Volumetric 3D Printing of Endoskeletal Soft Robots.

Computed Axial Lithography (CAL)is an emerging technology for manufacturing complex parts, all at once, by circumventing the traditional layered approach using tomography. Overprinting, a unique additive manufacturing capability of CAL, allows for a 3D geometry to be formed around a prepositioned insert where the occlusion of light is compensated for by the other angular projections. This method opens the door for novel applications within additive manufacturing for multi-material systems such as endoskeletal robots. Herein, this work presents one such application with a simple Gelatin Methacrylate (GelMA)hydrogel osmotic actuator with an embedded endoskeletal system. GelMA is an ideal material for this application as it is swellable and has reversible thermal gelation, enabling suspension of the endoskeleton during printing. By tuning the material formulation, the actuator design, and post-processing, swelling-induced bending actuation of 60 degrees was achieved. To aid in the printing process, a simple computational method for determining the absolute dose absorbed by the resin allowing for print time prediction is also proposed. This article is protected by copyright. All rights reserved.

Gene Electrotransfer via Conductivity-Clamped Electric Field Focusing Pivots Sensori-Motor DNA Therapeutics: "A Spoonful of Sugar Helps the Medicine Go Down".

Viral vectors and lipofection-based gene therapies have dispersion-dependent transduction/transfection profiles that thwart precise targeting. The study describes the development of focused close-field gene electrotransfer (GET) technology, refining spatial control of gene expression. Integration of fluidics for precise delivery of "naked" plasmid deoxyribonucleic acid (DNA) in sucrose carrier within the focused electric field enables negative biasing of near-field conductivity ("conductivity-clamping"-CC), increasing the efficiency of plasma membrane molecular translocation. This enables titratable gene delivery with unprecedently low charge transfer. The clinic-ready bionics-derived CC-GET device achieved neurotrophin-encoding miniplasmid DNA delivery to the cochlea to promote auditory nerve regeneration; validated in deafened guinea pig and cat models, leading to improved central auditory tuning with bionics-based hearing. The performance of CC-GET is evaluated in the brain, an organ problematic for pulsed electric field-based plasmid DNA delivery, due to high required currents causing Joule-heating and damaging electroporation. Here CC-GET enables safe precision targeting of gene expression. In the guinea pig, reporter expression is enabled in physiologically critical brainstem regions, and in the striatum (globus pallidus region) delivery of a red-shifted channelrhodopsin and a genetically-encoded Ca2+ sensor, achieved photoactivated neuromodulation relevant to the treatment of Parkinson's Disease and other focal brain disorders.

Unveiling a CAAX Protease-Like Protein Involved in Didemnin Drug Maturation and Secretion.

The assembly line biosynthesis of the powerful anticancer-antiviral didemnin cyclic peptides is proposed to follow a prodrug release mechanism in Tristella bacteria. This strategy commences with the formation of N-terminal prodrug scaffolds and culminates in their cleavage during the cellular export of the mature products. In this study, a comprehensive exploration of the genetic and biochemical aspects of the enzymes responsible for both the assembly and cleavage of the acylated peptide prodrug scaffolds is provided. This process involves the assembly of N-acyl-polyglutamine moieties orchestrated by the nonribosomal peptide synthetase DidA and the cleavage of these components at the post-assembly stage by DidK, a transmembrane CAAX hydrolase homolog. The findings not only shed light on the complex prodrug mechanism that underlies the synthesis and secretion of didemnin compounds but also offer novel insights into the expanded role of CAAX hydrolases in microbes. Furthermore, this knowledge can be leveraged for the strategic design of genome mining approaches aimed at discovering new bioactive natural products that employ similar prodrug biochemical strategies.

Powerful, soft combustion actuators for insect-scale robots.

Insects perform feats of strength and endurance that belie their small stature. Insect-scale robots-although subject to the same scaling laws-demonstrate reduced performance because existing microactuator technologies are driven by low-energy density power sources and produce small forces and/or displacements. The use of high-energy density chemical fuels to power small, soft actuators represents a possible solution. We demonstrate a 325-milligram soft combustion microactuator that can achieve displacements of 140%, operate at frequencies >100 hertz, and generate forces >9.5 newtons. With these actuators, we powered an insect-scale quadrupedal robot, which demonstrated a variety of gait patterns, directional control, and a payload capacity 22 times its body weight. These features enabled locomotion through uneven terrain and over obstacles.

