Particle manipulation under X-force fields

Abstract

Particle manipulation is a central technique that enhances numerous scientific and medical applications by exploiting micro- and nanoscale control within fluidic environments. In this review, we systematically explore the multifaceted domain of particle manipulation under the influence of various X-force fields, integral to lab-on-a-chip technologies. We dissect the fundamental mechanisms of hydrodynamic, gravitational, optical, magnetic, electrical, and acoustic forces and detail their individual and synergistic applications. In particular, our discourse extends to advanced multi-modal manipulation strategies that harness the combined power of these forces, revealing their enhanced efficiency and precision in complex assays and diagnostic frameworks. The integration of cutting-edge technologies such as artificial intelligence and autonomous systems further enhances the capabilities of these microfluidic platforms, leading to transformative innovations in personalized medicine and point-of-care diagnostics. This review not only highlights current technological advances, but also forecasts the trajectory of future developments, emphasizing the escalating precision and scalability essential for advancing lab-on-a-chip applications.

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Chundong Xue

Chundong Xue: Chundong Xue is currently an associate professor at Faculty of Medicine and Central Hospital, Dalian University of Technology (DUT). He received his bachelor degree in Engineering Mechanics from Shandong University (SDU) in 2012, and received a PhD degree in Fluid Mechanics from the University of Chinese Academy of Sciences (UCAS) in 2017. His research interests include microfluidics/nanofluidics, biological fluids, and intelligent nanomedicine.

Yifan Yin

Yifan Yin: Yifan Yin is currently undertaking his PhD in Faculty of Medicine, Dalian University of Technology (DUT), China. He has received his bachelor's degree from the Henan University (HNU) in 2021 and master's degree in engineering from DUT in 2024. His research interests include artificial intelligence, intelligent fluid information, and microfluidics.

Xiaoyu Xu

Xiaoyu Xu: Xiaoyu Xu graduated from Dalian University of Technology (DUT) with a Bachelor of Engineering degree. She is currently pursuing her master's degree and her research focuses on non-Newtonian fluid flow instabilities in microfluidic chips. Her research interests include microfluidics, viscoelastic instabilities, and lab-on-a-chip biomedical applications.

Kai Tian

Kai Tian: Kai Tian is currently undertaking his PhD in School of Mechanical Engineering, Dalian University of Technology (DUT), China. His research focuses on microscale flow instability and the biomedical applications. His research interests include viscoelastic instabilities, computational fluid dynamics (CFD) modeling, and microfluidics.

Jinghong Su

Jinghong Su: Jinghong Su received his PhD degree from the University of Chinese Academy of Sciences (UCAS), China, in 2022. After graduation, he joined the Department of Energy and Power Engineering at Tsinghua University as a postdoctoral fellow. His research interests include multiphase flow, computational fluid dynamics (CFD) modeling, and microfluidics.

Guoqing Hu

Guoqing Hu: Guoqing Hu is a Qiushi Chair Professor at Zhejiang University, a position held since 2019. Previously, Professor Hu served at the Chinese Academy of Sciences from 2007. He received his bachelor's and master's degrees from Nanjing University of Aeronautics and Astronautics in 1992 and 1995, respectively, and his Ph.D. from the Chinese Academy of Sciences in 2000. His research expertise lies in microfluidics/nanofluidics, lab-on-a-chip technologies, nano-bio interactions, and multiphase flows.

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1. Introduction

1.1 Overview of particle manipulation

In the rapidly advancing field of microfluidics, particle manipulation is emerging as a fundamental technology that catalyzes diverse applications across multiple scientific disciplines. Particle manipulation involves the control and guidance of micro- and nanoscale entities within a fluidic milieu, utilizing the meticulous management of minute volumes of fluid and the integration of diverse systems onto a single chip. This capability is critical to lab-on-a-chip technologies, which aim to miniaturize and replicate laboratory functions on a chip scale.^1,2 The sophisticated manipulation of particles in microfluidics and lab-on-a-chip technologies is essential to driving innovation in fields such as biology, medicine, chemistry, materials science, and more.^3,4

The precise manipulation of circulating tumor cells (CTCs), extracellular vesicles (EVs), chemical agents, and various other particles is critical for applications such as high-throughput screening, diagnostics, and cellular level biological studies.^5,6 By directing particles to specific locations or channels, complex assays and processes can be performed in a compact and automated format.^7–9 In addition, the integration of particle manipulation techniques into lab-on-a-chip systems is ushering in new paradigms for point-of-care diagnostics, personalized medicine, and portable analytical systems. These systems are capable of performing diverse laboratory functions, including cell culture, chemical synthesis, and DNA analysis.^10–13 Particle manipulation is also crucial for creating novel materials and probing fundamental physical and chemical phenomena at the microscale. By orchestrating particle interactions and motions, researchers can fabricate intricate microstructures and patterns essential for various applications including targeted drug delivery and tissue engineering.^14,15

1.2 Scope of the review

Over the past five years, dozens of excellent reviews have thoroughly explored the microfluidic manipulation of particles by various force fields.^2,7,16–21 These comprehensive analyses have laid a substantial foundation, detailing the intricacies and advances in the field. Here, our review stands out for its unique focus. We delve deeper into the synergistic effects and interactions between the various forces within the X-force framework, an area that has not been exhaustively covered in the previous literature. In addition, we place significant emphasis on the latest technological integration, such as artificial intelligence (AI) and autonomous systems, and their transformative impact on particle manipulation (Fig. 1). This focus not only highlights the current state of the art, but also maps the future trajectory of innovation in microfluidic technologies, providing new perspectives and insights that are critical for advancing the field.

Fig. 1 An overview of recent progress in particle manipulation under X-force fields. Particle manipulation can be realized using single-modal approaches based on single classical or innovative forces. The multi-modal approaches have been extensively developed based on multiple force coupling, where the multiple forces can be classical, innovative or the hybrid forces. The new technologies have emerged in the field of particle manipulation, always working in conjunction with single or multiple force fields, aiming to achieve high-throughput manipulation of smaller-sized particles in more complex application scenarios.

Structured to methodically traverse this expansive topic, the review begins with a discussion of the theoretical underpinnings of the X-force in section 2, providing a solid foundation for its fundamental principles. Six primary forces, i.e., hydrodynamic,^18,22,23 gravitational,^24,25 optical,^26–28 magnetic,^29–31 electrical,^32–35 and acoustic^36–38 forces are covered here. Section 3 extends this discussion by exploring the practical applications of each force. Section 4 explores the complex interactions and synergies between the combined forces, highlighting advanced multi-modal manipulation techniques. Section 5 underscores cutting-edge innovations and emerging technologies that are transforming particle manipulation, including the integration of AI, autonomous systems and channel structure reformation. Finally, section 6 summarizes the current progress and future outlook of the field, addressing the ongoing challenges and emerging opportunities in the realm of particle manipulation under the influence of X-force fields.

2. Theoretical background

For the fluid phase, the momentum equation is:where ρ_f is the density of fluid, u_f the velocity vector of fluid phase, P the pressure, τ the fluid stress tensor, and F_p the additional source term. The motion of a particle in the Lagrangian framework is governed by Newton's second law,³⁹where m_p is the particle mass, u_p the particle velocity, and F_ext the external force acting on particles, which originates from X-force fields. In microfluidic systems, inertial forces become significant due to scale effect at medium Reynolds numbers (Re ∼ 1 to ∼100), leading to nonlinear and irreversible motion of particles in microchannels.⁴⁰ For example, in purely viscous fluid flow, particles migrate away from the wall or center due to inertial lift forces.⁴¹ In non-Newtonian fluid flow, viscoelastic effect can lead to inhomogeneous shear stresses, causing deviations in particle migration.⁴² In fluid flow with acoustic field, the radiative force generated by sound waves can be used to flexibly drive and position the particles.¹⁰Table 1 lists these commonly used forces in particle manipulation and the related references. For more detailed theoretical analysis of force fields, please refer to ref. 2, 7 and 10.

