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Scientists around the world have long aimed to produce miniature robots that can be controlled inside the human body to aid doctors in identifying and treating diseases. Such microrobots hold the potential to access hard-to-reach areas of the body through the natural lumina. Wireless access has the potential to overcome drawbacks of systemic therapy, as well as to enable completely new minimally invasive procedures. The aim of this review is fourfold: first, to provide a collection of valuable anatomical and physiological information on the target working environments together with engineering tools for the design of medical microrobots; second, to provide a comprehensive updated survey of the technological state of the art in relevant classes of medical microrobots; third, to analyze currently available tracking and closed-loop control strategies compatible with the in-body environment; and fourth, to explore the challenges still in place, to steer and inspire future research.

Over the past decade, there has been a growing interest in the development of an artificial pancreas for intraperitoneal insulin delivery. Intraperitoneal implantable pumps guarantee more physiological glycemic control than subcutaneous wearable ones, for the treatment of type 1 diabetes. In this work, a fully implantable artificial pancreas refillable by ingestible pills is presented. In particular, solutions enabling the communication between the implanted pump and external user interfaces and novel control algorithms to intraperitoneally release an adequate amount of insulin based on glycemic data are shown. In addition, the powering and the wireless battery recharging are addressed. Specifically, the design and optimization of a customized transcutaneous energy transfer with two independent wireless channels are presented. The system was tested in terms of recharging efficacy, possible temperature rise within the body, during the recharging process and reliability of the wireless connection in the air and in the presence of ex vivo tissues.Clinical Relevance- This work aims to improve the control, battery recharging, and wireless communication of a fully implantable artificial pancreas for type 1 diabetes treatment.

In bioinspired soft robotics, very few studies have focused on fluidic transmissions and there is an urgent need for translating fluidic concepts into realizable fluidic components to be applied in different fields. Nature has often offered an inspiring reference to design new efficient devices. Inspired by the working principle of a marine worm, the sipunculid species Phascolosoma stephensoni (Sipunculidae, Annelida), a soft linear fluidic actuator is here presented. The natural hydrostatic skeleton combined with muscle activity enables these organisms to protrude a part of their body to explore the surrounding. Looking at the hydrostatic skeleton and protrusion mechanism of sipunculids, our solution is based on a twofold fluidic component, exploiting the advantages of both pneumatic and hydraulic actuations and providing a novel fluidic transmission mechanism. The inflation of a soft pneumatic chamber is associated with the stretch of an inner hydraulic chamber due to the incompressibility of the liquid. Actuator stretch and forces have been characterized to determine system performance. In addition, an analytical model has been derived to relate the stretch ability to the inlet pressure. Three different sizes of prototypes were tested to evaluate the suitability of the proposed design for miniaturization. The proposed actuator features a strain equal to 40-50% of its initial length-depending on size-and output forces up to 18 N in the largest prototypes. The proposed bioinspired actuator expands the design of fluidic actuators and can pave the way for new approaches in soft robotics with potential application in the medical field.

The gold standard treatment for bladder cancer is radical cystectomy that implies bladder removal coupled to urinary diversions. Despite the serious complications and the impossibility of controlled active voiding, bladder substitution with artificial systems is a challenge and cannot represent a real option, yet. In this article, we present hydraulic artificial detrusor prototypes to control and drive the voiding of an artificial bladder (AB). These prototypes rely on two actuator designs ( origami and bellows ) based either on negative or positive operating pressure, to be combined with an AB structure. Based on the bladder geometry and size, we optimized the actuators in terms of contraction/expansion performances, minimizing the liquid volume required for actuation and exploring different actuator arrangements to maximize the voiding efficiency. To operate the actuators, an ad hoc electrohydraulic circuit was developed for transferring liquid between the actuators and a reservoir, both of them intended to be implanted. The AB, actuators, and reservoir were fabricated with biocompatible flexible thermoplastic materials by a heat-sealing process. We assessed the voiding efficiency with benchtop experiments by varying the actuator type and arrangement at different simulated patient positions (horizontal, 45° tilted, and vertical) to identify the optimal configuration and actuation strategy. The most efficient solution relies on two bellows actuators anchored to the AB. This artificial detrusor design resulted in a voiding efficiency of about 99%, 99%, and 89%, in the vertical, 45° tilted, and horizontal positions, respectively. The relative voiding time was reduced by about 17, 24, and 55 s compared with the unactuated bladder.