Sheptide A: an antimalarial cyclic pentapeptide from a fungal strain in the Herpotrichiellaceae.

As part of ongoing efforts to isolate biologically active fungal metabolites, a cyclic pentapeptide, sheptide A (1), was discovered from strain MSX53339 (Herpotrichiellaceae). The structure and sequence of 1 were determined primarily by analysis of 2D NMR and HRMS/MS data, while the absolute configuration was assigned using a modified version of Marfey's method. In an in vitro assay for antimalarial potency, 1 displayed a pEC50 value of 5.75 ± 0.49 against malaria-causing Plasmodium falciparum. Compound 1 was also tested in a counter screen for general cytotoxicity against human hepatocellular carcinoma (HepG2), yielding a pCC50 value of 5.01 ± 0.45 and indicating a selectivity factor of ~6. This makes 1 the third known cyclic pentapeptide biosynthesized by fungi with antimalarial activity.

Comparison of Treatment Outcomes for Fluoroscopic and Fluoroscopy-free Endourological Procedures: A Systematic Review on Behalf of the European Association of Urology Urolithiasis Guidelines Panel.

CONTEXT: Endourological procedures frequently require fluoroscopic guidance, which results in harmful radiation exposure to patients and staff. One clinician-controlled method for decreasing exposure to ionising radiation in patients with urolithiasis is to avoid the use of intraoperative fluoroscopy during stone intervention procedures. OBJECTIVE: To comparatively assess the benefits and risks of "fluoroscopy-free" and fluoroscopic endourological interventions in patients with urolithiasis. EVIDENCE ACQUISITION: A systematic review of the literature from 1970 to 2022 was performed using the MEDLINE/PubMed, Embase, and Cochrane controlled trials databases and ClinicalTrials.gov. Primary outcomes assessed were complications and the stone-free rate (SFR). Studies reporting data on ureteroscopy and percutaneous nephrolithotomy (PCNL) were eligible for inclusion. Secondary outcomes were operative duration, hospital length of stay, conversion from a fluoroscopy-free to a fluoroscopic procedure, and requirement for an auxiliary procedure to achieve stone clearance. EVIDENCE SYNTHESIS: In total, 24 studies (12 randomised and 12 observational) out of 834 abstracts screened were eligible for analysis. There were 4564 patients with urolithiasis in total, of whom 2309 underwent a fluoroscopy-free procedure and 2255 underwent a comparative fluoroscopic procedure for treatment of urolithiasis. Pooled analysis of all procedures revealed no significant difference between the groups in SFR (p = 0.84), operative duration (p = 0.11), or length of stay (p = 0.13). Complication rates were significantly higher in the fluoroscopy group (p = 0.009). The incidence of conversion from a fluoroscopy-free to a fluoroscopic procedure was 2.84%. Similar results were noted in subanalyses for ureteroscopy (n = 2647) and PCNL (n = 1917). When only randomised studies were analysed (n = 12), the overall complication rate was significantly in the fluoroscopy group (p < 0.001). CONCLUSIONS: For carefully selected patients with urolithiasis, fluoroscopy-free and fluoroscopic endourological procedures have comparable stone-free and complication rates when performed by experienced urologists. In addition, the conversion rate from a fluoroscopy-free to a fluoroscopic endourological procedure is low at 2.84%. These findings are important for clinicians and patients, as the detrimental health effects of ionising radiation are negated with fluoroscopy-free procedures. PATIENT SUMMARY: We compared treatments for kidney stones with and without the use of radiation. We found that kidney stone procedures without the use of radiation can be safely performed by experienced urologists in patients with normal kidney anatomy. These findings are important, as they indicate that the harmful effects of radiation can be avoided during kidney stone surgery.

European Association of Urology Guidelines on Testicular Cancer: 2023 Update.