Table 1 Summary of various forces for manipulating particles

Forces	Equation	Symbols	Ref.
Inertial forces	F iL = CiLρfa^4[small gamma, Greek, dot above]^2	F iL inertial lift force	40, 41, 43
		C iL inertial lift coefficient
		[small gamma, Greek, dot above] shear rate
		F Dean Dean drag force
		C D drag coefficient
		V average fluid velocity
		D h hydraulic diameter
		R radius of curvature of the channel
Viscoelastic forces	F eL = CeLa^3ηpλ∇[small gamma, Greek, dot above]^2	F eL viscoelastic lift force	42, 44
		C eL elastic lift coefficient
		η p polymer contribution to the fluid viscosity
		λ fluid relaxation time
Centrifugal forces		ω angular velocity of the device rotation	10, 45
		r distance between the particle and the center of rotation
Electrophoresis	F EP = ZeE	Ze charge of particle	46, 47
		E electrical field magnitude
Electro-osmosis	F EO ∼ μaμEOE	a particle diameter	46, 47
		μ liquid viscosity
		μ EO electro-osmotic mobility
		E electrical field magnitude
Dielectrophoresis	F DEP = 2πr^3Re(fCM)∇Erms^2	r particle radius	48, 49
		E rms rms of the applied electrical field
		f CM Clausius–Mossotti factor
		complex permittivity of the particle
		complex permittivity of the liquid
Magnetic forces		V p particle volume	50
		Δχ difference in magnetic susceptibility between particle and fluid
		μ 0 permeability of vacuum
		B magnetic flux density
Acoustic forces	F rad = 4πa^3ϕEack sin(2kz)	F rad acoustic radiation force	46, 51
		ϕ acoustic contrast factor
		E ac acoustic energy density
		k wave number distance from the pressure anti-node
		ρ p particle density
		c p speed of sound in the particle material
		c f speed of sound in the fluid
Optical forces		F scat scattering force in the direction of wave propagation	52, 53
		n f refractive index of the fluid
		c speed of light
		m = np/nf relative refractive index between the particle and fluid
		I light intensity
		ẑ unit vector in the wave propagation direction
		F grad gradient force toward the highest light intensity

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3. Application of single-modal approaches

In the realm of particle manipulation, single-modal approaches have emerged as fundamental techniques for exerting control over particles in various fields. These methods utilize a single type of force to manipulate particles, providing a clear and focused way to understand the interactions between particles and their environment. This section delves into the applications of six distinct forces, i.e., hydrodynamic, gravitational, electrical, acoustic, magnetic, and optical force, providing a brief overview of each force and highlighting their applications as well as recent advancements. Notably, this section is not to delve into the intricate details of force field but to offer a concise description and an update on the literature. To gain a more in-depth explanation of individual forces, please refer to ref. 7 and 35.

3.1 Hydrodynamic force

Particle manipulation based on hydrodynamic forces is often termed as passive methods. It utilizes inherent fluid dynamics and channel geometry to manipulate particles without external force fields. Specifically, it mainly includes inertial manipulation, deterministic lateral displacement (DLD), microfluidic filtration, pinched flow fractionation (PFF), and viscoelastic manipulation, etc. Due to its simplicity and low cost benefit, hydrodynamic manipulation has extensive applications in blood analysis, urinary tract testing, water quality testing, and microbial testing.^18,33,54

Inertial manipulation approach uses the inertial force of fluid to manipulate particles. The advantages are simplicity, high throughput, and good biocompatibility.²³ For instance, Zhang et al.⁵⁵ proposed a novel inertial microfluidics method to achieve size-based continuous particle separation by introducing a symmetrical sheath flow in a straight microchannel, as shown in Fig. 2(A). This method works at the medium Re (∼1 < Re < ∼100) and is suitable for high-throughput and label-free particle separation.⁵⁶ However, it is challenging to manipulate the nanoscale particles solely by inertial force. Tay et al.⁵⁷ proposed a novel microfluidic platform that can directly separate nanoscale EVs from blood based on inertial force. Zhu et al.⁵⁸ proposed a novel method combining inertial microfluidic technology with proximal tumor biopsy, achieving efficient size-based enrichment of CTCs through a helical channel. In their study, portal venous blood samples have twice the yield of CTCs (21.4 cells per 5 mL) compared with the peripheral blood.

Fig. 2 Application of six fundamental forces in particle manipulation. (A) Blood separation using inertial microfluidics assisted by sheath flows in a straight microchannel.⁵⁵ (B) Microfluidic device consists of two sequential modules: a cell-depletion module and an sEV-isolation module.⁵⁹ (C) Using ultrasonic phased array for non-contact manipulation of droplets under reduced gravity conditions, including suspension, transportation, merging, mixing, separation, evaporation, and extraction.⁶⁰ (D) Working principle of optically-induced dielectrophoresis (ODEP) for EVs and extracellular vesicle (EV) sorting by ODEP.⁶¹ (E) Schematic of the liposome synthesis platform based on an SMR. Fluorescence images depict the flow distribution when the power is switched on and off. Scale bars, 200 μm.⁶² (F) Schematic diagram of the integrated microfluidic chip system for immunolabeling, magnetic separation, and focusing of HepG2 cells.⁶³ (G) Schematic illustrations of the top view and side view of OHT, respectively, along with the major various forces acting on the particle flowing in the microfluidic channel.⁶⁴

DLD approach uses a microfluidic array to generate unique streamlines that move along a predetermined path based on particle size. The particle either follows a zigzag mode or enters a bumping mode to achieve size-dependent particle sorting. Its advantages are simple operation, high separation rate and high resolution, while its disadvantages are low throughput, possible channel blockage, and complex structure.⁶⁵ In addition to the traditional DLD design, Razaulla et al.⁶⁶ developed a new DLD geometry based on patterns of self-assembly of nanospheres, which was termed as hexagonally arranged triangle (HAT) geometry. Experiments have shown that the HAT structure has the ability to sort smaller particles compared to the parallelogram DLD array with circular columns. Zhao et al.⁶⁷ designed a triangular column structure to overcome the channel blockage problem in DLD approach, thereby improving the sorting resolution.

In contrast to inertial manipulation approach at medium Re, viscoelastic approach can take advantage of elastic effects in non-Newtonian fluids to manipulate particles at lower Re. The advantages lie in label-free, simple chip structure and good biocompatibility. However, the processing throughputs are always low and special preparation of viscoelastic fluids is needed. For instance, Zhang et al.⁶⁸ proposed a viscoelastic approach to realize size-based continuous separation of three types of bacteria. Meng et al.⁵⁹ proposed a simple, viscoelasticity-based microfluidic platform for label-free isolation of EVs from human blood. The separation performance of the device was evaluated by isolating fluorescent EVs from whole blood with purity and recovery exceeding 97% and 87%, respectively, as shown in Fig. 2(B).

The three methods above are the most common passive methods of particle manipulation. There are also some ingenious passive approaches. For example, microfluidic filtration uses porous membranes to achieve particle separation. Depending on the size of the membrane pores, particles smaller than the pore size pass through while larger particles are captured. Its advantages are simplicity, label-free, and flexibility, while disadvantages may include membrane clogging and shear stress during filtration that may affect the biological integrity of the particles.^69,70 PFF uses hydrodynamic flow to “pinch” particles and separate them according to their sizes.⁷¹ In the contracting and expanding channels, particles of different sizes are distributed to different outlets. Its advantages are simple design and easy manufacturing, while the disadvantages include low throughput, low efficiency and sample dilution.⁷²

3.2 Gravitational force

Gravity is a universal natural force, originated from the mutual attraction of objects with mass. The effect of gravity can not be ignored in X-force fields based particle manipulation. In general, gravity in manipulation of particles can be divided into normal and micro gravity (i.e., zero gravity). Most studies place the microfluidic platform horizontally so that it is perpendicular to the direction of gravity as possible, thus ignoring the effects of normal gravity. In microgravity environments, it is possible to modify the sedimentation and focusing of particles, as well as the interaction with the active force fields.⁷³ By exploiting and controlling gravity, it is possible to improve the efficiency and precision of particle manipulation, thus developing new techniques for particle or cell manipulation. It may find important applications in space experiments, biomedical research, and materials science, etc.