The efficient motility of invertebrates helps them survive under evolutionary pressures. Reconstructing the locomotion of invertebrates and decoupling the influence of individual basic motion are crucial for understanding their underlying mechanisms, which, however, generally remain a challenge due to the complexity of locomotion gaits. Herein, a magnetic soft robot to reproduce midge larva's key natural swimming gaits is developed, and the coupling effect between body curling and rotation on motility is investigated. Through the authors' systematically decoupling studies using programmed magnetic field inputs, the soft robot (named LarvaBot) experiences various coupled gaits, including biomimetic side-to-side flexures, and unveils that the optimal rotation amplitude and the synchronization of curling and rotation greatly enhance its motility. The LarvaBot achieves fast locomotion and upstream capability at the moderate Reynolds number regime. The soft robotics-based platform provides new insight to decouple complex biological locomotion, and design programmed swimming gaits for the fast locomotion of soft-bodied swimmers., (© 2022 Wiley-VCH GmbH.)

Microrobots (MRs) have attracted significant interest for their potentialities in diagnosis and non-invasive intervention in hard-to-reach body areas. Fine control of biomedical MRs requires real-time feedback on their position and configuration. Ultrasound (US) imaging stands as a mature and advantageous technology for MRs tracking, but it suffers from disturbances due to low contrast resolution. To overcome these limitations and make US imaging suitable for monitoring and tracking MRs, we propose a US contrast enhancement mechanism for MR visualization in echogenic backgrounds (e.g., tissue). Our technique exploits the specific acoustic phase modulation produced by the MR characteristic motions. By applying this principle, we performed real-time visualization and position tracking of a magnetic MR rolling on a lumen boundary, both in static flow and opposing flow conditions, with an average error of 0.25 body-lengths. Overall, the reported results unveil countless possibilities to exploit the proposed approach as a robust feedback strategy for monitoring and tracking biomedical MRs in-vivo., (© 2021. The Author(s).)

Creating fully implantable robots that replace or restore physiological processes is a great challenge in medical robotics. Restoring blood glucose homeostasis in patients with type 1 diabetes is particularly interesting in this sense. Intraperitoneal insulin delivery could revolutionize type 1 diabetes treatment. At present, the intraperitoneal route is little used because it relies on accessing ports connecting intraperitoneal catheters to external reservoirs. Drug-loaded pills transported across the digestive system to refill an implantable reservoir in a minimally invasive fashion could open new possibilities in intraperitoneal delivery. Here, we describe PILLSID (PILl-refiLled implanted System for Intraperitoneal Delivery), a fully implantable robotic device refillable through ingestible magnetic pills carrying drugs. Once refilled, the device acts as a programmable microinfusion system for precise intraperitoneal delivery. The robotic device is grounded on a combination of magnetic switchable components, miniaturized mechatronic elements, a wireless powering system, and a control unit to implement the refilling and control the infusion processes. In this study, we describe the PILLSID prototyping. The device key blocks are validated as single components and within the integrated device at the preclinical level. We demonstrate that the refilling mechanism works efficiently in vivo and that the blood glucose level can be safely regulated in diabetic swine. The device weights 165 grams and is 78 millimeters by 63 millimeters by 35 millimeters, comparable with commercial implantable devices yet overcoming the urgent critical issues related to reservoir refilling and powering., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Octopus suckers that possess the ability to actively control adhesion through muscle actuation have inspired artificial adhesives for safe manipulation of thin and delicate objects. However, the design of adhesives with fast adhesion switching speed to transport cargoes in confined spaces remains an open challenge. Here, we present an untethered magnetic adhesive pad combining the functionality of fast adhesion switching and remotely controlled locomotion. The adhesive pad can be activated from low-adhesion state to high-adhesion state by near infrared laser within 30 s, allowing to fulfill a high-throughput task of retrieving and releasing objects. Moreover, under the guidance of external magnetic field, the proposed pad is demonstrated to transport thin and fragile electronic components across a tortuous path, thus indicating its potential for dexterous delivery in complex working environments., (© 2021 IOP Publishing Ltd.)