CONTEXT: Each year the European Association of Urology (EAU) produce a document based on the most recent evidence on the diagnosis, therapy, and follow-up of testicular cancer (TC). OBJECTIVE: To represent a summarised version of the EAU guidelines on TC for 2023 with a focus on key changes in the 2023 update. EVIDENCE ACQUISITION: A multidisciplinary panel of TC experts, comprising urologists, medical and radiation oncologists, and pathologists, reviewed the results from a structured literature search to compile the guidelines document. Each recommendation in the guidelines was assigned a strength rating. EVIDENCE SYNTHESIS: For the 2023 EAU guidelines on TC, a review and restructure were undertaken. The key changes incorporated in the 2023 update include: new supporting text regarding venous thromboembolism prophylaxis in males with metastatic germ cell tumours receiving chemotherapy; quality of life after treatment; an update of the histological classifications and inclusion of the World Health Organization 2022 pathological classification; inclusion of the revalidation of the 1997 International Germ Cell Cancer Collaborative Group prognostic risk factors; and a new section covering oncology treatment protocols. CONCLUSIONS: The 2023 version of the EAU guidelines on TC include the highest available scientific evidence to standardise the management of TC. Better stratification and optimisation of treatment modalities will continue to improve the high survival rates for patients with TC. PATIENT SUMMARY: This article presents a summary of the European Association of Urology guidelines on testicular cancer published in 2023 and includes the latest recommendations for management of this disease. The guidelines are a valuable resource that may help patients in understanding treatment recommendations.

Autonomous self-healing optical sensors for damage intelligent soft-bodied systems.

We introduce damage intelligent soft-bodied systems via a network of self-healing light guides for dynamic sensing (SHeaLDS). Exploiting the intrinsic damage resilience of light propagation in an optical waveguide, in combination with a tough, transparent, and autonomously self-healing polyurethane urea elastomer, SHeaLDS enables damage resilient and intelligent robots by self-healing cuts as well as detecting this damage and controlling the robot's actions accordingly. With optimized material and structural design for hyperelastic deformation of the robot and autonomous self-healing capacity, SHeaLDS provides reliable dynamic sensing at large strains (ε = 140%) with no drift or hysteresis, is resistant to punctures, and self-heals from cuts at room temperature with no external intervention. As a demonstration of utility, a soft quadruped protected by SHeaLDS detects and self-heals from extreme damage (e.g., six cuts on one leg) in 1 min and monitors and adapts its gait based on the damage condition autonomously through feedback control.

"We Cause a Ruckus": Exploring How Indigenous Youth Navigate the Challenges of Community Engagement and Leadership.

Using qualitative data from an interdisciplinary research project about mental health and community engagement with Indigenous youth in Kasabonika Lake First Nation (Ontario, Canada), this paper explores the factors that constrain and facilitate their ability to contribute to the well-being of their community. Case studies are employed to demonstrate how the youth navigate complex social and structural conditions within the context of on-going colonization through federal and provincial governance arrangements, to make a difference in the place they call home and forge unique in-roads that reflect their generational realities and aspirations. The paper contributes to ongoing discussions related to mental health, self-determination, and resilience research.

Magnetohydrodynamic levitation for high-performance flexible pumps.

We use magnetohydrodynamic levitation as a means to create a soft, elastomeric, solenoid-driven pump (ESP). We present a theoretical framework and fabrication of a pump designed to address the unique challenges of soft robotics, maintaining pumping performance under deformation. Using a permanent magnet as a piston and ferrofluid as a liquid seal, we model and construct a deformable displacement pump. The magnet is driven back and forth along the length of a flexible core tube by a series of solenoids made of thin conductive wire. The magnet piston is kept concentric within the tube by Maxwell stresses within the ferrofluid and magnetohydrodynamic levitation, as viscous lift pressure is created due to its forward velocity. The centering of the magnet reduces shear stresses during pumping and improves efficiency. We provide a predictive model and capture the transient nonlinear dynamics of the magnet during operation, leading to a parametric performance curve characterizing the ESP, enabling goal-driven design. In our experimental validation, we report a shut-off pressure of 2 to 8 kPa and run-out flow rate of 50 to 320 mL⋅min-1, while subject to deformation of its own length scale, drawing a total of 0.17 W. This performance leads to the highest reported duty point (i.e., pressure and flow rate provided under load) for a pump that operates under deformation of its own length scale. We then integrate the pump into an elastomeric chassis and squeeze it through a tortuous pathway while providing continuous fluid pressure and flow rate; the vehicle then emerges at the other end and propels itself swimming.