Gravity effect always works in combination with other field effects. For instance, Samiei et al.²⁴ proposed a digital microfluidic system based on the cumulative effects of gravity and negative dielectrophoresis (nDEP). By controlling the voltage applied to the electrodes, particles sediment (dominated by gravity) and concentrate (dominated by the horizontal component of the nDEP force) simultaneously. Hawkes et al.⁷³ investigated the manipulation of yeast cells and latex particles with diameters of 1.3, 12, and 20 μm in aqueous suspension by 1 MHz and 3 MHz standing acoustic wave under microgravity (0 g), 1 g, and 1.8 g conditions. Hasegawa et al.⁶⁰ designed an ultrasonic phased array for non-contact manipulation of droplets under low gravity conditions, providing a feasible pathway for non-contact manipulation technology for future space experiments (Fig. 2(C)). In fact, studies have shown that gravity has an important influence on particle separation efficiency, dynamics, acoustic manipulation, surface modification, and aggregation and dispersion.^{25,60,74–76}

3.3 Electrical force

The electrical field applied for particle manipulation can be either direct current (DC) or alternating current (AC). DC electrical manipulation of particles is based on the principle that the external electrical field interacts with the charge on the surface of particles to drive the motion of particles.⁷⁷ It is also known as electrophoresis when the DC field acts on the charged particles. Specifically, DC electrical manipulation can be divided into capillary electrophoretic,⁷⁸ gel electrophoresis,^79,80 and field flow separation,^81–83etc. The AC electrical field provides a non-uniform electrical field. Dielectrophoresis (DEP) occurs when a non-uniform electrical field induces a dipole in a polarizable particle, resulting in a net force. This force drives the particle towards regions of higher or lower electrical field intensity, depending on its relative polarizability to the surrounding medium.³³ In contrast to AC electrical manipulation, the manipulation in DC electrical field is more simple and stable, and it can avoid the thermal effect.⁸⁴

Compared with DC electrical field, the AC electrical field can avoid electrochemical reactions on the electrode surface, thus avoiding the bubbles and electrode pollution. The frequency and amplitude of AC electrical field can be flexibly adjusted, providing more regulatory parameters to meet different experimental needs.⁸⁵ However, it may cause the temperature increase of the sample and equipment, which may be unfavorable to the thermally sensitive biological samples.⁷⁷ DEP has a wide range of applications in terms of cancer cell separation,⁸⁶ cell capture,⁸⁷ and colloid sorting.⁸⁸ With the development of laser technology, the current dielectrical swimming particles can be easily induced by optics. By adjusting the power, wavelength, and irradiation time of laser, precise control of particle movement can be achieved.^61,89 For instance, Soong et al. developed an optically-induced dielectrophoresis (ODEP) technology to achieve label-free and contact-free separation and recovery of EVs on a pneumatically driven microfluidic platform, as shown in Fig. 2(D).⁶¹

3.4 Acoustic force

The basic principle of acoustic wave generation involves creating vibrations or oscillations in a medium. It can be achieved using piezoelectrical materials or other transducers that convert electrical energy into mechanical vibrations.^90,91 Particles experience forces due to the pressure variations associated with the acoustic wave, which can be modulated by the frequency, amplitude, and wavelength of the wave, as well as the properties of the particles themselves.^36,92 The bulk acoustic wave (BAW) devices and surface acoustic wave (SAW) devices have emerged as pivotal technologies for their ability to exert precise control over micro- and nanoscale particles.³⁷

SAW devices generate acoustic waves that propagate along the surface of the material. SAW offers the advantage of high spatial resolution and the potential to be highly integrated.³⁸ The interaction of SAW with particles can be finely tuned by adjusting the wave frequency and amplitude. Nonetheless, SAW may be more susceptible to environment interference and surface contamination, which can affect the wave propagation and the efficiency of manipulation. SAW is often integrated into microfluidic devices for precise control of particle sorting,^53,79–81 pollutant separation,⁸² blood analysis,^93,94 and cell separation.⁸³ For instance, Xu et al.⁶² introduced a novel microfluidic platform based on ultrahigh frequency acoustic resonators for the synthesis of size-tunable liposomes, as shown in Fig. 2(E).

In contrast, BAW devices generate acoustic waves that propagate through the bulk of the material, typically a piezoelectrical substrate.⁹⁵ These waves are characterized by their ability to produce large displacements and high energy density, making BAW suitable for applications requiring substantial force or energy transfer to particles.³⁷ The main advantage of BAW devices lies in their robustness and durability, as the waves are confined within the material's interior, reducing the risk of damage due to external factors.⁹⁶ However, BAW may suffer from limitations in the spatial resolution and the complexity of integrating them into microfluidic systems. This disadvantage also makes BAW to be less used in actual applications.^84,85

3.5 Magnetic force

The basic principle of utilizing magnetic field involves the interaction between the magnetic field and the magnetic materials or particles. Magnetic field exerts force on the moving charged particles.^86,87 When a magnetic particle is placed in a magnetic field, it experiences a force that can cause it to move or align, which can be affected by altering the strength and direction of the magnetic field.²⁹ Different particles respond differently based on their magnetic susceptibility.^97,98 Paramagnetic particles are weakly attracted to the field, while ferromagnetic particles have a strong response and can be magnetized and strongly influenced.⁹⁹ The movement of particles caused by a magnetic field is also termed as magnetophoresis. According to the interaction between particles and magnetic field, magnetophoresis can be divided into negative magnetophoresis and positive magnetophoresis.

In negative magnetophoresis, the movement of particles or cells in the direction opposite to the applied magnetic field.¹⁰⁰ This phenomenon occurs when the magnetic susceptibility of the particle is less than that of the surrounding medium. It has been applied in some scenarios such as certain types of cell sorting and isolation of biomarkers in biomedical research,^101,102 as well as microparticle manipulation and recovery.^103–106 In contrast, positive magnetophoresis shows the feature that the particles or cells migrate in the direction of the applied magnetic field.¹⁰⁷ This occurs when the magnetic susceptibility of the particle is greater than that of the surrounding medium, causing the particle to be attracted to the region of higher magnetic field strength. It has been widely used in biomedical applications¹⁰⁸ for targeted microparticle manipulation,^109,110 cell sorting,^111,112 protein separation,^113,114 and droplet manipulation.^30,115 For example, Xu et al.⁶³ proposed an integrated microfluidic chip system for immunolabeling, magnetic separation and focusing of HepG2 cells (as a CTC model), as shown in Fig. 2(F).

3.6 Optical force

Optical field manipulation of particles is a technology that uses the radiation pressure and gradient force of light to manipulate tiny objects.²⁶ The most famous application of this technology is optical tweezers, which is a groundbreaking tool that harnesses the principles of light field to exert forces on microscopic particles.^116–118 The fundamental concept of optical tweezers is rooted in the interaction between light and matter, where the momentum of light imparts a force on particles when they are illuminated.¹¹⁹ This phenomenon, known as radiation pressure, is the cornerstone of particle manipulation using light field. Two mechanisms, i.e., radiation pressure and gradient force, are involved. The former arises from the transfer of momentum between the photons of light and the particles, while the latter is due to the spatial variation in the intensity of the light field, which creates a force that pushes particles towards regions of higher light intensity.²⁸

In the context of single-particle manipulation, optical tweezers can generate a stable three-dimensional trap by focusing a laser beam to a diffraction-limited spot. The high intensity gradient at the focus of the beam creates a potential well that confines the particle. This allows for precise control over the position and orientation of the particle, enabling researchers to study its physical properties and the interaction with its environment.^120–122 Recently, Vasantham et al.⁶⁴ proposed a new type of opto-hydrodynamic fiber tweezers (OHT). By adjusting the light power and flow rate, the researchers were able to capture single particles at the desired position in the channel with a precision of 10 microns and manipulate them over up to 500 microns upstream or downstream, as shown in Fig. 2(G).

The manipulation of multiple particles introduces additional complexities and opportunities. By employing multiple beams or shaping the light field in sophisticated ways, it is possible to create multiple traps or to manipulate the relative positions of multiple particles. This opens up avenues for studying collective behaviors, such as the assembly of particles into specific structures or the investigation of interactions between multiple trapped entities.^123–127 Deng et al. proposed a capillary optical fiber tweezers that breaks through the limitations of traditional optical fiber tweezers (OFTs) in terms of capture direction and spatial range.¹²⁵ The versatility of optical tweezers extends beyond the manipulation of simple particles. They can also be used to manipulate biological entities like cells and viruses. Moreover, advancements in the field have led to the development of holographic optical tweezers, which offer even greater control over the light field, enabling the precise manipulation of multiple particles in three dimensions.^28,128

4. Application of multi-modal approaches

4.1 Dual force fields

The fundamental forces behind particle manipulation are often categorized into active and passive forces. Active forces, such as electrical force, magnetic force, and acoustic force, rely on external energy sources. In contrast, passive forces, such as inertial lift and elastic forces, depend on the inherent properties of the fluids and the particles. To tackle the complex application scenarios, single-modal approaches using individual forces are obviously insufficient. The utilization of dual force fields for particle manipulation is easy to think of and indeed the often operation. The configuration of the dual force fields can be described as cascaded connection or physical coupling.² In short, cascaded connection involves the sequential application of different manipulation forces along the flow path, akin to a “series circuit” in electronics. Physical coupling, on the other hand, is analogous to a “parallel circuit”, where multiple forces act on particles simultaneously.^7,10,129 More details about the two types of force configuration can be found in recent review articles.^7,10 Specifically, the basic force combination can be divided into passive force–passive force, active force–active force, passive force–active force and active force–passive force.

