Electrical stimulation system and method for functional rehabilitation and treatment of pelvic disorders

Abstract

An implantable stimulation system having a programmable controller, a stimulation circuit, and a stimulation unit coupled to 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 implantable stimulation system can be programmed to activate a first stimulation pulse sequence corresponding to a first mode for inducing a rapid erectile response for sexual intercourse and potentially ejaculation, a second mode for inducing a rapid erectile response sufficient to facilitate a medical procedure such as application of a urethral catheter, a third nerve function restoration stimulation mode for restoring nerve conduction and thereby treating urinary incontinence and / or bowel dysfunction, and / or a fourth penile function restoration mode for reducing penile fibrosis. Methods of operating the system are also provided.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of priority to U.S. Provisional Patent Application No. 63 / 487,859, filed March 1, 2023, the entire contents of which are incorporated herein by reference. This application is also related to U.S. Patent Application No. 17 / 450,392, filed October 8, 2021, U.S. Patent Application No. 17 / 174,033 (now U.S. Patent No. 11,141,590), filed February 11, 2021, and U.S. Patent Application No. 18 / 264,753, filed August 8, 2023, which claims priority to PCT / IB2022 / 051127, published as WO2022 / 172157, filed February 8, 2022, which claims priority to U.S. Patent Application No. 17 / 174,021 (now U.S. Patent No. 11,141,589), filed February 11, 2021, the entire contents of each of which are incorporated herein by reference.

[0002] FIELD OF THE INVENTION The present disclosure relates to improved implantable electrical stimulation systems and methods for treating and preventing pelvic disorders such as sexual disorders, including, for example, 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 cavernous nerve function, reduce penile fibrosis, treat urinary incontinence, and / or treat bowel dysfunction. [Background technology]

[0003] Sexual disorders (e.g., sexual dysfunction, sexual abnormalities) 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 an individual's quality of life. The most widely recognized sexual disorders are erectile dysfunction (ED) and female sexual arousal disorder (FSAD).

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

[0005] ED is a multicause disease with diverse etiologies and can be psychogenic, vascular, hormonal, or neurogenic. However, research indicates that neurogenic and vascular causes are most prevalent. In general, the primary mechanisms involved in ED are a breakdown in neuronal responses (e.g., prostatectomy, cystectomy, abdominoperineal resection, spinal cord injury, or diabetes) or increased tone and / or contractility of smooth muscle within the corpus cavernosum and penile arteries (e.g., hypertension, atherosclerosis, and diabetes). See Sadeghi-Nejad H., Penile prosthesis surgery: a review of prosthetic devices and associated complications, Sex Med. 2007 Mar;4(2):296-309.

[0006] Prostatectomy is known to cause serious erectile dysfunction (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 attempt to perform nerve-sparing surgery. However, in a real-world scenario, a surprising 70% of patients undergoing 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 effective for the majority of ED patients. However, they show low efficacy for ED resulting from prostatectomy or other causes associated with dysfunction in neuronal responses. Such drugs work 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 regulating several protein-dependent kinases, which relax smooth muscle cells and promote erection. Therefore, patients with disrupted erectile nerve responses do not respond well to such medications. One alternative for these patients is intrapenile injection of vasodilators, which directly produce an erection independent of the nerve 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 a 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 typically require irreversible and destructive surgery with associated risks of intraoperative and postoperative complications. Such prostheses frequently require revision surgery. Nevertheless, prosthesis implantation is a common procedure due to the lack of better treatment options. Therefore, there is a clear need for better therapeutic strategies for the treatment of erectile dysfunction resulting from neural pathway dysfunction, 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 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 perineal 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. Electrical nerve stimulation for erectile response is therefore considered an option for patients undergoing prostatectomy. However, a barrier to the development of such techniques 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, considerable anatomical variability exists in the location of the cavernous nerve. The pelvic plexus is a transparent veil of 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 nerve stimulation 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 identity of the pudendal nerve and / or other nerve pathway to be stimulated must be located prior to implantation.

[0011] Recently, significant progress has been made in achieving practical electrical nerve stimulation systems for the treatment of erectile dysfunction (ED) that allow for the localization and identification of cavernous nerves 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 electrical nerve stimulation systems in which electrodes are stimulated after implantation to experimentally determine a preferred electrode excitation configuration for achieving sexual arousal. While the inventions described in those patents represent a significant advance in the use of electrical nerve stimulation to treat erectile dysfunction (ED), it would be desirable to provide a method for reliably determining the electrode excitation configuration for producing excitation that 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 typically takes a long time, which may last for several years.During the recovery period, permanent damage to the penis occurs, and some 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 penile function restoration 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, RLet al., Current penile-rehabilitation strategies: Clinical evidence, Arab J Urol,2013.11(3):230-6, Gandaglia, G., et al., Penile See 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 leads to internal fibrosis, deterioration of penile structure, and progressive worsening of ED, leading to a permanent state 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 erections and spontaneous erections during sleep play important roles in maintaining organ oxygenation and function. In contrast, prolonged inability to achieve erection leads to chronic penile hypoxia and consequent profibrogenic 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):562-70. This unfavorable local intrapenile environment can lead to increased apoptosis and collagen production, altering cavernous architecture. 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):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 treatments should preferably be applied until nerve regeneration is achieved, which can take 12 to 18 months, or even several years, after prostatectomy. Currently, the state-of-the-art involves 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):998-1008. Collectively, clinical trials using these approaches have reported little or no improvement. See Clavell-Hernandez, Fode.

[0016] Furthermore, the reproductive potential of patients with spinal cord injury (SCI) is considered to be eliminated or severely impaired. See Beretta, G., et al., Reproductive Aspects in Spinal Cord Injured Males, Paraplegia 27 (1989): 113-18. Infertility in paraplegic men is determined by two major factors: (1) the inability of most patients with SCI to ejaculate, and (2) when ejaculation is possible, the characteristics of semen are always abnormal. Most men with SCI have severely impaired fertility characterized by erectile dysfunction (ED), ejaculatory dysfunction, and semen abnormalities. See Brackett, N.L., et al., Treatment of Infertility in Men with Spinal Cord Injury, Urology 7 (2010): 162-72. Specifically, men with SCI have a unique semen profile characterized by normal sperm counts but abnormally low sperm motility and viability. Despite the abnormality, sperm from men with SCI can successfully induce pregnancy. In selected couples, the simple method of intravaginal insemination is a viable option. Another option is intrauterine insemination (IUI), whose effectiveness increases as the total number of motile sperm inseminated increases. In vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) are additional options in cases of extremely low total motile sperm counts. For men with SCI, penile vibratory stimulation (PVS) is recommended as a first-line treatment for eliciting ejaculation because it is a simple procedure and safe enough to be employed at home after short training. Patients for whom penile vibratory stimulation does not work can be referred to electroejaculation, in which a probe is inserted into the rectum and an electric current is delivered through the probe to induce semen release. If this approach is not possible, the physician may attempt to mechanically force the sperm out through the ejaculatory duct system by performing a prostate massage and using a finger inserted into the rectum to compress the prostate and seminal vesicles. As a last resort, surgical sperm retrieval may be considered when other methods fail.Therefore, assisted ejaculation methods should be employed before proceeding to methods that avoid ejaculation, as the former approach is less invasive and results in a higher number of total motile sperm than the latter. A higher total motile sperm yield expands options when choosing a method of assisted conception.

[0017] The drawback to surgical sperm retrieval as a first option is that it forces couples to undertake IVF / ICSI, the most invasive and expensive form of assisted conception treatment. In contrast, the ejaculates of men with SCI often contain enough motile sperm to consider the options of IUI or even intravaginal insemination. It is recommended that intravaginal insemination or IUI procedures be considered before proceeding with assisted reproductive technologies such as IVF / ICSI. The reality of having a very reasonable chance of achieving biological paternity has a positive impact on couples' relationships and resulted in improved quality of life. See Ibrahim, E., et al., Male Fertility Following Spinal Cord Injury: An Update, Andrology 4 (2016): 13-26. Comparison of baseline semen characteristics with those after repeated weekly PVS over a 3-month period was found to have higher sperm concentrations, improved motility, and a decrease in abnormal sperm morphology. See Trofimenko, V., et al., Fertility Treatment in Spinal Cord Injury and Other Neurologic Disease, Translational Andrology and Urology, 5(1)(2016):102-116. Another study of SCI patients with antegrade ejaculation assigned weekly PVS for 4 to 6 months demonstrated not only improved osmotic capacity but also increased seminal volume and fructose content in seminal plasma, the latter suggesting improved function of the seminal vesicles and prostate. While the semen extraction methods described above represent a significant advance in fertility for men with SCI, it would be desirable to provide methods for inducing ejaculation and improving sperm motility to improve the chances of biological fatherhood and quality of life for men with SCI.