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.

Simple synthesis of soft, tough, and cytocompatible biohybrid composites.

Collagen is the most abundant component of mammalian extracellular matrices. As such, the development of materials that mimic the biological and mechanical properties of collagenous tissues is an enduring goal of the biomaterials community. Despite the development of molded and 3D printed collagen hydrogel platforms, their use as biomaterials and tissue engineering scaffolds is hindered by either low stiffness and toughness or processing complexity. Here, we demonstrate the development of stiff and tough biohybrid composites by combining collagen with a zwitterionic hydrogel through simple mixing. This combination led to the self-assembly of a nanostructured fibrillar network of collagen that was ionically linked to the surrounding zwitterionic hydrogel matrix, leading to a composite microstructure reminiscent of soft biological tissues. The addition of 5-15 mg mL-1 collagen and the formation of nanostructured fibrils increased the elastic modulus of the composite system by 40% compared to the base zwitterionic matrix. Most notably, the addition of collagen increased the fracture energy nearly 11-fold ([Formula: see text] 180 J m-2) and clearly delayed crack initiation and propagation. These composites exhibit elastic modulus ([Formula: see text] 0.180 MJ) and toughness ([Formula: see text]0.617 MJ m-3) approaching that of biological tissues such as articular cartilage. Maintenance of the fibrillar structure of collagen also greatly enhanced cytocompatibility, improving cell adhesion more than 100-fold with >90% cell viability.

Haptic perception using optoelectronic robotic flesh for embodied artificially intelligent agents.

Flesh encodes a variety of haptic information including deformation, temperature, vibration, and damage stimuli using a multisensory array of mechanoreceptors distributed on the surface of the human body. Currently, soft sensors are capable of detecting some haptic stimuli, but whole-body multimodal perception at scales similar to a human adult (surface area ~17,000 square centimeters) is still a challenge in artificially intelligent agents due to the lack of encoding. This encoding is needed to reduce the wiring required to send the vast amount of information transmitted to the processor. We created a robotic flesh that could be further developed for use in these agents. This engineered flesh is an optical, elastomeric matrix "innervated" with stretchable lightguides that encodes haptic stimuli into light: temperature into wavelength due to thermochromic dyes and forces into intensity due to mechanical deformation. By exploiting the optical properties of the constitutive materials and using machine learning, we infer spatiotemporal, haptic information from light that is read by an image sensor. We demonstrate the capabilities of our system in various assemblies to estimate temperature, contact location, normal and shear force, gestures, and damage from temporal snapshots of light coming from the entire haptic sensor with errors <5%.

Polychlorinated cyclopentenes from a marine derived Periconia sp. (strain G1144).

Studies on an organic extract of a marine fungus, Periconia sp. (strain G1144), led to the isolation of three halogenated cyclopentenes along with the known and recently reported rhytidhyester D; a series of spectrometric and spectroscopic techniques were used to elucidate these structures. Interestingly, two of these compounds represent tri-halogenated cyclopentene derivatives, which have been observed only rarely from Nature. The relative and absolute configurations of the compounds were established via mass spectrometry (MS), nuclear magnetic resonance (NMR) spectroscopy, Mosher's esters method, optical rotation and GIAO NMR calculations, including correlation coefficient calculations and the use of both DP4+ and dJ DP4 analyses. Several of the isolated compounds were tested for activity in anti-parasitic, antimicrobial, quorum sensing inhibition, and cytotoxicity assays and were shown to be inactive.

Pump Up the Jam: Granular Media as a Quasi-Hydraulic Fluid for Independent Control Over Isometric and Isotonic Actuation.