4.1.1 Passive force–passive force. This force combination is inherently simple to implement, eliminating the need for external energy sources, which reduces not only system complexity but also the associated costs and potential for operational error.¹³⁰ In cascaded connection, it is achieved through the sequential combination of dual forces.^131,132 For instance, inertial force is applied to first focus particles into a central stream within a microchannel. Subsequently, elastic forces, arising from the viscoelastic properties of the fluid, could further refine the particle alignment or separation by pushing particles toward regions of lower shear rates. This combination allows for a more nuanced control over particle dynamics compared to a single force.^130,133 According to this principle, Tottori et al.¹³⁴ proposed a two-stage method in combination of inertial focusing module and sheath-free DLD module, where the length of side-focusing channel can be effectively reduced, as shown in Fig. 3(A).

Fig. 3 Application of multiple force coupling in microparticle manipulation. (A) Sheath-free DLD separation with inertial focusing in a straight rectangular input channel.¹³⁴ (B) Right image shows a schematic illustration of working principle and vDLD device structure. The top and bottom panel images at left are the schematic depiction of the PDMS microchannel device placed at a 50° angle to the main flow, and the side view of the electrical and acoustic fields in the vicinity of the electrodes, respectively.¹³⁵ (C) Schematic diagram of the whole blood detection and CTCs separation based on magnetophoresis and dielectrophoresis.¹³⁶ (D) Working principle of the inertial-FCS. Cells in a custom-made biocompatible ferrofluid are inertially focused into a narrow stream in curved microchannels (inertial focusing stage). This stream is then ferrohydrodynamically separated into multiple streams based on the cells' physical diameter (ferrohydrodynamic separation stage). The black arrow with gradient shows the magnetic field distribution in the microchannel.¹³⁷ (E) The trajectory of the same particle smaller than the critical diameter in the absence and presence of an electrical field.¹³⁸ (F) Schematic illustration of the integrated microfluidic system designed to achieve multitarget separation.¹³⁹ (G) Schematic of the TIME sorting of 9 and 15 μm magnetic particles (MP) and 15 μm non-magnetic particles (NMP) in a viscoelastic fluid and particle focusing positions in a square microchannel with viscoelastic focusing, inertial focusing, and elasto-inertial focusing.¹⁴⁰ (H) Schematic diagram and working principle of the proposed microfluidic device, including two stages of elasto-inertial focusing and magnetophoretic separation.¹⁴¹

In physical coupling, each passive force can enhance the role of another force on targeted particles through additive effect or elimination of negative effect on particle manipulation. The most common is inertia-enhanced pinched flow fractionation (iPFF).¹⁴² Wang et al.¹⁴³ further introduced a novel method called reverse flow enhanced inertia pinched flow fraction (RF-iPFF). Size-dependent separation of particles was obtained by inertial force and the separation distance between different particles can be adjusted in the area where the channel is suddenly widened. By reverse flow, the separation performance can be significantly improved. Compared with the situation without reverse flow, the RF-iPFF technology can increase the processing throughput by about 10 times.

4.1.2 Active force–active force. This force combination aims to gain the synergistic effect of two active forces to achieve enhanced manipulation capabilities, enhanced separation resolution, as well as increased separation efficiency and purity.¹²⁹ The electrical, magnetic, and acoustic forces are frequently used. For instance, the intensity and distribution of the electrical field in DEP can be adjusted quickly to achieve real-time control of particle movement.¹⁰ However, it can only manipulate particles near the electrode and fail when the particles are far away from the electrode.⁷ The acoustic wave can exert force on particles over a long distance, which is suitable for long-distance manipulation and can penetrate certain media, such as liquids, to flexibly manipulate the particles therein. However, it cannot quickly regulate the movement of particles just by altering the frequency of acoustic wave.¹⁴⁴ In combination with advantages of both electrical and acoustic fields, Tayebi et al.¹³⁵ developed a technique for deterministically sorting submicron particles and EVs, as shown in Fig. 3(B).

Similar to acoustic field, the magnetic field exerts force on magnetic particles over long distances, making them suitable for long-distance manipulation.¹⁴⁵ The directionality of magnetic field allows precise control of the direction of particle movement and can generate strong force. Since the electric and magnetic fields have different mechanisms of action, they can complement with each other to achieve more efficient manipulation in real-time fusion. Accordingly, Tran Thi et al.¹³⁶ designed a composite method with magnetophoresis and DEP to separate CTCs from whole blood. It used an electrode array to generate an external electrical field. The electrodes were located on the channel wall and an alternating current was applied to construct a comb-shaped permanent magnet to enhance the magnetoelectrophoretic effect on cells, as shown in Fig. 3(C).

4.1.3 Passive force–active force. Compared with the above two strategies, this force combination can achieve a balance between manipulation efficiency and device complexity.² The effect of passive forces may be highly dependent on environmental conditions, such as fluid viscosity, temperature, etc., which make it difficult to achieve selective manipulation of specific types of particles, especially when the physical properties of multiple particles are similar.¹³⁷ The above problems can be overcome by adding some active force. Specifically, when passive force is combined with active force, its main function is to pre-focus or coarsely separate particles as well as to stabilize the fluids. The active force plays the role in precise manipulation, dynamic control and multi-particle separation.

Peng et al.¹⁴⁶ designed a novel microfluidic device that uses inertial force and acoustic wave to separate CTCs from whole blood without sheath fluid and labeling. The first stage utilizes spiral channels for coarse sorting of cells, while the second stage introduces standing SAW to further improve sorting efficiency and purity. Similarly, Liu et al.¹³⁷ proposed a two-staged label-free separation technology of CTCs, which is termed inertial-ferrohydrodynamic cell separation (iFCS), as shown in Fig. 3(D). Chen et al.¹³⁸ proposed an electrophoresis-assisted hydrophobic microdevice for enhanced separation of blood cells. The device combines electrophoresis and hydrophobic techniques to expand the size range of separated particles by changing the cell position in the microchannel, as shown in Fig. 3(E). Luo et al.¹⁴⁷ proposed a simplified sheathless cell separation method that combines gravity-based pre-focusing and DEP separation. The gravity sedimentation was used to pre-focus the cells in the upstream area of the microchannel, while the DEP was applied to actively separate the cells downstream.

4.2 Triple force fields

To seek more efficient and precise manipulation of particles/cells, one simple but useful strategy is to integrate more active/passive forces in particle manipulation technology. The composite approaches with triple force fields may offer enhanced control and versatility of particle manipulation, allowing for precise and stable manipulation across various applications. Based on this logic, Wu et al.¹³⁹ have reported an integrated chip that combines DLD, DEP and SAW to achieve efficient, label-free separation of solid particles, oil droplets, and living cells, as shown in Fig. 3(F). DLD is used as the first separation stage to distribute larger and smaller particles or cells to different outlet channels. SAW then is used to further separate specific particles from the DLD stage. Finally, cells with different electrical properties, such as live cells and dead cells, were separated using DEP.

Dibaji et al.¹⁴⁰ developed a microfluidic setup in combination with inertial, magnetic, and elastic forces on focusing of magnetic and nonmagnetic microparticles, which can realize sorting of these particles with purity and efficiency exceeding 92%, as shown in Fig. 3(G). Amouzadeh et al.¹⁴¹ proposed a novel “square wave with cavity” microchannel for separation of different-sized particles by elasto-inertial focusing and negative magnetophoretic separation, as shown in Fig. 3(H). Notably, although highly efficient particle separation can be achieved by precisely controlling the coupling of three or more forces, even reaching sub-micron resolution, these benefits always come with increased complexity, higher costs, and potential difficulties in optimization and scalability. How to tackle the complexity of design and manufacture of sophisticated systems, how to accurately coordinate multiple forces, and how to ensure long-term operational stability and reproducibility in particle manipulation are topics worth to be explored in future work.

