Ultrasound-Based Real-Time Imaging of Hydrogel-Based Millirobots with Volume Change Capability.

Soft-bodied robots driven by external fields have better environmental adaptability, extending their applications. Nature also provides lots of inspiration for shape-morphing robot development, for example, larvae and jellyfish. This paper presents magnetically propelled hydrogel-based millirobots with volume changeability. The millirobot can be imaged in real time in a completely enclosed space with an ultrasound imaging system. Firstly, a custom-designed magnetic generating system with six square coils was introduced to generate a uniform field to propel the robot. The robot was fabricated using hydrogel with a thickness of around 300 µm. After programmable magnetization, the robot could change its shape and move using the rotating magnetic field. With the near-infrared illumination, the robot could shrink and could recover when the illumination stopped. Even when the robot shrank, it could be propelled by the external field, showing its potential usage in complex environments. Moreover, the posture information of the robot including the position and shape could be obtained in real time using ultrasound image technology.

Biomineralization-inspired mineralized hydrogel promotes the repair and regeneration of dentin/bone hard tissue.

Maxillofacial hard tissue defects caused by trauma or infection often affect craniofacial function. Taking the natural hard tissue structure as a template, constructing an engineered tissue repair module is an important scheme to realize the functional regeneration and repair of maxillofacial hard tissue. Here, inspired by the biomineralization process, we constructed a composite mineral matrix hydrogel PAA-CMC-TDM containing amorphous calcium phosphates (ACPs), polyacrylic acid (PAA), carboxymethyl chitosan (CMC) and dentin matrix (TDM). The dynamic network composed of Ca2+·COO- coordination and ACPs made the hydrogel loaded with TDM, and exhibited self-repairing ability and injectability. The mechanical properties of PAA-CMC-TDM can be regulated, but the functional activity of TDM remains unaffected. Cytological studies and animal models of hard tissue defects show that the hydrogel can promote the odontogenesis or osteogenic differentiation of mesenchymal stem cells, adapt to irregular hard tissue defects, and promote in situ regeneration of defective tooth and bone tissues. In summary, this paper shows that the injectable TDM hydrogel based on biomimetic mineralization theory can induce hard tissue formation and promote dentin/bone regeneration.

Parallel Manipulation and Flexible Assembly of Micro-Spiral via Optoelectronic Tweezers.

Micro-spiral has a wide range of applications in smart materials, such as drug delivery, deformable materials, and micro-scale electronic devices by utilizing the manipulation of electric fields, magnetic fields, and flow fields. However, it is incredibly challenging to achieve a massively parallel manipulation of the micro-spiral to form a particular microstructure in these conventional methods. Here, a simple method is reported for assembling micro-spirals into various microstructures via optoelectronic tweezers (OETs), which can accurately manipulate the micro-/bio-particles by projecting light patterns. The manipulation force of micro-spiral is analyzed and simulated first by the finite element simulation. When the micro-spiral lies at the bottom of the microfluidic chip, it can be translated or rotated toward the target position by applying control forces simultaneously at multiple locations on the long axis of the micro-spiral. Through the OET manipulation, the length of the micro-spiral chain can reach 806.45 µm. Moreover, the different parallel manipulation modes are achieved by utilizing multiple light spots. The results show that the micro-spirulina can be manipulated by a real-time local light pattern and be flexibly assembled into design microstructures by OETs, such as a T-shape circuit, link lever, and micro-coil pairs of devices. This assembly method using OETs has promising potential in fabricating innovative materials and microdevices for practical engineering applications.

Magnetically Actuated Cell-Robot System: Precise Control, Manipulation, and Multimode Conversion.

Border-nearing microrobots with self-propelling and navigating capabilities have promising applications in micromanipulation and bioengineering, because they can stimulate the surrounding fluid flow for object transportation. However, ensuring the biosafety of microrobots is a concurrent challenge in bioengineering applications. Here, macrophage template-based microrobots (cell robots) that can be controlled individually or in chain-like swarms are proposed, which can transport various objects. The cell robots are constructed using the phagocytic ability of macrophages to load nanomagnetic particles while maintaining their viability. The robots exhibit high position control accuracy and generate a flow field that can be used to transport microspheres and sperm when exposed to an external magnetic field near a wall. The cell robots can also form chain-like swarms to transport a large object (more than 100 times the volume). This new insight into the manipulation of macrophage-based cell robots provides a new concept by converting other biological cells into microrobots for micromanipulation in biomedical applications.