Elastomer-granule composites have been used to switch between soft and stiff states by applying negative pressure differentials that cause the membrane to squeeze the internal grains, inducing dilation and jamming. Applications of this phenomenon have ranged from universal gripping to adaptive mobility. Previously, the combination of this jamming phenomenon with the ability to transport grains across multiple soft actuators for shape morphing has not yet been demonstrated. In this paper, the authors demonstrate the use of hollow glass spheres as granular media that functions as a jammable "quasi-hydraulic" fluid in a fluidic elastomeric actuator that better mimics a key featur of animal musculature: independent control over i) isotonic actuation for motion; and ii) isometric actuation for stiffening without shape change. To best implement the quasi-hydraulic fluid, the authors design and build a fluidic device. Leveraging this combination of physical properties creates a new option for fluidic actuation that allows higher specific stiffness actuators using lower volumetric flow rates in addition to independent control over shape and stiffness. These features are showcased in a robotic catcher's mitt by stiffening the fluid in the glove's open configuration for catching, unjamming the media, then pumping additional fluid to the mitt to inflate and grasp.

Polymer interdigitated pillar electrostatic (PIPE) actuators.

This work reports a three-dimensional polymer interdigitated pillar electrostatic actuator that can produce force densities 5-10× higher than those of biological muscles. The theory of operation, scaling, and stability is investigated using analytical and FEM models. The actuator consists of two high-density arrays of interdigitated pillars that work against a restoring force generated by an integrated flexure spring. The actuator architecture enables linear actuation with higher displacements and pull-in free actuation to prevent the in-use stiction associated with other electrostatic actuators. The pillars and springs are 3D printed together in the same structure. The pillars are coated with a gold-palladium alloy layer to form conductive electrodes. The space between the pillars is filled with liquid dielectrics for higher breakdown voltages and larger electrostatic forces due to the increase in the dielectric constant. We demonstrated a prototype actuator that produced a maximum work density of 54.6 µJ/cc and an electrical-to-mechanical energy coupling factor of 32% when actuated at 4000 V. The device was operated for more than 100,000 cycles with no degradation in displacements. The flexible polymer body was robust, allowing the actuator to operate even after high mechanical force impact, which was demonstrated by operation after drop tests. As it is scaled further, the reported actuator will enable soft and flexible muscle-like actuators that can be stacked in series and parallel to scale the resulting forces. This work paves the way for high-energy density actuators for microrobotic applications.

Towards enduring autonomous robots via embodied energy.

Autonomous robots comprise actuation, energy, sensory and control systems built from materials and structures that are not necessarily designed and integrated for multifunctionality. Yet, animals and other organisms that robots strive to emulate contain highly sophisticated and interconnected systems at all organizational levels, which allow multiple functions to be performed simultaneously. Herein, we examine how system integration and multifunctionality in nature inspires a new paradigm for autonomous robots that we call Embodied Energy. Whereas most untethered robots use batteries to store energy and power their operation, recent advancements in energy-storage techniques enable chemical or electrical energy sources to be embodied directly within the structures and materials used to create robots, rather than requiring separate battery packs. This perspective highlights emerging examples of Embodied Energy in the context of developing autonomous robots.

Fluid Flow Stimulation Modulates Expression of S100 Genes in Normal Breast Epithelium and Breast Cancer.

INTRODUCTION: S100 proteins are intracellular calcium ion sensors that participate in cellular processes, some of which are involved in normal breast functioning and breast cancer development. Despite several S100 genes being overexpressed in breast cancer, their roles during disease development remain elusive. Human mammary epithelial cells (HMECs) can be exposed to fluid shear stresses and implications of such interactions have not been previously studied. The goal of this study was to analyze expression profiles of S100 genes upon exposing HMECs to fluid flow. METHODS: HMECs and breast cancer cell lines were exposed to fluid flow in a parallel-plate bioreactor system. Changes in gene expression were quantified using microarrays and qPCR, gene-gene interactions were elucidated using network analysis, and key modified genes were examined in three independent clinical datasets. RESULTS: S100 genes were among the most upregulated genes upon flow stimulation. Network analysis revealed interactions between upregulated transcripts, including interactions between S100P, S100PBP, S100A4, S100A7, S100A8 and S100A9. Overexpression of S100s was also observed in patients with early stage breast cancer compared to normal breast tissue, and in most breast cancer patients. Finally, survival analysis revealed reduced survival times for patients with elevated expression of S100A7 and S100P. CONCLUSION: This study shows that exposing HMECs to fluid flow upregulates genes identified clinically to be overexpressed during breast cancer development, including S100A7 and S100P. These findings are the first to show that S100 genes are flow-responsive and might be participating in a fundamental adaptation pathway in normal tissue that is also active in breast cancer.