[0018] Another complication that can 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 can 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) can improve urinary incontinence. Early EPFS was performed with external stimulation devices such as anal and / or vaginal electrodes, but these devices are associated with several side effects, including pain during stimulation or leakage of electrical current from the device into the applied mucosa, which can cause damage to the mucosa.

[0019] The primary cause of post-prostatectomy urinary incontinence has been attributed to sphincter insufficiency. Currently, pelvic floor muscle training (PFMT) is the most widely recommended non-invasive method for preventing urinary incontinence following radical prostatectomy. Nevertheless, it can take several months to regain continence, and some patients may have persistent incontinence despite continued attempts to restore function. Electrical stimulation of the pudendal nerve and its branches can produce direct and reflex responses in 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 promote nerve regeneration and thus help improve urinary function following radical prostatectomy.See 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 biofeedback associated treatment," The Journal of Urology, Vol. 181, 4 (2009): 1788-93; and Yokoyama, Teruhiko et al., "Comparative study of effects of extracorporeal magnetic innervation versus electrical stimulation for urinary incontinence after radical prostatectomy," Urology, Vol. 63, 2 (2004): 264-7. Patients with spinal cord injury also typically face problems with bowel function.

[0020] 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 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]

[0021] [Patent Document 1] U.S. Patent No. 4,585,005 [Patent Document 2] U.S. Patent No. 9,821,163 Summary of the Invention [Means for solving the problem]

[0022] The present disclosure provides neuroelectrical stimulation systems and methods for treating sexual disorders, including in patients who are unable to spontaneously obtain penile erections (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.

[0023] An electrical stimulation system for treating a sexual disorder, e.g., 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, the entireties of which are incorporated herein by reference. The implantable stimulation unit includes an array of electrodes disposed on an implantable paddle and a power supply, which may be rechargeable.

[0024] In accordance with the principles of the present invention, the programmable controller of the implantable stimulation unit is pre-programmed with a routine 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 function after implantation, and / or reduce penile fibrosis. The pre-programmed routine may subsequently 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.

[0025] In a preferred embodiment, the implantable stimulation unit includes an array of electrodes disposed on a pair of flexible paddles sized and shaped for implantation 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 nonvolatile memory, and a microprocessor coupled to the stimulation circuit and the nonvolatile memory. According to one aspect of the invention, the programmable controller is preprogrammed to selectively scan the electrode arrays on the paddles with a series of directional current flows in at least two regions and in at least two directions, optimizing electrode selection for use in stimulating the patient's cavernous nerve.

[0026] Upon completion of the electrode selection and 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 induce 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.

[0027] In a preferred embodiment, the programmable controller initiates a preprogrammed electrode configuration process, causing the stimulation circuit to selectively activate a first series of electrode pairs in the electrode array and generate a first current flow therebetween in a first direction, stimulating the cavernous nerve and eliciting a first erectile response. Subsequently, the electrode configuration process selectively activates a second series of electrode pairs in the electrode array and generates a second current flow therebetween in a second direction that is different from and may be oblique to the first direction, stimulating the cavernous nerve and eliciting 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 can 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.

[0028] The programmable controller then causes the stimulation circuitry to selectively activate subsets of the electrode array to stimulate the cavernous nerve in at least first and second regions 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.

[0029] The programmable controller then causes the stimulation circuit 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.

[0030] Once the preferred excitation region, including the preferred excitation electrodes with directional current flow, has been determined, the programmable controller selectively activates the stimulation circuit and defines at least a first stimulation mode in which the applied electrical stimulation induces a rapid erectile response. Specifically, the programmable controller causes the stimulation circuit to sequentially apply first and second stimulation regimens employing different stimulation parameters, 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 non-volatile memory. In a preferred embodiment, the system of the present invention may include an external controller that the patient can operate in an "on-demand" mode, for example, by pressing a button to activate the implantable stimulation unit and induce a rapid erectile response.

[0031] According to another aspect of the present invention, the programmable controller may also determine a second nerve function restoration stimulation mode corresponding to a lower current intensity than the first stimulation mode. For example, the nerve function restoration stimulation mode may have a set of stimulation parameters that apply a current amplitude within a range of 0.1 to 2 mA with a pulse width of 0.01 to 1.0 milliseconds at a frequency of 10 to 48 Hz, while the first stimulation mode may have a set of stimulation parameters that apply a current amplitude within a 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 nerve function restoration 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 a nerve function restoration stimulation pulse sequence at one or more predetermined times, for example, immediately before the patient awakens, at least once daily.

[0032] According to another aspect of the present invention, the programmable controller may also provide a third penile function restoration stimulation mode corresponding to a higher current intensity than the second stimulation mode. For example, the penile function restoration stimulation mode may have a set of stimulation parameters that apply a current amplitude within the range of 0.5 to 25 mA at a frequency of 10 to 48 Hz, with a pulse width of 0.1 to 1.0 milliseconds. The penile function restoration mode is designed to induce at least a partial penile erection, 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 erection, and the programmed instructions may store the set of stimulation parameters that produces the highest degree of penile erection as the optimal set of stimulation parameters. More preferably, the programmable controller may be programmed to automatically execute the penile function restoration stimulation pulse sequence at one or more predetermined times, for example, immediately before the patient awakens, at least once daily. 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 daily.

[0033] Furthermore, in accordance with the principles of the present invention, the programmable controller can 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 can be reoptimized to address, for example, tissue encapsulation and take into account the healing response of the tissue surrounding the implantable stimulation unit. Additionally, such reoptimization programming can 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 initially required after implantation. Such adjustments can be made under physician or patient control. Alternatively, adjustments to the excitation electrode configuration and / or stimulation regimen of the first, second, and / or third stimulation modes can be made using at least one of machine learning or other forms of artificial intelligence.

[0034] The external patient controller may be configured to respond to patient input to selectively activate the implantable stimulation unit, activate the excitation electrode configuration process, and / or refine the stimulation prescription 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 re-optimizing the electrode configuration and stimulation prescription 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.

[0035] 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. 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.

[0036] 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.

[0037] The flexible paddles with electrode arrays 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 flexible paddle 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 a 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 within and / or through the paddle and anchor the paddle adjacent to the pelvic plexus.

[0038] Also provided herein are 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 produce a rapid erectile response, restore neural conduction, or reduce penile fibrosis, and methods of using the system. The implantable stimulation unit and flexible paddles can be sized and shaped for implantation using a robotically guided surgical system or laparoscopically.

[0039] According to another aspect of the present invention, the system can be used to treat urinary incontinence, for example, by electrically stimulating one or more nerves in the lower urinary tract. Electrical stimulation of the pelvic floor can promote nerve regeneration and thus help improve urinary function following radical prostatectomy. In particular, low-intensity stimulation can re-establish nerve function by promoting axonal regrowth and reconnection.

[0040] The programmable controller may cause the stimulation circuit 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 to 2 mA, a frequency in the range of 10 to 48 Hz, and a pulse width in the range of 0.01 to 1 millisecond, and may be performed automatically for at least one hour per day following prostatectomy.

[0041] The flexible paddle may further include a second array of electrodes disposed on a second side opposite the first side, and 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.

[0042] Also provided herein is a method for treating urinary incontinence using the system described above. 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 location adjacent to a pelvic plexus, coupling a programmable controller to the array of electrodes, and executing programmed instructions in 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 control of the bladder sphincter.

