SonoTransformers: Transformable acoustically activated wireless microscale machines.

Shape transformation, a key mechanism for organismal survival and adaptation, has gained importance in developing synthetic shape-shifting systems with diverse applications ranging from robotics to bioengineering. However, designing and controlling microscale shape-shifting materials remains a fundamental challenge in various actuation modalities. As materials and structures are scaled down to the microscale, they often exhibit size-dependent characteristics, and the underlying physical mechanisms can be significantly affected or rendered ineffective. Additionally, surface forces such as van der Waals forces and electrostatic forces become dominant at the microscale, resulting in stiction and adhesion between small structures, making them fracture and more difficult to deform. Furthermore, despite various actuation approaches, acoustics have received limited attention despite their potential advantages. Here, we introduce "SonoTransformer," the acoustically activated micromachine that delivers shape transformability using preprogrammed soft hinges with different stiffnesses. When exposed to an acoustic field, these hinges concentrate sound energy through intensified oscillation and provide the necessary force and torque for the transformation of the entire micromachine within milliseconds. We have created machine designs to predetermine the folding state, enabling precise programming and customization of the acoustic transformation. Additionally, we have shown selective shape transformable microrobots by adjusting acoustic power, realizing high degrees of control and functional versatility. Our findings open new research avenues in acoustics, physics, and soft matter, offering new design paradigms and development opportunities in robotics, metamaterials, adaptive optics, flexible electronics, and microtechnology.

Medical Microrobots.

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.

OPTICAL COHERENCE TOMOGRAPHY AND OCT ANGIOGRAPHY CHARACTERISTICS OF INDOCYANINE GREEN ANGIOGRAPHIC PLAQUES IN NONEXUDATIVE AGE-RELATED MACULAR DEGENERATION.

PURPOSE: To describe characteristics of indocyanine green (ICG) angiographic plaques in the nonexudative fellow eye of White patients with unilateral treatment-naïve exudative neovascular age-related macular degeneration through optical coherence tomography (OCT) and OCT angiography (OCTA). METHODS: In this retrospective cross-sectional study, nonexudative eyes with ICG angiographic plaques were analyzed by OCT B-scans for the sensitivity of a double-layer sign, a pigment epithelium detachment, outer retinal atrophy, hyperreflective dots, and subretinal hyperreflective material (SRHM). The ICG angiographic plaque was matched with a macular neovascularization in OCTA en face scans and color-coded B scans. RESULTS: In total, 35 ICG angiographic plaques in 33 of 291 (11%) nonexudative eyes were diagnosed. OCT revealed 27 double-layer sign (78%), eight pigment epithelium detachment (23%), 8 outer retinal atrophy (23%), eight hyperreflective dots (23%), and one subretinal hyperreflective material (3%). OCTA confirmed a macular neovascularization in 28 plaques (80%): 7 (20%) in en face scans, 3 (9%) in color-coded B scans, and 18 (51%) in both. The area size in OCTA was significantly smaller than that of ICG angiography ( P = 0.002). CONCLUSION: The diagnosis of an ICG angiographic plaque in nonexudative fellow eyes of Whites with unilateral treatment-naïve exudative neovascular age-related macular degeneration was highly suggestive of a typical macular neovascularization type 1 as characterized by OCT and OCTA.

'This is hardcore': a qualitative study exploring service users' experiences of Heroin-Assisted Treatment (HAT) in Middlesbrough, England.

BACKGROUND: Heroin-Assisted Treatment (HAT) is well evidenced internationally to improve health and social outcomes for people dependent on opioids who have not been helped by traditional treatment options. Despite this evidence base, England has been slow to implement HAT. The first service outside of a trial setting opened in 2019, providing twice-daily supervised injections of medical-grade heroin (diamorphine) to a select sample of high-risk heroin users in Middlesbrough. This paper explores their experiences, including the negotiation of the strict regularly controls required of a novel intervention in the UK context. METHODS: We conducted in-depth interviews with service providers and users of the Middlesbrough HAT service between September and November 2021. Data from each group were thematically analysed and reported separately. This paper details the experiences of the twelve heroin dependent men and women accessing HAT. RESULTS: Participants' accounts of HAT treatment evidenced a tension between the regulatory constraints and uncertainty of treatment provision, and the positive outcomes experienced through supportive service provision and an injectable treatment option. Limited confidence was held in treatment efficacy, longevity of funding, and personal capacity for treatment success. This was counteracted by a strong motivation to cease engagement with the illicit drug market. While attendance requirements placed restrictions on daily activities, participants also experienced benefits from strong, supportive bonds built with the service providers through their continued engagement. CONCLUSIONS: The Middlesbrough HAT programme provided benefits to a high-risk population of opioid dependent people who were unable or disinclined to participate in conventional opioid substitution treatments. The findings in this paper highlight the potential for service modifications to further enhance engagement. The closure of this programme in 2022 prohibits this opportunity for the Middlesbrough community, but holds potential to inform advocacy and innovation for future HAT interventions in England.

