous nerve while accommodating the anatomy of that region, as described below with respect to Figures 8A and 8B. At least one electrode 204 may be disposed on the protruding portion 203 of the paddle.

[0082] Still referring to FIG. 2B, a two-paddle embodiment is described. In this embodiment, the stimulation unit 200 (see FIG. 1) includes a first flexible paddle 202a and a second flexible paddle 202b, each having an array of electrodes 204 and a suture hole 206. Each of the first flexible paddle 202a and the second flexible paddle 202b is coupled to a programmable controller 300 via a cable 208. Alternatively, a single cable 208 may include branches that couple the paddles 202a and 202b to the programmable controller 300. Since the pelvic plexus generally has two nerve groups, each of the first flexible paddle 202a and the second flexible paddle 202b may cover a portion or the entire area of ​​one nerve group such that at least one of the arrays of electrodes 204 contacts the cavernous nerve. For example, the first flexible paddle 202a and the second flexible paddle 202b may be implanted in the patient such that the protruding portion 203 of each hemispherical paddle faces each other, as shown in FIG. 2B. The protruding portion 203 may thus allow the flexible paddle to be placed around the urethra, as shown in FIGS. 9A and 9B and described below. In a preferred embodiment, each flexible paddle 202 has a thickness of about 2 mm, a length of about 32.5 mm, and a width of about 18 mm, except that the protruding portion 203 extends to a width of about 22 mm. The first flexible paddle 202a and the second flexible paddle 202b may have the same or different dimensions. The distance between the two paddles, when implanted, may be about 0.5 mm to about 8 cm.

[0083] 4A and 4B, exemplary electrode shapes for use in the implantable stimulation unit 200 are described. Each of the electrodes 204a, 204b, and 204c has a tissue-friendly shape configured to reduce adverse tissue reactions that may lead to fibrosis formation around the electrodes. Electrode 204a has a bulbous portion extending from the flexible substrate portion 212 and is independently coupled to the circuitry of the programmable controller 300 by a wire of a cable 214a. Electrode 204b has a flat portion extending above the height of the flexible substrate portion 212 and is independently coupled to the circuitry of the programmable controller 300 by a wire of a cable 214b. Electrode 204c is flat and flush with the surface of the flexible substrate portion 212 and is independently coupled to the circuitry of the programmable controller 300 by a wire of a cable 214c. Advantageously, each of the electrode shapes does not have sharp surfaces that may damage or inflame tissue. As will be appreciated by one of ordinary skill in the art, the array of electrodes 204 may use one, two, or three of these electrode shapes, or other suitable tissue-friendly shapes.

[0084] 4C-4E, exemplary electrode shapes are further described, which depict the surface charge density for each electrode shape. As shown in FIG. 4C, the hemispherical shape of electrode 204a allows for homogenous charge distribution across the surface of the electrode, thereby providing efficient transfer of energy from the electrode to the cavernous nerve without damage to the surrounding tissue. In contrast, as depicted in FIG. 4D and 4E, the charge distribution of flat disk electrodes 204b and 204c shows a large accumulation of charge on the periphery of the electrode, which may impede energy transfer and potentially affect tissue damage.

[0085] 5, a generalized schematic diagram of the internal functional components of the programmable controller 300 will now be described. The programmable controller 300 is programmed to cause stimulation of the preferred excitation electrodes according to a stimulation regimen stored in the memory of the programmable controller 300. The programmable controller 300 preferably includes a microprocessor 302, a non-volatile memory 304, a communication unit 306, a system sensor 308, a power supply 310, a stimulation circuit 312, and a demultiplexer 314.

[0086] The microprocessor 302 is electrically coupled to and controls the functional components of the programmable controller 300. The microprocessor 302 may comprise a commercially available microcontroller unit including a programmable microprocessor, a volatile memory, a non-volatile memory 304 such as an EEPROM for storing programming, and non-volatile storage, e.g., flash memory, for storing firmware and logs of system operating parameters and patient data. The memory of the microprocessor 302 stores program instructions that, when executed by the microprocessor 302, cause the processor and functional components of the programmable controller 300 to provide the functionality attributed thereto herein. The microprocessor 302 is preferably programmable such that programming data (e.g., stimulation regimens, excitation electrode identities, stimulation parameters, etc.) are stored within the non-volatile memory 304 of the microprocessor 302 and can be adjusted using the external patient controller 400 and / or the external physician controller 500.

[0087] The microprocessor 302 may be programmable to allow electrical stimulation of any selected combination of electrodes 204 on the array, thus providing a simple bipolar configuration. The microprocessor 302 may be further programmed with routines to selectively activate a desired subset of the array of electrodes 204, determine the subset of the array of electrodes that provides beneficial stimulation and one or more stimulation regimens, and store that information in the non-volatile memory 304 for subsequent use by the microprocessor 302. As used in this disclosure, the term "excitation electrodes" refers to a subset of electrodes that have been determined to provide a preferred erectile response for a preferred current flow direction. Additionally, as used in this disclosure, the term "stimulation regimen" refers to a set of stimulation parameters that, when applied to the excitation electrodes, are determined by the patient or physician to elicit a preferred rapid erectile response, or provide stimulation that has been determined by the patient or physician to be preferred for restoring or reinforcing neural transmission through at least one cavernous nerve.

[0088] For example, the microprocessor 302 may direct the power supply 310 to transmit electrical signals to the set of excitation electrodes 204 via the stimulation circuit 312 using the demultiplexer 314 that emits power. The stimulation regimen used by the microprocessor 302 provides sufficient electrical stimulation to at least one cavernous nerve via the stimulation circuit 312 and the pelvic plexus to induce sexual arousal, e.g., erection, or for nerve or penile function restoration. The routine may activate a subset of the identified and stored electrodes automatically and / or in response to user input at the external patient controller 400 and / or the external physician controller 500. In addition, as described below, the non-volatile memory 304 stores pre-programmed routines for scanning the array of electrodes to enable identification of the set of excitation electrodes and stimulation parameters for a preferred stimulation regimen, both initially after implantation of the implantable stimulation unit 200 and at later times after implantation, as may be instructed by the external patient controller 400 or the external physician controller 500. The set of excitation electrodes that results in the best sexual arousal, e.g., erectile response, is stored in memory. The identity of the set of excitation electrodes may be stored for later stimulation and further transmitted to the external patient controller 400 and / or the external physician controller 500.