5. Role of new technologies in particle manipulation

5.1 Recent innovations of force in particle manipulation

In addition to six primary forces introduced above, several other forces have also emerged in particle manipulation, such as interfacial force,^148,149 thermal gradient force,^150,151 buoyancy force,^152,153 diffusiophoresis force,^154,155 chemical gradient force,^156,157 and adhesion force,^158,159etc. These forces, work independently or take effect in combination with above primary forces,^160,161 providing more possibilities for particle manipulation in complex application scenarios.

5.1.1 Interfacial force. Interfacial force occurs at the interface between two different phases and mainly involves surface tension, capillary force, and Marangoni effect.¹⁶² Interfacial force can affect the attachment and movement of particles on the interface. Surface tension can adsorb particles to the surface of liquid, while capillary force can push particles away.¹⁶³ The competition of these two can also be precisely used to aggregate or separate particles.^160,164 The Marangoni effect, induced by chemical concentration gradients, can also be used to drive particles along specific paths of liquid interface.¹⁶⁵ By heating or changing the composition of an aqueous solution, the movement of particles across the liquid surface can be precisely controlled.¹⁶⁶ McGlasson et al.¹⁴⁸ studied the assembly behavior of anisotropic amphiphilic Janus particles at interfaces. Mejia et al.¹⁴⁹ proposed a micromanipulator system that uses the interfacial forces between the liquid crystal and the isotropic phase to capture particles. They demonstrated that the nematic isotropic interface of liquid crystals (12CB) can be used to develop new manipulation or driving systems as shown in Fig. 4(A).

Fig. 4 Other forces that have emerged in recent years for use in particle manipulation. (A) Schematic representation of the experimental setup. The liquid crystal cell, made of two glass plates with a 188 μm spacer and a homeotropic anchoring layer, was sandwiched between high-conductivity copper plates. Peltier modules attached to the copper plates controlled the temperatures with 0.03 K precision using a Peltier controller.¹⁴⁹ (B) Schematic of the microchannel and microheater array design and the portable microfluidic platform used for thermally controlled granular sample manipulation.¹⁵³ (C) General procedure for fabricating microtextured chemical gradients. (B) Gradient intensities for the steep, intermediate, and shallow chemical gradients.¹⁵⁶ (D) Schematic and micrographs of a single Ψ-junction device. Efficient pre-focusing, sorting, and characterization of charged nanobeads and liposomes is achieved by generating salt concentration gradients in straight micrometer-scale channels.¹⁶⁷ (E) Rolling and bouncing condition of droplets with different volumes during the experiment. Larger droplets exhibit an initial acceleration followed by deceleration, whereas smaller droplets experience a rebound effect before being pinned upon the surface. The smallest droplets are directly pinned upon the surface.¹⁵¹ (F) The measured migration velocity u(z) of different PS particles at different heights of the microchannel.¹⁶⁸ (G) Schematic diagram of the sheathless oscillating viscoelastic microfluidic method, which classifies particles into three size ranges: micrometer, submicrometer, and nanometer.¹⁶⁹

5.1.2 Buoyancy force. Buoyancy force is an upward force in a fluid due to density discrepancy. Buoyancy force depends on the existence and strength of the gravity field. The balance of buoyancy with gravity determines the suspend or rise of particles. The movement and positioning of particles can be achieved by adjusting the fluid density and volume as well as the way of fluid flow.¹⁵³ Under different gravity conditions, such as in the earth versus space, the effect of buoyancy differs significantly.¹⁵² Since regulation of buoyancy is limited by the physical properties of the particles and the media, precise manipulation of particles by its sole effect is difficult. It always works in combination with other forces/effects. Zhang et al.¹⁵³ proposed a portable microfluidic device based on buoyancy, which uses thermal fields to control the manipulation of particle samples, including particle focusing, migration, and double emulsion droplet release. Five heaters at the bottom of the microfluidic chip were designed to heat the fluid unevenly to generate thermal buoyancy flow and thermal capillary effect, thereby achieving the purpose of droplet manipulation, as shown in Fig. 4(B).

5.1.3 Chemical gradient force. Chemical gradient force is generated by the chemical concentration gradient, which drives particles to move in the direction of the concentration gradient. This phenomenon is widely present in chemical and biological systems, such as chemotaxis of cells and molecular diffusion.¹⁷⁰ According to the principle of Fickian diffusion, substances will spontaneously diffuse from high-concentration areas to low-concentration areas until the concentration is uniform. In this process, particles will be subject to the chemical gradient force. The biggest advantage is its high selectivity. According to different needs, specific chemicals can be selected to achieve selective manipulation of specific types of particles, such as proteins or nanoparticles.¹⁷¹ However, chemical gradients are easy to diffuse and dissipate, thus the effective effect may be short-lived.¹⁷⁰ How to maintain the stability of chemical gradients is challenging.

Perez-Toralla et al.¹⁷² established surface chemical gradients by patterning the deposition of volatile molecules from the gas phase. It provides the ability to precisely control both chemical and physical conditions (e.g., concentration, evaporation rate, and diffusion flux direction) and geometric parameters (e.g., size, shape, and position) simultaneously. Further, Mazaltarim et al.¹⁵⁷ proposed to create mechanically adjustable microtextured chemical gradients on elastomeric films and use them to control the transport of microdroplets, as shown in Fig. 4(C). Specifically, by creating chemical gradients on pre-stretched silicone rubber films, these gradients spontaneously form with specific microtextures (wrinkles) when the pre-stretching is released. Mechanical strain is used to control the spacing/amplitude of these wrinkled microtextures, thereby achieving dynamic control of the transport of microdroplets along the chemical gradient. This research group has also proposed a technology to achieve programmable droplet transport and adaptive routing using mechanically adaptive chemical gradients and anisotropic microtopography.

5.1.4 Diffusiophoresis force. Diffusiophoresis force originates from the interaction between the particle surface and solute molecules, which drives particle motion due to the solute concentration gradient.¹⁷³ The main factor affecting the diffusiophoresis force is the concentration gradient of the solute. The larger the solute concentration gradient, the stronger the diffusiophoresis force and the more obvious the driving effect on the particles.¹⁷³ Diffusiophoresis-based particle manipulation utilizes naturally existing concentration gradients, does not require additional energy input, thus is simple and low-cost. However, similar to chemical gradient, the concentration gradient is also easy to diffuse and dissipate. How to maintain the effective effect for enough time is one key issue. Stone's group conducted a series of works about diffusiophoresis and successfully realized size-dependent control of nanoparticles, as shown in Fig. 4(D).^167,174 Chakra et al.¹⁵⁴ developed a specific microfluidic channel to generate a stable salt concentration gradient perpendicular to the flow direction, achieving the accumulation of nanoparticles to form two symmetrical stripes. Lee et al.¹⁷⁵ studied the role of variable zeta potential in diffusion-induced nanoparticle motion (diffusiophoresis) and liquid motion (diffusioosmosis), thus providing theoretical guidance for the diffusiophoresis-based manipulation of nanoparticles.

5.1.5 Thermal gradient force. Thermal gradient force refers to the force generated by the temperature gradient, which drives the particles to move in the direction of the temperature gradient. Its main mechanisms are thermophoresis and intermolecular interactions.^176–178 Thermophoresis can be stimulated by heat source heating, e.g., laser heating, Seebeck effect, light heating, and microwave heating, and is mainly affected by the intensity and direction of the temperature gradient.¹⁷⁹ The larger the temperature gradient, the stronger the thermal gradient force, and the more obvious the driving effect on the particles. The direction of the temperature gradient determines the direction of particle movement. Xu et al.¹⁸⁰ investigated the migration behavior of nano/micro particles in confined spaces under temperature gradients, especially how surface hydrophilicity affects such migration. It suggested the thermal affinity migration behavior of particles near the hydrophobic substrate, and the thermal repulsion migration behavior in the middle and upper regions of the microchannel. Based on thermophoresis mechanism, Liu et al.¹⁵¹ built a low-cost thermophoretic profiling of extracellular-vesicle surface proteins for the early detection and classification of cancers, as shown in Fig. 4(E). Combined the thermophoretic focusing and the pulsatile filtration, the same group has further develop a novel cascaded microfluidic method for isolating and detecting nanosized EVs.¹⁸¹ In addition, thermophoresis effect has also been used in the detection of cancer biomarkers.¹⁵⁰

5.1.6 Adhesion force. Adhesion force refers to the attraction between the surfaces of two different materials when they come into contact with each other. The mechanisms include van der Waals force, electrostatic force, chemical bonding force and capillary force, etc. The adhesion force is affected by the surface roughness and material properties, e.g., hydrophilicity/hydrophobicity.¹⁸² By designing reversible adhesion mechanisms, such as thermal response and pH response, the controllable grasping and release of particles can be achieved. However, strong adhesion force may also make it difficult to release particles, affecting the manipulation efficiency. For instance, Li et al.¹⁶⁸ created a super-hydrophobic surface using the “glue + powder” method and achieved the regulation of droplet adhesion by embedding particles with different shapes, as shown in Fig. 4(F). Hu et al.¹⁵⁸ studied the dynamic adhesion characteristics of charged particles and proposed the evolution model of particle adhesion. The authors revealed the adhesion mechanism of charged particles and obtained the adhesion standard of charged particles, thus providing theoretical guidance for adhesion force-based manipulation of charged particles.