[0043] According to another aspect of the present invention, an implantable system for treating pelvic disorders is provided. The system may include a flexible paddle having an array of electrodes disposed on a first side thereof, the flexible paddle configured to be positioned adjacent to a patient's pelvic plexus, and a programmable controller including a stimulation circuit, a microprocessor, and a memory, the stimulation circuit operably coupled to the array, the microprocessor configured to execute programmed instructions stored in the memory to cause the stimulation circuit to activate at least one electrode pair of the array of electrodes to stimulate at least one nerve to promote functional recovery of the at least one nerve. The programmed instructions may cause activation of the stimulation circuit at least once daily.

[0044] For example, the microprocessor may be configured to execute programmed instructions stored in the memory to cause 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 the patient's bladder sphincter to promote functional recovery of the at least one nerve, thereby treating urinary incontinence. Additionally or alternatively, the microprocessor may be configured to execute programmed instructions stored in the memory to cause 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 the patient's lower intestinal tract to promote functional recovery of the at least one nerve, thereby treating bowel dysfunction. [Brief explanation of the drawings]

[0045] 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.

[0046] [Figure 1] FIG. 1 is a schematic diagram of an exemplary electrical stimulation system constructed in accordance with the principles of the present disclosure.

[0047] [Figure 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.

[0048] [Figure 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.

[0049] [Figure 4-1] 4A and 4B are side cross-sectional and perspective views, respectively, of different electrode shapes for use in the flexible paddles of FIGS. 2 and 3, while FIGS. 4C-4E depict the charge distribution across the various electrode shapes depicted in FIGS. 4A and 4B. [Figure 4-2] 4A and 4B are side cross-sectional and perspective views, respectively, of different electrode shapes for use in the flexible paddles of FIGS. 2 and 3, while FIGS. 4C-4E depict the charge distribution across the various electrode shapes depicted in FIGS. 4A and 4B.

[0050] [Figure 5] FIG. 5 depicts a generalized block diagram of an exemplary programmable controller of the implantable stimulation unit of the stimulation system of FIG.

[0051] [Figure 6] FIG. 6 depicts a generalized block diagram of an exemplary external patient controller of the stimulation system of FIG.

[0052] [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.

[0053] [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.

[0054] [Figure 9] 9A and 9B are plan views each showing an alternative placement of a flexible paddle of the present invention relative to a patient's urethra.

[0055] [Figure 10] 10A-10C depict various directional current flows between adjacent electrode pairs disposed on the flexible paddle of FIG. 2A.

[0056] [Figure 11] 11A-11C depict illustrative regions within the electrode array of the flexible paddle of FIG. 2A.

[0057] [Figure 12] 12A-12C depict the selection of preferred electrode pairs within various electrode regions according to the present invention.

[0058] [Figure 13] FIG. 13 depicts an exemplary method of defining preferred excitation electrodes and regions for use in electrical neurostimulation to obtain sexual arousal.

[0059] [Figure 14] FIG. 14 illustrates a method for intraoperative scanning of sequentially adjacent electrode pairs in accordance with the principles of the present invention.

[0060] [Figure 15] FIG. 15 is a flowchart 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.

[0061] [Figure 16]FIG. 16 is a flowchart 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.

[0062] [Figure 17] FIG. 17 is a flowchart illustrating steps of an exemplary method for determining an optimal stimulation regimen for producing an erection, for restoring function of at least one cavernous nerve, and / or for restoring penile function to reduce penile fibrosis.

[0063] [Figure 18] FIG. 18 is a flow chart illustrating steps of an exemplary method for adjusting the optimal mode for functional recovery after a time interval after implantation.

[0064] [Figure 19A] 19A-19E illustrate the results of a Qualiveen questionnaire completed by a spinal cord injury patient suffering from urinary problems. [Figure 19B] 19A-19E illustrate the results of a Qualiveen questionnaire completed by a spinal cord injury patient suffering from urinary problems. [Figure 19C] 19A-19E illustrate the results of a Qualiveen questionnaire completed by a spinal cord injury patient suffering from urinary problems. [Figure 19D] 19A-19E illustrate the results of a Qualiveen questionnaire completed by a spinal cord injury patient suffering from urinary problems. [Figure 19E] 19A-19E illustrate the results of a Qualiveen questionnaire completed by a spinal cord injury patient suffering from urinary problems.

[0065] [Figure 20] FIG. 20 is a schematic diagram of the local anatomy in the male pelvic region.

[0066] [Figure 21-1]21A and 21B are cross-sectional side views of an exemplary flexible paddle.

[0067] [Figure 21-2] 21C and 21D are perspective views with inset details showing placement of the flexible paddles of FIGS. 21A and 21B positioned over the patient's pelvic plexus, respectively.

[0068] [Figure 22] FIG. 22 is a plan view of another alternative embodiment of a flexible paddle suitable for use with the electrical stimulation system of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0069] The systems and methods described herein may be used to treat sexual disorders, e.g., 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), and pelvic disorders such as female sexual arousal disorder (FSAD), as well as other pelvic disorders such as urinary incontinence and bowel dysfunction.

[0070] 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 triggers the erectile response is parasympathetic input originating from the pelvic splanchnic plexus. The pelvic splanchnic plexus is composed of branches from the second, third, and fourth sacral nerves, intertwining with the inferior hypogastric plexus and forming a network of nerves within the pelvis. The cavernous nerve derives from the pelvic splanchnic nerve and travels through and along the prostatic plexus, located approximately around the prostate, to supply parasympathetic fibers to the corpora cavernosa and corpora spongiosum of the penis. Therefore, locating the optimal site for electrical nerve stimulation is challenging because the human cavernous nerve travels through complex anastomoses from the pelvic plexus to the penis. Furthermore, considerable anatomical variability exists 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 of microscopic nerves, and the cavernous nerves do 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.

[0071] Referring 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.

[0072] 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 paddle includes an array of electrodes 204 and a suture hole 206), a cable 208, and a programmable controller 300. Each electrode 204 can 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 a physician controller 500). The electrodes 204 can be uniformly spaced and / or arranged in different spatial configurations. For example, the electrodes 204 can 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 example, the electrodes 204 may be arranged in multiple rows and columns, with the number of electrodes 204 varying from approximately 10 to over 50 electrodes, as needed. The electrodes 204 may apply bipolar stimulation such that current passes from one electrode to another, stimulating the nerve or nerve group 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 so that convex, spherical, or flat portions 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.

[0073] The flexible paddle 202 is preferably sized and shaped to be adjacent to at least a portion of a patient's pelvic plexus. As shown in FIGS. 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 paddles 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 part or all of the area of ​​the pelvic plexus so that the electrodes 204 optimally contact the cavernous nerves. 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 be designed in a suitable shape (e.g., hemispherical, rectangular, square, oval, elliptical, or trapezoidal) and have a flat structure sized to better fit the anatomy and needs of each patient.

[0074] 1, implantable stimulation unit 200 includes a first array of electrodes 204 disposed on first flexible paddle 202a and a second array of electrodes 204 disposed on second flexible paddle 202b. Programmable controller 300 is preferably programmed to activate stimulation circuitry to simultaneously apply bilateral electrical stimulation to the patient's erectile function to one or more electrodes 204 disposed on first flexible paddle 202a and one or more electrodes 204 disposed on second flexible paddle 202b.

[0075] The implantable stimulation unit 200 may preferably include at least one anchor individually coupled to the flexible paddle to maintain the flexible paddle in contact with the pelvic plexus. The anchor may be comprised of 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 sutures may anchor the flexible paddle to the pelvic plexus. The implantable stimulation unit 200 may be encapsulated within one or more biocompatible materials (e.g., titanium cage, silicone cage) suitable for long-term implantation. 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, enhancing anchorage and fixation within the pelvic cavity.

[0076] A cable 208 electrically couples the electrodes 204 of the flexible paddles 202 a and 202 b 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 202 a and the second flexible paddle 202 b.

[0077] 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.

[0078] 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, or caregiver, to adjust a limited number of operating parameters of the programmable controller 300, including starting and stopping stimulation sessions. The programmable controllers 300 communicate with the external patient controller 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.

[0079] 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, e.g., the electrodes used to apply the stimulation, the pulse duration, the frequency, voltage, current, and duration of the AC 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 in 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.

[0080] The external patient controller 400 may be specifically designed for use with the implantable stimulation unit 200 and 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® protocols for communication with those devices. TM Specifically, the external patient controller can be programmed to selectively activate the programmable controller 300 in response to patient input.