[0089] Stimulation parameters are selected to provide sexual arousal, promote nerve regeneration, and / or improve nerve regeneration, and treat sexual disorders such as erectile dysfunction and sexual arousal disorder in women. For example, the stimulation may produce and maintain an erection, and promote and / or improve nerve (e.g., nerves of the pelvic plexus and / or cavernous nerve) regeneration over time. By way of example, the pulse duration may be programmed to be about 0.5 milliseconds to about 10 milliseconds, about 0.5 milliseconds to about 5 milliseconds, about 1 millisecond to about 4 seconds, or about 1 millisecond to about 3 milliseconds. The frequency of the alternating current may be programmed to be about 10 Hz to about 30 Hz, about 10 Hz to about 25 Hz, about 10 Hz to about 20 Hz, or about 15 Hz to about 25 Hz. The voltage may be programmed to be about 1 V to about 15 V, about 5 V to about 10 V, about 1 V to about 5 V, or about 10 V to about 15 V. The current may be programmed to be about 1 milliamp to about 100 milliamp, about 1 milliamp to about 50 milliamp, about 1 milliamp to about 20 milliamp, about 20 milliamp to about 50 milliamp, about 50 milliamp to about 100 milliamp, or about 75 milliamp to about 100 milliamp. The period of stimulation may be programmed to stimulate automatically for a predetermined time, or may stimulate in response to a user input, for example, at the user interface 402. For example, stimulation may be maintained for a portion or the entirety of the desired period of erection. For nerve regeneration, it may be preferable to stimulate over time at predetermined time intervals. For example, automatic stimulation can occur hourly, once a day, twice a day, three times a day, four times a day, every other day, every third day, or every week for a period of 10 minutes to 2 hours, 10 minutes to 1 hour, 10 minutes to 30 minutes, 10 minutes to 20 minutes, or 1 hour to 2 hours. Preferably, stimulation for nerve regeneration occurs using oscillatory current or low frequency electrical stimulation.

[0090] The microprocessor 302 is coupled to a communication unit 306 having circuitry configured to communicate with an external patient controller 400 and / or an external physician controller 500. The communication unit 306 enables the transfer of stimulation commands, and optionally power, between the programmable controller 300 and the external patient controller 400 such that the programmable controller 300 may be powered, programmed, and / or controlled by the external patient controller 400. For example, the microprocessor 302 may start or stop a stimulation session or assess and determine a preferred subset of the array of electrodes 204 in response to stimulation commands received from a corresponding communication unit (e.g., an inductive unit with a telemetry system and a coil and / or an RF unit with a transceiver and an antenna) of the external patient controller 400. The communication unit 306 further enables the transfer of programming data, and optionally power, between the programmable controller 300 and the external physician controller 500 such that the programmable controller 300 may be powered, programmed, and / or controlled by the external physician controller 500. For example, the microprocessor 302 may, in response to programming data received from a corresponding communications unit (e.g., a telemetry system and an induction unit having a coil and / or an RF unit having a transceiver and an antenna) of the external physician controller 500, direct changes to a preferred stimulation regimen including the pulse duration, AC frequency, voltage, current, and / or duration of stimulation as well as the electrodes included in the set of excitation electrodes used for stimulation.

[0091] The communications unit 306 may include a telemetry system electrically coupled to the inductive coil. Technology for telemetry systems and coils is well known to those skilled in the art and may include magnets, short-range telemetry systems, longer-range telemetry systems (such as using MICS RF Telemetry available from Zarlink Semiconductor, Ottawa, Canada), or technology similar to a pacemaker programmer. Alternatively, the coil may be used to transmit power only, and a separate radio frequency transmitter may be provided within the programmable controller 300, the external patient controller 400, and / or the external physician controller 500 to establish bidirectional or unidirectional data communications.

[0092] The communications unit 306 may also include communications circuitry (with or without a telemetry system and coil) employing a transceiver coupled to an antenna (which may be inside or outside the sealed housing). The transceiver preferably comprises a radio frequency (RF) transceiver and is configured for bidirectional communication with similar transceiver circuitry located in the external patient controller 400 and / or external physician controller 500 via the antenna. For example, the transceiver may receive stimulation commands from the external patient controller 400 and programming data from the external physician controller 500. In response to programming data and / or stimulation commands received from corresponding transceivers and antennas of the external patient controller 400 and / or external physician controller 500 via the antenna and transceiver of the communications unit 306, the microprocessor 302 may direct changes to the electrodes included in the set of excitation electrodes used for stimulation, and a preferred stimulation regimen including pulse duration, alternating current frequency, voltage, current, and / or duration of stimulation, start or stop a stimulation session, and / or assess and reassess a preferred subset of electrodes. The transceiver may also include a low power mode of operation whereby it periodically wakes up, listens for incoming messages, and responds only to those messages that include the unique device identifier assigned to that programmable controller. In addition, the transceiver may employ encryption routines to ensure that messages sent from or received by the programmable controller 300 cannot be intercepted or forged. The communication unit 306 may include a wireless chipset, e.g., Wifi, Bluetooth, TM , cellular, Zigbee, etc., thereby allowing the programmable controller 300 to communicate wirelessly with the external patient controller 400 and / or the external physician controller 500.

[0093] System sensors 308 may comprise one or more sensors that monitor the operation of the system of the programmable controller 300, log data related to system operation and system faults, Log data may be stored in a log for later retrieval using the external physician controller 500. The microprocessor 302 may be programmed to receive sensor signals from the system sensors 308 and adjust stimulation parameters based on the sensor signals. The sensors 308 may include, for example, a humidity sensor to measure moisture within the housing of the programmable controller 300, which may measure, for example, the battery temperature during charging and provide information related to the status of electronic components and / or temperature sensors to ensure safe operation of the battery. Data from the system sensors may be logged by the microprocessor 302 and stored in the non-volatile memory 304 for later transmission to the external physician controller 500.

[0094] The power supply 310 powers the electrical components of the programmable controller 300 and may comprise a primary cell or battery, a secondary (rechargeable) cell or battery, or a combination of both. Alternatively, the power supply 310 may not include a cell or battery, but instead comprises a capacitor that stores energy that is transferred through the skin via a transepidermal energy transfer system (TET), e.g., by inductive coupling. In a preferred embodiment, the power supply 310 comprises a lithium ion battery.

[0095] The stimulation circuitry 312 is configured to transmit pulses, using energy provided by the power supply 310, to the electrodes 204 such that selected electrodes deliver electrical stimulation at desired parameters.

[0096] The microprocessor 302 may further be coupled to a demultiplexer 314 such that any subset of the electrodes 204 of the array may be selectively coupled to the stimulation circuitry 312. In this manner, an appropriate electrode set may be selected from the entire selection of electrodes implanted within the patient's body to achieve a desired therapeutic effect. The demultiplexer 314 preferably operates at high speed, thereby allowing successive stimulation pulses to be applied to different electrode combinations.

[0097] With reference to FIG. 6, a generalized schematic diagram of the internal functional components of the external patient controller 400 will now be described. The external patient controller 400 may include a user interface 402, a programmable microprocessor 404, a communication unit 406, a power supply 408, and input and output circuitry (I / O) 410. As discussed above, the external patient controller 400 may be specifically designed for use with the implantable stimulation unit 200, or alternatively may be a general-purpose smartphone, laptop, tablet, smartwatch, etc., programmed to communicate with the implantable stimulation unit 200 and / or the external physician controller 500. In the latter case, the user interface 402, programmable microprocessor 404, communication unit 406, power supply 408, and I / O 410 may be pre-installed hardware on the smartphone, laptop, tablet, smartwatch, etc.

