URINARY CONTINENCE RESTORATION THROUGH AN ENDOURETHRAL DEVICE: A 3-MONTH PILOT STUDY ON TEN PATIENTS.

BACKGROUNDː Stress urinary incontinence (SUI) is a widespread and frustrating condition that affects millions of people worldwide, with severe consequences on patients' quality of life and healthcare systems' costs. Currently, the most severe cases of SUI are treated using implanted (and rather invasive) extraurethral artificial sphincters. The authors propose an innovative, minimally invasive endourethral device for the treatment of SUI. METHODSː Ten patients with SUI were enrolled in three Italian centers and underwent device implantation. After 10, 30, 60 and 90 days, correct device position was confirmed by ultrasonography. Improvements in continence and quality of life were evaluated through a 24 h pad-test, an International Consultation on Incontinence Questionnarie- Short Form (ICI-Q) and a custom checklist. The device was explanted after 90 days. RESULTSː The proposed device was successfully implanted and explanted in 8 out of 10 patients. The results of the pad-test, ICI-Q and custom checklist demonstrated remarkable improvements in continence (median improvement: 82% with respect to the initial condition) and quality of life (mean reduction of the impact of urine losses on the quality of life: 61%). No major pain or discomfort was reported. CONCLUSIONSː The results demonstrate the efficacy of the proposed endourethral artificial sphincter in addressing SUI. The proposed device was successfully implanted and explanted in a short time (~ 10 min) without intrinsic side effects and without triggering pain or discomfort.

A magnetic endourethral sphincter against stress urinary incontinence: preliminary pilot study in humans.

BACKGROUND: Urinary incontinence (UI) is a common and frustrating condition that affects patients' quality of life as well as the Healthcare systems. Currently, the most severe cases of UI are treated using implanted, invasive artificial sphincters. We propose an innovative, minimally invasive magnetic endourethral sphincter for the treatment of stress UI (SUI) in patients for whom previous medical and surgical treatments have failed. METHODS: Six patients with severe SUI were enrolled at a single center and underwent cystoscopic sphincter implantation. After 10 days, correct device position was confirmed by ultrasonography. The sphincter was explanted after 28 days. RESULTS: In all patients, the sphincter was successfully implanted using an endoscopic approach. One patient reached the end of the pilot test (28 days) with the sphincter correctly placed. Patients' responses on the International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form questionnaire improved from a score of 18 out of 21 at the screening visit (UI without reasons) to a score of 3 out of 21 (almost perfect continence). No major pain and discomfort were reported. CONCLUSIONS: This study showed the feasibility of sphincter implantation, explantation, and overall tolerability, although a redesign of the sphincter distal part is needed.

Erythro-Magneto-HA-Virosome: A Bio-Inspired Drug Delivery System for Active Targeting of Drugs in the Lungs.

Over the past few decades, finding more efficient and selective administration routes has gained significant attention due to its crucial role in the bioavailability, absorption rate and pharmacokinetics of therapeutic substances. The pulmonary delivery of drugs has become an attractive target of scientific and biomedical interest in the health care research area, as the lung, thanks to its high permeability and large absorptive surface area and good blood supply, is capable of absorbing pharmaceuticals either for local deposition or for systemic delivery. Nevertheless, the pulmonary drug delivery is relatively complex, and strategies to mitigate the effects of mechanical, chemical and immunological barriers are required. Herein, engineered erythrocytes, the Erythro-Magneto-Hemagglutinin (HA)-virosomes (EMHVs), are used as a novel strategy for efficiently delivering drugs to the lungs. EMHV bio-based carriers exploit the physical properties of magnetic nanoparticles to achieve effective targeting after their intravenous injection thanks to an external magnetic field. In addition, the presence of hemagglutinin fusion proteins on EMHVs' membrane allows the DDS to anchor and fuse with the target tissue and locally release the therapeutic compound. Our results on the biomechanical and biophysical properties of EMHVs, such as the membrane robustness and deformability and the high magnetic susceptibility, as well as their in vivo biodistribution, highlight that this bio-inspired DDS is a promising platform for the controlled and lung-targeting delivery of drugs, and represents a valuable alternative to inhalation therapy to fulfill unmet clinical needs.

PDMS and DLC-coated unidirectional valves for artificial urinary sphincters: Opening performance after 126 days of immersion in urine.