[0081] 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 executed 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 so 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 also 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, voltage, current of the alternating current, and duration of stimulation. The external physician controller 500 may also 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 identification of those electrodes and a stimulation routine sufficient to induce, for example, sexual arousal for sexual intercourse and potentially ejaculation, an erection sufficient to facilitate a medical procedure such as application of a urinary catheter, or nerve or penile function restoration, as further described below.

[0082] 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 protocol may cause the microprocessor of the programmable controller 300 to deliver electrical stimulation via the stimulation circuitry in a predetermined manner by selectively activating the electrodes 204 of the array in a predetermined manner, 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, for example, at least one of a stimulation pulse sequence corresponding to an erectile mode of activation for causing an erection sufficient for sexual activity, including an ejaculatory response; a stimulation pulse sequence corresponding to an erectile mode of activation for causing an erection sufficient to facilitate a medical procedure, such as application of a urethral catheter; a nerve function 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 function recovery stimulation pulse sequence corresponding to a functional recovery mode of activation for inducing at least a partial penile erection and reducing penile fibrosis.

[0083] 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 neural or penile functional restoration) in the 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, when activated on demand by the external patient controller 400, will elicit a rapid erectile response sufficient for, e.g., sexual activity; a second stimulation regimen that, when activated on demand by the external patient controller 400, will elicit a rapid erectile response sufficient to facilitate a medical procedure, e.g., application of a urinary catheter; and / or a third stimulation regimen that, when activated at a preset time via the external patient controller 400 or automatically by the programmable controller 300, will provide a lower current intensity and restore neural transmission via at least one cavernous nerve. The stimulation regimen is stored in the memory of the programmable controller 300 so that an erection can be achieved at a later time using those parameters in response to user input, for example, at the external patient controller 400.

[0084] 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 an application or “app” downloaded from an app store, and may use cellular, 802.11 Wifi, Zigbee, and / or Bluetooth 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.

[0085] An external charger 600 may be in electrical communication with the programmable controller 300 and transepidermically charge the programmable controller 300 via a respective induction 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.

[0086] 2A, 2B, and 3, exemplary paddle designs for an implantable stimulation unit are 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 with 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.

[0087] The flexible paddle 202 may bend, e.g., assume an arc shape, and may be implanted to contact the pelvic plexus (e.g., during a prostatectomy surgery). Preferably, the flexible paddle 202 may conform to the anatomical shape of a portion of the pelvic plexus. The flexible paddle 202 may include at least two electrode rows and at least two electrode columns 204. In the preferred embodiment depicted in FIG. 2B , the array of electrodes 204 may include 12 electrodes on each of the first flexible paddle 202 a and the second flexible paddle 202 b. The flexible paddle 202 may have a substantially hemispherical shape including a protruding portion 203, which extends from the corner of the flexible paddle farthest from the cable 208. The hemispherical shape is selected to avoid damaging soft tissue, minimize injury, and reduce fibrous encapsulation that may interfere with the transmission of stimulation pulses from the electrode to the nerve. The protruding portion 203 also allows the 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.

[0088] Still referring to FIG. 2B, a two-paddle embodiment is described. In this embodiment, stimulation unit 200 (see FIG. 1) includes first and second flexible paddles 202a and 202b, each having an array of electrodes 204 and suture holes 206. First and second flexible paddles 202a and 202b are each coupled to programmable controller 300 via cable 208. Alternatively, a single cable 208 may include branches coupling paddles 202a and 202b to programmable controller 300. Because the pelvic plexus generally has two nerve groups, first and second flexible paddles 202a and 202b may each cover part or all of the area of ​​one nerve group such that at least one of the arrays of electrodes 204 contacts the cavernous nerve. For example, first flexible paddle 202a and second flexible paddle 202b may be implanted within a patient with the protruding portions 203 of each hemispherical paddle facing each other, as shown in FIG. 2B. Protruding portions 203 may therefore allow the flexible paddles 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 approximately 2 mm, a length of approximately 32.5 mm, and a width of approximately 18 mm, except that protruding portions 203 extend to a width of approximately 22 mm. First flexible paddle 202a and second flexible paddle 202b may have the same or different dimensions. The distance between the two paddles, once implanted, may be from about 0.5 mm to about 8 cm.

[0089] 4A and 4B, exemplary electrode shapes for use in the implantable stimulation unit 200 are described. Electrodes 204a, 204b, and 204c each have a tissue-friendly shape configured to reduce adverse tissue reactions that can lead to fibrosis formation around the electrode. Electrode 204a has a bulbous portion extending from flexible substrate portion 212 and is independently coupled to the circuitry of programmable controller 300 by cable wire 214a. Electrode 204b has a flat portion extending above the height of flexible substrate portion 212 and is independently coupled to the circuitry of programmable controller 300 by cable wire 214b. Electrode 204c is flat and flush with the surface of flexible substrate portion 212 and is independently coupled to the circuitry of programmable controller 300 by cable wire 214c. Advantageously, each of the electrode shapes does not have sharp surfaces that could damage or inflame tissue. As will be appreciated by those skilled in the art, the array of electrodes 204 may use one, two, or three of these electrode shapes, or other suitable tissue-friendly shapes.

[0090] 4C-4E, exemplary electrode shapes are further described, depicting the surface charge density for each electrode shape. As shown in FIG. 4C, the hemispherical shape of electrode 204a allows for a homogeneous charge distribution across the surface of the electrode, thereby providing efficient transfer of energy from the electrode to the cavernous nerve without damage to surrounding tissue. In contrast, as depicted in FIG. 4D and 4E, the charge distribution of flat disk electrodes 204b and 204c exhibits a large accumulation of charge on the periphery of the electrode, which can impede energy transfer and potentially contribute to tissue damage.

[0091] 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 communications unit 306, system sensors 308, a power supply 310, stimulation circuitry 312, and a demultiplexer 314.

[0092] 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, volatile memory, 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 identification, stimulation parameters, etc.) are stored in 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.

[0093] 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 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 determined to provide a favorable erectile response for a preferred current flow direction. Furthermore, 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 a patient or physician to elicit a favorable, rapid erectile response, or a set of stimulation parameters that provide stimulation determined by a patient or physician to be favorable for restoring or reinforcing neural transmission via at least one cavernous nerve.

[0094] For example, the microprocessor 302 may direct the power supply 310 to send electrical signals to the set of excitation electrodes 204 via the stimulation circuit 312 using a power-discharging demultiplexer 314. The stimulation regimen used by the microprocessor 302 delivers electrical stimulation to at least one cavernous nerve via the stimulation circuit 312 and the pelvic plexus, the electrical stimulation being sufficient to induce sexual arousal (e.g., erection sufficient for sexual activity), to facilitate a medical procedure such as application of a urinary catheter, 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 external physician controller 500. Additionally, as described below, the non-volatile memory 304 stores pre-programmed routines for scanning the array of electrodes to enable identification of excitation electrode sets and stimulation parameters for a preferred stimulation regimen, both initially and at later times after implantation of the implantable stimulation unit 200, as may be directed by the external patient controller 400 or the external physician controller 500. The excitation electrode sets, which provide the best erectile response, for example, for sexual arousal or to facilitate a medical procedure such as application of a urinary catheter, are stored in memory. The identification of the excitation electrode sets may also be stored and transmitted to the external patient controller 400 and / or the external physician controller 500 for later stimulation.

[0095] Stimulation parameters are selected to provide sexual arousal, promote and / or improve nerve regeneration, and treat sexual disorders such as erectile dysfunction and female sexual arousal disorder. For example, stimulation can produce and maintain an erection and promote and / or improve nerve (e.g., pelvic plexus nerves and / or cavernous nerve) regeneration over time. By way of example, pulse duration can 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 AC current can 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 can 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 can be programmed to be about 1 milliamp to about 100 milliamps, about 1 milliamp to about 50 milliamps, about 1 milliamp to about 20 milliamps, about 20 milliamps to about 50 milliamps, about 50 milliamps to about 100 milliamps, or about 75 milliamps to about 100 milliamps. The duration of stimulation can be programmed to stimulate automatically for a predetermined time, or can stimulate in response to user input, for example, at user interface 402. For example, stimulation can be maintained for part or the entire duration of the desired erection. For nerve regeneration, it may be preferable to stimulate over time at predetermined time intervals. For example, automated 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 weekly 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.