[0098] The microprocessor 404 is electrically coupled to and configured to control the internal functional components of the external patient controller 400. The microprocessor 404 may comprise a commercially available microcontroller unit including a programmable microprocessor, a volatile memory, a non-volatile memory such as an EEPROM for storing programming, and non-volatile storage, e.g., flash memory, for storing firmware and logs of system operating parameters and patient data. The memory of the microprocessor 404 may store program instructions that, when executed by the processor of the microprocessor 404, cause the processor and the functional components of the external patient controller 400 to provide the functionality attributed thereto herein. Preferably, the microprocessor 404 is programmable and is programmed to store changes to the electrodes included in the set of excitation electrodes used for stimulation, and the preferred stimulation regimen, including pulse duration, frequency of alternating current, voltage, current, and / or duration of stimulation, in response to user input received at the user interface 402 and / or at the external physician controller 500, and to transmit stimulation commands and programming data to the programmable controller 300 via the communication unit 406.

[0099] The microprocessor 404 may be coupled to a communication unit 406, which may communicate with the programmable controller 300 and the external physician controller 500. The communication unit 406 may include an induction unit and coil with a telemetry system, and / or an RF unit with a transceiver and antenna, and a wireless chipset, e.g., Wifi, Bluetooth. TM , cellular, Zigbee (registered trademark), etc., thereby allowing the external patient controller 400 to wirelessly communicate with the programmable controller 300 and / or the external physician controller 500 and, optionally, to supply power to the programmable controller 300.

[0100] The user interface 402 receives user input and displays information to the user. The user interface 402 may include buttons, LEDs, displays, touch screens, keypads, microphones, speakers, trackballs, etc., to receive user input and / or display information to the user. For example, the user interface 402 may display current stimulation parameters and allow the user to adjust the stimulation parameters. In a preferred embodiment, a limited number of stimulation parameters may be adjusted in the user interface 402 to reduce the chance of injury caused by adjustments made by a non-physician user. For example, the user interface 402 may only allow the user to start or stop a stimulation session using an excitation electrode, such as a first stimulation pulse sequence corresponding to a first mode for inducing a rapid erectile response, a second nerve function restoration stimulation mode selected to restore function to nerve conduction within the cavernous nerve, or a third penile function restoration mode selected to reduce penile fibrosis.

[0101] The power supply 408 powers the electrical components of the external patient controller 400 and may comprise a primary cell or battery, a secondary (rechargeable) cell or battery, or a combination of both. Alternatively, the power supply 408 may be a port, allowing the external patient controller 400 to be plugged into a conventional wall socket to power the components.

[0102] The input and output circuitry (I / O) 410 may include a port for data communication, such as wired communication with a computer, and / or a port for receiving removable memory (e.g., an SD card) on which program instructions or data related to use of the external patient controller 400 may be stored.

[0103] Referring to FIG. 7, the software implemented on the external physician controller 500 will now be described. The software comprises several functional blocks, depicted diagrammatically in FIG. 7, including a main block 502, an event log block 504, a data download block 506, a configuration settings block 508, a user interface block 510, an alarm detection block 512, a sensor calibration block 514, a firmware upgrade block 516, a device identifier block 518, and a status information block 520. The software is preferably written in C++ and employs an object-oriented format. In one preferred embodiment, the software is configured to run on a Microsoft Windows® (a trademark of Microsoft Corporation, Redmond, Wash.) or Unix®-based operating system as conventionally employed on desktop and laptop computers. As discussed above, the computer may include a transceiver, antenna, and wireless card, e.g., IEEE 802.11 standard, cellular, Bluetooth®, etc. TM , Zigbee®, or the like, thereby allowing the programmable controller 300 and / or the external patient controller 400 to communicate wirelessly with the external physician controller 500.

[0104] The main block 502 preferably contains the main software routines that run on the physician's computer and control the overall operation of the other functional blocks. The main block 502 allows the physician to download event data and alarm information stored on the programmable controller 300 and / or the external patient controller 400 to his / her office computer, and also allows the external physician controller 500 to directly control the operation of the programmable controller 300. The main block 502 also allows the physician to upload firmware updates and configuration data to the programmable controller 300.

[0105] The event log block 504 is a record of operational data downloaded from the programmable controller 300, which may include, for example, therapy session start and stop times, current stimulation parameters, stimulation parameters from a previous therapy session, sensor data, battery current, battery voltage, battery status, etc. The event log may also include the occurrence of events, such as alarms or other abnormal conditions.

[0106] The data download block 506 is a routine that commands the programmable controller 300 to transfer data to the external physician controller 500 for downloading after the programmable controller 300 is coupled to the external physician controller 500. The data download block 506 may initiate the download of data stored in the event log automatically or at the direction of a physician via a user interface block 510.

[0107] The configuration settings block 508 is a routine that configures parameters stored within the programmable controller 300 that control the operation of the programmable controller 300. The time interval timing parameters may determine, for example, how long the processor remains in a sleep mode before being awakened to listen for wireless communications or to control the operation of the programmable controller 300. The time interval timing parameters may control, for example, the duration of a stimulation session. The time interval timing settings transmitted to the programmable controller 300 may also determine when and how often event data is written to memory within the microprocessor 302. In an embodiment, the external physician controller 500 is also configured to transfer data to the external patient controller 400, which may also be used to configure timing parameters used by firmware executed by the microprocessor 404 of the external patient controller 400. Block 508 may also be used by the physician to configure parameters stored in the memory of the microprocessor 302 that relate to operational limits of the microprocessor 302. These values ​​may include times when the programmable controller 300 may be operating and may not be operating, etc.

[0108] Block 508 may also configure parameters stored in the memory of the microprocessor 302 associated with controlling the operation of the programmable controller 300. These values ​​may include stimulation parameters.

[0109] The user interface block 510 handles the display of information read from the programmable controller 300 and / or external patient controller 400 and the data download block 506, and presents that information for the physician's review in an intuitive, easily understood format. Such information may include the status of the programmable controller 300, treatment session start and stop times, current stimulation parameters, stimulation parameters from previous treatment sessions, sensor data, battery status, etc. The user interface block 510 also generates user interface screens that allow the physician to enter information to configure session timing, stimulation parameters and requests, determine or redetermine excitation electrode subsets, etc.

[0110] The alarm detection block 512 may include routines that evaluate data read from the programmable controller 300 and flag abnormal conditions for a physician's attention. For example, the alarm detection block 512 may flag when a parameter measured by a system sensor 308 rises above or falls below a predetermined threshold.

