Development of Magnet-Driven and Image-Guided Degradable Microrobots for the Precise Delivery of Engineered Stem Cells for Cancer Therapy.

Precise delivery of therapeutic cells to the desired site in vivo is an emerging and promising cellular therapy in precision medicine. This paper presents the development of a magnet-driven and image-guided degradable microrobot that can precisely deliver engineered stem cells for orthotopic liver tumor treatment. The microrobot employs a burr-like porous sphere structure and is made with a synthesized composite to fulfill degradability, mechanical strength, and magnetic actuation capability simultaneously. The cells can be spontaneously released from the microrobots on the basis of the optimized microrobot structure. The microrobot is actuated by a gradient magnetic field and guided by a unique photoacoustic imaging technology. In preclinical experiments on nude mice, microrobots carrying cells are injected via the portal vein and the released cells from the microrobots can inhibit the tumor growth greatly. This paper reveals for the first time of using degradable microrobots for precise delivery of therapeutic cells in vascular tissue and demonstrates its therapeutic effect in preclinical test.

Translational and rotational manipulation of filamentous cells using optically driven microrobots.

Optical cell manipulation has become increasingly valuable in cell-based assays. In this paper, we demonstrate the translational and rotational manipulation of filamentous cells using multiple cooperative microrobots automatically driven by holographic optical tweezers. The photodamage of the cells due to direct irradiation of the laser beam can be effectively avoided. The proposed method will enable fruitful biomedical applications where precise cell manipulation and less photodamage are required.

Dielectrically-Loaded Cylindrical Resonator-Based Wireless Passive High-Temperature Sensor.

The temperature sensor presented in this paper is based on a microwave dielectric resonator, which uses alumina ceramic as a substrate to survive in harsh environments. The resonant frequency of the resonator is determined by the relative permittivity of the alumina ceramic, which monotonically changes with temperature. A rectangular aperture etched on the surface of the resonator works as both an incentive and a coupling device. A broadband slot antenna fed by a coplanar waveguide is utilized as an interrogation antenna to wirelessly detect the sensor signal using a radio-frequency backscattering technique. Theoretical analysis, software simulation, and experiments verified the feasibility of this temperature-sensing system. The sensor was tested in a metal-enclosed environment, which severely interferes with the extraction of the sensor signal. Therefore, frequency-domain compensation was introduced to filter the background noise and improve the signal-to-noise ratio of the sensor signal. The extracted peak frequency was found to monotonically shift from 2.441 to 2.291 GHz when the temperature was varied from 27 to 800 °C, leading to an average absolute sensitivity of 0.19 MHz/°C.

A Wireless Passive LC Resonant Sensor Based on LTCC under High-Temperature/Pressure Environments.

In this work, a wireless passive LC resonant sensor based on DuPont 951 ceramic is proposed and tested in a developed high-temperature/pressure complex environment. The test results show that the measured resonant frequency varies approximately linearly with the applied pressure; simultaneously, high temperature causes pressure signal drift and changes the response sensitivity. Through the theoretical analysis of the sensor structure model, it is found that the increase in the dielectric constant and the decrease in the Young's modulus of DuPont 951 ceramic are the main causes that affect the pressure signal in high-temperature measurement. Through calculations, the Young's modulus of DuPont 951 ceramic is found to decrease rapidly from 120 GPa to 65 GPa within 400 °C. Therefore, the LC resonant pressure sensor needs a temperature compensation structure to eliminate the impact of temperature on pressure measurement. Finally, a temperature compensation structure is proposed and fabricated, and the pressure response after temperature compensation illustrates that temperature drift is significantly reduced compared with that without the temperature compensation structure, which verifies the feasibility the proposed temperature compensation structure.

Development of Cell-Carrying Magnetic Microrobots with Bioactive Nanostructured Titanate Surface for Enhanced Cell Adhesion.

Cell-carrying magnet-driven microrobots are easily affected by blood flow or body fluids during transportation in the body, and thus cells often fall off from the microrobots. To reduce the loss of loaded cells, we developed a microrobot with a bioactive nanostructured titanate surface (NTS), which enhances cell adhesion. The microrobot was fabricated using 3D laser lithography and coated with nickel for magnetic actuation. Then, the microrobot was coated with titanium for the external generation of an NTS through reactions in NaOH solution. Enhanced cell adhesion may be attributed to the changes in the surface wettability of the microrobot and in the morphology of the loaded cells. An experiment was performed on a microfluidic chip for the simulation of blood flow environment, and result revealed that the cells adhered closely to the microrobot with NTS and were not obviously affected by flow. The cell viability and protein absorption test and alkaline phosphatase activity assay indicated that NTS can provide a regulatory means for improving cell proliferation and early osteogenic differentiation. This research provided a novel microrobotic platform that can positively influence the behaviour of cells loaded on microrobots through surface nanotopography, thereby opening up a new route for microrobot cell delivery.

