Innovative neurotechnologies to restore the biomimetic control of the lower urinary tract

Restoring normal urinary function is often one of the most desired outcomes for patients suffering from neurological disorders due to the profound daily life disruptions it causes. Symptoms such as incontinence and the inability to control urination lead to social embarrassment, anxiety, and severe health complications impacting their quality of life, independence, and emotional well-being. Conventional treatments include medications or catheters. Medications often have limited effectiveness and cause undesirable side effects. Catheters are invasive, uncomfortable, and prone to complications such as infections. Bioelectronic medicine emerges as a promising alternative to conventional therapies for urinary dysfunction. Injecting electrical currents into nerves to modulate neural activity, bioelectronic devices received approval for treating conditions such as overactive bladder and urinary retention. Existing neuromodulation devices are limited by their continuous or intermittent stimulation paradigm, which fails to adapt to real-time changes in bladder fullness. The nervous system often becomes less responsive to the constant stimuli over time, reducing therapeutic benefits for patients in the long term. This thesis begins with the exploration of the porcine pudendal nerve as a model for developing innovative neurotechnologies to restore lower urinary tract dysfunction with a biomimetic approach. We described the procedure to access the porcine pudendal nerve reducing the invasiveness and avoiding muscle resection. We characterized the nerve morphophysiology at the level of surgical exposure by using histological and immunohistochemical analysis, showing the fasciculate nature of the nerve and the presence of spatially organized sensory and motor fibers. A subsequent set of experiments demonstrated that pudendal nerve signals recorded with state-of-the-art intraneural interface during bladder filling can be used as predictors to decode three bladder states corresponding to empty, full, and micturition phases. Intraneural pudendal nerve stimulation with the same devices enabled to contract or relax the external urethral sphincter, which ultimately regulates urine flow, adjusting stimulation frequency and simulating micturition-like or continence-like behaviors. However, the selectivity obtained for external urethral sphincter recruitment was highly dependent on the position of the implanted devices. The simulation results highlighted the need for intraneural devices with a more homogeneous distribution of the electrically active sites within the cross-sectional area of the nerve without increasing the invasiveness. To address these issues, we designed an innovative peripheral intraneural device that autonomously achieves a selective, stable, and simultaneously safe interaction with nervous fibers when implanting the device for long-term application with high repeatability. Finite element models confirmed the potential of the proposed technology in terms of fascicular selectivity. A possible fabrication approach to realize such devices was then explored. The results presented in this thesis pave the way for further pudendal neuromodulation studies by using a clinically relevant animal model and innovative intraneural devices to implement closed-loop control strategies for restoring biomimetic control of the lower urinary tract.