[0111] The sensor calibration block 514 may include routines for testing or measuring variations in the system sensors 308 employed in the programmable controller 300 due to, for example, aging or changes in humidity. The block 514 may then calculate offset values ​​to correct the measured data from the sensors and transmit that information to the programmable controller 300 for storage in the non-volatile memory of the microprocessor 302.

[0112] The firmware upgrade block 516 may include routines to check the version number of the controller firmware installed on the programmable controller 300 and / or external patient controller 400 and identify whether upgraded firmware is present. If so, the routine may notify the physician and allow the physician to download revised firmware into the non-volatile memory of the programmable controller 300 and / or external patient controller 400.

[0113] The device identifier block 518 may include a unique identifier for the programmable controller 300 stored in the non-volatile memory 304 of the microprocessor 302 and routines for reading that data when the external physician controller 500 is coupled to the programmable controller 300. The device identifier may also be used by the programmable controller 300 to verify that communications received from the external patient controller 400 and / or external physician controller 500 are intended for that particular programmable controller. Similarly, this information may be employed by the external patient controller 400 and / or external physician controller 500 to determine whether a received message was generated by a programmable controller associated with that system. Finally, the device identifier information may be employed by the external physician controller 500 to verify that the external patient controller 400 and programmable controller 300 form a matched pair.

[0114] The status information block 520 includes routines for interrogating and reading current status data from the programmable controller 300. Such information may include, for example, battery status, stimulation parameters, the date and time on an internal clock of a therapy session, version control information for firmware and hardware currently in use, and sensor data.

[0115] 8A and 8B illustrate the positioning of flexible paddles 202a and 202b on the prostate and pelvic plexus, respectively. As described above with respect to FIGS. 2A and 2B, each of the flexible paddles 202a and 202b has an array of electrodes 204 and suture holes 206, and is coupled to a programmable controller 300 via one or more cables 208. The system can be implanted laparoscopically, for example, by folding the flexible paddles and passing them through a trocar. The insets in FIGS. 8A and 8B depict the local anatomy, showing the bladder, prostate, urethra, and pelvic floor. In FIG. 8A, the flexible paddle 202 is shown positioned relative to the prostate. Alternatively, the flexible paddle 202 can be positioned relative to the pelvic plexus such that the paddle 202 surrounds the urethra, as shown in FIG. 8B. Implantation above the pelvic plexus may be preferred for patients who have had a prostatectomy in which the prostate has been partially or completely removed.

[0116] 9A and 9B, the positioning of the flexible paddles 202 will be described. As described above with respect to FIGS. 2A and 2B, each flexible paddle 202 preferably has a substantially hemispherical shape with a protruding portion 203 extending from the corner of the flexible paddle furthest from the cable 208. The first flexible paddle 202a and the second flexible paddle 202b may be positioned such that the side of the flexible paddle with the exposed electrodes contacts the pelvic plexus, the flexible paddles surround the urethra, and the protruding portions 203 face each other. The flexible paddles 202 include suture holes 206 through which sutures may anchor the flexible paddles to the pelvic plexus. In FIG. 9A, the first position is illustrated such that the protruding portions 203 of the paddles are proximate to each other. In FIG. 9B, a second position is shown with the protruding portions 203 of the paddles spaced farther apart from each other, which may be advantageous if the patient's cavernous nerve is located farther away from the urethra.

[0117] A programmable controller 300 operably coupled to the array of electrodes may be programmed to selectively activate the electrodes 204 during implantation of the paddles to determine an optimal location for implanting the flexible paddles, e.g., the first or second positions as shown in Figures 9A and 9B. For example, the flexible paddles may be placed in a first position adjacent to the pelvic plexus and in the vicinity of at least one cavernous nerve (e.g., Figure 9A). The programmable controller may then cause the stimulator circuit to activate the electrodes 204 in the first position to generate a first position response. Activation of the cavernous nerve may be measured, for example, using a penile plethysmograph to measure penile diameter or circumference variation and penile tumescence.

[0118] The flexible paddle may then be moved to a second position adjacent the pelvic plexus and different from the first position near at least one cavernous nerve (e.g., FIG. 9B). The programmable controller may again selectively activate the electrodes 204 at the second position to generate a second position response. The programmable controller may also compare the first and second position responses via feedback from the sensor system 308 or in response to input from the external patient controller 400 or external physician controller 500 to determine the position that elicits an erectile response. If more than one position elicits an erectile response, the position that elicits the strongest or most rapid erectile response without causing significant discomfort or side effects may be selected as the preferred paddle placement position.

[0119] 10A-10C, a process for assessing tissue stimulation using sequentially varied directions of current flow within an array of electrodes 204 is described. As explained above, each of the electrodes 204 on flexible paddles 202a and 202b may be individually accessed and act as a source or sink, allowing current flow in multiple directions, as shown by the arrows between the electrodes 204 in FIGS. 10A-10C. In FIG. 10A, a first direction of current flow is shown by arrow 220a in a diagonal direction toward the other flexible paddle. For example, current flows from electrode 1 to electrode 2, but not between electrode 1 and electrodes 3 or 4. FIG. 10B shows a second direction of current flow 220b, where current flows diagonally between the electrodes 204 within each flexible paddle and away from the other flexible paddle. As shown in FIG. 10B, the second direction of current flow is preferably oblique to the first direction of current flow to increase the probability that activation of the electrode pair will stimulate the nerve and thereby elicit a response. As depicted in FIG. 10B, current flows from electrode 1 to electrode 3, but not between electrode 1 and electrodes 2 or 4. FIG. 10C shows a third direction of current flow 220c, where current flows in a downward direction between the electrodes 204 in each flexible paddle. For example, current may flow from electrode 1 to electrode 4, but not from electrode 1 to electrodes 2 or 3. As will be understood by one skilled in the art, depending on the number and arrangement of the array of electrodes 204, the direction of current flow may differ from that shown in FIGS. 10A-10C.

[0120] With reference to Figures 11A-11C, the grouping of electrodes 204 into exemplary regions is described. Figures 11A-11C correspond to the current flow directions depicted in Figures 10A-10C, respectively. Each array of electrodes 204, e.g., the first array and the second array, has at least two predefined regions of electrodes 222. For example, the first region of electrodes 222a and the second region of electrodes 222b may be disposed on a first flexible paddle, and the third region of electrodes 222c and the fourth region of electrodes 222d may be disposed on a second flexible paddle. As will be understood by one skilled in the art, each paddle may have three or more regions of electrodes, and the regions of electrodes may be varied to include different subset pairs of electrodes. The number and composition of electrodes 204 included within each region may depend on the direction of current flow. For example, the first region of electrodes 222a in FIG. 11A may include electrodes 1-5, while the first region of electrodes 222a in FIG. 11B may include electrodes 1-4 and 6, and the first region of electrodes 222a in FIG. 11C may include electrodes 1, 3, 4, 6, 7, 10, and 11.