Substituting the natural bladder with an artificial solution, after cancer and other pathologies, is an ambitious challenge in biomedical engineering. In this work we propose a fully implantable smart artificial bladder system (ABS) that collects urinary fluids and provides the subject with real-time feedback on the implant status. To achieve long term duration, the ABS was designed to be unstretchable in order to be treated with urine resistant coatings and included built-in passive check valves preventing reflux to kidneys. To estimate the amount of fluid collected, the ABS was provided with four electromagnetic distance sensing units and a control unit. An algorithm implemented on an embedded controller enabled the reconstruction of the bladder volume through sensors readings. A wireless data transfer system allows for providing a real-time feedback to the subject. Bench tests validated volume reconstruction accuracy and ex-vivo experiments verified the implantability of the proposed device on a human cadaver, proving the reliability of a Bluetooth data transmission system and paving the way towards an in-body/out-body communication. The proposed solution has the potential to overcome the limitations of currently available replacement strategies towards a new generation of implantable devices for lost organ functions replacement.

Rare earth magnets are the elective choice when high magnetic field density is required and they are particularly intriguing for inclusion in implantable devices. A safe implantation of NdFeB magnets in muscles would enable the control of limb prostheses using a myokinetic interface i.e. , direct control of artificial limb movements by means of magnetic tracking of residual muscle contractions. However, myokinetic prosthesis control is prevented by NdFeB magnets poor biocompatibility, at present. Here we investigated three biocompatible materials as NdFeB magnet coating candidates, namely gold, titanium nitride and parylene C, which have not been analyzed in a systematic way for this purpose, so far. In vitro testing in a tissue-mimicking environment and upon contact with C2C12 myoblasts enabled assessment of the superiority of parylene C coated magnets in terms of corrosion prevention and lack of cytotoxicity. In addition, parylene C coated magnets implanted in rabbit muscles for 28 days confirmed, both locally and systemically, their biocompatibility, with a lack of irritation and toxicity associated with the implant. These findings pave the way towards the development of implantable devices based on permanent magnets and of a new generation of limb prostheses., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The invertebrates ability to adapt to the environment during motion represents an intriguing feature to inspire robotic systems. We analysed the sipunculid species Phascolosoma stephensoni (Sipunculidae, Annelida), and quantitatively studied the motion behaviour of this unsegmented worm. The hydrostatic skeleton and the muscle activity make the infaunal P . stephensoni able to extrude part of its body (the introvert) from its burrow to explore the environment by remaining hidden within the rocky substrate where it settled. The introvert protrusion is associated with changes in the body shape while keeping the overall volume constant. In this study, we employed a marker-less optical tracking strategy to quantitatively study introvert protrusion (i.e. kinematics, elongation percentage and forces exerted) in different navigation media. When P . stephensoni specimens were free in sea water (outside from the burrow), the worms reached lengths up to three times their initial ones after protrusion. Moreover, they were able to elongate their introvert inside a viscous medium such as agar-based hydrogel. In this case, the organisms were able to break the hydrogel material, exerting forces up to 3 N and then to navigate easily inside it, producing stresses of some tens of kPa. Our measurements can be used as guidelines and specifications to design and develop novel smart robotic systems., (© 2020 IOP Publishing Ltd.)

