An integrated design and fabrication strategy for entirely soft, autonomous robots.

Soft robots possess many attributes that are difficult, if not impossible, to achieve with conventional robots composed of rigid materials. Yet, despite recent advances, soft robots must still be tethered to hard robotic control systems and power sources. New strategies for creating completely soft robots, including soft analogues of these crucial components, are needed to realize their full potential. Here we report the untethered operation of a robot composed solely of soft materials. The robot is controlled with microfluidic logic that autonomously regulates fluid flow and, hence, catalytic decomposition of an on-board monopropellant fuel supply. Gas generated from the fuel decomposition inflates fluidic networks downstream of the reaction sites, resulting in actuation. The body and microfluidic logic of the robot are fabricated using moulding and soft lithography, respectively, and the pneumatic actuator networks, on-board fuel reservoirs and catalytic reaction chambers needed for movement are patterned within the body via a multi-material, embedded 3D printing technique. The fluidic and elastomeric architectures required for function span several orders of magnitude from the microscale to the macroscale. Our integrated design and rapid fabrication approach enables the programmable assembly of multiple materials within this architecture, laying the foundation for completely soft, autonomous robots.

Leaks after Left Atrial Appendage Closure: Ignored or Neglected?

Left atrial appendage (LAA) closure has recently been approved as an alternative management for stroke prevention in patients with chronic atrial fibrillation who have difficulties with long-term oral anticoagulation. The various shapes and sizes of LAA and orientation of the atrial ostium may contribute to the incomplete LAA closure from circular design devices and orientation of the non-steerable delivery catheter. Incomplete closure of LAA leads to a high-velocity blood flow through the peri-device gap, resulting in peri-device leak (PDL). Residual leaks are frequently diagnosed after LAA closure procedures, regardless of closure methods. There is a controversy in the clinical significance of the leaks, particularly about its association with thromboembolic events. PDL <5 mm was not associated with any increase of risk for thromboembolism. Current literatures with small study population have not been sufficient to clarify the role of the leaks after LAA closure. Nevertheless, management of severe leaks has been a challenging concern for cardiologists. Leaks after epicardial LAA closures are at the neck of the incompletely closed LAA and have shown to increase the risk of thromboembolism. Percutaneous closure of the leaks after LAA closure has been attempted with good safety and success, but long-term safety and efficacy remains unclear. Further large long-term studies which aim to assess the role of leaks or PDLs in predicting thromboembolic events and management strategies are warranted.

Blood Pressure Sensors: Materials, Fabrication Methods, Performance Evaluations and Future Perspectives.

Advancements in materials science and fabrication techniques have contributed to the significant growing attention to a wide variety of sensors for digital healthcare. While the progress in this area is tremendously impressive, few wearable sensors with the capability of real-time blood pressure monitoring are approved for clinical use. One of the key obstacles in the further development of wearable sensors for medical applications is the lack of comprehensive technical evaluation of sensor materials against the expected clinical performance. Here, we present an extensive review and critical analysis of various materials applied in the design and fabrication of wearable sensors. In our unique transdisciplinary approach, we studied the fundamentals of blood pressure and examined its measuring modalities while focusing on their clinical use and sensing principles to identify material functionalities. Then, we carefully reviewed various categories of functional materials utilized in sensor building blocks allowing for comparative analysis of the performance of a wide range of materials throughout the sensor operational-life cycle. Not only this provides essential data to enhance the materials' properties and optimize their performance, but also, it highlights new perspectives and provides suggestions to develop the next generation pressure sensors for clinical use.

Paper-Based Electrical Respiration Sensor.

Current methods of monitoring breathing require cumbersome, inconvenient, and often expensive devices; this requirement sets practical limitations on the frequency and duration of measurements. This article describes a paper-based moisture sensor that uses the hygroscopic character of paper (i.e. the ability of paper to adsorb water reversibly from the surrounding environment) to measure patterns and rate of respiration by converting the changes in humidity caused by cycles of inhalation and exhalation to electrical signals. The changing level of humidity that occurs in a cycle causes a corresponding change in the ionic conductivity of the sensor, which can be measured electrically. By combining the paper sensor with conventional electronics, data concerning respiration can be transmitted to a nearby smartphone or tablet computer for post-processing, and subsequently to a cloud server. This means of sensing provides a new, practical method of recording and analyzing patterns of breathing.

Disulfide-Based Diblock Copolymer Worm Gels: A Wholly-Synthetic Thermoreversible 3D Matrix for Sheet-Based Cultures.

