Roadmap for Clinical Translation of Mobile Microrobotics

Medical microrobotics is an emerging field to revolutionize clinical applications in diagnostics and therapeutics of various diseases. On the other hand, the mobile microrobotics field has important obstacles to pass before clinical translation. This article focuses on these challenges and provides a roadmap of medical microrobots to enable their clinical use. From the concept of a “magic bullet” to the physicochemical interactions of microrobots in complex biological environments in medical applications, there are several translational steps to consider. Clinical translation of mobile microrobots is only possible with a close collaboration between clinical experts and microrobotics researchers to address the technical challenges in microfabrication, safety, and imaging. The clinical application potential can be materialized by designing microrobots that can solve the current main challenges, such as actuation limitations, material stability, and imaging constraints. The strengths and weaknesses of the current progress in the microrobotics field are discussed and a roadmap for their clinical applications in the near future is outlined.


Introduction
In medical sciences, groundbreaking ideas have often acted as catalysts for revolutionary advancements.One such visionary concept, famously introduced by the renowned immunologist and Nobel Laureate Paul Ehrlich, is that of the "magic bullet". [1]hrlich observed the selective accumulation of injected dyes in various organs of laboratory animals based on chemical properties.Therefore, he proposed the idea of a therapeutic agent capable of selectively seeking out and destroying disease-causing DOI: 10.1002/adma.202311462agents within the human body without harming healthy tissues.This concept laid the foundation for targeted drug delivery.Ehrlich's "magic bullet" concept emerged as a response to the limitations of conventional therapies, which often exhibited systemic side effects and suboptimal efficacy.His visionary idea sparked the imagination of researchers and paved the way for a new era in medicine, a quest for precision and efficiency, and there is plenty of room for discoveries in this theory even today. [2]ligned with Paul Ehrlich's vision, the emergence of nanomedicine holds immense promise for achieving precise and targeted therapies, especially in tackling challenging diseases such as cancer.By leveraging their distinct physical and chemical properties, nanoparticles have been acclaimed as potential carriers for delivering therapeutic payloads to specific disease sites, aiming to minimize off-target effects and enhance treatment efficacy. [3]However, the realization of this vision has encountered fundamental challenges.Despite remarkable advancements in nanotechnology, achieving absolute control over the biodistribution and targeting of nanomedicine within the human body remains a significant hurdle. [4]The dynamic interplay between nanoparticles and biological components, such as proteins, cells, and tissues, can lead to unintended interactions and subsequent off-target distribution.These interactions may compromise the selectivity initially envisioned for "magic bullet" therapies, resulting in suboptimal therapeutic outcomes and risk of complications and serious side effects. [5]As we strive to navigate the intricate landscape of nanomedicine, addressing the issue of off-target distribution emerges as a pivotal consideration in the ongoing pursuit of precision medicine and the realization of Ehrlich's visionary concept.The emerging field of medical microrobotics presents a promising avenue to overcome these challenges and bring us closer to achieving precise and targeted medical therapy options (Figure 1).
Medical microrobotics is a research field where microrobots operate at the cell-size scale to diagnose and treat diseases; it mainly aims to fabricate, actuate, control, and track such tiny robots to operate in the human body. [6]Over the past few years, such robots have shown great potential for enabling revolution in various biomedical applications, such as localized and precise drug delivery.However, the clinical translation process of the micro-scale robots has been characterized by a slow and challenging journey. [7]While papers on medical microrobotics increase exponentially yearly, clinical scenarios with high-value propositions by using microrobots still seem a long way off. [8,9]Despite the exponentially increasing number of articles, the number of granted patents has plateaued in recent years (Figure 2).In this review, we aim to elucidate the development of microrobots up to their present status and outline a roadmap for their near-future integration and utilization in clinical settings.The first chapter introduces the fundamentals of medical microrobotics, serving as an introduction.The second chapter delves into the considerations of microrobot locomotion in complex in vivo environments, which significantly differ from controlled in vitro settings.The third chapter focuses on the current practical challenges in the clinical use of medical microrobots.Finally, the review concludes with the future roadmap for medical microrobotics to provide insights from the perspectives of clinicians and microrobotic researchers.

What is a Medical Microrobot?
The term "microrobot" holds diverse interpretations within the literature.Microrobotics has emerged as a specialized branch of robotics with a wide range of applications in micromanipulation, microassembly, and biomedicine. [6]Microrobots distin- guish themselves from conventional robotic systems in many senses.In the sense of physics, the dynamics of microrobots are dominated by surface area-and perimeter-based microscale forces, such as surface tension, van der Waals forces, friction, drag forces, and chemical, biological, or electrostatic surface interactions, while dynamics of macroscale robots are dominated by volume-based forces, such as weight, inertia, and buoyancy.In the sense of design, macroscale robots contain onboard actuators, sensors, controllers and power sources, enabling them to interact with their environment to achieve the desired tasks and possess onboard computational units providing cognitive and perceptive capabilities.However, microrobots are often too small to contain onboard actuators, sensors, power sources, or computational units.They mostly embody smart, functional materials that interact with remote stimuli to generate actuation, sensing, and desired functions.Moreover, intelligent behavior in microrobots, such as adaptation and learning, manifests itself from physical, chemical, or biological interactions of their smart materials, structures, or mechanisms on their body with the stimuli in their surroundings, which is referred to as physical intelligence. [10]While these interactions are very simple in nature, they can result in effective cell targeting mechanisms [11] or complex swarm behaviors with vast collective locomotion modes. [12]Notably, their adeptness at active and precise navigation and control has garnered considerable attention in medical research, particularly in contexts where precise drug localization and other related applications hold important significance. [13]edical microrobotics constitute a specialized category of microrobotics explicitly intended for medical purposes.Thanks to their small scale, they could be useful for non-invasive or minimally invasive diagnostic or therapeutic medical operations inside the human body.They could be used in medical imaging, [14] cellular diagnosis, [15] drug delivery, [16] hyperthermia, [17] immunotherapy, [18] and even in neurostimulation applications. [19]In such applications, the interactions between microrobots and biological tissues, as well as the choice of materials, medical imaging, and actuation methods, become pivotal factors influencing their effectiveness.Due to the variety of physical and biochemical interactions, the desired tasks of the medical microrobot should be precisely defined before their Figure 3. Currently proposed biomedical applications for medical microrobots in sensory, [17,28,29] central nervous, [30,31] respiratory, [32] cardiovascular, [14,33,34] hepatic, [35,36] digestive, [37][38][39] urinary, [40][41][42] and genital [43,44] systems.design phase.In this way, they could be applicable to realistic clinical scenarios.