Optimization of Nanoparticles for Smart Drug Delivery: A Review.

Nanoparticle delivery systems have good application prospects in the treatment of various diseases, especially in cancer treatment. The effect of drug delivery is regulated by the properties of nanoparticles. There have been many studies focusing on optimizing the structure of nanoparticles in recent years, and a series of achievements have been made. This review summarizes the optimization strategies of nanoparticles from three aspects-improving biocompatibility, increasing the targeting efficiency of nanoparticles, and improving the drug loading rate of nanoparticles-aiming to provide some theoretical reference for the subsequent drug delivery of nanoparticles.

Interaction between positive and negative dielectric microparticles/microorganism in optoelectronic tweezers.

Optoelectronic tweezers (OET) is a noncontact micromanipulation technology for controlling microparticles and cells. In the OET, it is necessary to configure a medium with different electrical properties to manipulate different particles and to avoid the interaction between two particles. Here, a new method exploiting the interaction between different dielectric properties of micro-objects to achieve the trapping, transport, and release of particles in the OET system was proposed. Besides, the effect of interaction between the micro-objects with positive and negative dielectric properties was simulated by the arbitrary Lagrangian-Eulerian (ALE) method. In addition, compared with conventional OET systems relying on fabrication processes involving the assembly of photoelectric materials, a contactless OET platform with an iPad-based wireless-control interface was established to achieve convenient control. Finally, this platform was used in the interaction of swimming microorganisms (positive-dielectric properties) with microparticles (negative-dielectric properties) at different scales. It showed that one particle could interact with 5 particles simultaneously, indicating that the interaction can be applied to enhance the high-throughput transportation capacities of the OET system and assemble some special microstructures. Owing to the low power, microorganisms were free from adverse influence during the experiment. In the future, the interaction of particles in a simple OET platform is a promising alternative in micro-nano manipulation for controlling drug release from uncontaminated cells in targeted therapy research.

Precise Control of Customized Macrophage Cell Robot for Targeted Therapy of Solid Tumors with Minimal Invasion.

Injecting micro/nanorobots into the body to kill tumors is one of the ultimate ambitions for medical nanotechnology. However, injecting current micro/nanorobots based on 3D-printed biocompatible materials directly into blood vessels for targeted therapy is often difficult, and mistakes in targeting can cause serious side effects, such as blood clots, oxidative stress, or inflammation. The natural affinity of macrophages to tumors, and their natural phagocytosis and ability to invade tumors, make them outstanding drug delivery vehicles for targeted tumor therapy. Hence, a magnetically controlled cell robot (MCR) based on a macrophage drug carrier is proposed. Here, living macrophages are converted into MCRs through endocytosis of specially-designed magnetic nanoparticles loaded with doxorubicin and indocyanine green. Following this, the MCRs can be transported to tumors through the blood vessels using external magnetic fields, and penetrate the blood vessels into the interior of the tumor due to their deformability. With the MCR's cascaded drug release, targeted killing of tumors in mice is demonstrated, with minimal effects on the normal surrounding tissue. The ability to impart precise drug doses onto natural cells, such as macrophages, and load various functional components into the MCRs, offers an efficient method for precise targeted therapy.

Bone formation recovery with gold nanoparticle-induced M2 macrophage polarization in mice.

The prevention of fractures induced by inflammatory bone disease remains a clinical challenge. This is because of a lack of bone formation to fill in the bone defects, which are believed to be due in part to persistent inflammation caused by the imbalance of M1 over M2 macrophages. In this study, gold nanoparticles (AuNPs) were synthesized to shift the balance of macrophages at the site of bone damage to improve osteanagenesis in a mouse model of LPS-induced inflammatory bone erosion. Specifically, the AuNPs treatment improved bone structure and increased bone mineral density (BMD) by ~14% compared with model group. Macrophages recruited by LPS treatment were reduced by ~11% after AuNPs injection. Compared to LPS treatment only, the percentage of M2 macrophages increased threefold by AuNPs, while the proportion of M1 macrophages decreased by 59%. This promoted the regeneration of bone matrix proteins in the bone defect site, which finally leads to increased bone mass and improved bone structure in model mice. These data suggest that AuNPs could be a novel candidate therapeutic for inflammatory bone disease rather than a drug carrier.