Medical microrobots (MRs) have been demonstrated for a variety of non-invasive biomedical applications, such as tissue engineering, drug delivery, and assisted fertilization, among others. However, most of these demonstrations have been carried out in in vitro settings and under optical microscopy, being significantly different from the clinical practice. Thus, medical imaging techniques are required for localizing and tracking such tiny therapeutic machines when used in medical-relevant applications. This review aims at analyzing the state of the art of microrobots imaging by critically discussing the potentialities and limitations of the techniques employed in this field. Moreover, the physics and the working principle behind each analyzed imaging strategy, the spatiotemporal resolution, and the penetration depth are thoroughly discussed. The paper deals with the suitability of each imaging technique for tracking single or swarms of MRs and discusses the scenarios where contrast or imaging agent's inclusion is required, either to absorb, emit, or reflect a determined physical signal detected by an external system. Finally, the review highlights the existing challenges and perspective solutions which could be promising for future in vivo applications.

Flexible colonoscopy remains the prime mean of screening for colorectal cancer (CRC) and the gold standard of all population-based screening pathways around the world. Almost 60% of CRC deaths could be prevented with screening. However, colonoscopy attendance rates are affected by discomfort, fear of pain and embarrassment or loss of control during the procedure. Moreover, the emergence and global thread of new communicable diseases might seriously affect the functioning of contemporary centres performing gastrointestinal endoscopy. Innovative solutions are needed: artificial intelligence (AI) and physical robotics will drastically contribute for the future of the healthcare services. The translation of robotic technologies from traditional surgery to minimally invasive endoscopic interventions is an emerging field, mainly challenged by the tough requirements for miniaturization. Pioneering approaches for robotic colonoscopy have been reported in the nineties, with the appearance of inchworm-like devices. Since then, robotic colonoscopes with assistive functionalities have become commercially available. Research prototypes promise enhanced accessibility and flexibility for future therapeutic interventions, even via autonomous or robotic-assisted agents, such as robotic capsules. Furthermore, the pairing of such endoscopic systems with AI-enabled image analysis and recognition methods promises enhanced diagnostic yield. By assembling a multidisciplinary team of engineers and endoscopists, the paper aims to provide a contemporary and highly-pictorial critical review for robotic colonoscopes, hence providing clinicians and researchers with a glimpse of the major changes and challenges that lie ahead.

Untethered small-scale robots have great potential for biomedical applications. However, critical barriers to effective translation of these miniaturized machines into clinical practice exist. High resolution tracking and imaging in vivo is one of the barriers that limit the use of micro- and nanorobots in clinical applications. Here, the inclusion of radioactive compounds in soft thermoresponsive magnetic microrobots is investigated to enable their single-photon emission computed tomography imaging. Four microrobotic platforms differing in hydrogel structure and four 99m Tc[Tc]-based radioactive compounds are investigated in order to achieve optimal contrast agent retention and optimal imaging. Single microrobot imaging of structures as low as 100 µm in diameter, as well as tracking of shape switching from tubular to planar configurations by inclusion of 99m Tc[Tc] colloid in the hydrogel structure, is reported., (© 2019 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Micro dosing pumps are the beating heart of infusion systems. Among many technologies to inject micro quantities of fluids, peristaltic pumps show high precision and the possibility to not alter the fluid properties. However, in real drug delivery applications, the continuous release behavior of typical peristaltic pumps is not favorable. In this paper, we investigate the intermittent performance of two prototypes of peristaltic pumps, based on four and five rollers, used to occlude the tube. The pump performances are reported for different rotation speeds and lag times between consecutive infusions. The proposed pumps showed a good volumetric precision (2.88 μL for the five rollers pump and 4.11 μL for the four rollers pump) without any dependency on rotation speed and lag time.