Medical Applications of Microrobots
Medical microrobots could have a wide range of usability in healthcare, from interventional radiological applications [20] to cell sorting from patient blood samples [21] (Figure 3).Their potential medical applications can be categorized according to four pillars of healthcare services: prevention, diagnosis, treatment, and rehabilitation. [22]As a preventive healthcare tool, they could help clinicians as vaccination carrier agents, [23] early diagnostic tools for preventable diseases by continuous monitoring of health parameters, [24] and rapid point-of-care cellular marker screening devices. [21,25]In incurable medical conditions, including retinal blindness and neurodegenerative diseases, the microrobots could be functional to carry nano-or micro-scale stimulators to the targeted tissues. [26,27]These microrobots can deliver electrical or chemical stimuli to specific areas of the nervous system, including the retina, nuclei of the brain, or spinal cord, to modulate neural activity and promote functional recovery. [19]While disease prevention and rehabilitation research with microrobots are in their early stages, the medical microrobotics field is currently focused on diagnostics, imaging, drug delivery, and combined therapeutic modalities.
Microrobots can be used for diagnostic purposes, similar to macroscale medical robots, to collect tissue or cell samples from the environment without human intervention, espe-cially for a completely sterile sample collection from confined spaces outside or inside of the human body. [45,46]Their small size could enable them to screen and monitor commonly occurring metabolic diseases without compromising patient quality of life. [28,47]To monitor various physiological parameters or detect specific biomarkers in the body, microrobots can be equipped with miniature sensors. [15]These miniature sensors enable continuous monitoring and early detection of health problems by providing real-time data, including cell surface, metabolites, and chemical levels. [48]They could be conjugated with miniature therapeutic modules that could enable spontaneous treatment of the diseased cells with diagnosis; in this way, the waiting time between diagnosis and treatment can be eliminated. [49,50]The flow generated by microrobot actuation can enhance the diffusion of drugs or nanoparticles into target tissues in these types of microrobots. [51,52]They also allow surgeons and interventional radiologists to obtain tissue samples from hard-to-reach areas of the body. [53,54]edical microrobots, as surgical, physical, and pharmaceutical treatment tools, could reduce postoperative pain, hospitalization time, patient recovery time, infection risk, and overall costs, thereby increasing the quality of care.Microrobots can operate untethered for minimally invasive surgical techniques, and their design is based on the task they need to accomplish and the type of environment in which they will operate. [13]Microrobotassisted minimally invasive surgery can reduce the size of incisions, reduce physical trauma, and promote faster wound healing. [29]These robots can be remotely controlled or guided by imaging techniques to access and treat delicate areas that are difficult to reach with conventional surgical methods. [55]While medical microrobotics research has begun surgical and physical treatment modalities, [56,57] the current focus has shifted to pharmaceutical, genetic, and cellular therapy options. [17,20,23]Thanks to advances in materials science, microrobots can be designed to deliver drugs on demand and directly to specific target sites in the body after navigating through various body fluids. [17,58]Their targeted approach improves efficacy, reduces side effects, enables controlled release, and minimizes required dosage. [9]These advantages of microrobots could enable us to create a new "magic bullet" concept for smart, personalized medicines in the near future.

Current Status of Medical Microrobotics
With its potential to revolutionize healthcare and enable precise interventions at the microscale, the medical microrobotics field offers a multitude of exciting prospects.In recent years, the focus of research in this field has primarily been directed toward the development of novel actuation mechanisms, advanced fabrication techniques, and integration of other biomedical developments with microrobotic systems. [6]However, it is essential to acknowledge that the claims in medical microrobotics must be thoroughly substantiated.To ensure the credibility and progress of the field, it is crucial to focus on rigorous validation and thorough evaluation of microrobotic technologies, ensuring that their potential benefits are supported by scientific evidence and clinical feasibility.Therefore, it is important to consider the common pitfalls and create strong networks between microrobotic researchers and clinicians while conducting medical microrobotics research.
Due to the early infancy phase of the field, it also faces various misconceptions among scientists inside and outside the field.Indeed, one of the most common misconceptions is that the successful movement of microrobots in simplified laboratory environments, for instance, Petri dishes, directly translates to their ability to navigate within complex physiological environments, including the bloodstream or connective tissues. [59]The conditions and challenges faced inside the human body are vastly different, where complex fluid flows, cellular/tissue interactions, organ motions, and varying, patient-specific cell/tissue properties can significantly affect microrobotic locomotion and functions (Figure 4).For example, non-Newtonian behavior and highspeed pulsatile flow of the blood in different vessels is one of the most important challenges for all mobile microrobots that target the cardiovascular system. [11,60]While most of the medical microrobot prototypes can actuate and function in the 2D cell culture environments, none of them can successfully actuate in the 3D extracellular matrices (ECM) of the softest tissues of the human body, including adipose and brain tissues, due to their adhesive and heterogeneous reticular ECM structure. [61,62]Thus, the researchers must acknowledge the need for realistic testing and validation in physiologically relevant settings to ensure that the performance of microrobots aligns with their intended biomedical applications.
Another issue in the medical microrobotics field is that some researchers have proposed novel microrobotic technologies without studying and clarifying their clinical translation needs and unique value. [63]However, fostering close collaboration between clinicians and microrobotics researchers from the beginning is indispensable for the clinical translation and success of the field. [64]

Building Bridges Between Microrobotics and Clinical Medicine
At the current stage of the medical microrobotics field, it is crucial to identify the specific needs and requirements for medical applications thoroughly by building bridges between microrobotics and medicine. [65]Conducting microrobotic research solely for the sake of curiosity or publication is no longer sufficient, given the substantial amount of information already accumulated about the capabilities of various microrobots in the field. [66]herefore, the field must focus on identifying precise biomedical questions and clinical applications to propel its advancement.However, these detailed and substantial identifications should be made by collaborating with medical experts and avoiding superficial claims. [67]The complexity of the problem is often overlooked, and the entire assumption of achieving success is solely based on successful locomotion in artificial environments, such as Petri dishes.That's why engaging with clinicians outside the laboratory is crucial for meaningful progress.Their insights help align research with real-world medical needs and foster innovative solutions for improved healthcare.Many funding organizations are currently establishing structures to support this clinician and researcher collaboration from the earliest stages of biomedical studies to accelerate the translation of scientific discoveries. [68,69]t is crucial to establish a strong and seamless connection between clinical and basic research to make substantial progress in this direction.Bridging the gap between theory and practical implementation holds the key to unlocking the true potential of innovative medical technologies. [70]Efforts should be directed toward fostering collaborative endeavors between microrobotics researchers, clinicians, and industry experts to ensure that advancements made in the laboratory are effectively translated into tangible benefits in clinical settings.By fostering these collaborations, we can pave the way for transformative breakthroughs that significantly impact healthcare and lead to improved patient outcomes.
To begin, it is imperative to gain a comprehensive understanding of the fundamental interactions between microrobots and the complex environments within the human body to ensure successful applications.Equally important is a deep comprehension of the technical aspects, including actuation mechanisms, imaging techniques, and precise control methods for microrobots.Such in-depth understanding forms the basis for unlocking the full potential of these tiny agents in diverse medical applications.

