Current Landscape of Sonodynamic Therapy for Treating Cancer.

Recent advancements have tangibly changed the cancer treatment landscape. However, curative therapy for this dreadful disease remains an unmet need. Sonodynamic therapy (SDT) is a minimally invasive anti-cancer therapy involving a chemical sonosensitizer and focused ultrasound. A high-intensity focused ultrasound (HIFU) beam is used to destroy or denature targeted cancer tissues. Some SDTs are based on unfocused ultrasound (US). In some SDTs, HIFU is combined with a drug, known as a chemical sonosensitizer, to amplify the drug's ability to damage cancer cells preferentially. The mechanism by which US interferes with cancer cell function is further amplified by applying acoustic sensitizers. Combining multiple chemical sonosensitizers with US creates a substantial synergistic effect that could effectively disrupt tumorigenic growth, induce cell death, and elicit an immune response. Therefore, the minimally invasive SDT treatment is currently attracting attention. It can be combined with targeted therapy (double-targeting cancer therapy) and immunotherapy in the future and is expected to be a boon for treating previously incurable cancers. In this paper, we will consider the current state of this therapy and discuss parts of our research.

Locally operated assistant manipulators with selectable connection system for robotically assisted laparoscopic solo surgery.

PURPOSE: By integrating locally operated surgical assistant robots in a sterilized area, a surgeon can perform safe robotically assisted laparoscopic solo surgery while controlling a laparoscope-holding robot and a forceps robot. At present, there is no leader-follower control system with switchable connection for the leader device in which each assistant follower robot can provide the manipulation intuitively and easily. In the present study, a new locally operated leader-follower selectable control system has been developed. METHODS: The leader-follower system was developed to connect one leader operating device and one of two selectable follower assistant manipulator devices with different numbers of axes, kinematics models, sensors, and actuators for view stabilization and pulling organs. The system is constructed using the middleware of the ORiN-based medical robot architecture MRLink. The system is regulated by the robot integrator application with unilateral leader-follower PTP using the relative displacement between the leader device and the selected follower device through providers of device interface including the information and control commands. RESULTS: The execution cycle for updating the position was 50 ms, and the time delay to catch up with the same position was 100 ms. Two assistant manipulators controlled by the leader-follower selectable system could successfully produce the desired view and handle the target organ model for 17 min in a simulated laparoscopic cholecystectomy. CONCLUSIONS: A locally operated leader-follower selectable control system was constructed to facilitate minimally invasive, robotically assisted laparoscopic solo surgery by a doctor working near the patient. This system could be used for such applications.

Sonodynamic Therapy With Anticancer Micelles and High-Intensity Focused Ultrasound in Treatment of Canine Cancer.

Sonodynamic therapy (SDT) is a minimally invasive anticancer therapy involving a chemical sonosensitizer and high-intensity focused ultrasound (HIFU). SDT enables the reduction of drug dose and HIFU irradiation power compared to those of conventional monotherapies. In our previous study, mouse models of colon and pancreatic cancer were used to confirm the effectiveness of SDT vs. drug-only or HIFU-only therapy. To validate its usefulness, we performed a clinical trial of SDT using an anticancer micelle (NC-6300) and our HIFU system in four pet dogs with spontaneous tumors, including chondrosarcoma, osteosarcoma, hepatocellular cancer, and prostate cancer. The fact that no adverse events were observed, suggests the usefulness of SDT.

Function of Epirubicin-Conjugated Polymeric Micelles in Sonodynamic Therapy.

The combinatory use of high-intensity focused ultrasound (HIFU) and epirubicin (EPI)-conjugated polymeric micellar nanoparticles (NC-6300) is thought to be a less invasive and more efficient method of cancer therapy. To investigate the mechanism underlying the combination effect, we examined the effect of trigger-pulsed HIFU (TP-HIFU) and NC-6300 from the perspective of reactive oxygen species (ROS) generation, which is considered the primary function of sonodynamic therapy (SDT), and changes in drug characteristics. TP-HIFU is an effective sequence for generating hydroxyl radicals to kill cancer cells. EPI was susceptible to degradation by TP-HIFU through the production of hydroxyl radicals. In contrast, EPI degradation of NC-6300 was suppressed by the hydrophilic shell of the micelles. NC-6300 also exhibited a sonosensitizer function, which promoted the generation of superoxide anions by TP-HIFU irradiation. The amount of ROS produced by TP-HIFU reached a level that caused structural changes to the cellular membrane. In conclusion, drug-conjugated micellar nanoparticles are more desirable for SDT because of accelerated ROS production and drug protection from ROS. Furthermore, a combination of NC-6300 and TP-HIFU is useful for minimally invasive cancer therapy with cooperative effects of HIFU-derived features, antitumor activity of EPI, and increased ROS generation to cause damage to cancer cells.

FBG-based sensorized light pipe for robotic intraocular illumination facilitates bimanual retinal microsurgery.

