Xiaohui Yan

Magnetic Actuation Based Motion Control for Microrobots: An Overview

Untethered, controllable, mobile microrobots have been proposed for numerous applications, ranging from micro-manipulation, in vitro tasks (e.g., operation of microscale biological substances) to in vivo applications (e.g., targeted drug delivery; brachytherapy; hyperthermia, etc.), due to their small-scale dimensions and accessibility to tiny and complex environments. Researchers have used different magnetic actuation systems allowing custom-designed workspace and multiple degrees of freedom (DoF) to actuate microrobots with various motion control methods from open-loop pre-programmed control to closed-loop path-following control. This article provides an overview of the magnetic actuation systems and the magnetic actuation-based control methods for microrobots. An overall benchmark on the magnetic actuation system and control method is also discussed according to the applications of microrobots.

Multifunctional biohybrid magnetite microrobots for imaging-guided therapy

A biohybrid microrobot with one-step fabrication provides multiple functions for imaging-guided therapy. Magnetic microrobots and nanorobots can be remotely controlled to propel in complex biological fluids with high precision by using magnetic fields. Their potential for controlled navigation in hard-to-reach cavities of the human body makes them promising miniaturized robotic tools to diagnose and treat diseases in a minimally invasive manner. However, critical issues, such as motion tracking, biocompatibility, biodegradation, and diagnostic/therapeutic effects, need to be resolved to allow preclinical in vivo development and clinical trials. We report biohybrid magnetic robots endowed with multifunctional capabilities by integrating desired structural and functional attributes from a biological matrix and an engineered coating. Helical microswimmers were fabricated from Spirulina microalgae via a facile dip-coating process in magnetite (Fe3O4) suspensions, superparamagnetic, and equipped with robust navigation capability in various biofluids. The innate properties of the microalgae allowed in vivo fluorescence imaging and remote diagnostic sensing without the need for any surface modification. Furthermore, in vivo magnetic resonance imaging tracked a swarm of microswimmers inside rodent stomachs, a deep organ where fluorescence-based imaging ceased to work because of its penetration limitation. Meanwhile, the microswimmers were able to degrade and exhibited selective cytotoxicity to cancer cell lines, subject to the thickness of the Fe3O4 coating, which could be tailored via the dip-coating process. The biohybrid microrobots reported herein represent a microrobotic platform that could be further developed for in vivo imaging–guided therapy and a proof of concept for the engineering of multifunctional microrobotic and nanorobotic devices.

Transdermal Delivery of siRNA through Microneedle Array.

Successful development of siRNA therapies has significant potential for the treatment of skin conditions (alopecia, allergic skin diseases, hyperpigmentation, psoriasis, skin cancer, pachyonychia congenital) caused by aberrant gene expression. Although hypodermic needles can be used to effectively deliver siRNA through the stratum corneum, the major challenge is that this approach is painful and the effects are restricted to the injection site. Microneedle arrays may represent a better way to deliver siRNAs across the stratum corneum. In this study, we evaluated for the first time the ability of the solid silicon microneedle array for punching holes to deliver cholesterol-modified housekeeping gene (Gapdh) siRNA to the mouse ear skin. Treating the ear with microneedles showed permeation of siRNA in the skin and could reduce Gapdh gene expression up to 66% in the skin without accumulation in the major organs. The results showed that microneedle arrays could effectively deliver siRNA to relevant regions of the skin noninvasively.