Interactions of Microrobots in Complex Biological Environments
The human body has complex 3D tissue structures, fluid flows, and organ movements compared to the simplified laboratory models. [71]Even the most commonly used experimental animals, including mice, rats, and rabbits, cannot mimic the complexity of the most crucial systems of the human body. [72]This complexity is also highly important for the locomotion physics of the medical microrobots.

The Physics of Microscale Locomotion and its Consequences in the Human Body
Microrobotics is primarily concerned with investigating the locomotion of robots at the micron scale within fluidic environments, aiming to achieve various tasks. [6]Small-scale locomotion brings its own complexities and simplifications.Therefore, a thorough understanding of the governing dynamics of micron-scale locomotion is crucial to achieve the desired locomotion.In general, locomotion in the fluid is governed by two fundamental forces: inertial and viscous effects. [73]Inertial effects refer to a fluid's resistance to changes in its motion.Once in motion, a fluid will continue moving in the same direction and at the same speed unless acted upon by an external force.Inertial effects are most pronounced at high fluid velocities.Viscous effects are based on the internal friction that arises within a fluid as it flows.Adjacent fluid layers resist relative motion, which leads to specific behaviors such as resistance to deformation and flow.The combined effect of these two forces is described by the Navier-Stokes equation, which describes the motion of fluid flow: where v is the velocity,  is the density, μ is the dynamic viscosity, p is the pressure of the fluid, ∇ 2 is the Laplace operator and t is the time.The relative effect of inertial over viscous effects is described by Reynolds number (Re) and expressed by the following: where L is the characteristic length.Locomotion in microscale refers to a range of low Reynolds numbers, where viscous forces dominate over inertial forces (Re< 1). [74]In this case, the inertial part of the Navier-Stokes equation drops: Therefore, the Navier-Stokes equation becomes independent from the time.This means the flow responds instantaneously to changes in the applied forces or boundary conditions.This brings the "time reversibility" property to low Re number flows; if we were to reverse the flow of time in the fluid, the particles within it would exactly retrace their previous paths. [75]The flow patterns would unfold in reverse, ultimately leading the system back to its original state.Thus, reciprocal or symmetric motions do not cause any net translational locomotion in this regime.To generate a directed motion, the concept of symmetry-breaking locomotion is necessary. [76]This involves breaking the symmetry of time reversal by introducing asymmetric interactions between organisms or particles and the fluid.By doing so, directed motion can be achieved, allowing for a specific and intentional movement in a particular direction.
Symmetry-breaking fluidic locomotion can be widely found in nature; the main examples are bacterial flagella motion, sperm cell swimming, and ciliary locomotion. [74,77]The locomotion mechanisms observed in nature have served as the initial inspiration for microrobotics as they strive to replicate such locomotion for diverse applications. [78]However, not until long ago, mimicking such motion at the microscale posed significant challenges due to limitations in microfabrication techniques.The advancement of microfabrication techniques has facilitated the achievement of symmetry-breaking locomotion through external actuation mechanisms, including magnetic, acoustic, and photochemical forces. [17,79,80]A significant milestone of the microrobotics field, the helical microswimmers, is the most famous example of synthetic replication, which closely mimics the structure and movement of bacterial helical flagella. [81,82]ature has indeed provided a valuable but suboptimal starting point for researchers in the field of microrobotics, enabling the development of synthetic locomotion in simplified environments. [78]However, when considering the applicability of these synthetic systems in biomedical engineering, significant concerns arise from the suboptimal physical design due to evolutionary trade-offs, Pareto efficiency, and limits of the phenotype space. [83]Microrobots must generate sufficient force to overcome environmental forces, such as high blood flow rates and viscoelastic forces, to achieve locomotion and move in the desired direction. [84]In contrast, it is unclear whether natural microorganisms can achieve effective locomotion in the various parts of the human body solely by symmetry breaking. [85]or instance, microalgae can reach very high speeds, up to 160 μms -1 , in their own medium, [32,86] but they cannot sustain their propulsion in most human body fluids due to their dependence on high concentrations of ammonium. [87]In another example, while researchers successfully emulate the helical motion observed in bacterial flagella, the reliance on external actuation alone may fall short in accurately replicating the intricacies of locomotion within the human body. [88]acteria generate forces tailored to their specific physiological environments, which may not be fully captured by externally actuated helical swimmers. [89]This disparity between the propulsive forces generated by bacteria and those required for effective locomotion in the human body raises concerns about the practicality of using helical swimmers in biomedical applications.On the other hand, surface microrollers can achieve much higher speeds of up to 600 μms -1 in static fluid conditions, [11] and they can also actuate against the physiological blood flows inside blood vessels without mimicking the actuation of microorganisms in nature. [59]Relying solely on nature may not be the best solution for achieving locomotion in the human body, given the fundamental challenges posed by these forces.Therefore, the overall approach could be different to overcome these limitations; future research in microrobotics should strive to uncover and replicate the intricate locomotion mechanisms exhibited by bacteria, [90] besides using the bacteria as biohybrid engines for microrobots. [91]For example, exploration of how the different bacteria strains invade the tissues or marginate to vessel walls could be a more meaningful starting point for microrobotic researchers to apply microrobots in a biomedical context. [92]he actuation forces for synthetic microrobots, required for directed motion, are typically generated through magnetic, [93] acoustic, [31] or optical forces, [94] with chemical actuation also being commonly employed. [95]Each actuation strategy presents distinct advantages and challenges when applied to microrobots within the human body, necessitating a tailored selection based on the specific requirements of the medical application.Understanding the strengths and limitations of each strategy is crucial for researchers and engineers to make informed decisions, ensuring the development of microrobotic systems optimized for effectiveness and safety within the intricate environment of the human body.Magnetic control offers significant penetration depth and precisely configurable field characteristics, but its reliance on magnetic materials restricts the available functional materials. [96]Similarly, acoustic methods exhibit high penetration depth and field adjustability without the need for specific materials; however, in medical scenarios, acoustic fields may encounter scattering by certain tissues like bones or teeth, limiting their application to soft tissues. [97]Light-based methods provide precise control but suffer from a low penetration depth, restricting their use to shallow body areas. [96]Chemical methods, while non-invasive, face challenges in control precision and require a non-toxic fuel molecule inside the human body.Consequently, the chemical actuation method finds primary use in body areas where such fuels are present, including gastrointestinal and genitourinary systems. [95,98,99]n a nutshell, nature does not always provide the optimal solutions for specific biomedical applications.Therefore, it is essential to have a comprehensive understanding of the requirements within the human body.Microrobots must be engineered to align with the specific needs and intricacies of the target application.Researchers can develop microrobotic systems that are purposefully designed to overcome obstacles and achieve desired functionalities within the complex environment of the human body, thoroughly grasping the unique constraints and forces at play.Therefore, the key is to harness knowledge and insights gained from nature while tailoring microrobots to the specific requirements of the intended biomedical applications.