In this work, unidirectional valves made of bare polydimethylsiloxane (PDMS) and PDMS provided with a micrometric diamond-like carbon (DLC) coating were fabricated and characterized, in terms of surface properties and opening pressure. The valve performance was also tested over 1250 repeated cycles of opening/closure in water, finding a slight decrease in the opening pressure after such cycles (10%) for the PDMS valves, while almost no variation for the PDMS + DLC ones. The valves were then immersed in urine for 126 days, evaluating the formation of encrustations and the trend of the opening pressure over time. Results showed that PDMS valves were featured by a thin layer of encrustations after 126 days, but the overall encrustation level was much smaller than the one shown by PDMS in static conditions. Furthermore, the opening pressure was almost not affected by such a thin layer of crystals. DLC-coated valves showed even less encrustations at the same time-point, with no significant loss of performance over time, although they were featured by a higher variability. These results suggest that most encrustations can be removed by the mechanical action of the valve during daily openings/closures. Such a self-cleaning behavior with respect to a static condition opens exciting scenarios for the long-term functionality of mobile devices operating in the urinary environment.

Comparative analysis of occlusion methods for artificial sphincters.

An artificial sphincter is a device that replaces the function of the biological sphincter by occluding the relative biological lumen. The investigation of occlusion methods for artificial sphincters is crucial for a reliable and effective design of such devices. The compression induced onto the tissue by a certain pressure depends on the biomechanical and physiological features of the lumen and on the specific occlusion method. A numerical model and an experimental evaluation are presented here to assess the efficiency of different occlusion methods. Numerical models of circumferential occlusion and clamping occlusion methods to simulate the compression of the biological lumen were developed. Results revealed a relationship between the efficiency of the occlusion method and the physiological condition of the lumen. With differences related to the testing setup, this relationship was also confirmed experimentally by conducting tests on biological simulators. We analyzed the occlusion method to adopt as the physiological pressure (ie, leakage pressure values) changed. In particular, we focused on the urinary incontinence, which is a dysfunction involving the external sphincter surrounding the urethra. In this scenario, we demonstrated that a clamping occlusion is an efficient method to compress the urethra, whose physiological pressures range between 4 and 12 kPa. The clamping occlusion method resulted up to 35% more efficient in terms of sealing pressure than the circumferential one for a closing pressure varying between 2.3 and 11.5 kPa.

Design of an innovative platform for the treatment of cerebral tumors by means of erythro-magneto-HA-virosomes.

Gliomas are the most common intracranial tumors, featured by a high mortality rate. They represent about 28% of all primary central nervous system (CNS) tumors and 80% of all malignant brain tumors. Cytotoxic chemotherapy is one of the conventional treatments used for the treatment, but it often shows rather limited efficacy and severe side effects on healthy organs, due to the low selectivity of the therapy for malignant cells and to a limited access of the drug to the tumor site, caused by the presence of the Blood-Brain Barrier. In order to resolve these limitations, recently an Erythro-Magneto-HA-Virosome (EMHV) drug delivery system (DDS), remotely controllable through an externally applied magnetic field, has been proposed. To accurately localize the EMHV at the target area, a system able to generate an adequate magnetic field is necessary. In this framework, the objective of this paper was to design and develop a magnetic helmet for the localization of the proposed EMHV DDS in the brain area. The results demonstrated, through the implementation of therapeutic efficacy maps, that the magnetic helmet designed in the study is a potential promising magnetic generation system useful for studying the possible usability of the magnetic helmet in the treatment of glioma and possibly other CNS pathologies by EMHV DDS.

Artificial Sphincters to Manage Urinary Incontinence: A Review.

Urinary incontinence affects more than 300 million people worldwide. The implantation of a medical device called an artificial urinary sphincter (AUS) is the gold standard treatment when conservative and minimally invasive therapies fail. In this article, the AUSs (extra-urethral and endo-urethral sphincters) available on the market, both presented at the research level and filed as patents, are reviewed. The ability of the different solutions to effectively replace the natural sphincter are discussed, together with advantages and some possible side effects, such as tissue atrophy, overall invasiveness of the implant, and so forth. Finally, future research priorities are discussed for both endo-urethral and extra-urethral approaches considering key engineering aspects, such as materials, compression and closure mechanisms, and implantation methods, with the long-term aim of developing an effective, reliable, durable, and minimally invasive AUS capable of restoring a normal quality of life for incontinent patients.

Magnetically driven drug delivery systems improving targeted immunotherapy for colon-rectal cancer.