[0121] 12A-12C, the selection of preferred electrode pairs within an array of electrodes is shown. Each of Figures 12A-12C corresponds to the directional current flow depicted in Figures 10A-10C, respectively, and to the regions of electrodes depicted in Figures 11A-11C, respectively. Each array of electrodes 204 has at least one electrode pair within each region 222 of electrodes, each electrode pair including two electrodes 204 from the array of electrodes. Each region 222 of electrodes may have the same or a different number of electrodes 204 and electrode pairs than the other regions 222 of electrodes.

[0122] 13, a programmed method for identifying a subset of excitation electrodes is described, and a preferred direction of current flow, electrode regions, and preferred electrode pairs are determined. Following the electrode selection process, a programmed method for determining parameters for a preferred stimulation regimen to elicit a preferred erectile response is completed. According to one aspect of the invention, a programmable controller 300 is operatively coupled to the array of electrodes and programmed to selectively activate the electrodes 204 and determine the excitation electrodes and the preferred stimulation regimen.

[0123] More specifically, the programmable controller 300 is programmed to selectively activate the electrodes 204 in the array of electrodes in at least two directions of current flow, for example as shown in Figures 10A-10C. Sequential stimuli can be applied between each pair of electrodes on the array of electrodes, and an erectile response can be measured. To determine the erectile response, activation of the cavernous nerve can be measured, for example, using a penile plethysmograph to measure penile diameter or circumference variation and penile tumescence. For each array of electrodes, the direction of current flow that elicits an erectile response can be selected as the preferred direction of current flow. If two or more directions of current flow on each array of electrodes elicit an erectile response, the direction of current flow that elicits the strongest erectile response without significant discomfort or side effects can be selected as the preferred direction of current flow. For example, Figure 13 shows that the second direction of current flow 220b has been selected as the preferred direction of current flow for each of the arrays of electrodes. As will be understood by one of ordinary skill in the art, the preferred direction of current flow on the first flexible paddle may be the same as or different from the preferred direction of current flow on the second flexible paddle.

[0124] The programmable controller 300 may be further programmed to selectively activate the electrodes 204 in the array of electrodes by region using the preferred current flow direction from the preceding process. For example, if the second direction of current flow 220b is the preferred current flow direction, the region of the electrodes corresponding to the preferred current flow direction may be activated as illustrated in FIG. 11B. Sequential stimulation may be applied in each region between each electrode pair on each array of electrodes in the preferred current flow direction, and an erectile response is measured for each local stimulation, again using the same method as described above. For each array of electrodes, the region of the electrodes that elicits an erectile response may be selected as the preferred electrode region. If more than one region electrode elicits an erectile response, the region of the electrodes that elicits the strongest erectile response without causing significant discomfort or side effects is selected as the preferred region. For example, FIG. 13 depicts the second region 222b of the electrode on the first flexible paddle and the third region 222c of the electrode on the second flexible paddle being selected as preferred regions.

[0125] The programmable controller 300 then selectively activates the electrodes 204 in the array of electrodes in the preferred current flow direction and preferred region. For example, FIG. 13 depicts that the second direction of current flow 220b is the preferred current flow direction, and the second region 222b of the electrodes on the first flexible paddle and the third region 222c of the electrodes on the second flexible paddle are the preferred regions. Sequential stimulation can be applied between each electrode pair on the array of electrodes in the preferred direction of current flow and in the preferred region, and erectile responses can be measured using the same method described above. For each array of electrodes, one or more electrode pairs that elicit an erectile response can be selected as the preferred electrode pair. If two or more electrode pairs elicit an erectile response, one or more electrode pairs that elicit the strongest erectile response without causing significant discomfort or side effects can be selected as the preferred electrode pair. In FIG. 13, three preferred electrode pairs 224 are identified as a subset of excitation electrodes. As will be understood by one of ordinary skill in the art, the number of preferred electrode pairs on the first flexible paddle can be the same as or different from the number of preferred electrode pairs on the second flexible paddle.

[0126] After the preferred electrode pair 224 is determined, multiple stimulation parameters having unique combinations of frequency and intensity amplitude may be applied to the preferred electrode pair. Stimulation pulse sequences for different uses may be determined by comparing responses generated by activating the preferred electrode pair in different modes with different stimulation parameters. For example, a stimulation pulse sequence corresponding to a mode of activation for erection may be determined. A stimulation regimen for producing an erection may apply a current amplitude in the range of 0.5-25 mA, a frequency in the range of 10-48 Hz, and a pulse width in the range of 0.1-1 ms. Alternatively, or in addition, the device may be used to restore function to at least one cavernous nerve and to determine a nerve function restoration stimulation regimen corresponding to a mode of activation for nerve function restoration. The nerve function restoration stimulation regimen may comprise stimulation parameters with a lower current intensity than the stimulation regimen for producing an erection. For example, the nerve function restoration stimulation regimen may apply a current amplitude in the range of 0.1-2 mA, a frequency in the range of 10-48 Hz, and a pulse width in the range of 0.01-1 ms. The neurological recovery stimulation regimen can be programmed to run automatically at least once per day.

[0127] Alternatively, the device may be used to determine a penile function recovery stimulation regimen corresponding to a mode of activation for penile function recovery. If the cavernous nerve is injured or completely severed after prostatectomy, a penile function recovery stimulation regimen may be used to induce at least partial penile tumescence, increase tissue oxygenation, and maintain penile function, thereby reducing penile fibrosis. Such a stimulation regimen may be performed at least once a day while the cavernous nerve re-establishes itself naturally or reconnects and regenerates with assistance from a nerve function recovery stimulation regimen. The penile function recovery stimulation regimen may comprise stimulation parameters with a higher current intensity than the nerve function recovery stimulation regimen and a lower current intensity than the stimulation regimen for producing an erection. For example, the penile function recovery stimulation regimen may apply a current amplitude in the range of 0.5-25 mA, a frequency in the range of 10-48 Hz, and a pulse width in the range of 0.1-1 milliseconds. The penile function restoration stimulation regimen may be programmed to run automatically at least once per day, and such operation may occur at a different time than the neural function restoration program.

[0128] The preferred direction of current flow, electrode areas, electrode pairs, and stimulation parameters may be stored in the non-volatile memory of the programmable controller 300, the external patient controller 400, and / or the external physician controller 500. Multiple stimulation regimens may also be stored in the memory of the programmable controller 300, the external patient controller 400, and / or the external physician controller 500 such that the programmable controller may be selectively activated in response to patient or physician input. For example, a patient may selectively activate a stimulation regimen to produce an erection. Alternatively, if so programmed, the programmable controller may automatically execute the neural function recovery stimulation regimen and / or the penile function recovery stimulation regimen following prostatectomy at least once a day, preferably for one hour for each function recovery stimulation regimen.