Physical Constraints on Microscale Locomotion in the Human Body
The human body is a complex system with diverse variations among individuals, making it challenging to understand the physical interactions and characteristics within our bodies.The discovery of essential phenomena like pressure differences through the vascular networks in the cardiac cycle took over a century, and many aspects of our body's functionalities remain unclear. [100]This complexity arises from hundreds of thousands of years of evolution, which optimized our bodies to maintain functionality in several aspects and defend against intruders. [83]s researchers apply microrobots in such complex and intricate environments, they face the major challenge of overcoming physiological barriers and physical constraints without disrupting body homeostasis.
Physical constraints play a crucial role in determining the capabilities of microrobots within biological systems or microenvironments, and addressing these constraints is essential for developing efficient and effective medical applications.The specific constraints faced by medical microrobots depend on the delivery and retrieval routes, tracking method, targeted location, and desired function.Microrobots are proposed to function within fluid-filled spaces of the body, including blood vessels, the gastrointestinal tract, [101] and the central nervous system. [9,102]These anatomical regions, however, impose distinct physiological constraints on microrobot locomotion.The fundamental requirement is for a microrobot to generate sufficient propulsive force to counteract external forces, enabling it to navigate along the intended trajectory.Yet, various fluid-filled cavities present unique challenges for microrobotic actuation.
Navigating within the vascular system stands as a significant challenge, one that offers substantial prospects for advancements in medical applications.The prospect of navigating through blood vessels presents an opportunity to reshape the treatment strategies for specific medical conditions, notably cancer and endovascular diseases. [59,103,104]However, it exhibits high geometrical and topological complexity, requiring precise navigation and control for safe microrobotic operations. [105]essel diameters range from millimeters to micrometers, and flow speeds vary from micrometers per second to centimeters per second. [13,106]Together with both Newtonian and non-Newtonian behavior of blood, the different blood flow regimes, for instance, pulsatile and laminar flows, further complicate navigation and control. [107,108][112] The primary challenge encountered while navigating within blood vessels appears to be the substantial flow velocities inherent in these conduits. [113][116] These characteristics pose significant challenges to the effective movement of microrobots; it is worth noting that there are limited instances of such occurrences documented in the existing literature. [59]till, microrobots appear to encounter fewer impediments when functioning within the walls of larger vessels like veins or arteries, [117] which is attributed to the parabolic flow pattern and significantly reduced flow velocities on the vessel walls.Nevertheless, the increased microrobot-to-vessel ratio leads to their exposure to relatively higher flow velocities in the case of smaller vessels, consequently hindering their effective movement in microcirculation. [117]n addition to flow-rate-related limitations, our recent investigations have revealed that the surface texture of blood vessels may pose a significant fluidic hurdle to the locomotion of microrobots. [59,79]Furthermore, the operation of microrobots within tightly confined small vessels is inherently demanding due to the intensified effects resulting from fluid-boundary interactions. [118]Beyond the investigated aspects related to vessel walls, studying the effects of gravity on microrobots and delving into their tendency to adhere to vessel walls present promising research questions.Moreover, the non-Newtonian nature of blood, especially prominent in smaller vessels, could also bring additional complexities to the operation of microrobots. [107,119]n addition to physical limitations, they also face biological and chemical barriers due to contact with numerous immune system components and proteins in the blood. [120]Immune system-derived opsonins, including antibodies and the complement system, can mark the microrobots for phagocytes, triggering an immune response that limits their ability to perform medical tasks. [121]Inspired by nanomedicine, surface coatings like Polyethylene glycol (PEG) have been applied to delay the opsonization process. [121,122]However, these coatings can also cause allergic reactions in certain patients. [123]Hence, alternative options, such as using zwitterionic coatings, have been suggested. [124]icrorobotics systems also face physical constraints in other body areas, including the reproductive system, [105] the eye, [17] the central nervous system (CNS), [62] and the gastrointestinal (GI) system [101] (Figure 4).Even if flow rates are significantly lower in these regions, a combination of varied physical hurdles emerges, encompassing elements such as non-Newtonian characteristics, viscoelastic effects, non-specific chemical reactions, and external flows.The body fluids exhibit different viscoelastic behaviors, posing inherent challenges for locomotion.For instance, mucus exhibits a heterogeneous non-Newtonian environment for microrobots, which creates significant problems for directional locomotion with propulsion. [125,126]Despite a limited presence of illustrative studies in current literature, a more profound comprehension is required to unlock the potential of microrobotic locomotion in these environments. [17,88,127]Moreover, the complexity extends beyond viscoelastic fluid dynamics with other physical constraints, including air-liquid interfaces, nonspecific attachments to the residues of ECM components, and physical clearance mechanisms, which could potentially arise. [17,62,128]Consequently, a more intensive research endeavor is necessary for each distinct anatomical site and its fluid biomechanics, aiming to uncover and address any counter-intuitive and latent physical restrictions for microrobots.
[131] In the GI tract, one of the most frequently targeted organs for microrobotic applications, microrobots encounter gastric acid, digestive enzymes, and mu-cosal membranes, which act as biological barriers for any external intruders. [132]Maintaining functional material stability within this harsh environment is challenging due to continuous chemical corrosion. [133]While most microrobots propose ambitious locomotion possibilities in the GI tract, they do not mention the importance of material stability for full-scale clinical functionality.Similar challenges were faced in the development of wireless capsule endoscopes, and there is a clear roadmap to clinical translation, thanks to their tremendous efforts. [134]lthough microrobotic experiments have predominantly focused on fluids like phosphate-buffered saline (PBS) or deionized (DI) water, biological fluids present a distinct challenge due to the presence of macromolecules, sugars, and various other compounds, introducing non-Newtonian (and mostly shear-thinning) behavior. [135]Commonly employed fluids in microrobotic research exhibit Newtonian behavior, where viscosity remains constant in the microrobot's vicinity, independent of shear rate.In contrast, biological fluids exhibit more intricate behavior, with properties dependent on shear rate, demonstrating the size and time-dependent viscoelastic characteristics. [135]ertain biofluids, such as blood, display pronounced shearthinning properties of macromolecules, sugars, and various other compounds, introducing non-Newtonian behavior. [107,136]his shear-thinning property is particularly evident in smaller blood vessels like capillaries, where high shear rates along the vessel walls prevail. [137]Although the locomotion of microrobots in capillaries is not extensively explored, literature provides insights into the complexity of locomotion in such fluids.For instance, a noteworthy example reveals that the performance of surface microrollers is significantly influenced by the shear-thinning nature of the fluid, leading to the potential reversal of their locomotion direction based on fluid properties. [138]n terms of tissue penetration, microrobots often encounter challenges in media with strong meshy and viscoelastic tissue properties, [139,140] as their forces are generally insufficient to deform or penetrate such environments.However, the literature highlights instances where this barrier is overcome by utilizing micropropellers that can travel in such meshes. [88]Beyond tissues, propulsion in viscoelastic fluids has been demonstrated by inducing extreme shear rates and disrupting the inherent symmetry of such heterogeneous fluids. [76,127]After all, microrobot locomotion in tissues and viscoelastic fluids poses a formidable challenge, and achieving robust tissue locomotion may be physically unattainable with currently explored mechanisms.Addressing this challenge requires additional experimental and theoretical efforts to thoroughly investigate the feasibility of locomotion in non-Newtonian environments.
Overall, physical, biological, and chemical barriers pose considerable challenges for microrobotics within the human body.There is a pressing need for further extensive exploration of microrobotic locomotion in such intricate environments to ascertain the potential of medical microrobotic applications in these specific body regions.The current literature lacks comprehensive findings concerning the practical movement of microrobots in these anatomical spaces.Therefore, conducting additional feasibility studies is essential to validate and substantiate the claims regarding the viability of medical microrobotic applications within these contexts.These studies will play a pivotal role in providing a clearer understanding of the actual capabilities and limitations of microrobots when navigating the intricate landscape of the human body, and they will guide the future development of microrobotics, facilitate the design of systems that can adeptly navigate and interact within these complex physiological spaces.