Embedded Microbubbles for Acoustic Manipulation of Single Cells and Microfluidic Applications.

Acoustically excited microstructures have demonstrated significant potential for small-scale biomedical applications by overcoming major microfluidic limitations. Recently, the application of oscillating microbubbles has demonstrated their superiority over acoustically excited solid structures due to their enhanced acoustic streaming at low input power. However, their limited temporal stability hinders their direct applicability for industrial or clinical purposes. Here, we introduce the embedded microbubble, a novel acoustofluidic design based on the combination of solid structures (poly(dimethylsiloxane)) and microbubbles (air-filled cavity) to combine the benefits of both approaches while minimizing their drawbacks. We investigate the influence of various design parameters and geometrical features through numerical simulations and experimentally evaluate their manipulation capabilities. Finally, we demonstrate the capabilities of our design for microfluidic applications by investigating its mixing performance as well as through the controlled rotational manipulation of individual HeLa cells.

Correction to: Drusen characteristics of type 2 macular neovascularization in age-related macular degeneration.

An amendment to this paper has been published and can be accessed via the original article.

Drusen characteristics of type 2 macular neovascularization in age-related macular degeneration.

BACKGROUND: Type 2 macular neovascularization (MNV) is supposed to be a rare condition in age-related macular degeneration (AMD). The main purpose of this study was to assess accompanying factors of type 2 MNV in AMD. METHODS: Retrospective data analysis of eyes previously diagnosed with neovascular AMD in a tertiary eye care center (Medical Retina Unit, Rudolf Foundation Hospital, Vienna, Austria) between June 2008 and December 2017. Drusen subtypes, fibrosis, atrophy and subfoveal choroidal thickness (SFCT) of both eyes in patients with type 2 MNV lesions were categorized based on multimodal imaging. RESULTS: Type 2 MNV was diagnosed in 27 (3.2%) of 835 eyes (749 patients). Drusen characteristics in type 2 MNV were observed as followed: drusen < 63 µm in 2 eyes (7.4%), drusen ≥63 µm in 10 eyes (37%), subretinal drusenoid deposits (SDD) in 8 eyes (29.6%), cuticular drusen in 2 eye (7.4%) and no drusen were evident in 10 eyes (37%). Drusen distribution in 23 fellow eyes was detected as followed: drusen < 63 µm in 2 eyes (8.7%), drusen ≥63 µm in 9 eyes (39.1%), SDD in 5 eyes (21.7%), cuticular drusen in 1 eye (4.3%) and no drusen were evident in 9 eyes (39.1%). Mean SFCT was 140 ± 49 µm in affected eyes and 152 ± 41 µm in the fellow eyes. Patients with drusen or SDD were significantly younger (mean 70.88 ± 6.85, p = 0.04) than patients without deposits (mean 77.40 ± 5.74). CONCLUSIONS: Type 2 MNV remains a rare entity in AMD. It was frequently seen in the absence of drusen, a hallmark of AMD. These findings contribute to the heterogeneity of phenotypes related to pure type 2 lesions.

Dynamic intraoperative optical coherence tomography for inverted internal limiting membrane flap technique in large macular hole surgery.

BACKGROUND/OBJECTIVES: To assess the efficacy of dynamic intraoperative spectral-domain optical coherence tomography (iSD-OCT) imaging for inverted internal limiting membrane (ILM) flap technique (IILMFT) in large macular hole (MH) surgery. SUBJECTS/METHODS: Prospective, non-randomized, observational study was conducted on 8 eyes of 7 patients with large, chronic and recurrent MHs, which were treated by pars plana vitrectomy (PPV) with IILMFT. All patients underwent standard pre- and postoperative examination. The iSD-OCT imaging was performed using microscope integrated systems before, during, and after ILM peeling. The iSD-OCT data were post-processed using graphic software and reviewed for tissue behavior and instruments position. RESULTS: The real-time iSD-OCT-assisted IILMFT allowed for real-time imaging of the entire surgery with visualization of the MH, vitreoretinal instruments, and all steps of inverted ILM flap formation. In spite of shadowing created by the steel instruments, it was possible to follow and control the distance between the instrument tips and retinal layers. Dynamic imaging of the surgical maneuvers including ILM peeling and mechanical apposition of MH edges revealed the iatrogenic impact on the retina (depression and appearance of hyporeflective zones). iSD-OCT imaging could confirm the proper position of the inverted ILM flap at the very end of the surgery after fluid-air exchange. CONCLUSIONS: iSD-OCT imaging is an effective tool for learning and performing a well-controlled and safe inverted ILM flap technique in patients with large MH. Clinical significance of the structural iSD-OCT findings has to be further studied.