[0129] With reference to FIG. 14, a schematic of the operation of the intraoperative scanning process is described. Sequential stimulation will be applied between each electrode pair in each array of electrodes. Stimulation of each electrode pair will be automatically applied during the interpulse period of the other electrode pairs. Intraoperative stimulation allows activation of the cavernous nerve, which is detected by a penile plethysmograph to measure penile diameter or circumference variation and penile tumescence. During the scanning procedure, a 1-2 minute period of stimulation per configuration may be required to allow for adequate measurement. A 5 minute rest period between each stimulation may be allowed for stabilization and to avoid tumescence refractory effects.

[0130] In FIG. 15, an exemplary method is described for determining a subset of an array of electrodes that is preferably positioned to deliver electrical stimulation to at least one cavernous nerve via the pelvic plexus after implantation to induce sexual arousal, e.g., erection. In method 700, at 702, stimulation parameters are set, which may include the pair of electrodes 204 in the array to be used, the pulse duration, the frequency of the alternating current, the voltage, the current, and the duration of stimulation. The stimulation parameters may be set in the external patient controller 400, but are preferably set in the external physician controller 500. At 704, electrical stimulation is delivered to tissue, e.g., the pelvic plexus, between selected electrode pairs of the array at the set stimulation parameters. The selected electrode pairs of the array at the set stimulation parameters may be selected by the physician via the external physician controller 500 and / or may be determined as a result of the scanning protocol described above. At 706, it is observed whether sexual arousal, e.g., erection, has been achieved. If not, the stimulation parameters may be reset for the selected electrode pair or a different electrode pair may be selected for stimulation with the same parameters or at adjusted parameters. If sexual arousal is achieved, the stimulation parameters including the electrode pair are stored in memory in the programmable controller 300, the external patient controller 400, and / or the physician controller 500.

[0131] Optionally, after sexual arousal is achieved, further stimulation may be performed on the electrode pair using the adjusted stimulation parameters at 710, or a different electrode pair may be selected for stimulation with the same parameters or with the adjusted parameters to determine at 712 whether greater sexual arousal may be achieved. If not, stimulation may be repeated at 710 with a different configuration, or the test may end and the parameters stored at 708 may be used. If greater sexual arousal is achieved, the stimulation parameters, including the electrode pair, may be stored in memory at the programmable controller 300, the external patient controller 400, and / or the physician controller 500 as preferred parameters, and the previously stored parameters at 708 may be overwritten. Optionally, after greater sexual arousal is achieved, further stimulation may be performed at 710 on the electrode pair using adjusted stimulation parameters, or a different electrode pair may be selected for stimulation with the same parameters or at adjusted parameters to determine at 712 whether greater sexual arousal can be achieved.

[0132] Once the user is satisfied that the preferred parameters have been determined, either because all electrode pairings in the array have been tested, or because suitable sexual arousal has been achieved, the preferred parameters are stored. In this manner, a stimulation routine at the preferred parameters may be initiated by the patient-external controller 400 and / or the external physician controller 500 at a later time, e.g., minutes, hours, days, months, years, to induce sexual arousal, e.g., an erection.

[0133] Now referring to FIG. 16, an exemplary method for determining an optimal positioning for a flexible paddle is described. In method 800, in step 802, an array of electrodes is placed at a first location adjacent to a pelvic plexus and in the vicinity of at least one cavernous nerve. At least one electrode pair is selectively activated to stimulate at least one cavernous nerve and generate a first position response. In step 804, the same process is repeated at a second location adjacent to a different pelvic plexus from the first location and in the vicinity of at least one cavernous nerve. Specifically, at least one electrode pair is selectively activated to stimulate at least one cavernous nerve and generate a second position response. In step 806, the first position response and the second position response are compared to determine which response elicits a stronger position erectile response. If two or more locations elicit an erectile response, the location that elicits the strongest erectile response without causing significant discomfort or side effects may be selected as the optimal location. The process may be repeated at a third location to further determine the optimal location for implanting the flexible paddle.

[0134] 17, an exemplary method for determining a preferred stimulation regimen for inducing an erection, and optionally for nerve function recovery and / or for penile function recovery, is described. In method 900, at step 902, an array of at least one electrode pair is selectively activated to stimulate at least one cavernous nerve. At least one electrode pair may be selectively activated in a first direction and a second direction to generate a first directional response and a second directional response, respectively. At step 904, a direction of current flow that elicits a first erectile response may be determined by comparing the first directional response and the second directional response. At step 906, an array of at least one electrode pair is selectively activated in a preferred direction to stimulate at least one cavernous nerve. At least one electrode pair in the first region and at least one electrode pair in the second region can be selectively activated in a preferred orientation to generate a first localized response and a second localized response, respectively.

[0135] In step 908, a region of the electrodes that elicits a second erectile response may be determined by comparing the first and second local responses. The process is then repeated to determine a preferred electrode pair. In step 910, an array of at least one electrode pair is selectively activated in a preferred region in a preferred orientation. A first electrode pair and a second electrode pair in the preferred region may be selectively activated in a preferred orientation to generate a first paired response and a second paired response, respectively. In step 912, one or more electrode pairs that elicit a third erectile response may be determined by comparing the first and second paired responses.

[0136] In step 914, the preferred electrode pair may be selectively activated at different frequencies and current intensities. The preferred electrode pair may be selectively activated in a first mode with a first simulation regimen and in a second mode with a second stimulation regimen employing different stimulation parameters than the first stimulation regimen to generate a first response and a second response. Optionally, in step 916, a mode of activation for erection may be determined by comparing the first mode response and the second mode response. Optionally, in step 918, the comparison may be repeated to determine a mode of activation for functional restoration of at least one cavernous nerve. Optionally, in step 920, the comparison may be repeated to determine a mode of activation for penile functional restoration to reduce penile fibrosis. In step 922, the determined mode of activation may be stored in memory of the programmable controller 300, the external patient controller 400, and / or the physician controller 500.

[0137] 18, an exemplary method for adjusting a preferred mode having a stimulation regimen for functional recovery of nerve transmission in a cavernous nerve is described. In method 1000, steps 1002-1010 are similar to steps 914-918 in method 900. In step 1002, a preferred electrode pair may be selectively activated in a first mode having a first stimulation regimen to generate a first response. In step 1004, a preferred electrode pair may be selectively activated in a second mode having a second stimulation regimen to generate a second response. In step 1006, the first response and the second response may be compared. Optionally, in step 1008, a rapid erection mode of activation may be determined based on the comparison. Optionally, in step 1010, a mode of activation for promoting functional recovery of at least one cavernous nerve may be determined based on the comparison. The nerve functional recovery mode may provide a lower current intensity stimulation than the rapid erection mode of activation. Optionally, in step 1012, the neural recovery mode of activation may be adjusted using machine learning or other types of artificial intelligence. In addition, the preferred electrodes may also be used to measure neural activity, and those measurements may be used in conjunction with artificial intelligence to adjust the neural recovery mode of activation to allow for more efficient or effective neural transmission. Alternatively, the method of FIG. 18 may be used to adjust a stimulation regimen to produce an erection or a penile recovery stimulation regimen to reduce fibrosis.