Sulfated hyaluronic acid hydrogels with retarded degradation and enhanced growth factor retention promote hMSC chondrogenesis and articular cartilage integrity with reduced hypertrophy

Recently, hyaluronic acid (HA) hydrogels have been extensively researched for delivering cells and drugs to repair damaged tissues, particularly articular cartilage. However, the in vivo degradation of HA is fast, thus limiting the clinical translation of HA hydrogels. Furthermore, HA cannot bind proteins with high affinity because of the lack of negatively charged sulfate groups. In this study, we conjugated tunable amount of sulfate groups to HA. The sulfated HA exhibits significantly slower degradation by hyaluronidase compared to the wild type HA. We hypothesize that the sulfation reduces the available HA octasaccharide substrate needed for the effective catalytic action of hyaluronidase. Moreover, the sulfated HA hydrogels significantly improve the protein sequestration, thereby effectively extending the availability of the proteinaceous drugs in the hydrogels. In the following in vitro study, we demonstrate that the HA hydrogel sulfation exerts no negative effect on the viability of encapsulated human mesenchymal stem cells (hMSCs). Furthermore, the sulfated HA hydrogels promote the chondrogenesis and suppresses the hypertrophy of encapsulated hMSCs both in vitro and in vivo. Moreover, intra-articular injections of the sulfated HA hydrogels avert the cartilage abrasion and hypertrophy in the animal osteoarthritic joints. Collectively, our findings demonstrate that the sulfated HA is a promising biomaterial for the delivery of therapeutic agents to aid the regeneration of injured or diseased tissues and organs. STATEMENT OF SIGNIFICANCE In this paper, we conjugated sulfate groups to hyaluronic acid (HA) and demonstrated the slow degradation and growth factor delivery of sulfated HA. Furthermore, the in vitro and in vivo culture of hMSCs laden HA hydrogels proved that the sulfation of HA hydrogels not only promotes the chondrogenesis of hMSCs but also suppresses hypertrophic differentiation of the chondrogenically induced hMSCs. The animal OA model study showed that the injected sulfated HA hydrogels significantly reduced the cartilage abrasion and hypertrophy in the animal OA joints. We believe that this study will provide important insights into the design and optimization of the HA-based hydrogels as the scaffold materials for cartilage regeneration and OA treatment in clinical setting.

Magnetically Tuning Tether Mobility of Integrin Ligand Regulates Adhesion, Spreading, and Differentiation of Stem Cells

Cells sense and respond to the surrounding microenvironment through binding of membranous integrin to ligands such as the Arg-Gly-Asp (RGD) peptide. Previous studies show that the RGD tether properties on substrate influence cell adhesion and spreading, but few studies have reported strategies to control the tether mobility of RGD on substrate via a physical and noncontact approach. Herein, we demonstrate a novel strategy to tune the tether mobility of RGD on substrate via magnetic force. We conjugate a monolayer of RGD-bearing magnetic nanoparticles (MNPs) on a glass substrate via the flexible and coiled poly(ethylene glycol) linker of large molecular weight (PEG, average MW: 2000), and this increases the RGD tether mobility, which can be significantly reduced by applying magnetic attraction on MNPs. Our data show that high RGD tether mobility delays the early adhesion and spreading of human mesenchymal stem cells (hMSCs), leading to compromised osteogenic differentiation at later stage. In contrast, hMSCs cultured on substrate with restricted RGD tether mobility, achieved either via a shorter PEG linker (MW: 200) or magnetic force, show significantly better adhesion, spreading, and osteogenic differentiation. The control utilizing RGD-bearing nonmagnetic nanoparticles shows no such enhancing effect of magnetic field on cellular events, further supporting our conjecture of magnetic tuning of RGD tether mobility. We hypothesize that high tether mobility of RGD entails additional time and effort by the cells to fully develop traction force and mechanical feedback, thereby delaying the maturation of FAs and activation of subsequent mechanotransduction signaling. Our staining results of vinculin, a critical component of FAs, and Yes-associated protein (YAP), an important mechanosensitive transcriptional factor, support our hypothesis. We believe that our work not only sheds light on the impact of dynamic presentation of cell adhesive ligands on cellular behaviors, which should be taken into consideration for designing novel biomaterials, but also formulate an effective noncontact strategy that enables further investigation on the mechanobiological mechanisms underlying such cellular responses.