DETECTION OF TREATMENT-NAIVE CHOROIDAL NEOVASCULARIZATION IN AGE-RELATED MACULAR DEGENERATION BY SWEPT SOURCE OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY.

PURPOSE: To compare the detection rate of choroidal neovascularization (CNV) in treatment-naive neovascular age-related macular degeneration by swept source optical coherence tomography angiography (SS-OCTA, Topcon's DRI Triton) working at 1,050 nm wavelength versus fluorescence angiography. METHODS: Cross-sectional analysis of 156 eyes (107 neovascular age-related macular degeneration and 49 dry AMD) in 98 patients, previously diagnosed by multimodal imaging using fluorescein (FA) and indocyanine green angiography (Heidelberg's Spectralis) in a tertiary retina center, evaluated by SS-OCTA 4.5 mm × 4.5 mm and 6 mm × 6 mm macular cubes. Main outcome measures were sensitivity and specificity of SS-OCTA in AMD. Potential factors influencing CNV detection rate were analyzed. RESULTS: Swept source optical coherence tomography angiography detected CNV in 81 of 107 eyes, resulting in a sensitivity of 75.7%. In 49 eyes with dry AMD, no CNV could be identified (specificity 100%). A statistical significance was calculated for nondetection of treatment-naive CNV by SS-OCTA in pigment epithelial detachment over 400 µm (P = 0.0238). CONCLUSION: Topcon's SS-OCTA was not able to detect all CNV lesions. Large pigment epithelial detachments were associated with signal loss. Fluorescence angiography still remains the gold standard, but the tested SS-OCTA device can be considered as a feasible additional diagnostic tool in AMD.

Artificial Swimmers Propelled by Acoustically Activated Flagella.

Recent studies have garnered considerable interest in the field of propulsion to maneuver micro- and nanosized objects. Acoustics provide an alternate and attractive method to generate propulsion. To date, most acoustic-based swimmers do not use structural resonances, and their motion is determined by a combination of bulk acoustic streaming and a standing-wave field. The resultant field is intrinsically dependent on the boundaries of their resonating chambers. Though acoustic based propulsion is appealing in biological contexts, existing swimmers are less efficient, especially when operating in vivo, since no predictable standing-wave can be established in a human body. Here we describe a new class of nanoswimmer propelled by the small-amplitude oscillation of a flagellum-like flexible tail in standing and, more importantly, in traveling acoustic waves. The artificial nanoswimmer, fabricated by multistep electrodeposition techniques, compromises a rigid bimetallic head and a flexible tail. During acoustic excitation of the nanoswimmer the tail structure oscillates, which leads to a large amplitude propulsion in traveling waves. FEM simulation results show that the structural resonances lead to high propulsive forces.

An acoustofluidic micromixer via bubble inception and cavitation from microchannel sidewalls.

During the deep reactive ion etching process, the sidewalls of a silicon mold feature rough wavy structures, which can be transferred onto a polydimethylsiloxane (PDMS) microchannel through the soft lithography technique. In this article, we utilized the wavy structures of PDMS microchannel sidewalls to initiate and cavitate bubbles in the presence of acoustic waves. Through bubble cavitation, this acoustofluidic approach demonstrates fast, effective mixing in microfluidics. We characterized its performance by using viscous fluids such as poly(ethylene glycol) (PEG). When two PEG solutions with a resultant viscosity 54.9 times higher than that of water were used, the mixing efficiency was found to be 0.92, indicating excellent, homogeneous mixing. The acoustofluidic micromixer presented here has the advantages of simple fabrication, easy integration, and capability to mix high-viscosity fluids (Reynolds number: ~0.01) in less than 100 ms.

Acoustofluidic chemical waveform generator and switch.