[0138] In addition to stimulation regimens for causing rapid erectile response, restoring neural transmission within the cavernous nerve, or reducing penile fibrosis, the systems and methods described herein may be used to treat urinary incontinence, for example, by electrically stimulating one or more nerves of the lower urinary tract.As described above, electrical stimulation of the pelvic floor may promote nerve regeneration and thus help improve urinary function following radical prostatectomy.In particular, low-intensity stimulation may re-establish nerve function by promoting axonal regrowth and reconnection.

[0139] 19, a schematic diagram of the local anatomy is shown. Nerves that control the lower urinary tract include the pelvic parasympathetic nerve, the hypogastric sympathetic nerve, and the pudendal nerve. The flexible paddle is preferably configured such that the pudendal nerve, which controls the external sphincter, is stimulated. However, depending on the implantation location of the flexible paddle and the configuration of the electrodes, additional nerves not in direct contact with the electrodes may also be restored to function, including the hypogastric sympathetic nerve.

[0140] 20A and 20B, cross-sectional side views of an exemplary flexible paddle are shown. Flexible paddles 202 similar to those shown in FIGS. 2A and 2B may be used to treat urinary incontinence. In particular, an implantable stimulation unit may include first and second flexible paddles 202, each with an array of electrodes 204 and suture holes, a cable, and a programmable controller, as described above. The electrodes 204 may be arranged in multiple rows and multiple columns, and may apply bipolar stimulation such that current passes from one electrode to another to stimulate a nerve or nerve group disposed therebetween. The flexible paddles 202 are preferably sized and shaped to be adjacent to at least a portion of a patient's pelvic plexus. The first flexible substrate is configured to conform to a first half of the pelvic plexus, and the second flexible paddle is configured to conform to a second half of the pelvic plexus. The flexible paddle can bend and form an arc shape to conform to the pelvic plexus, for example, implanted over the pelvic plexus during a prostatectomy surgery. Preferably, the flexible paddle 202 conforms to the anatomical shape of a portion of the pelvic plexus and covers part or all of the area of ​​the pelvic plexus so that the electrode 204 is in optimal contact with the pudendal nerve. The flexible paddle can comprise a structural matrix of silicone or other flexible, electrically non-conductive material that allows it to conform and mold to the local anatomy, optimizing placement and minimizing tissue reaction. The flexible paddle can have a flat structure designed in a suitable shape (e.g., hemispherical, rectangular, square, oval, elliptical, or trapezoidal) and sized to better fit each patient's anatomy and needs.

[0141] As shown in Fig. 20A, the flexible paddle 202 may include a first plurality of electrodes 204a on a first surface of the paddle. As shown in Fig. 20B, the flexible paddle 202 may additionally include a second plurality of electrodes 204b on a second surface opposite the first surface of the paddle. The embodiment of Fig. 20B may be particularly beneficial for treating urinary incontinence, since damaged nerves, such as the hypogastric sympathetic nerve, may not be adjacent to the pelvic floor. Because low intensity stimulation is used to restore function to one or more nerves that control the lower urinary tract, a larger portion of the pelvic plexus may be stimulated without adverse effects.

[0142] 20C and 20D are perspective views with inset detail views showing the placement of the flexible paddle of FIG. 20A and 20B positioned on the patient's pelvic plexus. Preferably, the flexible paddle 202 is positioned relative to the pelvic plexus such that the paddle surrounds the urethra and is adjacent to the pudendal nerve. FIG. 20D shows the implantation of the flexible paddle of FIG. 20B with a first plurality of electrodes 204c and a second plurality of electrodes 204d on opposing surfaces of the paddle. The first plurality of electrodes 204c may be configured to stimulate nerves near the pelvic floor, and the second plurality of electrodes 204d may be configured to stimulate nerves near the bladder neck and internal sphincter. Notably, this configuration allows a larger area to be stimulated, which may result in functional recovery and regeneration of the pudendal nerve as well as the hypogastric sympathetic nerve, or other nerves not in direct contact with the electrodes.

[0143] The low intensity stimulation can be designed to promote the regrowth of damaged axons and reconnection of nerves, and preferably not activate nerves. Thus, the patient should not be able to perceive the stimulation and there should be no physiological response. In some embodiments, the optimal electrode pair does not need to be determined. Instead, preferably, all electrodes on each flexible paddle are activated, which increases the area of ​​the pelvic plexus, stimulating all nerves in the region and promoting their regeneration. Alternatively, only one electrode pair or multiple electrode pairs on each flexible paddle can be activated.

[0144] Preferably, the bladder nerve function recovery stimulation mode has a low current intensity similar to the current intensity for the nerve function recovery stimulation mode for restoring at least one cavernous nerve. For example, the bladder nerve function recovery stimulation regimen may apply a current amplitude in the range of 0.1-2 mA, a frequency in the range of 10-48 Hz, and a pulse width in the range of 0.01-1 ms. The programmable controller may be programmed to automatically execute the bladder nerve function recovery stimulation pulse sequence at least once a day for at least one hour, at one or more defined times (e.g., immediately before the patient awakens).

[0145] As described above, the programmable controller may be controlled by an external patient controller. The external patient controller preferably includes a user interface that allows a user, e.g., a patient, a physician, a caregiver, to adjust a limited number of operating parameters of the programmable controller, including starting and stopping a bladder nerve function recovery stimulation session. The external physician controller may be programmed to communicate with the external patient controller and the programmable controller. The external physician controller may be used to store in the non-volatile memory of the programmable controller a bladder nerve function recovery stimulation regimen that, when activated on demand by the external patient controller or automatically by the programmable controller at a pre-set time, restores neural transmission in the nerves that control the lower urinary tract.

[0146] Although various illustrative embodiments of the present invention are described above, it will be apparent to those skilled in the art that various changes and modifications can be made therein without departing from the invention. The appended claims are intended to cover all such changes and modifications that fall within the true scope of the present invention.

Claims

1. 1. An implantable system for treating erectile dysfunction, comprising: a flexible paddle having an array of electrodes; a programmable controller having a stimulation circuit, a microprocessor and a memory; Equipped with The stimulation circuitry is operably coupled to the array, and the microprocessor comprises: causing the stimulation circuit to selectively activate a first pair of electrodes of the array to generate a first current flow therebetween in a first direction, the first current flow configured to stimulate the cavernous nerve and elicit a first erectile response; causing the stimulation circuit to selectively activate a second pair of electrodes of the array to generate a second current flow therebetween in a second direction, the second direction being different from the first direction, the second current flow being configured to stimulate the cavernous nerve and elicit a second erectile response; identifying either the first erectile response or the second erectile response as a first preferred erectile response; storing an identification of either the first direction or the second direction as a preferred current direction for subsequent stimulation of the cavernous nerve; 20. An embeddable system configured to execute programmed instructions stored in the memory to perform the steps of:

2. 2. The implantable system of claim 1, wherein the programmed instructions identify either the first erectile response or the second erectile response as the first preferred erectile response in response to input generated by a sensor system associated with the programmable controller.