In retinal surgery, microsurgical instruments such as micro forceps, scissors and picks are inserted through the eye wall via sclerotomies. A handheld intraocular light source is typically used to visualize the tools during the procedure. Retinal surgery requires precise and stable tool maneuvers as the surgical targets are micro scale, fragile and critical to function. Retinal surgeons typically control an active surgical tool with one hand and an illumination source with the other. In this paper, we present a "smart" light pipe that enables true bimanual surgery via utilization of an active, robot-assisted source of targeted illumination. The novel sensorized smart light pipe measures the contact force between the sclerotomy and its own shaft, thereby accommodating the motion of the patient's eye. Forces at the point of contact with the sclera are detected by fiber Bragg grating (FBG) sensors on the light pipe. Our calibration and validation results demonstrate reliable measurement of the contact force as well as location of the sclerotomy. Preliminary experiments have been conducted to functionally evaluate robotic intraocular illumination.

Mobile locally operated detachable end-effector manipulator for endoscopic surgery.

PURPOSE: Local surgery is safer than remote surgery because emergencies can be more easily addressed. Although many locally operated surgical robots and devices have been developed, none can safely grasp organs and provide traction. A new manipulator with a detachable commercial forceps was developed that can act as a third arm for a surgeon situated in a sterile area near the patient. This mechanism can be disassembled into compact parts that enable mobile use. METHODS: A mobile locally operated detachable end-effector manipulator (LODEM) was developed and tested. This device uses crank-slider and cable-rod mechanisms to achieve 5 degrees of freedom and an acting force of more than 5 N. The total mass is less than 15 kg. The positional accuracy and speed of the prototype device were evaluated while performing simulated in vivo surgery. RESULTS: The accuracy of the mobile LODEM was 0.4 mm, sufficient for handling organs. The manipulator could be assembled and disassembled in 8 min, making it highly mobile. The manipulator could successfully handle the target organs with the required level of dexterity during an in vivo laparoscopic surgical procedure. CONCLUSIONS: A mobile LODEM was designed that allows minimally invasive robotically assisted endoscopic surgery by a surgeon working near the patient. This device is highly promising for robotic surgery applications.

A novel locally operated master-slave robot system for single-incision laparoscopic surgery.

PURPOSE: Single-incision laparoscopic surgery (SILS) provides more cosmetic benefits than conventional laparoscopic surgery but presents operational difficulties. To overcome this technical problem, we have developed a locally operated master-slave robot system that provides operability and a visual field similar to conventional laparoscopic surgery. MATERIAL AND METHODS: A surgeon grasps the master device with the left hand, which is placed above the abdominal wall, and holds a normal instrument with the right hand. A laparoscope, a slave robot, and the right-sided instrument are inserted through one incision. The slave robot is bent in the body cavity and its length, pose, and tip angle are changed by manipulating the master device; thus the surgeon has almost the same operability as with normal laparoscopic surgery. To evaluate our proposed system, we conducted a basic task and an ex vivo experiment. RESULTS: In basic task experiments, the average object-passing task time was 9.50 sec (SILS cross), 22.25 sec (SILS parallel), and 7.23 sec (proposed SILS). The average number of instrument collisions was 3.67 (SILS cross), 14 (SILS parallel), and 0.33 (proposed SILS). In the ex vivo experiment, we confirmed the applicability of our system for single-port laparoscopic cholecystectomy. CONCLUSION: We demonstrated that our proposed robot system is useful for single-incision laparoscopic surgery.

Development and evaluation of a master-slave robot system for single-incision laparoscopic surgery.

PURPOSE : Single-incision laparoscopic surgery (SILS) brings cosmetic benefits for patients, but this procedure is more difficult than laparoscopic surgery. In order to reduce surgeons' burden, we have developed a master-slave robot system which can provide robot-assisted SILS as if it were performing conventional laparoscopic surgery and confirmed the feasibility of our proposed system. METHODS : The proposed system is composed of an input device (master side), a surgical robot system (slave side), and a control PC. To perform SILS in the same style as regular laparoscopic surgery, input instruments are inserted into multiple incisions, and the tip position and pose of the left-sided (right-sided) robotic instrument on the slave side follow those of the right-sided (left-sided) input instruments on the master side by means of a control command from the PC. To validate the proposed system, we defined four operating conditions and conducted simulation experiments and physical experiments with surgeons under these conditions, then compared the results. RESULTS : In the simulation experiments, we found learning effects between trials (P = 0.00013 < 0.05). Our proposed system had no significant difference from a condition simulating classical laparoscopic surgery (P = 0.23 > 0.1), and the task time of our system was significantly shorter than the simulated SILS (P = 0.011 < 0.05). In the physical experiments, our system performed SILS more easily, efficiently, and intuitively than the other operating conditions. CONCLUSION : Our proposed system enabled the surgeons to perform SILS as if they were operating conventionally with laparoscopic techniques.