Eliciting a cellular response to a changing chemical microenvironment is central to many biological processes including gene expression, cell migration, differentiation, apoptosis, and intercellular signaling. The nature and scope of the response is highly dependent upon the spatiotemporal characteristics of the stimulus. To date, studies that investigate this phenomenon have been limited to digital (or step) chemical stimulation with little control over the temporal counterparts. Here, we demonstrate an acoustofluidic (i.e., fusion of acoustics and microfluidics) approach for generating programmable chemical waveforms that permits continuous modulation of the signal characteristics including the amplitude (i.e., sample concentration), shape, frequency, and duty cycle, with frequencies reaching up to 30 Hz. Furthermore, we show fast switching between multiple distinct stimuli, wherein the waveform of each stimulus is independently controlled. Using our device, we characterized the frequency-dependent activation and internalization of the ß2-adrenergic receptor (ß2-AR), a prototypic G-protein coupled receptor (GPCR), using epinephrine. The acoustofluidic-based programmable chemical waveform generation and switching method presented herein is expected to be a powerful tool for the investigation and characterization of the kinetics and other dynamic properties of many biological and biochemical processes.

Ultrasound robotics for precision therapy.

In recent years, the application of microrobots in precision therapy has gained significant attention. The small size and maneuverability of these micromachines enable them to potentially access regions that are difficult to reach using traditional methods; thus, reducing off-target toxicities and maximizing treatment effectiveness. Specifically, acoustic actuation has emerged as a promising method to exert control. By harnessing the power of acoustic energy, these small machines potentially navigate the body, assemble at the desired sites, and deliver therapies with enhanced precision and effectiveness. Amidst the enthusiasm surrounding these miniature agents, their translation to clinical environments has proven difficult. The primary objectives of this review are threefold: firstly, to offer an overview of the fundamental acoustic principles employed in the field of microrobots; secondly, to assess their current applications in medical therapies, encompassing tissue targeting, drug delivery or even cell infiltration; and lastly, to delve into the continuous efforts aimed at integrating acoustic microrobots into in vivo applications.

Steerable acoustically powered starfish-inspired microrobot.

Soft polymeric microrobots that can be loaded with nanocargoes and driven via external field stimuli can provide innovative solutions in various fields, including precise microscale assembly, targeted therapeutics, microsurgery, and the capture and degradation of unwanted wastewater fragments. However, in aquatic environments, it remains challenging to operate with microrobotic devices due to the predominant viscous resistances and the robots' limited actuation and sensing capabilities attributed to their miniaturization. The miniature size prevents the incorporation of onboard batteries that can provide sufficient power for propulsion and navigation, necessitating a wireless power supply. Current research examines untethered microrobot manipulation using external magnetic, electric, thermodynamic, or acoustic field-guided technologies: all strategies capable of wireless energy transmission towards sensitive and hard-to-reach locations. Nonetheless, developing a manipulation strategy that harnesses simple-to-induce strong propulsive forces in a stable manner over extended periods of time remains a significant endeavor. This study presents the fabrication and manipulation of a microrobot consisting of a magnetized soft polymeric composite material that enables a combination of stable acoustic propulsion through starfish-inspired artificial cilia and magnetic field-guided navigation. The acousto-magnetic manipulation strategy leverages the unique benefits of each applied field in the viscous-dominated microscale, namely precise magnetic orientation and strong acoustic thrust.

SonoPrint: Acoustically Assisted Volumetric 3D Printing for Composites.

Advances in additive manufacturing in composites have transformed aerospace, medical devices, tissue engineering, and electronics. A key aspect of enhancing properties of 3D-printed objects involves fine-tuning the material by embedding and orienting reinforcement within the structure. Existing methods for orienting these reinforcements are limited by pattern types, alignment, and particle characteristics. Acoustics offers a versatile method to control the particles independent of their size, geometry, and charge, enabling intricate pattern formations. However, integrating acoustics into 3D printing has been challenging due to the scattering of the acoustic field between polymerized layers and unpolymerized resin, resulting in unwanted patterns. To address this challenge, SonoPrint, an innovative acoustically assisted volumetric 3D printer is developed that enables simultaneous reinforcement patterning and printing of the entire structure. SonoPrint generates mechanically tunable composite geometries by embedding reinforcement particles, such as microscopic glass, metal, and polystyrene, within the fabricated structure. This printer employs a standing wave field to create targeted particle motifs-including parallel lines, radial lines, circles, rhombuses, hexagons, and polygons-directly in the photosensitive resin, completing the print in just a few minutes. SonoPrint enhances structural properties and promises to advance volumetric printing, unlocking applications in tissue engineering, biohybrid robots, and composite fabrication.

A vibrating capillary for ultrasound rotation manipulation of zebrafish larvae.