3. 2. The implantable system of claim 1, wherein the programmed instructions identify either the first erectile response or the second erectile response as the first preferred erectile response in response to input provided by an external patient controller or an external physician controller.

4. The array of electrodes comprises a first region and a second region, and the microprocessor comprises: causing the stimulation circuit to selectively activate electrodes in the first region with the preferred current direction to generate a third erectile response; causing the stimulation circuit to selectively activate electrodes in the second region with the preferred current direction to generate a fourth erectile response; identifying either the third erectile response or the fourth erectile response as a second preferred erectile response; storing an identification of either said first region or said second region as a preferred region; 10. The embeddable system of claim 1, further configured to execute programmed instructions stored in the memory for:

5. 5. The implantable system of claim 4, wherein the programmed instructions identify either the third erectile response or the fourth erectile response as a second preferred erectile response in response to input generated by a sensor system associated with the programmable controller.

6. 5. The implantable system of claim 4, wherein the programmed instructions identify either the third erectile response or the fourth erectile response as a second preferred erectile response in response to input provided by an external patient controller or an external physician controller.

7. The microprocessor includes: causing the stimulation circuit to sequentially activate a subset of electrodes in the preferred region with the preferred current direction to elicit a sequence of erectile responses; identifying a preferred erectile response from among said range of erectile responses; storing an identification of at least a subset of electrodes within said preferred region as a set of preferred excitation electrodes for subsequent stimulation of said cavernous nerve; 5. The implantable system of claim 4, further configured to execute programmed instructions stored in the memory for:

8. 8. The implantable system of claim 7, wherein the programmed instructions identify the preferred erectile response from among the range of erectile responses in response to inputs generated by a sensor system associated with the programmable controller.

9. 8. The implantable system of claim 7, wherein the programmed instructions identify the preferred erectile response from among the range of erectile responses in response to input provided by an external patient controller or an external physician controller.

10. The microprocessor includes: causing the stimulation circuit to selectively activate the preferred set of excitation electrodes with a series of stimulation parameters in the preferred current direction to elicit a further series of erectile responses; identifying an optimal response from among said series of further erectile responses; storing the stimulation parameters that elicit the optimal response as preferred stimulation parameters.

8. The implantable system of claim 7, further configured to execute programmed instructions stored in the memory for:

11. 11. The implantable system of claim 10, wherein the programmed instructions identify the optimal response from among the series of further erectile responses in response to inputs generated by a sensor system associated with the programmable controller.

12. 11. The implantable system of claim 10, wherein the programmed instructions are responsive to input provided by an external patient controller or an external physician controller to identify the optimal response from among the series of further erectile responses.

13. 11. The implantable system of claim 10, wherein the programmed instructions storing the preferred stimulation parameters store stimulation parameters that elicit a rapid erectile response.

14. 11. The implantable system of claim 10, wherein the programmed instructions storing the preferred stimulation parameters store stimulation parameters that restore neurotransmission through the cavernous nerve.

15. 11. The implantable system of claim 10, wherein the programmed instructions determining the preferred current direction, the preferred region, the preferred set of excitation electrodes, and the preferred stimulation parameters are configured to be executed periodically after the implantable system is implanted in response to commands from an external patient controller or an external physician controller.

16. 11. The implantable system of claim 10, wherein the programmable controller is configured to adjust the preferred stimulation parameters using at least one of machine learning or artificial intelligence.

17. 14. The implantable system of claim 13, wherein the programmable controller is configured to activate the stimulation circuitry and apply the stimulation parameters that elicit a rapid erectile response in response to commands received from an external patient controller.

18. 15. The implantable system of claim 14, wherein the programmable controller is configured to automatically activate the stimulation circuitry and apply the stimulation parameters to restore neurotransmission at least once per day.

19. The implantable system of claim 1 , wherein the flexible paddle is configured to be implanted in a pelvic plexus via laparoscopic surgery.

20. The implantable system of claim 1 , wherein the flexible paddle has a hemispherical shape and the array of electrodes comprises at least two electrode rows and at least two electrode columns.

21. The implantable system of claim 1 , wherein the second direction of the second current flow is oblique to the first direction of the first current flow.

22. 1. An implantable system for reducing penile fibrosis following prostatectomy, the system comprising: a flexible paddle having an array of electrodes configured to be placed adjacent a pelvic plexus of a patient; a programmable controller having a stimulation circuit, a microprocessor and a memory; Equipped with the stimulation circuitry is operably coupled to the array, and the microprocessor is configured to execute programmed instructions stored in the memory, the instructions causing the stimulation circuitry to selectively activate a set of excitation electrodes in the array of electrodes to stimulate one or more nerves of a pelvic plexus of the patient to induce at least partial penile tumescence; An implantable system, wherein the programmed instructions cause activation of the stimulation circuitry at least once per day during the recovery period following a prostatectomy to reduce the risk of penile fibrosis.

23. 1. An implantable system for treating erectile dysfunction, comprising: a flexible paddle having an array of electrodes configured to be placed adjacent a pelvic plexus of a patient; a programmable controller having a stimulation circuit, a microprocessor and a memory; Equipped with The stimulation circuitry is operably coupled to the array, and the microprocessor comprises: in response to "on-demand" input from an external patient controller or an external physician controller, causing the stimulation circuitry to activate a subset of electrodes in the array in accordance with a first set of stimulation parameters to elicit an erection; at least daily, in response to a schedule input from the external patient controller or the external physician controller, activating a subset of the electrodes in the array with a second set of stimulation parameters to elicit an erectile response that promotes recovery of penile function.

20. An embeddable system configured to execute programmed instructions stored in the memory to perform the steps of:

24. 1. An implantable system for treating urinary incontinence, the system comprising: a flexible paddle having an array of electrodes disposed on a first side thereof, the flexible paddle being configured to be positioned adjacent a pelvic plexus of the patient; a programmable controller having a stimulation circuit, a microprocessor and a memory; Equipped with the stimulation circuit is operably coupled to the array, and the microprocessor is configured to execute programmed instructions stored in the memory, the instructions causing the stimulation circuit to activate at least one electrode pair of the array of electrodes to stimulate at least one nerve associated with control of a bladder sphincter and promote functional recovery of the at least one nerve; The programmed instructions cause activation of the stimulation circuitry at least once per day.

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