Aspects of Biocompatibility
Biocompatibility, as an umbrella concept of the interactions between a device and the body, is also a critical consideration in the development and use of medical microrobots.It encompasses various aspects that collectively ensure their safe and effective interaction with living organisms, which includes material stability, degradability, cytotoxicity, and immune compatibility. [141]Not only in the targeted region but also systemic distribution and possible adverse effects on various organs should be considered for the biocompatibility of the microrobots.These aspects should be carefully evaluated to minimize any potential adverse effects and promote positive outcomes for the patients.
Chemical stability is an important aspect of biocompatibility from a materials science perspective.The material, including medical microrobots, should maintain its structural integrity and chemical composition over the desired duration of use. [63]It should not degrade, corrode, or release harmful substances that could harm cells or tissues, even for decades.For instance, while photocatalytic-propelled microswimmers move, they induce redox reactions around the microswimmer.After being actuated for a long time, their surface chemistry, material stability, and drug delivery efficiency are negatively affected due to continuous redox reactions. [142]Especially, accelerated aging tests should be conducted to simulate the chemical stability of microrobots in physiological environments to assess their biochemical safety. [143]Unfortunately, there are not a lot of microrobotic studies that demonstrate long-term chemical stability, although it is a gold standard test for other research fields on medical devices, including various medical implants. [144]This aspect should definitely be examined before starting any in vivo or in vitro tests, especially for long-term medical applications of microrobots exposed to various physiological conditions.In addition to chemical stability in physiological conditions, material compatibility with various sterilization methods is crucial for realistic medical applications with microrobots.Medical microrobots should withstand the chosen sterilization processes, including heat, chemical, and radiation sterilization, without compromising their biocompatibility or structural integrity.Ensuring that the material remains safe and functional after sterilization is essential for clinical applications. [145]s a second aspect of biocompatibility, mechanical compatibility refers to the material's ability to withstand physiological forces and mimic the mechanical behavior of natural tissues when necessary.It should possess suitable flexibility, strength, and elasticity to avoid mechanical failure or disruption of tissue functionality. [96]This aspect is essential for medical microrobots, similar to prosthetics, orthopedic implants, and other load-bearing devices, due to the high forces they are subjected to relative to their small size. [146]Also, mechanical effects on cellular behavior should be considered if the microrobot physically interacts with the cells.For example, stem cell carrier microrobots are proposed as novel cellular therapy options for stem cell deficiencies, but mostly they are made of commercially available inks for nanoscale photolithography systems. [20,147]Although the various effects of stiff surfaces on stem cell differentiation are well known, this issue has not been explored in detail in microrobot studies. [148,149]To illuminate cell behavior on different surface physics of microrobots, differentiation-related cell-surface markers and cytokines should be investigated, and possible foreign body response, followed by fibrotic tissue induction, should be prevented for healthy stem cell transplantation. [150,151]hile material stability is an important feature for permanent devices, biodegradability could also be a better option for temporary devices than surgical retrieval of the device.While most of the microrobotic systems are designed for retrieval after the accomplished functionality, some microrobots can degrade after their use. [23,152,153]These microrobots should degrade over time without passing excessive levels of byproducts and be safely absorbed or eliminated by the targeted tissue while delivering their cargo effectively.The degradation process should not cause harm to surrounding tissues by releasing toxic byproducts, inducing immune cell reactivity, or neutralizing therapeutic agents. [154]his aspect is particularly relevant for biodegradable microrobots with a cargo delivery ability. [155]Although most of the in vivo studies on biodegradable microrobots investigate cargo delivery and therapeutic efficiency, degradation products, and their local and systemic biodistribution remain in the blind spot in these studies. [23,153]Without detailed characterization of biodegradation products and their biodistribution, metabolism, and excretion pathways, the clinical safety of the microrobots cannot be assessed completely. [156]All these tests on material stability and on-demand degradability on microrobots will play a crucial role in clinical decision-making for their use in clinics as drug carriers or medical devices. [157]fter material properties, the cytotoxicity of the microrobots is the next important point in biocompatibility analyses.It involves assessing whether the microrobot causes harm to cells by affecting any intracellular vital processes. [158]Cell membrane integrity, cellular metabolism, especially ATP and DNA metabolisms, cell death pathways, and cell proliferation markers are used for the cytotoxicity analyses. [159]There is no universal standard cytotoxicity measurement method.Each cytotoxicity measurement method has advantages and disadvantages; the cytotoxicity methods should be selected according to the targeted medical application, physical properties, and propulsion mechanism of microrobots.Unfortunately, cytotoxicity assays in some of the microrobot studies did not give sufficient information about clinical applicability due to incorrect or insufficient cytotoxicity analyses. [160]Medical microrobots should not stop cell proliferation, induce cell death, create cell membrane leakage, or interfere with any cellular metabolism.While most microrobot studies consider metabolic tests, including tetrazolium reduction assays (e.g., MTT, MTS), sufficient for analyzing cell viability in vitro, it has long been known that metabolic assays alone are not sufficient to measure cell viability.Furthermore, while many studies only demonstrate in vitro cell viability with cancer cell lines and fibroblasts, they overlook the fact that cell viability tests are only meaningful when performed on healthy cell lines from target organs.Metabolic cell viability tests must be performed in healthy cell lines (e.g., stem cells, primary endothelial and epithelial cells) in conjunction with other cell viability assays, including membrane integrity or DNA synthesis assays (e.g., calcein-AM and 5bromo-2-deoxyuridine (BrdU), respectively), for accurate in vitro results.For more specific recommendations on cytotoxicity analyses, ISO-10993 guidelines [161] and FDA medical device guidance documents [162] could be reference sources.
Together with cytotoxicity, hemocompatibility is also specifically relevant for microrobots that encounter blood. [120]emocompatibility involves assessing how the material interacts with blood components, including the complement system, immune cells, and vessel endothelium.The microrobots should not promote thrombogenicity, platelet activation, or hemolysis unless these functions are targeted. [153]While the microrobots achieve selective attachment to the targeted area in the vascular system, they should not be internalized by other blood components, including innate and adaptive immune cells. [11]Ensuring compatibility with the complex and dynamic nature of blood is essential for medical microrobots for vascular imaging, thrombolysis, embolization, or intravascular drug release functions.Thanks to the previous extensive literature on the hemocompatibility of stents, we have comprehensive guidelines for medical microrobots that are proposed for intravascular applications.
In addition to hemocompatibility, as a last pillar of biocompatibility, immunological compatibility should be reached by not provoking infections or excessive immune responses, including hypersensitivity reactions or immune rejections. [164]They should avoid triggering inflammatory or immune reactions that could negatively impact the surrounding tissue and the whole body. [165]lso, they should not activate immune cells or disrupt the normal functioning of the immune system. [166]This aspect is particularly relevant to material surface properties, especially surface charge, stiffness, roughness, and chemical composition, of the microrobots. [124]In addition to immunogenicity, the foreign body response is also a key consideration in biocompatibility. [167]he foreign body response is mostly an inescapable cascade, which hampers the functionality and structural integrity of the microrobots.There are various ways to escape from the immune response of the body, which include changing the surface charges, [124] surface modifications, [168] and encapsulating with the cellular membrane. [169]Instead of induction of inflammation, medical microrobots should promote physiological cell metabolism and growth and integrate with the surrounding tissue while functioning.
In summary, biocompatibility encompasses various aspects that collectively ensure the safe and effective interactions of medical microrobots with surrounding biological systems.Extensive evaluation and correct reporting of biocompatibility aspects according to guidelines are crucial to minimizing risks, enhancing patient outcomes, and promoting the successful integration of medical microrobots in healthcare systems.