[0096] The microprocessor 302 is coupled to a communications unit 306 having circuitry configured to communicate with an external patient controller 400 and / or an external physician controller 500. The communications unit 306 enables the transfer of stimulation commands, and optionally power, between the programmable controller 300 and the external patient controller 400 so that the programmable controller 300 can be powered, programmed, and / or controlled by the external patient controller 400. For example, the microprocessor 302 can 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 communications unit (e.g., an induction unit having a telemetry system and a coil and / or an RF unit having a transceiver and an antenna) of the external patient controller 400. The communications unit 306 further enables the transfer of programming data, and optionally power, between the programmable controller 300 and the external physician controller 500 so that the programmable controller 300 can 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., an induction unit with a telemetry system and coil and / or an RF unit with a transceiver and 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.

[0097] The communications unit 306 may include a telemetry system electrically coupled to the induction 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 communication.

[0098] 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 via the antenna with similar transceiver circuitry located in the external patient controller 400 and / or the external physician controller 500. 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 the corresponding transceivers and antennas of the external patient controller 400 and / or the 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 to a preferred stimulation regimen, including pulse duration, AC 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. Additionally, 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 be a wireless chipset, e.g., Wi-Fi, 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.

[0099] 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, The logged 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 enclosure of the programmable controller 300, which may measure, for example, battery temperature during charging and provide information related to the status of electronic components and / or temperature sensors to ensure safe battery operation. 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.

[0100] 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), for example, by inductive coupling. In a preferred embodiment, the power supply 310 comprises a lithium-ion battery.

[0101] The stimulation circuit 312 is configured to use energy provided by the power supply 310 to transmit pulses to the electrodes 204 such that the selected electrodes deliver electrical stimulation at the desired parameters.

[0102] The microprocessor 302 may further be coupled to a demultiplexer 314 so that any subset of the electrodes 204 in 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.

[0103] 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 communications unit 406, a power supply 408, and input and output circuitry (I / O) 410. As explained 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, communications unit 406, power supply 408, and I / O 410 may be pre-installed hardware on the smartphone, laptop, tablet, smartwatch, etc.

[0104] 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, volatile memory, 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, in response to user input received at the user interface 402 and / or at the external physician controller 500, store changes to the electrodes included in the set of excitation electrodes used for stimulation and to a preferred stimulation regimen, including pulse duration, frequency, voltage, current, and / or duration of stimulation, and transmit stimulation commands and programming data to the programmable controller 300 via the communication unit 406.

[0105] 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 may include a wireless chipset, e.g., Wifi, Bluetooth, TM , cellular, Zigbee®, etc., thereby allowing the external patient controller 400 to communicate wirelessly with the programmable controller 300 and / or the external physician controller 500 and, optionally, to provide power to the programmable controller 300.

[0106] The user interface 402 receives user input and displays information to the user. The user interface 402 may include buttons, LEDs, displays, touchscreens, keypads, microphones, speakers, trackballs, etc. for receiving user input and / or displaying 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 excitation electrodes, such as a first stimulation pulse sequence corresponding to a first erection mode for inducing a rapid erectile response to induce sexual arousal for sexual activity, a second erection mode for inducing a rapid erectile response to induce an erection sufficient to facilitate a medical procedure such as the application of a urethral catheter, a third nerve function restoration stimulation mode selected to restore nerve conduction within the cavernous nerve, or a fourth penile function restoration mode selected to reduce penile fibrosis.

[0107] 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 that allows the external patient controller 400 to be plugged into a conventional wall socket to power the components.

[0108] 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.

[0109] 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 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® (trademark of Microsoft Corporation, Redmond, Wash.) or Unix®-based operating system, such as those 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®, etc., thereby allowing the programmable controller 300 and / or the external patient controller 400 to communicate wirelessly with the external physician controller 500.

[0110] 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 or 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.

[0111] The event log block 504 is a record of operational data downloaded from the programmable controller 300; the event log block 504 may include, for example, therapy session start and stop times, current stimulation parameters, stimulation parameters from previous therapy sessions, 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.

[0112] The data download block 506 is a routine that commands the programmable controller 300 to transfer data to the external physician controller 500 for download 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 the user interface block 510.

[0113] The configuration setting block 508 is a routine that configures parameters stored in 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 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 one embodiment, the external physician controller 500 is also configured to transfer data to the external patient controller 400, and the external physician controller 500 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 a physician to configure parameters stored in the memory of the microprocessor 302 related to operational limits of the microprocessor 302. These values ​​may include times when the programmable controller 300 may be operational and may not be operational, etc.

[0114] Block 508 may also configure parameters stored in the memory of microprocessor 302 associated with controlling the operation of programmable controller 300. These values ​​may include stimulation parameters.

[0115] 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 physician 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.

[0116] 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 exceeds or falls below a predetermined threshold.

[0117] 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.

[0118] The firmware upgrade block 516 may comprise a routine 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 the revised firmware into the non-volatile memory of the programmable controller 300 and / or external patient controller 400.

[0119] 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 a routine 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.

[0120] 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.

[0121] 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. Insets in FIGS. 8A and 8B depict 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 so that the paddle 202 surrounds the urethra, as shown in FIG. 8B. Implantation above the pelvic plexus may be preferred for patients undergoing a prostatectomy in which the prostate has been partially or completely removed.

[0122] 9A and 9B, the positioning of 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 protruding portions 203 extending from the corner of the flexible paddle farthest from cable 208. First flexible paddle 202a and second flexible paddle 202b may be positioned so 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. Flexible paddle 202 includes suture holes 206 through which sutures may secure the flexible paddle to the pelvic plexus. In FIG. 9A, the first position is illustrated with the protruding portions 203 of the paddles proximal to each other. In FIG. 9B, a second position is shown in which the protruding portions 203 of the paddles are spaced farther apart from each other, which may be advantageous if the patient's cavernous nerves are located farther away from the urethra.

[0123] A programmable controller 300 operably coupled to the array of electrodes can be programmed to selectively activate the electrodes 204 during paddle implantation to determine an optimal location for implanting the flexible paddle, e.g., the first or second position as shown in Figures 9A and 9B. For example, the flexible paddle can be placed in a first position adjacent to the pelvic plexus and near at least one cavernous nerve (e.g., Figure 9A). The programmable controller can then cause the stimulator circuit to activate the electrodes 204 at the first position to generate a first position response. Activation of the cavernous nerve can be measured, for example, using a penile plethysmograph to measure penile diameter or circumference variation and penile erection.

[0124] The flexible paddle may then be moved to a second position different from the first position adjacent the pelvic plexus and 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 the external physician controller 500 to determine the position that elicits an erectile response. If two or more positions elicit 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.

[0125] 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 can be individually accessed and act as a source or sink, allowing current flow in multiple directions, as indicated by the arrows between the electrodes 204 in FIGS. 10A-10C. In FIG. 10A, a first direction of current flow is indicated 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, in which 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 does not flow between electrode 1 and electrodes 2 or 4. FIG. 10C shows a third direction of current flow 220c, in which current flows downward between the electrodes 204 within 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.

[0126] 11A-11C, the grouping of electrodes 204 into exemplary regions is described. FIGS. 11A-11C correspond to the current flow directions depicted in FIGS. 10A-10C, respectively. Each array of electrodes 204, e.g., a first array and a second array, has at least two predetermined regions of electrodes 222. For example, a first region of electrodes 222a and a second region of electrodes 222b may be disposed on a first flexible paddle, and a third region of electrodes 222c and a fourth region of electrodes 222d may be disposed on a second flexible paddle. As will be understood by those skilled in the art, each paddle may have three or more electrode regions, and the electrode regions may be varied to include different subset pairs of electrodes. The number and configuration 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.

[0127] 12A-12C, the selection of preferred electrode pairs within an array of electrodes is shown. Each of FIGS. 12A-12C corresponds to the directional current flow depicted in FIGS. 10A-10C, respectively, and to the electrode regions depicted in FIGS. 11A-11C, respectively. Each array of electrodes 204 has at least one electrode pair within each electrode region 222, with each electrode pair including two electrodes 204 from the array of electrodes. Each electrode region 222 can have the same or a different number of electrodes 204 and electrode pairs than the other electrode regions 222.