It is well-known that 3D in vitro cell cultures provide a much better model than 2D cell cultures for understanding the in vivo microenvironment of cells. However, significant technical challenges in handling and analyzing 3D cell cultures remain, which currently limits their widespread application. Herein, we demonstrate the application of wholly synthetic thermoresponsive block copolymer worms in sheet-based 3D cell culture. These worms form a soft, free-standing gel reversibly at 20-37 °C, which can be rapidly converted into a free-flowing dispersion of spheres on cooling to 5 °C. Functionalization of the worms with disulfide groups was found to be essential for ensuring sufficient mechanical stability of these hydrogels to enable long-term cell culture. These disulfide groups are conveniently introduced via statistical copolymerization of a disulfide-based dimethacrylate under conditions that favor intramolecular cyclization and subsequent thiol/disulfide exchange leads to the formation of reversible covalent bonds between adjacent worms within the gel. This new approach enables cells to be embedded within micrometer-thick slabs of gel with good viability, permits cell culture for at least 12 days, and facilitates recovery of viable cells from the gel simply by incubating the culture in buffer at 4 °C (thus, avoiding the enzymatic degradation required for cell harvesting when using commercial protein-based gels, such as Matrigel).

Folding analytical devices for electrochemical ELISA in hydrophobic R(H) paper.

This work describes a device for electrochemical enzyme-linked immunosorbent assay (ELISA) designed for low-resource settings and diagnostics at the point of care. The device is fabricated entirely in hydrophobic paper, produced by silanization of paper with decyl trichlorosilane, and comprises two zones separated by a central crease: an embossed microwell, on the surface of which the antigen or antibody immobilization and recognition events occur, and a detection zone where the electrodes are printed. The two zones are brought in contact by folding the device along this central crease; the analytical signal is recorded from the folded configuration. Two proof-of-concept applications, an electrochemical direct ELISA for the detection of rabbit IgG as a model antigen in buffer and an electrochemical sandwich ELISA for the detection of malarial histidine-rich protein from Plasmodium falciparum (Pf HRP2) in spiked human serum, show the versatility of this device. The limit of detection of the electrochemical sandwich ELISA for the quantification of Pf HRP2 in spiked human serum was 4 ng mL(-1) (10(2) pmol L(-1)), a value within the range of clinically relevant concentrations.

Distilling Knowledge From an Ensemble of Vision Transformers for Improved Classification of Breast Ultrasound.

RATIONALE AND OBJECTIVES: To develop a deep learning model for the automated classification of breast ultrasound images as benign or malignant. More specifically, the application of vision transformers, ensemble learning, and knowledge distillation is explored for breast ultrasound classification. MATERIALS AND METHODS: Single view, B-mode ultrasound images were curated from the publicly available Breast Ultrasound Image (BUSI) dataset, which has categorical ground truth labels (benign vs malignant) assigned by radiologists and malignant cases confirmed by biopsy. The performance of vision transformers (ViT) is compared to convolutional neural networks (CNN), followed by a comparison between supervised, self-supervised, and randomly initialized ViT. Subsequently, the ensemble of 10 independently trained ViT, where the ensemble model is the unweighted average of the output of each individual model is compared to the performance of each ViT alone. Finally, we train a single ViT to emulate the ensembled ViT using knowledge distillation. RESULTS: On this dataset that was trained using five-fold cross validation, ViT outperforms CNN, while self-supervised ViT outperform supervised and randomly initialized ViT. The ensemble model achieves an area under the receiver operating characteristics curve (AuROC) and area under the precision recall curve (AuPRC) of 0.977 and 0.965 on the test set, outperforming the average AuROC and AuPRC of the independently trained ViTs (0.958 ± 0.05 and 0.931 ± 0.016). The distilled ViT achieves an AuROC and AuPRC of 0.972 and 0.960. CONCLUSION: Both transfer learning and ensemble learning can each offer increased performance independently and can be sequentially combined to collectively improve the performance of the final model. Furthermore, a single vision transformer can be trained to match the performance of an ensemble of a set of vision transformers using knowledge distillation.

Toward Development of Novel Remote Ultrasound Robotic System Using Soft Robotics Technology.