Targeting Strategies and Biodistribution
Targeting, imaging, sensing, and elimination are the most crucial considerations for medical microrobotics, determining the function of a microrobot upon successful locomotion and navigation in targeted medical conditions.These considerations are pivotal due to their role in orchestrating microrobots' actions and inter-actions within the intricate landscapes of the human body.For the functionality of microrobots, targeting strategies play a crucial role in understanding and manipulating natural processes within the body.To maintain their functions, effective targeting mechanisms are needed to avoid off-target effects that can lead to pathological reactions.Even if the biocompatibility of the microrobot is demonstrated in various laboratory models, the side effects and biodistribution are still important considerations for the targeting strategies. [170]As bridging processes between biocompatibility and functionality, global and local modes of drug action, [171] target identification, [172] biodistribution, and mechanism of action in the targeted area should be identified during the microrobotic design process. [173]Also, biodistribution and pharmacokinetic changes during the targeted disease should be considered to effectively target the diseased area. [174]A microrobotic intervention that does not take into account the impaired physiology will do more harm than good.
In contemplating the evolution of microrobotic research, there is substantial merit in assimilating the insights garnered by the well-established field of drug delivery.The achievements made in steering drug delivery toward high-precision medicine offer a reservoir of lessons that can be instrumental for microrobotic researchers.Noteworthy milestones encompass the augmentation of targeting efficacy and bioavailability through the utilization of kinase inhibitors and innovative constructs like nanoparticle-drug conjugates such as liposomes and polymer-drug conjugates. [175]While advancements have been made in overcoming biological barriers, as evidenced by concepts such as nanoparticle-cell constructs and stimuli-responsive materials, [176] the field grapples with a persistent challenge: a targeting efficacy plateauing at around 1%. [177] This limited success prompts significant uncertainties about the clinical translation of nanoparticle-based precision medicine methods. [175]Consequently, researchers advocate for a paradigm shift within the drug delivery field, urging a departure from singularly emphasizing targeting efficacy.Instead, they propose a holistic approach that considers the patient's general well-being, including reduced side effects and enhanced therapeutic tolerance. [178]These considerations should also motivate parallel research endeavors in medical microrobots.
An additional stride in innovation involves conceptualizing microrobots as novel, steerable active targeting devices.Building on drug delivery principles, this paradigm shift moves beyond conventional carriers, accentuating the distinct capabilities of microrobots to navigate within the body and reach specific locations with unprecedented precision. [173]Beyond conceptual alignment, we assert the importance of adopting performance evaluation procedures from pharmacodynamics and pharmacokinetics to microrobotics.Scrutinizing parameters such as the minimal effective dose and median lethal dose for microrobotic applications becomes paramount for establishing optimal therapeutic concentrations while mitigating potential adverse effects.We advocate for a closer collaboration between microrobotic and drug delivery researchers to propel both fields forward.This collaborative effort aims to avoid redundant exploration of existing concepts, fostering synergistic research that elevates both microrobotic and pharmaceutical research fields to new heights.
In medical microrobotics, the processes of pinpointing specific locations within the body and detecting relevant information are simplified through a more direct and elementary approach due to size-related constraints.Because of that, primarily, two versions of targeting mechanisms can be used together or separately: passive targeting, which is enabled by the surface of the microrobot, and active targeting, which is enabled by external physical forces. [9,179]ne of the most common mechanisms of passive targeting is ligand-receptor interactions.Microrobots, especially synthetic ones, can be engineered with specific ligands on their surfaces that correspond to surface markers, including receptors and ion channels, of target cells or extracellular matrix elements. [11]hen these ligands and receptors match, the microrobot adheres to the desired location, enabling precise targeting, which may even lead to the activation of intracellular pathways. [180]his mechanism is akin to a key fitting into a lock, ensuring a specific and controlled interaction between the microrobot and the target.The selection of ligands depends on the microrobot's specific targeting goal and can include peptides, antibodies, aptamers, small molecules, or other biomolecules with an affinity for certain receptors. [84]Each type of ligand possesses unique bioconjugation characteristics that determine its binding specificity and strength to the corresponding targeted cellular marker. [181]ompared to passive targeting strategies, active targeting requires complex coordination actuation and imaging modalities for microrobot-tissue interactions.While passive targeting strategies can be useful in the systemic administration of the microrobots, active targeting could be useful in focused areas of interest to enable effective physical and pharmaceutical therapy of the targeted diseased tissue. [182]Because of that, the combination of passive and active targeting mechanisms could be the most effective way to engineer medical microrobots.These targeting and sensing processes should be designed together to realize several key steps.In a realistic medical scenario, these microrobots travel through the delivery platform, for instance, a catheter or injector, bloodstream, or other body fluids, until they encounter their target cells.Upon contact, the ligands on the microrobot's surface bind to matching receptors on the cell surface, leading to unbreakable adhesion between the microrobot and the target cell.This adhesion facilitates various actions, including targeted drug delivery, cell manipulation, and localized physical treatments. [9]epending on the microrobot's design and purpose, it can carry payloads, including imaging or pharmaceutical agents, nanoparticles, or genetic materials, contacting or releasing them at the target site on the cell surface.In addition to the ligand-receptor interactions, thanks to the precise actuation control in microscale with active targeting, the microrobots could break diffusion limits in various extracellular matrices and enhance therapeutic efficiency of their cargos [17,127] and ensures the specific delivery of the payload to the intended location.In addition to these physical and chemical targeting mechanisms, more complex sensing and targeting strategies can be achieved by utilizing biohybrid microrobots. [16]igand-receptor interactions and active targeting micro-/nanoparticles have been extensively studied in the fields of nanomaterials and biophysics.However, the exploration of these interactions in the context of medical microrobotics remains limited. [63]This scarcity of research is primarily due to the ab-sence of well-defined medical scenarios within the body, a challenge closely related to the exploration of microrobot locomotion in the complex body environment.Consequently, existing studies are predominantly proof-of-concept works conducted in controlled laboratory environments, for instance, microfluidic channels or phantom organ models.This approach creates a blind spot in microrobotic research to understand the pharmacokinetics and biodistribution of microrobots.A distinguishing feature of microrobots, in contrast to biological swimmers like bacteria, is their integration with biomedical imaging.[185][186] However, it is noteworthy that only a limited number of studies have thus far demonstrated this functionality in in-vivo scenarios. [187]Because of the limited number of in vivo studies on microrobots with closed-loop feedback control, there is still room for scientific progress to enhance the functionality of microrobots in clinical scenarios.
Although targeting and sensing strategies are crucial aspects of medical microrobotics, they currently receive less attention than the challenges outlined earlier, and microrobotic researchers should take lessons from previous successful wireless medical device development stories. [134,188]Addressing these initial challenges is essential, but it is equally imperative to shift research efforts toward exploring targeting and sensing aspects once these foundational obstacles are overcome.