[0128] 13, a programmed method for identifying a subset of excitation electrodes is described, whereby preferred directions 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 for eliciting a preferred erectile response is completed. According to one aspect of the present invention, a programmable controller 300 is operably coupled to the array of electrodes and programmed to selectively activate the electrodes 204 and determine the excitation electrodes and preferred stimulation regimen.

[0129] More specifically, the programmable controller 300 is programmed to selectively activate electrodes 204 in the electrode array in at least two directions of current flow, for example, as shown in FIGS. 10A-10C. Sequential stimulation can be applied between each electrode pair on the electrode array, and an erectile response can be measured. To determine the erectile response, cavernous nerve activation can be measured, for example, using a penile plethysmograph to measure penile diameter or circumference variation and penile erection. For each electrode array, 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 electrode array 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, FIG. 13 shows that the second direction of current flow 220b has been selected as the preferred direction of current flow for each of the electrode arrays. As will be understood by one skilled 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.

[0130] The programmable controller 300 can 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 can be activated as illustrated in FIG. 11B. Sequential stimulation can be applied between each electrode pair on each array of electrodes in each region in the preferred current flow direction, and the erectile response can be 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 can be selected as the preferred electrode region. If two or more region electrodes elicit 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 that 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 are selected as preferred regions.

[0131] The programmable controller 300 then selectively activates the electrodes 204 in the array of electrodes in preferred current flow directions and preferred regions. For example, FIG. 13 depicts the second direction of current flow 220b as 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 as 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 within the preferred regions, 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 preferred electrode pairs. 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 preferred electrode pairs. In FIG. 13, three preferred electrode pairs 224 are identified as a subset of excitation electrodes. As will be understood by one skilled in the art, the number of preferred electrode pairs on the first flexible paddle may be the same as or different from the number of preferred electrode pairs on the second flexible paddle.

[0132] After the preferred electrode pair 224 is determined, multiple stimulation parameters having unique combinations of frequency and intensity amplitude can be applied to the preferred electrode pair. Stimulation pulse sequences for different uses can be determined by comparing the responses generated by activating the preferred electrode pair in different modes with different stimulation parameters. For example, stimulation pulse sequences corresponding to modes of activation for one or more levels of erection can be determined. For example, a stimulation regimen to produce an erection, e.g., a full erection for sexual performance, can 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. Patients receiving such stimulation have been shown to not only achieve a full erection for sexual performance, but also an ejaculatory response. For example, it is expected that such an ejaculatory response in men with spinal cord injuries who may otherwise be unable to ejaculate due to sexual arousal will improve fertility outcomes for such patients. For example, it is expected that the ejaculatory response enabled by electrical stimulation as described herein may improve semen quality, e.g., motility, over time and / or improve the chances of success in having natural fertilization for reproduction.

[0133] Alternatively, or in addition, a level of erection less than full may be desired to facilitate a medical procedure that may require a non-flaccid penis. For example, for some men, having a partial or full erection may facilitate the application of a urinary catheter. A stimulation regimen for producing such an erection, e.g., an erection sufficient to facilitate a medical procedure such as the application of a urinary catheter, may include stimulation parameters with a lower current intensity than a stimulation regimen for producing a full erection for sexual arousal and potency. For example, the stimulation regimen may apply a current amplitude in the range of 1-6 mA, preferably 3 mA, a frequency in the range of 6-100 Hz, preferably 12 Hz, and a pulse width in the range of 0.1-1 ms, preferably 1 ms.

[0134] Alternatively, or in addition, the device may be used to restore function to at least one cavernous nerve and determine a nerve restoration stimulation regimen corresponding to a mode of activation for nerve restoration. The nerve restoration stimulation regimen may include stimulation parameters with a lower current intensity than a stimulation regimen for producing an erection. For example, the nerve restoration stimulation regimen may apply a current amplitude within the range of 0.1 to 2 mA, a frequency within the range of 10 to 48 Hz, and a pulse width within the range of 0.01 to 1 millisecond. The nerve restoration stimulation regimen may be programmed to run automatically at least once daily.

[0135] Alternatively, the device can be used to determine a penile function restoration stimulation regimen corresponding to the mode of activation for penile function restoration. If the cavernous nerve is injured or completely severed after prostatectomy, a penile function restoration stimulation regimen can be used to induce at least a partial penile erection, increase tissue oxygenation, maintain penile function, and thereby reduce penile fibrosis. Such a stimulation regimen can be performed at least once daily while the cavernous nerve reestablishes itself or reconnects and regenerates with assistance from a nerve function restoration stimulation regimen. A penile function restoration stimulation regimen can include stimulation parameters with a higher current intensity than a nerve function restoration stimulation regimen and a lower current intensity than a stimulation regimen for producing an erection. For example, a penile function restoration stimulation regimen can apply a current amplitude within the range of 0.5 to 25 mA, a frequency within the range of 10 to 48 Hz, and a pulse width within the range of 0.1 to 1 millisecond. The penile function restoration stimulation regimen may be programmed to run automatically at least once a day, and such operation may occur at a different time than the neural function restoration program.

[0136] The preferred direction of current flow, electrode areas, electrode pairs, and stimulation parameters may be stored in 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, so that the programmable controller may be selectively activated in response to patient or physician input. For example, a patient may selectively activate stimulation regimens to produce one or more levels of 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 at least once daily following prostatectomy, preferably for one hour for each function recovery stimulation regimen.

[0137] With reference to Figure 14, a schematic of the operation of the intraoperative scanning process is described. Sequential stimulation will be applied between each electrode pair within each electrode array. Stimulation of each electrode pair will be automatically applied during the interpulse period of 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 erection. 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 is allowed for stabilization and may avoid the penile atrophy refractoriness effect.

[0138] 15 illustrates an exemplary method for determining a subset of an array of electrodes 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, stimulation parameters are set at 702, which may include the pair of electrodes 204 in the array to be used, pulse duration, AC frequency, voltage, current, and 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 a 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.

[0139] 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 at the adjusted parameters to determine at 712 whether greater sexual arousal can be achieved. If not, stimulation may be repeated at 710 using 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, overwriting the parameters previously stored at 708. 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.

[0140] Once the user is satisfied that the preferred parameters have been determined, either because all electrode pairs 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 can 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, or years, to induce sexual arousal, e.g., erection.

[0141] Referring now to FIG. 16 , an exemplary method for determining 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 near 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 near 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 positional 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.

[0142] Referring now to FIG. 17 , an exemplary method for determining a preferred stimulation regimen for inducing one or more levels of erection, optionally for neural function recovery and / or for penile function recovery, is described. In method 900, at least one electrode pair of the array is selectively activated to stimulate at least one cavernous nerve in step 902. 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. In step 904, a direction of current flow eliciting a first erectile response may be determined by comparing the first directional response and the second directional response. In step 906, at least one electrode pair of the array 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 direction to generate a first localized response and a second localized response, respectively.

[0143] 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, at least one electrode pair of the array is selectively activated in a preferred region in a preferred direction. A first electrode pair and a second electrode pair in the preferred region may be selectively activated in a preferred direction 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.

[0144] In step 914, preferred electrode pairs may be selectively activated at different frequencies and current intensities. The preferred electrode pairs 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 from the first stimulation regimen to generate a first response and a second response. Optionally, in step 916, a mode of activation for full erection, for example, for sexual activity performance, may be determined by comparing the first mode response with the second mode response. Optionally, in step 918, a mode of activation for less than full erection, for example, for facilitating a medical procedure, such as application of a urethral catheter, may be determined by comparing the first mode response with the second mode response. Optionally, in step 920, the comparison may be repeated to determine a mode of activation for functional restoration of at least one cavernous nerve. Optionally, in step 922, the comparison may be repeated to determine a mode of activation for penile function restoration, for reducing penile fibrosis. In step 924 , 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 .