Remote Control of Multimodal Nanoscale Ligand Oscillations Regulates Stem Cell Adhesion and Differentiation

Cellular adhesion is regulated by the dynamic ligation process of surface receptors, such as integrin, to adhesive motifs, such as Arg-Gly-Asp (RGD). Remote control of adhesive ligand presentation using external stimuli is an appealing strategy for the temporal regulation of cell-implant interactions in vivo and was recently demonstrated using photochemical reaction. However, the limited tissue penetration of light potentially hampers the widespread applications of this method in vivo. Here, we present a strategy for modulating the nanoscale oscillations of an integrin ligand simply and solely by adjusting the frequency of an oscillating magnetic field to regulate the adhesion and differentiation of stem cells. A superparamagnetic iron oxide nanoparticle (SPION) was conjugated with the RGD ligand and anchored to a glass substrate by a long flexible poly(ethylene glycol) linker to allow the oscillatory motion of the ligand to be magnetically tuned. In situ magnetic scanning transmission electron microscopy and atomic force microscopy imaging confirmed the nanoscale motion of the substrate-tethered RGD-grafted SPION. Our findings show that ligand oscillations under a low oscillation frequency (0.1 Hz) of the magnetic field promoted integrin-ligand binding and the formation and maturation of focal adhesions and therefore the substrate adhesion of stem cells, while ligands oscillating under high frequency (2 Hz) inhibited integrin ligation and stem cell adhesion, both in vitro and in vivo. Temporal switching of the multimodal ligand oscillations between low- and high-frequency modes reversibly regulated stem cell adhesion. The ligand oscillations further induced the stem cell differentiation and mechanosensing in the same frequency-dependent manner. Our study demonstrates a noninvasive, penetrative, and tunable approach to regulate cellular responses to biomaterials in vivo. Our work not only provides additional insight into the design considerations of biomaterials to control cellular adhesion in vivo but also offers a platform to elucidate the fundamental understanding of the dynamic integrin-ligand binding that regulates the adhesion, differentiation, and mechanotransduction of stem cells.

Electrostatically Assembled Magnetite Nanoparticles/Graphene Foam as a Binder-Free Anode for Lithium Ion Battery

Lithium ion batteries (LIBs) are promising candidates for energy storage, with the development of novel anode materials. We report the fabrication of Fe3O4 nanoparticles/graphene foam via electrostatic assembly and directly utilize it as a binder-free anode for LIBs. Owing to the integrated effect of the well-dispersed Fe3O4 nanoparticles and the conductive graphene foam network, such composite exhibited remarkable electrochemical performances. It delivered a large reversible specific capacity reaching to ∼1198 mAh g-1 at a current density of 100 mA g-1, a good rate capacity, and an excellent cyclic stability over 400 cycles. This work demonstrated a facile methodology to design and construct high-performance anode materials for LIBs.

Swimming Characteristics of Bioinspired Helical Microswimmers Based on Soft Lotus-Root Fibers

Various kinds of helical swimmers inspired by E. coli bacteria have been developed continually in many types of researches, but most of them are proposed by the rigid bodies. For the targeted drug delivery, the rigid body may hurt soft tissues of the working region with organs. Due to this problem, the biomedical applications of helical swimmers may be restricted. However, the helical microswimmers with the soft and deformable body are appropriate and highly adaptive in a confined environment. Thus, this paper presents a lotus-root-based helical microswimmer, which is fabricated by the fibers of lotus-root coated with magnetic nanoparticles to active under the magnetic fields. The helical microstructures are derived from the intrinsic biological structures of the fibers of the lotus-root. This paper aims to study the swimming characteristic of lotus-root-based microswimmers with deformable helical bodies. In the initial step under the uniform magnetic actuation, the helical microswimmers are bent lightly due to the heterogeneous distribution of the internal stress, and then they undergo a swimming motion which is a spindle-like rotation locomotion. Our experiments report that the microswimmers with soft bodies can locomote faster than those with rigid bodies. Moreover, we also find that the curvature of the shape decreases as a function of actuating field frequency which is related to the deformability of lotus-root fibers.