From Petri Dish to Inside of the Human Body
Besides the fundamental problems mentioned above, there are also many technical problems related to the translation of microrobots to clinical use.Although these technical problems vary for each microrobot, they can be summarized under three main headings: fabrication, actuation, and imaging.For medical microrobotics to realize itself, it needs to find solutions to these technical problems.

Material and Fabrication Challenges
The field of medical microrobotics stands at a crossroads where the trajectory of progress is closely related to the resolution of critical microfabrication challenges.Microfabrication methods can be classified as top-down, including additive manufacturing, and bottom-up, including sol-gel and hydrothermal treatments, fabrication methods. [189]While bottom-up fabrication methods could achieve high throughput for basic geometric structures, due to their dependency on specific materials and limited variable control, precise modification of bottom-up fabrication methods to transform or optimize the shape of the microrobots is practically impossible. [190]At the current stage of top-down microfabrication methods, one of the most significant hurdles seems to be the lack of production robustness exhibited by these microfabrication techniques, such as two-photon polymerization and manual assembly. [191,192]These microfabrication methods, often hindered by limitations in throughput or burdened by intricate procedures, impede the realization of the full potential of medical microrobotics.Because of these reasons, targeted medical application and tissue environment should be clarified before the selection of material and fabrication method.
The complex nature of microrobotics demands fabrication approaches that are both precise and efficient.However, there is a common negative correlation between throughput and complexity for nano-and microfabrication.For instance, the renowned fabrication method known as two-photon polymerization enables the intricate production of microrobots with nanometer-scale resolution. [193]As it stands out as the best method for fabricating complex structures, including helical swimmers and other complex geometries, the fabrication yield of this method is very low compared to the wafer-scale methods. [194]The low throughput of the system leads to some unconceived results: • Limited experimentation: Yielding low throughput impedes the comprehensive investigation of locomotion mechanisms, limiting the ability to conduct a diverse range of tests and trials to explore different functionalities and behaviors, [79] • Batch-to-batch variability: Variability due to imprecise fabrication could lead to validation problems, potentially leading to less reliable conclusions about their efficacy due to a limited number of experiments, [195] • Limited in vivo translation: If fabrication yields are low, it becomes challenging to generate sufficient quantities of microrobots for in vivo experimental studies and practical applications, hindering their translation into real-world medical scenarios. [196]art from these crucial practical factors, the maintenance of these systems is costly, complicated, and requires expertise.These factors can result in elevated costs per unit and technical and financial difficulties during the production processes and hinder the execution of extensive experiments on a larger scale. [197]Therefore, their eventual translation of medical applications would be economically challenging.Nevertheless, two-photon polymerization systems are the best for proof-of-concept experimentation, not only for fabricating microrobots and exploring their mechanisms. [80,81]Therefore, the same mechanisms can be replicated through the utilization of high-throughput fabrication methods, as successfully showcased in existing literature. [198]Furthermore, the two-photon polymerization technique can serve a different purpose, creating environments that resemble in vivo conditions to assess the locomotion capabilities of microrobots. [79,118]verall, it is imperative to integrate high-throughput fabrication techniques in medical microrobotics since these techniques not only facilitate the rapid production of microrobots but also empower researchers to undertake a multitude of experiments, thus enabling the exploration of diverse locomotion mechanisms and functionalities.The use of high-throughput fabrication accelerates this cycle of iterations, enhancing the comprehensive exploration of different methods of movement that could otherwise be left unexplored due to limitations caused by low production yields. [11]Additionally, the deployment of high throughput methods aligns with the practical requirements of medical applications.The ability to generate a substantial number of microrobots paves the way for comprehensive in vitro and in vivo testing, en-abling a robust assessment of their effectiveness and safety in realistic medical scenarios.This synergy between expansive experimentation and clinical feasibility underscores the transformative potential of high-throughput fabrication techniques in driving medical microrobotics from conceptual innovation to tangible medical solutions.Great examples of high throughput fabrication can be found in the literature for different types of microrobots, and it is crucial to invest research efforts toward these platforms. [15,194,198]