Magnetically Powered Biodegradable Microswimmers.

The propulsive efficiency and biodegradability of wireless microrobots play a significant role in facilitating promising biomedical applications. Mimicking biological matters is a promising way to improve the performance of microrobots. Among diverse locomotion strategies, undulatory propulsion shows remarkable efficiency and agility. This work proposes a novel magnetically powered and hydrogel-based biodegradable microswimmer. The microswimmer is fabricated integrally by 3D laser lithography based on two-photon polymerization from a biodegradable material and has a total length of 200 µm and a diameter of 8 µm. The designed microswimmer incorporates a novel design utilizing four rigid segments, each of which is connected to the succeeding segment by spring to achieve undulation, improving structural integrity as well as simplifying the fabrication process. Under an external oscillating magnetic field, the microswimmer with multiple rigid segments connected by flexible spring can achieve undulatory locomotion and move forward along with the directions guided by the external magnetic field in the low Reynolds number (Re) regime. In addition, experiments demonstrated that the microswimmer can be degraded successfully, which allows it to be safely applied in real-time in vivo environments. This design has great potential in future in vivo applications such as precision medicine, drug delivery, and diagnosis.

Automated In Vivo Navigation of Magnetic-Driven Microrobots Using OCT Imaging Feedback.

OBJECTIVE: The application of in vivo microrobot navigation has received considerable attention from the field of precision therapy, which uses microrobots in living organisms. METHODS: This study investigates the navigation of microrobots in vivo using optical coherence tomography (OCT) imaging feedback. The electromagnetic gradient field generated by a home-made electromagnetic manipulation system is magnetically modeled. With this model, the magnetic force acting on the microrobot is calculated, and the relationship between this force and the velocity of the microrobot is characterized. RESULTS: Results are verified through in vitro experiments wherein microrobots are driven in three types of fluid, namely, normal saline, gastric juice, and mouse urine. In vivo experiments are performed to navigate the microrobot in a mouse portal vein in which the OCT imaging system tracks the microrobot in vivo. CONCLUSIONS: Experimental results demonstrate the effectiveness of the proposed approach. The microrobots can be magnetically driven in the in vivo environment using the OCT imaging feedback. SIGNIFICANCE: The significance of this study lies in providing a new method of driving microrobots in vivo.

Gravitational sedimentation-based approach for ultra-simple and flexible cell patterning coculture on microfluidic device.

Combining patterning coculture technique with microfluidics enables the reconstruction of complex in-vivo system to facilitate in-vitro studies on cell-cell and cell-environment interactions. However, simple and versatile approaches for patterning coculture of cells on microfluidic platforms remain lacking. In this study, a novel gravitational sedimentation-based approach is presented to achieve ultra-simple and flexible cell patterning coculture on a microfluidic platform, where multiple cell types can be patterned simultaneously to form a well-organized cell coculture. In contrast to other approaches, the proposed approach allows the rapid patterning of multiple cell types in microfluidic channels without the use of sheath flow and a prepatterned functional surface. This feature greatly simplifies the experimental setup, operation, and chip fabrication. Moreover, cell patterning can be adjusted by simply modifying the cell-loading tubing direction, thereby enabling great flexibility for the construction of different cell patterns without complicating the chip design and flow control. A series of physical and biological experiments are conducted to validate the proposed approach. This research paves a new way for building physiologically realistic in-vitro coculture models on microfluidic platforms for various applications, such as cell-cell interaction and drug screening.

Precise Drug Delivery by Using PLGA-Based Microspheres and Optical Manipulators.

The accurate delivery of precise amounts of drugs to a specific location can considerably affect various clinical applications. The precise control of drug amount and position is crucial to a successful drug delivery. This paper proposes the use of poly(lactide-co-glycolicacid) (PLGA)-based microspheres to contain precise amounts of drugs and an optical tweezer manipulator to transport these drug-containing microspheres to their targeted sites in vivo. The drugs were delivered by the PLGA-based microspheres to the yolk sac of zebrafish embryos, and a sustained drug release was observed to examine the anti-angiogenesis and angiogenesis activities. The PLGA-based microspheres degraded in zebrafish, thereby verifying that these microspheres can be used as drug carriers in vivo to ensure good biocompatibility and biodegradation. The proposed precise drug delivery approach can be used in protein tests and drug property characterization in vivo.