5.1.7 Oscillatory flow. Oscillatory flow, characterized by the periodic motion of fluid, also shows effective ability for manipulating microparticles.^183,184 This flow is generated by applying oscillatory forces, which can be mechanical, such as vibrating membranes and pistons, or acoustic, such as standing sound waves.¹⁸⁵ One main advantage of oscillatory flow in particle manipulation is its ability to create well-defined and controlled flow patterns that can trap, sort, and transport particles gently and friendly. One major limitation is the complexity of generating and maintaining consistent oscillatory forces, which may require sophisticated equipment and precise control mechanisms.^186,187 The effectiveness of oscillatory flow can be highly dependent on the frequency and amplitude of the oscillations, as well as the properties of the particles and the fluid medium. Zhao et al.¹⁸⁵ proposed a method that can generate periodic dynamic flow with multiple mode outputs, including pulsating flow, oscillatory flow, steady flow and complex flow, and verified its performance through numerical simulation and flow experiments.

The interaction between oscillatory flow and particles is influenced by several factors, including the particle size, density, and shape, as well as the viscosity and density of the fluid.^186,188 The Re number plays a critical role in determining the behavior of particles within the oscillatory flow. At low Re, particles may follow the oscillatory motion of the fluid more closely, while at higher Re, inertial effects become significant, leading to more complex particle trajectories. The boundary conditions and geometric constraints of the microfluidic channels can also significantly affect the flow patterns and consequently the particle manipulation performance. In combination with other passive or active force fields, the oscillatory flow can be used to manipulate micro- and nanoparticles. With the strategy of time for space, the potential advantages lie in low flow rates and short processing channel. The low flow rates impose negligible shear stress to the sensitive biological particles, thus providing a friendly means of particle manipulation. The short channels occupy small space and can be paralleled for improving throughput.¹⁶¹ Asghari et al.¹⁶⁹ developed an oscillating viscoelastic manipulation method to efficiently focus and separate micro- and nanoparticles in biological fluids, as shown in Fig. 4(G).

5.2 X empower particle manipulation

Particle manipulation has been a cornerstone of various scientific disciplines, ranging from physics to chemistry and materials science. The advent of new technologies has not only expanded the horizons of what is possible but has also introduced a paradigm shift in how particles can be manipulated and studied. The fusion of artificial intelligence (AI) technology, nanorobots, self-powered systems, and integrated devices has catalyzed a significant evolution in the domain of particle manipulation.

5.2.1 AI. AI is revolutionizing particle manipulation by enabling more precise, efficient, and autonomous control over particles. The integration of AI into particle manipulation systems is unlocking new possibilities and applications, revolutionizing fields such as biomedicine, materials science, and environmental engineering. AI algorithms, particularly machine learning models, can be applied to analyze large datasets to portray the particle kinetics, predict the driving forces, and optimize the manipulation strategies, and seek real-time manipulation approaches. This section explores how AI empowers particle manipulation and its impact on various applications.

The applications of machine learning in particle manipulation are reflected in several aspects. First, to optimize manipulation strategies. Machine learning models can analyze particle behavior and influence factors to determine optimal manipulation strategies. This enables precise manipulation of particles with minimal energy consumption and time; second, to seek real-time adaptation. AI algorithms can adapt manipulation protocols in real-time based on feedback control from sensor or imaging systems. This capability allows for dynamic adjustment to changing conditions, improving overall performance; third, to recognize patterns of particle kinetics. Machine learning models can recognize patterns in particle behavior, such as aggregation, dispersion, or alignment. This information can be used to predict future particle movements and adjust manipulation strategies accordingly; fourth, to build data-driven approaches. By analyzing large datasets, machine learning algorithms can identify trends and patterns that are not apparent to human operators. This data-driven approach leads to more efficient and effective manipulation techniques.

Su et al.¹⁸⁹ proposed a fast numerical algorithm in conjunction with machine learning techniques for the analysis and design of inertial microfluidic devices, as shown in Fig. 5(A). A machine learning assisted model was developed to gain the inertial lift distribution and an explicit formula for inertial lift in confined flows was also built in their subsequent work.¹⁹⁰ Wang et al.¹⁹¹ proposed an adaptive manipulation microfluidic system for cell manipulation. It consists of an integrated network of distributed electrical sensors for on-chip tracking of cells and closed-loop feedback control that modulates chip parameters based on the sensor data, as shown in Fig. 5(B). The raw data is interpreted in real-time via deep learning-based algorithms, and a proportional-integral feedback controller updates a programmable pressure pump to maintain a desired cell flow speed. Yiannacou et al.^192,193 proposed a programmable microfluidic chip based on ultrasonic body waves and a closed-loop machine learning control algorithm for two-dimensional manipulation of droplets. The algorithm does not require prior knowledge of the acoustic field, but learns to control the droplets in real time, as shown in Fig. 5(C).

Fig. 5 Combining new technologies with particle manipulation. (A) A fast numerical algorithm in conjunction with machine learning techniques for the analysis and design of inertial microfluidic devices.¹⁸⁹ The inset represents the comparison between the inertial lift force from the direct numerical simulations (symbols) and the ANN prediction (lines). (B) A concept illustration shows the workflow of an adaptive microfluidic system with a feedback loop among a sensing unit, a signal processing unit, and a feedback control unit.¹⁹¹ (C) A programmable microfluidic chip based on ultrasonic body waves and a closed-loop machine learning control algorithm.¹⁹³ (D) Data-driven intelligent manipulation of multiple particles in a microfluidic flow at a vanishing Reynolds number Re ≪ 1.¹⁹⁴ (E) Transfection by fueled AuAg-nanorobots is markedly more efficient than transfection by non-fueled AuAg-nanorobots.¹⁹⁵ (F) The ROS robots alleviated osteoarthritis by scavenging reactive oxygen species (ROS) and inducing the phenotypic change in macrophages from M1 to M2.¹⁹⁶

Abe et al.¹⁹⁷ proposed a novel intelligent microfluidic system that uses the flow generated by chip microvalves to manipulate particles and autonomously control the valves through deep reinforcement learning. They applied the strategies learned from the simulator to the real environment, used a neural network to simulate the relationship between valve operation and particle displacement, and reintegrated it into the simulator. To further efficiently control particle motion in complex environments, Fang et al.¹⁹⁴ proposed a data-driven architecture that uses neural networks instead of hard-to-derive models to describe the kinematics of particles and determine the best actions to manipulate particles, as shown in Fig. 5(D). In their work, a variety of particle manipulation tasks have been successfully carried out, including target assembly, simultaneous path planning of multiple particles, and navigation through obstacles.

5.2.2 Micro- and nanorobots. Micro- and nanorobots represent a significant advancement and extension of particle manipulation technologies, offering unprecedented control precision at the nanoscale.¹⁹⁸ These tiny devices, often only a few nanometers to micrometers in size, are designed to perform specific tasks such as transporting, assembling, or modifying tiny particles. The development of nanorobots is driven by the need for highly controlled and efficient manipulation of particles, which is essential in fields like targeted drug delivery, molecular diagnostics, cell repair,¹⁹⁹ and molecular assembly.²⁰⁰ Nanorobots are typically made of nanomaterials such as carbon nanotubes, nano gold particles, etc., and can be fabricated using methods such as self-assembly, DNA origami, and atomic layer deposition.^201,202 Microrobots are more commonly used in minimally invasive surgery, target capture in microfluidic systems, microsensors, and other fields, and can perform fine operations in larger scale biological or physical systems.^203,204 The production methods rely more on microelectromechanical systems (MEMS) or high-precision machining techniques, and materials may polymers, metal alloys, silicon, etc.^205,206

Micro- and nanorobots can be divided into self-propelled and external-field-propelled depending on whether they are driven by external fields. Self-propelled nanorobots are at the forefront of this technological leap, characterized by their intrinsic ability to generate motion without external fields.²⁰⁷ This autonomy stems from the conversion of internal energy or environmental stimuli into mechanical work.²⁰⁸ Their self-sufficiency reduces the need for complex external control systems. Due to the large size of microrobots, it is often difficult to implement self-propelled driving schemes. Typically, external fields are applied and micro sensors are used for perception and navigation of microrobots. Both types of driving methods are applicable for nanorobots, but driving by external fields often requires higher control resolution. For self-propelled robots, the main challenges are the limited control over their motion and the difficulty in precisely directing their actions.