Colorectal cancer (CRC) is one of the major causes of cancer-associated mortality worldwide. The currently approved therapeutic agents show a rather limited efficacy. We have recently demonstrated that the atypical cadherin FAT1 is a specific marker of CRC and that the FAT1-specific monoclonal antibody mAb198.3 may offer new therapeutic opportunities for CRC, being efficiently internalized by cancer cells and reducing cancer growth in colon cancer xenograft models. In this study we explored the therapeutic efficacy of mAb198.3 using two drug delivery systems (DDS) for improving the targeted treatment of CRC. The mAb198.3 was either directly bound to super-paramagnetic nanoparticles (spmNPs) or embedded into human erythrocyte-based magnetized carriers, named Erythro-Magneto-Hemagglutinin Virosomes (EMHVs) to produce two different novel mAb198.3 formulations. Both DDS were endowed with magnetic properties and were anchored in the target tumor site by means of an external permanent magnet. The antibody loading efficiency of these two magnetically driven drug delivery systems and the overall therapeutic efficacy of these two formulations were assessed both in vitro and in a proof-of-concept in vivo study. We demonstrated that mAb198.3 bound to spmNPs or embedded into EMHVs was very effective in targeting FAT1-positive colon cancer cells in vitro and accumulating in the tumor mass in vivo. Although both in vivo administered mAb198.3 formulations have approximately 200 lower antibody doses needed, these showed to achieve a relevant therapeutic effect, thus reducing cancer growth more efficiently respect to the naked antibody. These results indicate that the two proposed magnetically driven drug delivery systems have a considerable potential as platforms to improve bioavailability and pharmacodynamics of anti-FAT mAb198.3 and raise new opportunities for a targeted therapy of CRC.

Electromagnetic Control System for Capsule Navigation: Novel Concept for Magnetic Capsule Maneuvering and Preliminary Study.

The gastrointestinal tract is home of some of the most deadly human diseases. The main problems are related to the difficulty of accessing it for diagnosis or intervention and concomitant patient discomfort. The flexible endoscopy technique has established itself in medical practice due to its high diagnostic accuracy and reliability; however, several technical limitations still remain and the procedure is poorly tolerated by patients. The use of magnetic fields to control and steer endoscopic capsules is increasing in minimally invasive procedures. In fact, magnetic coupling is one of the few physical phenomena capable of transmitting motion beyond a physical barrier, allowing for the compact design of the device itself. In this framework, the authors present the preliminary design and assessment of a magnetic coupling for magnetic endoscopic capsules considering an electromagnetic approach. In particular, a novel toroidal electromagnet is proposed as the control and driving system. The system concept, design, and preliminary results are reported.

Untethered magnetic millirobot for targeted drug delivery.

This paper reports the design and development of a novel millimeter-sized robotic system for targeted therapy. The proposed medical robot is conceived to perform therapy in relatively small diameter body canals (spine, urinary system, ovary, etc.), and to release several kinds of therapeutics, depending on the pathology to be treated. The robot is a nearly-buoyant bi-component system consisting of a carrier, in which the therapeutic agent is embedded, and a piston. The piston, by exploiting magnetic effects, docks with the carrier and compresses a drug-loaded hydrogel, thus activating the release mechanism. External magnetic fields are exploited to propel the robot towards the target region, while intermagnetic forces are exploited to trigger drug release. After designing and fabricating the robot, the system has been tested in vitro with an anticancer drug (doxorubicin) embedded in the carrier. The efficiency of the drug release mechanism has been demonstrated by both quantifying the amount of drug released and by assessing the efficacy of this therapeutic procedure on human bladder cancer cells.

Experimental assessment of a novel robotically-driven endoscopic capsule compared to traditional colonoscopy.

BACKGROUND: Despite colonoscopy represents the conventional diagnostic tool for colorectal pathology, its undeniable discomfort reduces compliance to screening programmes. AIMS: To evaluate feasibility and accuracy of a novel robotically-driven magnetic capsule for colonoscopy as compared to the traditional technique. METHODS: Eleven experts and eleven trainees performed complete colonoscopy by robotic magnetic capsule and by conventional colonoscope in a phantom ex vivo model (artificially clean swine bowel). Feasibility, overall accuracy to detect installed pins, procedure elapsed time and intuitiveness were measured for both techniques in both operator groups. RESULTS: Complete colonoscopy was feasible in all cases with both techniques. Overall 544/672 pins (80.9%) were detected by experimental capsule procedure, while 591/689 pins (85.8%) were detected within conventional colonoscopy procedure (P=ns), thus establishing non-inferiority. With the experimental capsule procedure, experts detected 74.2% of pins vs. 87.6% detected by trainees (P<0.0001). Overall time to complete colon inspection by robotic capsule was significantly higher than by conventional colonoscopy (556±188s vs. 194±158s, respectively; P=0.0001). CONCLUSION: With the limitations represented by an ex vivo setting (artificially clean swine bowel and the absence of peristalsis), colonoscopy by this novel robotically-driven capsule resulted feasible and showed adequate accuracy compared to conventional colonoscopy.