Artificial urinary devices are commonly employed to restore the lost functionalities of the urinary system, due to diseases, disfunctions or organ resections. However, the long-term operation of these devices in the urinary system is affected by encrustations. In this paper, three different nanostructured coatings, based on diamondlike carbon (DLC), molybdenum disulfide (MoS 2 ) and Tungsten disulfide (WS 2 ), were deposited on polydimethylsiloxane substrates, an elastomer suitable for coating different kinds of urinary devices, and tested in terms of resistance to urinary encrustations. DLC coatings were deposited using plasma enhanced-chemical vapor deposition ( T < 180 °C), whereas MoS 2 and WS 2 coatings were achieved through self-assembly at room temperature. All coatings showed good adhesion and stability on PDMS substrate over one month, relatively small roughness, a strongly hydrophobic behavior, and low surface energy. After immersion in artificial urine formulations and continuous mechanical agitation for 4 weeks, WS 2 coating resulted the most resistant to encrustations. This material had been never investigated in the urinary context. Our results pave the way to the adoption of WS 2 coatings for developing long-lasting stable urinary devices.

The clinical adoption of nanoscale agents for targeted therapy is still hampered by the quest for a balance between therapy efficacy and side effects on healthy tissues, due to nanoparticle biodistribution and undesired drug accumulation issues. Here, an intravascular catheter able to efficiently retrieve from the bloodstream magnetic nanocarriers not contributing to therapy, thus minimizing their uncontrollable dispersion and consequently attenuating possible side effects, is proposed. The device consists of a miniature module, based on 27 permanent magnets arranged in two coaxial series, integrated into a clinically used 12 French catheter. This device can capture ≈94% and 78% of the unused agents when using as carriers 500 and 250 nm nominal diameter superparamagnetic iron oxide nanoparticles, respectively. This approach paves the way to the exploitation of new "high-risk/high-gain" drug formulations and supports the development of novel therapeutic strategies based on magnetic hyperthermia or magnetic microrobots.

Introduction: Traditional drug release systems normally rely on a passive delivery of therapeutic compounds, which can be partially programmed, prior to injection or implantation, through variations in the material composition. With this strategy, the drug release kinetics cannot be remotely modified and thus adapted to changing therapeutic needs. To overcome this issue, drug delivery systems able to respond to external stimuli are highly desirable, as they allow a high level of temporal and spatial control over drug release kinetics, in an operator-dependent fashion., Areas Covered: On-demand drug delivery systems actually represent a frontier in this field and are attracting an increasing interest at both research and industrial level. Stimuli-responsive thin films, enabled by nanofillers, hold a tremendous potential in the field of triggerable drug delivery systems. The inclusion of responsive elements in homogeneous or heterogeneous thin film-shaped polymeric matrices strengthens and/or adds intriguing properties to conventional (bare) materials in film shape., Expert Opinion: This Expert Opinion review aims to discuss the approaches currently pursued to achieve an effective on-demand drug delivery, through nanocomposite thin films. Different triggering mechanisms allowing a fine control on drug delivery are described, together with current challenges and possible future applications in therapy and surgery.

The bioartificial pancreas (BAP) represents a viable solution for the treatment of type 1 diabetes (T1D). By encapsulating pancreatic cells in a semipermeable membrane to allow nutrient, insulin and glucose exchange, the side effects produced by islets and whole organ transplantation-related immunosuppressive therapy can be circumvented. Several factors, mainly related to materials properties, capsule morphology and biological environment, play a key role in optimizing BAP systems. The BAP is an extremely complex delivery system for insulin. Despite considerable efforts, in some instances meeting with limited degree of success, a BAP capable of restoring physiological pancreas functions without the need for immunosuppressive drugs and of controlling blood glucose levels especially in large animal models and a few clinical trials, does not exist. The state of the art in terms of materials, fabrication techniques and cell sources, as well as the current status of commercial devices and clinical trials, are described in this overview from an interdisciplinary viewpoint. In addition, challenges to the creation of effective BAP systems are highlighted including future perspectives in terms of component integration from both a biological and an engineering viewpoint., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Lab-on-a-chip applications, such as single cell manipulation and targeted delivery of chemicals, could greatly benefit from mobile untethered microdevices able to move in fluidic environments by using magnetic fields. In this paper a magnetically driven microrobotic system enabling the controlled locomotion of objects placed at the air/liquid interface is proposed and exploited for cell manipulation. In particular authors report the design, fabrication and testing of a polymeric thin film-based magnetic microrobot (called "FilmBot") used as a support for navigating cancer cells. By finely controlling magnetic film locomotion, it is possible to navigate the cells by exploiting their adhesion to the film without affecting their integrity. Preliminary in vitro tests demonstrated that the magnetic thin film is able to act as substrate for T24 bladder cancer cells without affecting their viability and that film locomotion can be magnetically controlled (with a magnetic field and a gradient of 6 mT and 0.6 T/m, respectively) along specific directions, with a mean speed of about 3 mm/s.