The power sources of self-propelled nanorobots mainly include chemical energy conversion, Brownian motion, molecular motors, environmental energy harvesting and structural asymmetry.^207,209,210 Wavhale et al.²¹¹ proposed a magnetofluorescent nanorobot (MFN) based on magnesium (Mg) and ferroferric oxide (Fe₃O₄), which can selectively and quickly separate cancer cells without any additives. Sun et al.²¹² introduced a novel self-propelled Janus nanocatalytic robots (JNCRs) that can be navigated in vivo by magnetic resonance imaging (MRI) for enhanced tumor therapy. These JNCRs exhibited active motion in H₂O₂ solution, and their migration in tumor tissues could be tracked in real time by non-invasive MRI. Simó et al.²¹³ proposed nanorobots based on mesoporous silica nanoparticles (MSNPs), which were functionalized with surface modification. It was experimentally demonstrated that they have stronger diffusive and mixing capabilities in urine than traditional drugs or passive nanoparticles. Ressnerova et al.¹⁹⁵ introduced a method for efficient protein transfection via chemically driven plasmonic nanorobots, as shown in Fig. 5(E).

External-field propelled micro- and nanorobots can be manipulated using the primary forces introduced in section 3. The common ones are magnetic-, acoustic-, and light-driven nanorobots.²¹⁴ Magnetic nanorobots typically contain magnetic materials or coatings that respond to magnetic field gradients. By adjusting the strength and direction of the magnetic field, one can guide the nanorobots through complex trajectories and even induce specific rotational or translational movements. Magnetic propulsion is advantageous due to its non-invasive nature and the ability to penetrate biological tissues, making it particularly useful for medical applications such as targeted drug delivery and minimally invasive surgery.²¹⁵ However, the need for external magnetic field sources and the potential interference from magnetic materials in the environment can limit their practical deployment. Wang et al.²¹⁶ proposed a group of magnetic nanoparticles that can be assembled into a vortex-shaped group under the guidance of a specially designed electromagnetic field. They can move along the blood vessel wall under the impact of blood flow and pass through narrow gaps to achieve targeted drug delivery. Zhao et al.¹⁹⁶ generated Prussian blue on the surface of MagRobots to block the production of ROS and transform MagRobots into magnetically driven ROS-scavenging nanorobots, as shown in Fig. 5(F). A new strategy for magnetic bio-hybrid microrobots (BMMs) based on Chlorella vulgaris has been proposed, which achieves diverse swimming modes including rolling and flipping, high maneuverability, low cytotoxicity, high DOX loading capacity, and pH triggered drug release.²¹⁷ It was validated through chemotherapy experiments for targeting HeLa cancer cells.

Acoustic-driven micro- and nanorobots harness sound waves to achieve propulsion and manipulation. These micro- and nanorobots are designed to respond to ultrasonic waves, which can induce rapid oscillations or acoustic streaming effects that propel them through fluids.^218,219 Acoustic propulsion offers benefits including the ability to operate in diverse environments and the capability to achieve high speeds. The ultrasonic waves can be focused and controlled with high precision, enabling targeted manipulation of nanorobots.¹⁹⁸ One of the main challenges is how to effectively convert acoustic energy into motion of nanorobots without causing damage to surrounding tissues or structures, especially in biomedical applications. To address the above issues, de Ávila et al. introduced a novel biofilm functionalized nanorobot composed of gold nanowires (AuNW) and encapsulated by red blood cell (RBC) and platelet (PL) membranes, which possess various functional proteins related to human RBC and PL. Further experiments have shown that these RBC–PL–nanorobots can selectively bind and rapidly isolate PL-adherent pathogens.²²⁰ Inspired by starfish larvae, Dillinger et al.²²¹ proposed a microrobot with a dynamically adjustable ciliary band, which achieves stable acoustic propulsion through acoustic wave-driven cilia and magnetic field navigation, as shown in Fig. 6(A). Wang et al.²²² developed a novel three-way symmetrical acoustic tweezer based on SAW. It was used to accurately capture and manipulate particles by adjusting the excitation of SAW. Bai et al.²²³ developed magnetized macrophages driven by a mixture of acoustic waves and magnetic fields to achieve precise attacks on cancer cells.

Fig. 6 (A) The navigation of a starfish larva-inspired microrobot along a 90-degree curved pathway using external magnetic field guidance and acoustic propulsion (f = 23.3 kHz, V_PP = 22.5 V).²²¹ (B) Schematic diagram of a light-irradiated nanorobot based on ultrasmall gold nanorods (sAuNR) loaded on the surface of MXene nanosheets.²²⁴ (C) Representative trajectories and time-frame images of rotational, random, and circular motion of B-TiO₂/Ag nanorobots after exposure to UV-light irradiation in 0.1% of H₂O₂.²²⁵ (D) Structure of the self-powered DEP microparticle manipulation platform based on TENG composed of an RF-TENG component, high-voltage rectifier/filter circuit module, and microfluidic chip. The SEM images of nylon and PTFE (scale bars: 20 μm). Photographs of the particle and separation convergence performance under power off and power up.²²⁶ (E) Illustration of 3D hydrodynamic focusing. The sheath flows confine the sample flow in the centre of the detection chamber and leave from the opposite side of the chamber.²²⁷ (F) After stretching the channel along the length direction. The inset illustrates the lateral migration of particles.²²⁸ (G) Schematic diagram of a size-tunable elastic-inertial sorting technique used to separate the microalga Haematococcus pluvialis in an ultra-scalable microfluidic device.²²⁹

Light-driven micro- and nanorobots can be powered through the interaction of light with photosensitive materials or structures. For instance, plasmonic nanorobots can harness the energy from laser beams to generate localized heating or photophoretic forces that drive their movement.²³⁰ Light propulsion allows for precise spatial and temporal control, thus is highly suitable for applications requiring high precision and control, such as the manipulation of individual cells or molecules.^231–233 However, the efficiency of light-based propulsion can be limited by the absorption and scattering of light in certain environments, and there is a risk of photothermal damage to sensitive biological nanosheets and used the plasmon resonance effect of sAuNR to enhance the light manipulation of nanorobots. This improves the mobility of nanorobots under light and may cause mechanical damage to the cell membrane of bacteria,²²⁴ as shown in Fig. 6(B). Ussia et al.²²⁵ proposed nanorobots with silver nanoparticle-modified B-TiO₂, which shows multiple motion modes under narrow band regions of light with different wavelengths, as shown in Fig. 6(C). A new type of photoactive and enzyme-active nanorobot that can simultaneously utilize light and glucose as energy sources for efficient degradation of organic pollutants has also been developed.²³⁴ To enhance the application of microrobots in multiple scenarios, a metal phenolic network (MPN) microrobot capable of responding to multiple wavelengths has been proposed. These MPN microrobots are able to move under near-infrared (NIR) and ultraviolet (UV) light irradiation, which greatly enhances their ability to remove reactive oxygen species and nitrogen species.²³⁵

5.2.3 Self-powered systems. The development of self-powered systems brings a transformative advancement in the field of particle manipulation. These systems, which derive energy from their surrounding environment, significantly enhance the autonomy, sustainability, and functionality of particle manipulation devices. There are several primary mechanisms of self-powered systems. First, photovoltaic energy harvesting, which involves the conversion of light energy into electrical energy using photovoltaic cells.²³⁶ Second, thermoelectrical energy harvesting, which takes use of thermoelectrical materials to generate electricity from temperature gradients.²³⁷ By exploiting differences in temperature within the environment or generated by the device itself, these materials can provide a continuous power supply. Third, piezoelectrical energy harvesting, which takes use of piezoelectrical materials to generate electrical energy from mechanical stress or vibrations.²³⁸ It is particularly useful in dynamic environments where mechanical movements are prevalent. Fourth, triboelectrical energy harvesting, which converts mechanical energy from contact and separation between materials into electrical energy. Triboelectrical nanogenerators (TENGs) are typical ones developed to capture energy from movements, such as fluid flow or surface interactions.²³⁹

The self-powered systems have been preliminarily integrated into particle manipulation devices to power sensors, actuators, and control systems. Zhou et al.²²⁶ proposed a self-driven DEP particle manipulation platform based on TENG, as shown in Fig. 6(D). It used an rotating free-hanging triboelectrical nanogenerator (RF-TENG) to generate a non-uniform electrical field to achieve controllable electrical particle manipulation. Zheng et al.²⁴⁰ developed a self-driven electrostatic actuation system based on TENG for manipulating motion of tiny solid objects in microfluidics. Compared to the TENG method, other methods are relatively rare in existing particle manipulation. Photovoltaic systems typically require a large surface area to collect sufficient light energy, which is unrealistic in tiny devices for microparticle manipulation. Thermoelectrical energy harvesting require significant temperature gradients to generate sufficient electrical energy, while maintaining a stable temperature gradient is challenging in applications, especially when manipulating biological entities, is challenging. Piezoelectrical energy harvesting requires periodic mechanical stress, which is also difficult to achieve in normal application scenarios. With the continuous advancement of technology, more efficient and new self-powered methods suitable for particle manipulation may emerge in the future.