Multifunctional micromanipulation systems have garnered significant attention due to the growing interest in biological and medical research involving model organisms like zebrafish (Danio rerio). Here, we report a novel acoustofluidic rotational micromanipulation system that offers rapid trapping, high-speed rotation, multi-angle imaging, and 3D model reconstruction of zebrafish larvae. An ultrasound-activated oscillatory glass capillary is used to trap and rotate a zebrafish larva. Simulation and experimental results demonstrate that both the vibrating mode and geometric placement of the capillary contribute to the developed polarized vortices along the long axis of the capillary. Given its capacities for easy-to-operate, stable rotation, avoiding overheating, and high-throughput manipulation, our system poses the potential to accelerate zebrafish-directed biomedical research.

An acoustically controlled helical microrobot.

As a next-generation toolkit, microrobots can transform a wide range of fields, including micromanufacturing, electronics, microfluidics, tissue engineering, and medicine. While still in their infancy, acoustically actuated microrobots are becoming increasingly attractive. However, the interaction of acoustics with microstructure geometry is poorly understood, and its study is necessary for developing next-generation acoustically powered microrobots. We present an acoustically driven helical microrobot with a length of 350 µm and a diameter of 100 µm that is capable of locomotion using a fin-like double-helix microstructure. This microrobot responds to sound stimuli at ~12 to 19 kHz and mimics the spiral motion of natural microswimmers such as spirochetes. The asymmetric double helix interacts with the incident acoustic field, inducing a propulsion torque that causes the microrobot to rotate around its long axis. Moreover, our microrobot has the unique feature of its directionality being switchable by simply tuning the acoustic frequency. We demonstrate this locomotion in 2D and 3D artificial vasculatures using a single sound source.

Acoustic microbubble propulsion, train-like assembly and cargo transport.

Achieving controlled mobility of microparticles in viscous fluids can become pivotal in biologics, biotechniques, and biomedical applications. The self-assembly, trapping, and transport of microparticles are being explored in active matter, micro and nanorobotics, and microfluidics; however, little work has been done in acoustics, particularly in active matter and robotics. This study reports the discovery and characterization of microbubble behaviors in a viscous gel that is confined to a slight opening between glass boundaries in an acoustic field. Where incident waves encounter a narrow slit, acoustic pressure is amplified, causing the microbubbles to nucleate and cavitate within it. Intermittent activation transforms microbubbles from spherical to ellipsoidal, allowing them to be trapped within the interstice. Continuous activation propels ellipsoidal microbubbles through shape and volume modes that is developed at their surfaces. Ensembles of microbubbles self-assemble into a train-like arrangement, which in turn capture, transport, and release microparticles.

Ultrasound trapping and navigation of microrobots in the mouse brain vasculature.

The intricate and delicate anatomy of the brain poses significant challenges for the treatment of cerebrovascular and neurodegenerative diseases. Thus, precise local drug delivery in hard-to-reach brain regions remains an urgent medical need. Microrobots offer potential solutions; however, their functionality in the brain remains restricted by limited imaging capabilities and complications within blood vessels, such as high blood flows, osmotic pressures, and cellular responses. Here, we introduce ultrasound-activated microrobots for in vivo navigation in brain vasculature. Our microrobots consist of lipid-shelled microbubbles that autonomously aggregate and propel under ultrasound irradiation. We investigate their capacities in vitro within microfluidic-based vasculatures and in vivo within vessels of a living mouse brain. These microrobots self-assemble and execute upstream motion in brain vasculature, achieving velocities up to 1.5 µm/s and moving against blood flows of ~10 mm/s. This work represents a substantial advance towards the therapeutic application of microrobots within the complex brain vasculature.

Single-shot characterization of enzymatic reaction constants Km and kcat by an acoustic-driven, bubble-based fast micromixer.

In this work we present an acoustofluidic approach for rapid, single-shot characterization of enzymatic reaction constants K(m) and k(cat). The acoustofluidic design involves a bubble anchored in a horseshoe structure which can be stimulated by a piezoelectric transducer to generate vortices in the fluid. The enzyme and substrate can thus be mixed rapidly, within 100 ms, by the vortices to yield the product. Enzymatic reaction constants K(m) and k(cat) can then be obtained from the reaction rate curves for different concentrations of substrate while holding the enzyme concentration constant. We studied the enzymatic reaction for ß-galactosidase and its substrate (resorufin-ß-D-galactopyranoside) and found K(m) and k(cat) to be 333 ± 130 µM and 64 ± 8 s(-1), respectively, which are in agreement with published data. Our approach is valuable for studying the kinetics of high-speed enzymatic reactions and other chemical reactions.