Postoperative evaluation of tumours based on label-free acoustic separation of circulating tumour cells by microstreaming.

Metastatic tumour recurrence caused by circulating tumour cells (CTCs) after surgery is responsible for more than 90% of tumour-related deaths. A postoperative evaluation system based on the long-term dynamic detection of CTCs helps in guiding the postoperative treatment of tumours in real time and preventing metastases and recurrence of tumours after treatment. In this study, a simple, rapid, and low-cost postoperative evaluation system was established based on the number of CTCs captured by a label-free acoustic separation device from whole blood samples of mice, of which breast tumours were surgically removed, and tumour metastasis was successfully predicted. First, an acoustofluidic device with a custom-designed bottom microcavity array was fabricated to induce highly localised acoustic microstreaming by applying acoustic vibration. Second, experiments of capturing 'defined' cells (artificially mixed individual 4T1 cancer cells into normal blood) based on optimal acoustic streaming were performed. The separation device exhibited a high capture efficiency (>96%). Further applications of capturing the 'true' CTCs derived from postoperative mice were successfully developed to predict tumour prognosis based on the number of captured CTCs. Finally, the prediction was verified through long-term observation of mice with excised tumours. The acoustofluidic device can efficiently capture CTCs and precisely predict tumour metastasis in a low-cost and non-invasive manner. This will help clinicians monitor patients that underwent surgical resection of tumours over a long period of time and facilitate optimal treatment strategies in a timely manner.

A Versatile Optoelectronic Tweezer System for Micro-Objects Manipulation: Transportation, Patterning, Sorting, Rotating and Storage.

Non-contact manipulation technology has a wide range of applications in the manipulation and fabrication of micro/nanomaterials. However, the manipulation devices are often complex, operated only by professionals, and limited by a single manipulation function. Here, we propose a simple versatile optoelectronic tweezer (OET) system that can be easily controlled for manipulating microparticles with different sizes. In this work, we designed and established an optoelectronic tweezer manipulation system. The OET system could be used to manipulate particles with a wide range of sizes from 2 µm to 150 µm. The system could also manipulate micro-objects of different dimensions like 1D spherical polystyrene microspheres, 2D rod-shaped euglena gracilis, and 3D spiral microspirulina. Optical microscopic patterns for trapping, storing, parallel transporting, and patterning microparticles were designed for versatile manipulation. The sorting, rotation, and assembly of single particles in a given region were experimentally demonstrated. In addition, temperatures measured under different objective lenses indicate that the system does not generate excessive heat to damage bioparticles. The non-contact versatile manipulation reduces operating process and contamination. In future work, the simple optoelectronic tweezers system can be used to control non-contaminated cell interaction and micro-nano manipulation.

On-chip rotational manipulation of microbeads and oocytes using acoustic microstreaming generated by oscillating asymmetrical microstructures.

The capability to precisely rotate cells and other micrometer-sized biological samples is invaluable in biomedicine, bioengineering, and biophysics. We propose herein a novel on-chip cell rotation method using acoustic microstreaming generated by oscillating asymmetrical microstructures. When the vibration is applied to a microchip with our custom-designed microstructures, two different modes of highly localized microvortices are generated that are utilized to precisely achieve in-plane and out-of-plane rotational manipulation of microbeads and oocytes. The rotation mechanism is studied and verified using numerical simulations. Experiments of the microbeads are conducted to evaluate the claimed functions and investigate the effects of various parameters, such as the frequency and the driving voltage on the acoustically induced flows. Accordingly, it is shown that the rotational speed and direction can be effectively tuned on demand in single-cell studies. Finally, the rotation of swine oocytes is involved as further applications. By observing the maturation stages of M2 after the exclusion of the first polar body of operated oocytes, the proposed method is proved to be noninvasive. Compared with the conventional approaches, our acoustofluidic cell rotation approach can be simple-to-fabricate and easy-to-operate, thereby allowing rotations irrespective of the physical properties of the specimen under investigation.