This paper reports on the development of a novel soft robotic system for remote ultrasound applications. Direct contact of the ultrasound probe with the patient's body represents a safety risk and therefore control of the probe's positioning and applied force is a crucial task. The proposed robot uses a passive control system that provides safe interaction between the robot and the patient by leveraging soft robotics technology. The soft robot's structure can be considered as a nonlinear spring which can be designed to exert a safe force within the robot's workspace to guarantee the safety of human-robot interaction. The literature suggests that effective ultrasound imaging of both the heart and abdomen requires six degrees-of-freedom. These degrees-of-freedom consist of three translational motions, which are achieved using a novel hybrid soft cable-driven parallel robot, and three wrist motions, which is based on a universal joint design. The experimental results show that the robot can achieve all these six degrees-of-freedom, and its blocking force can be engineered to generate a uniform force within the workspace.

Machine Learning-Assisted Short-Wave InfraRed (SWIR) Techniques for Biomedical Applications: Towards Personalized Medicine.

Personalized medicine transforms healthcare by adapting interventions to individuals' unique genetic, molecular, and clinical profiles. To maximize diagnostic and/or therapeutic efficacy, personalized medicine requires advanced imaging devices and sensors for accurate assessment and monitoring of individual patient conditions or responses to therapeutics. In the field of biomedical optics, short-wave infrared (SWIR) techniques offer an array of capabilities that hold promise to significantly enhance diagnostics, imaging, and therapeutic interventions. SWIR techniques provide in vivo information, which was previously inaccessible, by making use of its capacity to penetrate biological tissues with reduced attenuation and enable researchers and clinicians to delve deeper into anatomical structures, physiological processes, and molecular interactions. Combining SWIR techniques with machine learning (ML), which is a powerful tool for analyzing information, holds the potential to provide unprecedented accuracy for disease detection, precision in treatment guidance, and correlations of complex biological features, opening the way for the data-driven personalized medicine field. Despite numerous biomedical demonstrations that utilize cutting-edge SWIR techniques, the clinical potential of this approach has remained significantly underexplored. This paper demonstrates how the synergy between SWIR imaging and ML is reshaping biomedical research and clinical applications. As the paper showcases the growing significance of SWIR imaging techniques that are empowered by ML, it calls for continued collaboration between researchers, engineers, and clinicians to boost the translation of this technology into clinics, ultimately bridging the gap between cutting-edge technology and its potential for personalized medicine.

Creating Stretchable Electronics from Dual Layer Flex-PCB for Soft Robotic Cardiac Mapping Catheters.

The authors present in this study the development of a novel method for creating stretchable electronics from dual-layer flex printed circuit boards (flex-PCBs) as a platform for soft robotic sensor arrays (SRSAs) for cardiac voltage mapping applications. There is a crucial need for devices that utilize multiple sensors and provide high performance signal acquisition for cardiac mapping. Previously, our group demonstrated how single-layer flex-PCB can be postprocessed to create a stretchable electronic sensing array. In this work, a detailed fabrication process for creating a dual-layer multielectrode flex-PCB SRSA is presented, along with relevant parameters to achieve optimal postprocessing with a laser cutter. The dual-layer flex-PCB SRSA's ability to acquire electrical signals is demonstrated both in vitro as well as in vivo on a Leporine cardiac surface. These SRSAs could be extended into full-chamber cardiac mapping catheter applications. Our results show a significant contribution towards the scalable use of dual-layer flex-PCB for stretchable electronics.

Deep learning analysis of blood flow sounds to detect arteriovenous fistula stenosis.

For hemodialysis patients, arteriovenous fistula (AVF) patency determines whether adequate hemofiltration can be achieved, and directly influences clinical outcomes. Here, we report the development and performance of a deep learning model for automated AVF stenosis screening based on the sound of AVF blood flow using supervised learning with data validated by ultrasound. We demonstrate the importance of contextualizing the sound with location metadata as the characteristics of the blood flow sound varies significantly along the AVF. We found the best model to be a vision transformer trained on spectrogram images. Our model can screen for stenosis at a performance level comparable to that of a nephrologist performing a physical exam, but with the advantage of being automated and scalable. In a high-volume, resource-limited clinical setting, automated AVF stenosis screening can help ensure patient safety via early detection of at-risk vascular access, streamline the dialysis workflow, and serve as a patient-facing tool to allow for at-home, self-screening.

Micro-ring structures stabilize microdroplets to enable long term spheroid culture in 384 hanging drop array plates.