5.2.4 Channel structure reformation. Design of channel structure is one key issue in particle manipulation under X-force fields. By optimizing the channel structure, more realistic and accurate particle manipulation can be achieved in conjunction with single or multiple forces. Three-dimensional (3D) microfluidic manipulation^241,242 and stretchable microfluidic manipulation^243,244 have developed rapidly in recent years.
3D microfluidic manipulation. 3D microfluidic manipulation utilizes 3D microfluidic channels, allowing particles to move in a volumetric space. Unlike traditional two-dimensional microfluidic systems, 3D channels provide additional degrees of freedom.²⁴⁵ The 3D approach enables precise control over particle positioning and trajectory, enhancing the capability to sort, trap, and guide particles with high accuracy.²⁴⁶ In practical applications, 3D channels can create complex flow patterns and gradients that are not possible in 2D systems. For example, in tissue engineering,^247,248 3D manipulation facilitates the arrangement of cells in spatial configurations that mimic natural tissue structures.²⁴⁹ Moreover, 3D microfluidic systems can replicate the intricate environments of biological systems more effectively. This enhanced spatial control in 3D particle manipulation offers significant advantages in applications requiring meticulous spatial organization, such as the construction of organ-on-a-chip models and advanced drug delivery systems.²⁵⁰ For example, Yang et al.²⁴⁷ fabricated a 3D human adipose microtissue in a 3D microfluidic system and employed human adipose-derived stem cells (ADSCs) as a cell source to generate differentiated adipocytes.

Lyu et al.²²⁷ proposed an automated cell sorting technology based on Raman spectroscopy, which combined with 3D microfluidics to achieve label-free cell sorting, as shown in Fig. 6(E). Weng et al.²⁵¹ introduced a portable 3D microfluidic origami biosensor for detecting cortisol levels in human sweat. Notably, although 3D particle manipulation has advantages in practical applications, the complexity of microfluidic chip manufacturing and the difficulty of real-time observation bring about obvious challenge. Traditional manufacturing methods of microfluidic chips, such as photolithography and soft lithography, are usually limited to the fabrication of planar structures. Fabrication of complex 3D structures requires multi-step alignment, stacking and bonding processes, which is time-consuming and may reduce yield. In contrast to 2D particle movements in planar chip, the 3D particle trajectories can not be easily tracked using traditional microscope and high-speed camera. In addition, the newly developed 3D printing technology provides convenience in prototyping, but its printing resolution is usually limited to the micro level, which restricts the ability to design smaller channels.²⁴⁶

Stretchable microfluidic manipulation. Stretchable channel manipulation leverages flexible and deformable materials to create microfluidic channels that can adapt to different shapes and sizes.²⁵² Unlike traditional rigid channels, stretchable channels can be dynamically altered by stretching, compressing, or twisting, allowing for real-time adjustments to the micro-environment through which particles move. This flexibility is particularly beneficial in applications where the device must conform to varying external conditions, such as in wearable health monitors or implantable medical devices.²⁴⁴ In these contexts, the dynamic nature of stretchable channels enables precise control over particle paths and can accommodate a wide range of particle sizes and types. This adaptability not only improves the precision of operations like mixing, separation, and reaction control but also enhances the system's versatility in handling different particles.²²⁸ For instance, Fallahi et al.²²⁸ used a customized stretching platform to stretch the microfluidic device along the length direction using inertial force, and the width and height of the channel were reduced accordingly. This thereby improves the focusing performance of particles, as shown in Fig. 6(F).

Zhou et al.²⁵³ fabricated a stretchable microfluidic device with superamphiphobic surface for particle manipulation. The surface remains superamphiphobic in both water and n-hexadecane at tensile strains up to 225%. Jia et al.²²⁹ proposed a size-adjustable elastic inertial separation technique for microalgae cells using an ultra-stretchable channel. By adjusting the channel geometry, the separation threshold can be adjusted to be smaller, as shown in Fig. 6(G). However, in practical applications, microparticle manipulation based on stretchable channels still has problems such as limitations in material selection, repeatability and durability of stretchable channels. The traditional microfluidic material, i.e., PDMS, usually has a maximum elongation of about 70%, which limits the adjustment range of channel size and the flexibility of particle manipulation. Meanwhile, when performing microparticle manipulation, the channel needs to have good repeated stretching and release capabilities to ensure long-term operation stability and durability. Material fatigue and damage may affect the consistency and reliability of particle manipulation.²⁴⁴

6. Conclusion and perspectives

This review synthesizes recent advances in particle manipulation, emphasizing the integration of multi-force strategies, innovative forces and cutting-edge technologies including AI and autonomous systems. The use of composite forces, e.g., traditional ones like hydrodynamic, gravitational, optical, magnetic, electrical, and acoustic, etc., as well as innovative ones like interfacial, thermal gradient, buoyancy, chemical gradient, diffusiophoresis, and thermal gradient, etc., has greatly enhanced the precision and adaptability of particle manipulation techniques. These methods allow us to address the intricacies of particle behavior in diverse environments, paving the way for innovative applications in bioengineering, pharmaceuticals, and environmental sciences.

While the manipulation of micro- and nanoparticles has shown promising improvements, scalability remains a formidable challenge. Techniques that are effective at the microscale often struggle to scale up to larger, more complex systems without significant loss of efficiency and increased operating costs. In addition, the integration of multiple force fields, while beneficial for precision and versatility, adds complexity to system design, requiring sophisticated control mechanisms and real-time processing capabilities. Efficiency and precision, while improved, are often in conflict, especially in high-throughput systems where maintaining manipulation integrity is critical. These systems are particularly susceptible to variations in external conditions, such as temperature fluctuations and electromagnetic interference, which can significantly affect the operational accuracy of the system.

In the future, this field is likely to move toward harmonizing various manipulation forces within a single framework to further improve system efficiency and functionality. Developments in real-time feedback mechanisms and computational modeling are expected to play a critical role in this evolution. In addition, the integration of AI and machine learning will not only refine system control, but also extend the capabilities of these technologies to dynamically adapt to variable operating conditions. Innovative design approaches that reduce the cost and complexity of microfluidic devices will be critical. The potential for modular and multifunctional systems suggests a move toward more integrated and scalable solutions that could revolutionize particle manipulation technology and its applications in complex biological assays and targeted drug delivery systems. Ultimately, the convergence of advanced manipulation technologies and system integration will dictate the trajectory of lab-on-a-chip technologies and steer the future of microfluidic applications toward greater precision, adaptability, and cost-effectiveness.

Data availability

No primary research results, software or code have been included and no new data were generated or analysed as part of this review.

Author contributions

G. Hu conceived the idea and outlined the project. C. Xue and Y. Yin conducted the literature study, interpreted the collected data, and wrote the manuscript. X. Xu drew the figures. K. Tian and J. Su contributed to the theoretical analysis of forces. C. Xue and G. Hu contributed to the discussion and perspectives, and the revision of the whole manuscript. All authors provided critical feedback, read and approved the manuscript.

Conflicts of interest

The authors declare no conflicts of interest.

Acknowledgements

This work is supported by the National Key Research and Development Program of China (No. 2022YFA1203200) and National Natural Science Foundation of China (No. 12272345, 12172081).

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Footnote

† These authors have contributed equally.

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