[0145] Referring now to FIG. 18 , an exemplary method for adjusting a preferred mode with a stimulation regimen for functional restoration of nerve conduction in cavernous nerves 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 with a first stimulation regimen to generate a first response. In step 1004, a preferred electrode pair may be selectively activated in a second mode with 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 restoration of at least one cavernous nerve may be determined based on the comparison. The nerve function restoration mode may provide lower current intensity stimulation than the rapid erection mode of activation. Optionally, in step 1012, the neural restoration mode of activation may be adjusted using machine learning or other types of artificial intelligence. Additionally, 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 restoration mode of activation to enable more efficient or effective neural transmission. Alternatively, the method of FIG. 18 may be used to adjust a stimulation regimen to produce one or more levels of erection or a penile restoration stimulation regimen to reduce fibrosis.

[0146] In addition to stimulation regimens for eliciting rapid erectile response, restoring neural transmission within the cavernous nerve, or reducing penile fibrosis, the systems and methods described herein can 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 can promote nerve regeneration and thus help improve urinary function following radical prostatectomy. In particular, low-intensity stimulation can reestablish nerve function by promoting axonal regrowth and reconnection. For example, it is expected that such nerve regeneration in men suffering from spinal cord injury resulting in urinary dysfunction will improve not only urinary function but also the patient's quality of life, as described in further detail below with respect to Figures 19A-19E.

[0147] 19A-19E illustrate the results of the Qualiveen Questionnaire, a specific health-related quality of life assessment for urinary disorders in patients with spinal cord injury (designated CaverSTIM, n=2), provided by spinal cord injury patients with urinary disorders participating in a study using the implantable system described herein that applies a stimulation regimen to treat urinary incontinence. The results are compared against published data resulting from other therapies for treating urinary disorders to illustrate the improvement in quality of life for CaverSTIM patients, as measured, for example, by specific impact of urinary problems (SIUP), inconvenience, limitation, fear, and emotions. For example, FIG. 19A shows the results of the CaverSTIM Qualiveen questionnaire data and a study in which patients received a single dose of intrathecal injection of expanded Wharton's jelly mesenchymal stromal cells (WJ-MSCs) or placebo (n=7) (denoted Albu2020), a study with an exoskeleton training program targeting lower urinary tract function (n=4) (denoted Williams2021), a study in which patients received intradetrusor onabotulinumtoxinA (OnabotA, n=28) injections at baseline and week 24 (denoted Ferreira2018 injection OnabotA), and a study in which patients received oral ococcibutynin (Oxy, n=3) at baseline and week 24. The figures compare published data from the 2018 Oral Oxy study (denoted Ferreira 2018 Oral Oxy) and illustrate the reported change in SIUP, an index measuring the specific impact of urinary problems on quality of life in patients with spinal cord injury, after each intervention. As shown in Figure 19A, CaverSTIM patients reported a significant reduction in the specific impact of urinary problems on patients' quality of life after intervention with an implantable system that applies a stimulation regimen to treat urinary incontinence compared to Ferreira 2018 Oral Oxy patients, and particularly compared to Albu 2020 and Williams 2021 patients.

[0148] Figure 19B compares the CaverSTIM Qualiveen questionnaire data with published data from a study (n=7) in which patients received an intrathecal injection of a single dose of expanded Wharton's jelly mesenchymal stromal cells (WJ-MSCs) or placebo (denoted Albu 2020) and a study (n=4) involving an exoskeleton training program targeting lower urinary tract function (denoted Williams 2021), illustrating the reported change in perceived inconvenience by spinal cord injury patients after each intervention, as measured by identifying the locations and activities in which patients experience inconvenience related to their urinary problems. As shown in Figure 19B, CaverSTIM patients reported a significant decrease in the inconvenience associated with their urinary problems after intervention with an implantable system that applies a stimulation regimen to treat urinary incontinence compared to Albu 2020 patients, and particularly compared to Williams 2021 patients.

[0149] Figure 19C compares the CaverSTIM Qualiveen questionnaire data with published data from a study (n = 7) in which patients received an intrathecal injection of a single dose of expanded Wharton's jelly mesenchymal stromal cells (WJ-MSCs) or placebo (Albu 2020 mean, denoted Albu 2020), and a study (n = 4) involving an exoskeleton training program targeting lower urinary tract function (Williams 2021 mean, denoted Williams 2021). The data illustrates the reported change in perceived limitations by spinal cord injury patients after each intervention, as measured by how often patients needed to shorten their outings or take precautions in performing activities. As shown in Figure 19C, CaverSTIM patients reported a significant decrease in limitations associated with their urinary problems after intervention with an implantable system that applies a stimulation regimen to treat urinary incontinence compared to Albu 2020 and Williams 2021 patients.

[0150] Figure 19D compares the CaverSTIM Qualiveen questionnaire data with published data from a study (n = 7) in which patients received an intrathecal injection of a single dose of expanded Wharton's jelly mesenchymal stromal cells (WJ-MSCs) or placebo (Albu 2020 mean, denoted Albu 2020), and a study (n = 4) involving an exoskeleton training program targeting lower urinary tract function (Williams 2021 mean, denoted Williams 2021), illustrating the reported change in fear experienced by spinal cord injury patients after each intervention, as measured by the fear patients experienced regarding their health, physical appearance, social relationships, and financial situation. As shown in Figure 19D, CaverSTIM patients reported a significant decrease in fear related to their urinary system problems after intervention with an implantable system that applies a stimulation regimen to treat urinary incontinence compared to Albu 2020 and Williams 2021 patients.

[0151] Figure 19E compares the CaverSTIM Qualiveen questionnaire data with published data from a study (n=7) in which patients received an intrathecal injection of a single dose of expanded Wharton's jelly mesenchymal stromal cells (WJ-MSCs) or placebo (Albu2020 mean, denoted Albu2020), and a study (n=4) with an exoskeleton training program targeting lower urinary tract function (Williams2021 mean, denoted Williams2021), illustrating the reported changes in emotions experienced by spinal cord injury patients after each interventional therapy, as measured by the negative impact of urinary problems on patients' self-esteem, such as feelings of shame, humiliation, and anxiety. As shown in Figure 19E, CaverSTIM patients reported a significant reduction in feelings related to their urinary problems following intervention with an implantable system that applies a stimulation regimen to treat urinary incontinence compared to Willaims2021 patients, and particularly compared to Albu2020 patients.

[0152] Notably, in ongoing clinical trials involving spinal cord injury patients using the implantable systems disclosed herein to apply stimulation regimens to treat urinary incontinence, significant improvements in bowel function as well as urinary function have been observed. For example, one patient in the study reported that prior to device implantation, he spent an hour trying to defecate, and after intervention, he reported being able to manage a bowel movement within 30 minutes. Another patient in the study reported suffering from 10 to 20 days of constipation prior to device implantation, and after intervention, he reported that time was reduced in half. Thus, the implantable systems described herein can provide neuromodulation of the pelvic plexus nerves that control a patient's lower intestinal tract, which are in close proximity to the implanted electrodes.

[0153] 20, a schematic diagram of the local anatomy is shown. Nerves controlling the lower urinary tract include the pelvic parasympathetic nerve, the hypogastric sympathetic nerve, and the pudendal nerve. The flexible paddle is preferably configured to stimulate the pudendal nerve, which controls the external sphincter. However, depending on the implantation location of the flexible paddle and the configuration of the electrode, additional nerves not in direct contact with the electrode, including the hypogastric sympathetic nerve, may also be restored.

[0154] 21A and 21B, 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 including 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 columns to apply bipolar stimulation such that current passes from one electrode to another to stimulate a nerve or nerve group located 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 to form an arc shape that conforms to the pelvic plexus and can be implanted thereon, for example, during a prostatectomy surgery. Preferably, the flexible paddle 202 conforms to the anatomical shape of a portion of the pelvic plexus and can cover part or all of the area of ​​the pelvic plexus so that the electrode 204 optimally contacts 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 be designed in a suitable shape (e.g., hemispherical, rectangular, square, oval, elliptical, or trapezoidal) and can have a flat structure sized to better fit each patient's anatomy and needs.

[0155] As shown in FIG. 21A, the flexible paddle 202 may include a first plurality of electrodes 204a on a first surface of the paddle. As shown in FIG. 21B, 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. 21B may be particularly beneficial for treating urinary incontinence because 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 controlling the lower urinary tract, a larger portion of the pelvic plexus may be stimulated without adverse effects.