Using stereolithography, 20 different structural variations comprised of millimeter diameter holes surrounded by trenches, plateaus, or micro-ring structures were prepared and tested for their ability to stably hold arrays of microliter sized droplets within the structures over an extended period of time. The micro-ring structures were the most effective in stabilizing droplets against mechanical and chemical perturbations. After confirming the importance of micro-ring structures using rapid prototyping, we developed an injection molding tool for mass production of polystyrene 3D cell culture plates with an array of 384 such micro-ring surrounded through-hole structures. These newly designed and injection molded polystyrene 384 hanging drop array plates with micro-rings were stable and robust against mechanical perturbations as well as surface fouling-facilitated droplet spreading making them capable of long term cell spheroid culture of up to 22 days within the droplet array. This is a significant improvement over previously reported 384 hanging drop array plates which are susceptible to small mechanical shocks and could not reliably maintain hanging drops for longer than a few days. With enhanced droplet stability, the hanging drop array plates with micro-ring structures provide better platforms and open up new opportunities for high-throughput preparation of microscale 3D cell constructs for drug screening and cell analysis.

Improved Functional Assessment of Ischemic Severity Using 3D Printed Models.

Objective: To develop a novel in vitro method for evaluating coronary artery ischemia using a combination of non-invasive coronary CT angiograms (CCTA) and 3D printing (FFR3D). Methods: Twenty eight patients with varying degrees of coronary artery disease who underwent non-invasive CCTA scans and invasive fractional flow reserve (FFR) of their epicardial coronary arteries were included in this study. Coronary arteries were segmented and reconstructed from CCTA scans using Mimics (Materialize). The segmented models were then 3D printed using a Carbon M1 3D printer with urethane methacrylate (UMA) family of rigid resins. Physiological coronary circulation was modeled in vitro as flow-dependent stenosis resistance in series with variable downstream resistance. A range of physiological flow rates (Q) were applied using a peristaltic steady flow pump and titrated with a flow sensor. The pressure drop (ΔP) and the pressure ratio (Pd/Pa) were assessed for patient-specific aortic pressure (Pa) and differing flow rates (Q) to evaluate FFR3D using the 3D printed model. Results: There was a good positive correlation (r = 0.87, p < 0.0001) between FFR3D and invasive FFR. Bland-Altman analysis revealed a good concordance between the FFR3D and invasive FFR values with a mean bias of 0.02 (limits of agreement: -0.14 to 0.18; p = 0.2). Conclusions: 3D printed patient-specific models can be used in a non-invasive in vitro environment to quantify coronary artery ischemia with good correlation and concordance to that of invasive FFR.

Microprinted feeder cells guide embryonic stem cell fate.

We introduce a non-contact approach to microprint multiple types of feeder cells in a microarray format using immiscible aqueous solutions of two biopolymers. Droplets of cell suspension in the denser aqueous phase are printed on a substrate residing within a bath of the immersion aqueous phase. Due to their affinity to the denser phase, cells remain localized within the drops and adhere to regions of the substrate underneath the drops. We show the utility of this technology for creating duplex heterocellular stem cell niches by printing two different support cell types on a gel surface and overlaying them with mouse embryonic stem cells (mESCs). As desired, the type of printed support cell spatially direct the fate of overlaid mESCs. Interestingly, we found that interspaced mESCs colonies on differentiation-inducing feeder cells show enhanced neuronal differentiation and give rise to dense networks of neurons. This cell printing technology provides unprecedented capabilities to efficiently identify the role of various feeder cells in guiding the fate of stem cells.

A Review of Quantitative Instruments for Understanding Breastfeeding Dynamics.

Breastfeeding, as a unique behavior of the postpartum period and an ideal source of nourishment, is profoundly impacted by the physiology and behavior of both mothers and infants. For more than three-quarters of a century, there has been an ongoing advancement of instruments that permit insight into the complex process of latching during breastfeeding, which includes coordinating sucking, swallowing, and breathing. Despite the available methodologies for understanding latching dynamics, there continues to be a large void in the understanding of infant latching and feeding. The causes for many breastfeeding difficulties remain unclear, and until a clearer understanding of the mechanics involved is achieved, the struggle will continue in the attempts to aid infants and mothers who struggle to breastfeed. In this review, the history of development for the most prominent tools employed to analyze breastfeeding dynamics is presented. Additionally, the importance of the most advanced instruments and systems used to understand latching dynamics is highlighted and how medical practitioners utilize them is reported. Finally, a controversial argument amongst pediatric otolaryngolo gists concerning breastfeeding difficulties is reviewed and the urgent need for quantification of latching dynamics in conjunction with milk removal rate through prospective controlled studies is discussed.

Simultaneous fabrication of PDMS through-holes for three-dimensional microfluidic applications.