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.

We herein evaluated the analgesic effectiveness of low doses of buprenorphine with or without a primer and the practicality and usefulness of a constant flow disposable infusion set (Infusor Baxter 2 ml/h). Our series consists of 300 patients, seen between January 1992 and December 1993, randomly distributed in three groups of 100 patients each. All patients were informed before operation about the use of pain Visual Analogical Scale (VAS) and how the infusor works. At the end of the operation all patients had an infusor positioned with a 0.01 mg/kg supplied of buprenorphine diluted to 60 ml with Ringer's Lactate solution. In addition to this, group B patients received an i.v. primer of 0.003 mg/kg of buprenorphine diluted to 10 ml with saline solution and group C patients received an i.v. primer of 0.5 mg/kg of ketorolac diluted to 10 ml with saline solution. VAS, systolic arterial pressure, diastolic arterial pressure, heart rate, respiratory rate, request of analgesics and side effects were evaluated at one hour (T0), six hours (T1), 12 hours (T2), 24 hours (T3) and 36 hours (T4) after operation. Group B and C patients showed significant reduction in VAS compared to group A patients at T0 and T1 but the difference disappeared starting from T2. Group B and C patients showed blood pressure, heart rate and respiratory rate values significantly reduced compared to group A patients at T0 and T1. Such values however then stabilized. Side effects encountered were nausea and vomiting in different percentages in the three groups.(ABSTRACT TRUNCATED AT 250 WORDS)

The authors herein present their personal series on the clinical evaluation of the analgesic efficacy of 2 opiodes, peridural morphine hydrochloride (0.5 mg/kg) administered to group A patients, and sublingual buprenorphine (0.4 mg) administered to group B patients in the management of post-operative pain in major abdominal surgery. The study was conducted on 44 patients, both male and female, classified as ASA II and III. Statistical analysis of cardiovascular parameters (BP and cardiac frequency), respiratory frequency and pain score showed an overlapping progression among the two groups. Spontaneous pain decreased significantly to zero at T6 (p < 0.001). However, the necessity to administer buprenorphine more frequently after the sixth hour and the consequent increase in side effects, lead us to believe that the method used for group A patients is more advantageous.

Buprenorphine was used as a preanesthetic drug for peridural anaesthesia. The aim of the study was therefore to evaluate the sedative/anxiolitic activity of this drug as compared to prometazine and diazepam. Two hundred male patients, divided into two groups (A and B), who were to undergo urological surgery under peripheral anesthesia, were included in the study: L2/L3 or L3/L4 epidural block. The group A patients were premedicated with buprenorphine; the group B patients received traditional anesthetic. The following factors were evaluated: the course of the AP and CF, the state of intraoperative sedation, the presence of side effects and data obtained, elaborated with a statistical test constructed to compare the percentages in two independent samples. There were no statistically significant variations of the AP and CF in the two groups. Additional sedatives were administered to 56.2% of the patients in group B and to only 27.1% in group A, premedicated with buprenorphine. Thirty seven percent of the group A patients and 10% of the group B patients presented preoperative nausea. The authors believe that the buprenorphine/atrophine association should be encouraged for pre-anesthesia when operations in peridural anesthesia are to be conducted, as it provides a state of constant sedation, avoiding rather ineffective pharmacological mixtures.