[0156] 21C and 21D are perspective views with inset details showing the placement of the flexible paddle of FIGS. 21A and 21B positioned on a patient's pelvic plexus. Preferably, the flexible paddle 202 is positioned relative to the pelvic plexus so that the paddle surrounds the urethra and is adjacent to the pudendal nerve. FIG. 21D shows the implantation of the flexible paddle of FIG. 21B with a first plurality of electrodes 204c and a second plurality of electrodes 204d on opposite 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.

[0157] Low-intensity stimulation promotes regrowth of damaged axons and nerve reconnection, and preferably can be designed not to activate nerves. Therefore, 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 of the electrodes on each flexible paddle are activated, which stimulates all nerves in the region and increases the area of ​​the pelvic plexus, promoting their regeneration. Alternatively, only one electrode pair or multiple electrode pairs on each flexible paddle can be activated.

[0158] 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 to 2 mA, a frequency in the range of 10 to 48 Hz, and a pulse width in the range of 0.01 to 1 millisecond. 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).

[0159] 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, physician, or caregiver, to adjust a limited number of operating parameters of the programmable controller, including starting and stopping bladder nerve restoration stimulation sessions. 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 programmable controller's non-volatile memory a bladder nerve restoration stimulation regimen that, when activated on demand by the external patient controller or automatically by the programmable controller at a preset time, restores neural transmission in nerves controlling the lower urinary tract.

[0160] 22 , another exemplary flexible paddle for use with the electrical stimulation system described herein is provided. Specifically, instead of requiring an implantable programmable controller 300, the programmable controller may be integrated with, for example, an external patient controller and / or an external physician controller as described above, whereby the proximal end of the cable 208 may include a controller 1100 having an antenna for wireless communication with the external patient controller and / or the external physician controller. The antenna may be constructed using technology made available by Stimwave Technologies (Pompano Beach, Florida). For example, as shown in FIG. 22 , the patient controller 400 may be configured to wirelessly communicate one or more commands to the controller 1100 transepidermally via the antenna of the controller 1100 to start and / or stop a stimulation session under any one of the stimulation modes described above and / or to adjust operating parameters of the controller 1100. Additionally, the patient controller 400 may transmit power transepidermally to the controller 1100 during a stimulation session. Thus, the controller 1100 may further include a memory for storing operating parameters, for example, to selectively activate one or more electrode pairs according to a stimulation session. For example, the controller 1100 may receive a command to initiate a stimulation session via an antenna and cause activation of one or more preferred electrode pairs according to the operating parameters associated with the stimulation session. In addition to the antenna technology, the controller 1100 may include stimulation circuitry, a microprocessor, and memory (e.g., EEPROM), as described above. In this manner, the microprocessor may execute programmed instructions stored in the memory regarding preferred stimulation electrodes in response to transepidermal signals from the patient controller 400.

[0161] In some embodiments, the system includes a wearable device, such as a belt or harness, designed to hold the patient controller 400. In this manner, the patient controller 400 may be retained within the wearable device throughout the stimulation session to provide power and a stimulation regimen transepidermally to the antenna of the controller 1100. Once the session is over, for example, following the completion of a sexual or medical activity, the patient may remove the patient controller 400 and / or the wearable device.

[0162] While 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. It is intended that the appended claims cover all such changes and modifications that fall within the true scope of the invention.

Claims

1. 1. A system for treating erectile dysfunction, said system comprising: a flexible paddle having an array of electrodes, the flexible paddle configured to be implanted adjacent one or more cavernous nerves; a programmable controller having a stimulation circuit, a microprocessor, and a memory; Equipped with The stimulation circuit is operably coupled to the electrode array, and the microprocessor is configured to execute programmed instructions stored in the memory to cause the stimulation circuit to selectively activate a preferred set of excitation electrodes of the electrode array, within a preferred region of the electrode array, in a preferred current direction, in accordance with preferred stimulation parameters stored in the memory for stimulating the one or more cavernous nerves to elicit an erectile response.

2. 10. The system of claim 1, wherein the programmable controller is disposed within an implantable pulse generator configured to be operably coupled to the array of electrodes via one or more leads.

3. 3. The system of claim 2, wherein the programmable controller is configured to cause the stimulation circuit to selectively activate the preferred set of excitation electrodes in response to commands received from at least one of an external patient controller or an external physician controller.

4. 10. The system of claim 1, wherein the programmable controller is disposed within at least one of an external patient controller or an external physician controller, and the flexible paddle comprises an antenna configured to communicate with the at least one of the external patient controller or the external physician controller.

5. 5. The system of claim 4, wherein the flexible paddle comprises a controller comprising the antenna, the controller having a memory configured to store one or more operating parameters associated with the array of electrodes.

6. 6. The system of claim 5, wherein the programmable controller is configured to cause the stimulation circuit to cause the controller to selectively activate the preferred set of excitation electrodes in response to user input received by the at least one of the external patient controller or the external physician controller.

7. The system of claim 1 , wherein the erectile response comprises an erection sufficient for sexual activity.

8. The system of claim 1 , wherein the erectile response comprises an ejaculatory response.

9. 9. The system of claim 8, wherein the stimulation circuitry applies a current amplitude in the range of 0.5 to 25 mA at a frequency of 10 to 48 Hz with a pulse width of 0.1 to 1.0 milliseconds.

10. 10. The system of claim 1, wherein the erectile response comprises an erection sufficient to facilitate a medical procedure.

11. The system of claim 10 , wherein the medical procedure includes application of a urinary catheter.

12. 11. The system of claim 10, wherein the stimulation circuit applies a current amplitude in the range of 1 to 6 mA at a frequency of 6 to 100 Hz with a pulse width of 0.1 to 1.0 milliseconds.

13. The system of claim 1 , wherein the erectile response promotes functional recovery of neurotransmission through the one or more cavernous nerves.

14. 14. The system of claim 13, wherein the programmable controller is configured to automatically activate the stimulation circuitry to selectively activate the preferred set of excitation electrodes at least once a day to restore neural transmission.

15. 10. The system of claim 1, wherein the erectile response induces at least a partial penile erection, thereby reducing the risk of penile fibrosis.

16. The microprocessor causing the stimulation circuit to selectively activate a first pair of electrodes of the array of electrodes to generate a first current flow between the first pair of electrodes in a first direction, the first current flow configured to stimulate cavernous nerves to 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 between the second pair of electrodes in a second direction, the second direction being different from the first direction, the second current flow being configured to stimulate the cavernous nerve to 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 the preferred current direction; 10. The system of claim 1, configured to execute programmed instructions stored in the memory for:

17. The microprocessor causing the stimulation circuit to selectively activate electrodes in a first region of the array of electrodes with the preferred current direction to generate a third erectile response; causing the stimulation circuit to selectively activate electrodes in a second region of the array of electrodes 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 the first region or the second region as the preferred region; and 17. The system of claim 16, configured to execute programmed instructions stored in the memory to:

18. The microprocessor 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 said set of preferred excitation electrodes; 20. The system of claim 17, configured to execute programmed instructions stored in the memory to:

19. The microprocessor causing the stimulation circuit to selectively activate the set of preferred excitation electrodes in the preferred current direction using a series of stimulation parameters to elicit a further series of erectile responses; identifying an optimal response from said series of further erectile responses; storing the stimulation parameters that elicit the optimal response as the preferred stimulation parameters; 20. The system of claim 18, configured to execute programmed instructions stored in the memory to:

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

21. 1. An implantable system for treating a pelvic disorder, the system comprising: a flexible paddle having an array of electrodes disposed on a first side thereof, the flexible paddle configured to be placed 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 to cause the stimulation circuit to activate at least one electrode pair of the electrode array to stimulate at least one nerve to promote functional recovery of the at least one nerve; The programmed instructions cause activation of the stimulation circuitry at least once per day.

22. 22. The system of claim 21, wherein the microprocessor is configured to execute programmed instructions stored in the memory to cause 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 the patient's bladder sphincter to promote functional recovery of the at least one nerve, thereby treating urinary incontinence.

23. 22. The system of claim 21, wherein the microprocessor is configured to execute programmed instructions stored in the memory to cause 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 the patient's lower intestinal tract to promote functional recovery of the at least one nerve, thereby treating bowel dysfunction.

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