Here we describe a simple yet efficient approach to making through-holes in a bound polydimethylsiloxane membrane for use in 3D microfluidic applications. Localized tearing of an elastomeric membrane is achieved by ripping an elastomeric stamp that is bound to the membrane by posts at desired regions. The tears in the membrane are confined by the underlying channel architecture of the substrate to which the membrane is bound. By varying the membrane thickness and channel dimensions, holes of different sizes can be obtained. This high-throughput method of generating through-holes will enable the design of complex microfluidic devices that require crossing of channel networks.

Uniform cell seeding and generation of overlapping gradient profiles in a multiplexed microchamber device with normally-closed valves.

Generation of stable soluble-factor gradients in microfluidic devices enables studies of various cellular events such as chemotaxis and differentiation. However, many gradient devices directly expose cells to constant fluid flow and that can induce undesired responses from cells due to shear stress and/or wash out of cell-secreted molecules. Although there have been devices with flow-free gradients, they typically generate only a single condition and/or have a decaying gradient profile that does not accommodate long-term experiments. Here we describe a microdevice that generates several chemical gradient conditions on a single platform in flow-free microchambers which facilitates steady-state gradient profiles. The device contains embedded normally-closed valves that enable fast and uniform seeding of cells to all microchambers simultaneously. A network of microchannels distributes desired solutions from easy-access open reservoirs to a single output port, enabling a simple setup for inducing flow in the device. Embedded porous filters, sandwiched between the microchannel networks and cell microchambers, enable diffusion of biomolecules but inhibit any bulk flow over the cells.

Dynamics of liquid plugs of buffer and surfactant solutions in a micro-engineered pulmonary airway model.

We describe a bioinspired microfluidic system that resembles pulmonary airways and enables on-chip generation of airway occluding liquid plugs from a stratified air-liquid two-phase flow. User-defined changes in the air stream pressure facilitated by mechanical components and tuning the wettability of the microchannels enable generation of well-defined liquid plugs. Significant differences are observed in liquid plug generation and propagation when surfactant is added to the buffer. The plug flow patterns suggest a protective role of surfactant for airway epithelial cells against pathological flow-induced mechanical stresses. We discuss the implications of the findings for clinical settings. This approach and the described platform will enable systematic investigation of the effect of different degrees of fluid mechanical stresses on lung injury at the cellular level and administration of exogenous therapeutic surfactants.

Multilayer fabrication of durable catheter-deployable soft robotic sensor arrays for efficient left atrial mapping.

Devices that perform cardiac mapping and ablation to treat atrial fibrillation provide an effective means of treatment. Current devices, however, have limitations that either require tedious point-by-point mapping of a cardiac chamber or have limited ability to conform to the complex anatomy of a patient's cardiac chamber. In this work, a detailed, scalable, and manufacturable technique is reported for fabrication of a multielectrode, soft robotic sensor array. These devices exhibit high conformability (~85 to 90%) and are equipped with an array of stretchable electronic sensors for voltage mapping. The form factor of the device is intended to match that of the entire left atrium and has a hydraulically actuated soft robotic structure whose profile facilitates deployment from a 13.5-Fr catheter. We anticipate that the methods described in this paper will serve a new generation of conformable medical devices that leverage the unique characteristics of stretchable electronics and soft robotics.

A Catheter-Deployable Soft Robotic Inflatable Basket for Enhanced Conformability to the Left Atrium of the Heart.

This paper presents the design, fabrication, and test results for a novel basket catheter that utilizes soft robotic technology, which can conform to complex patient anatomy. Two designs of basket-shaped balloons in three sizes are fabricated based on a CO2 laser cutting method from thin (<50 µm) thermoplastic polyurethane. The balloons are deployed in four soft-material 3D printed left atria, whose geometries are based on volume rendered segmentation of cardiac computed tomography (CT) scans. The coverage and conformability to the realistic patient anatomies is tracked with the small patches of pH paper that indicate, via a color change, contact with a basic solution that lined the 3D printed atriums. The conformability of these inflatable basket catheters is demonstrated as high as (85%) for the optimized design. To visualize the balloon's performance, microCT images of balloons deployed in 3D printed models are shown. These images show the ability of the balloons to adapt to complex patient anatomy and do not exhibit any spline bunching or other deleterious mechanical behavior. This platform has the potential to be coupled with electrical sensors for simultaneous multisensor mapping of atrial fibrillation and other cardiac arrhythmias.