Feasibility of the Remote Actuation Control in Clinical Scenarios
The next challenge in the clinical translation of medical microrobots is the transfer of remote actuation systems used in research laboratories to clinical operation rooms.This seemingly straightforward task is the main reason for the failure of many medical microrobotic concepts.Even though chemically actuated microrobots solve wireless energy transfer problems by exploiting bodily fluids as energy sources, [199] due to their limited lifetime and uncontrollable nature, chemical actuation is not a viable option in the human body. [200]While the main consideration in adapting the microrobotic system to clinical usage is scaling up the actuation system to a patient-size platform, many microrobotic actuation systems scale up poorly, for instance, coil-based magnetic actuation systems, due to the maximum generated magnetic forces dependent on the cube of the coil dimensions. [201]Also, many microrobotic actuation systems suffer from penetration depth and actuation window issues in clinical scenarios, for instance, acoustic and light-based actuation methods, due to the high scattering and absorption properties of the biological tissues. [202,203]n addition to the scale-up challenge for the actuation systems, most of them cannot be used in clinical settings without interfering with other commonly used medical devices. [204]For instance, most of the microrobots that work with magnetic external forces cannot be used with magnetic resonance imaging (MRI) systems because their programmed magnetic polarization will be distorted by high magnetic field gradients of MRI. [205]Currently, the majority of research effort in medical microrobot actuation focuses on magnetic actuation, providing different locomotion approaches for microrobots through the magnetic field and its gradient. [206]The magnetic field exerts a torque on magnetic particles, aligning their magnetization direction with the field direction, and this torque could be used for both imaging and actuation of the particles. [15]Unfortunately, despite many preliminary studies going on the subject, the clinical feasibility of microrobot integration with MRI is still questionable. [153]or realistic clinical translation, the researchers must consider the integration of actuation modalities into clinically available medical imaging systems and the financial aspects of the proposed system, even in the early stages of the microrobotic studies.There are several wireless millimetric scale biomedical theranostic devices in clinical usage, including coronary stents, capsule endoscopes, and intraocular implants, [134,188,207] the medical microrobotic researchers should study these existing clinical examples and design the wireless control of moving systems accordingly.

Imaging Limitations for Biomedical Microrobots
The successful application of microrobots in clinical scenarios requires efficient imaging techniques for the detection of their locations and monitoring of their functionalities.In all imaging modalities, several key factors, including penetration depth, spatial resolution, temporal resolution, and field of view (FOV), play vital roles in ensuring the safety, functionality, and overall success of microrobot applications. [48]n clinical scenarios, medical imaging systems are mainly used to collect morphological or functional information about the current state of the patient body.While fluoroscopy, X-ray computed tomography (CT), magnetic resonance imaging (MRI), optical coherence tomography (OCT), and ultrasound imaging (US) are used for anatomical imaging, Positron emission tomography (PET), functional MRI (fMRI), Doppler US, and optoacoustic imaging are mainly used for functional imaging.All these imaging modalities highly differ in terms of imaging penetration depth, spatial-and temporal resolution, and radiation dose (Table 1).Depending on the stated symptoms, differential diagnosis, and targeted organ, a suitable medical imaging modality will be used to gather the necessary information for diagnosis, prognosis, and therapy.The microrobotic researchers should adopt a similar way of thinking when choosing an appropriate imaging modality to image the microrobots in targeted locations.
In addition, the design of the microrobots themselves, the medical purpose, pathology, and anatomy of the targeted organ will define the suitable imaging modality.Similar to the clinical radiology practice, a top-down approach for diagnostic imaging is more suitable than the common bottom-up approach used in microrobotics. [215]Currently, several imaging approaches aim to enhance the capabilities of current imaging systems for microrobot detection.Magnetic particle imaging allows quantification and imaging of paramagnetic materials, [216] but limited workspace and spatial resolution restrict its application. [217]Another approach involves utilizing the locomotion ability of microrobots to create dynamic imaging signals, such as tracking microrobots with infrared light using a blinking pattern generated by Janus-coated gold microrobots. [218]till, commercial medical imaging modalities were mainly developed to gather anatomical and functional information on the physiological or pathological state of the human body.Therefore, the collaboration and the production of medical imaging systems that monitor and track microrobotics is required. [63]Future developments should focus on dedicated medical imaging systems for microrobot detection and integration with actuation and control systems.The medical microrobotic systems should be designed for not only healthy anatomy and physiology but also pathological conditions that will be faced in the patients for better clinical integration.These considerations, including pathophysiology, medical imaging, clinical feasibility, and device compatibility, should be prioritized to accelerate the translation of microrobotics into clinical scenarios.

Designing Microrobots for Specific Medical Functions
Although microrobotics has an increasing focus on the treatment of various cancers, clinical therapy of cancer with microrobots is a much more far-fetched goal than the treatment of other health problems, such as infertility [98] and antibioticresistant infections. [32]Due to the heterogeneous, evolutionary, and dispersed nature of cancer, physically targeted therapy on a microscale cannot be a viable option compared to other cellular, genetic, or pharmaceutical therapy options.The microrobots should be designed specifically for each medical application. [219]Their cargo delivery ability can be used to carry biological materials, from DNA [23] to cellular structures. [20]However, when designing these robots, biological material should not be considered only as cargo, and all kinds of effects arising from synthetic material in biological material should be examined.
The idea of building a universal microrobot system that can treat all types of diseases is unrealistic.Therefore, each microrobot system should be developed from the beginning of the design and manufacturing process based on a specific medical problem it is intended to solve.In this way, more clinically realistic medical microrobot systems can be developed, and their clinical translation process can accelerate.For example, algaebased biohybrid microrobots can be beneficial in fighting against other microorganisms for infectious disease treatment due to their natural defense against bacteria. [32]While degradable magnetic microrobots can be used for regenerative medicine in the human body, [220] non-degradable microrobots can be used for the selection of specific cell populations, such as the selection of healthy sperms for the treatment of infertility. [105]The examples can be multiplied, but the important point is that the pathophysiology of the medical problem is taken into account during the design and manufacturing process of the medical microrobots.

Conclusion and Outlook
The main focus of the review is understanding current progress and challenges in the medical microrobotics area and investigating possible pathways to successful clinical translation.Despite the challenges, medical microrobotics hold the potential to provide revolutionary solutions for medical diagnostics and treatments, making investment and research efforts worthwhile.Still, transforming the potential of microrobotic systems into clinically valuable applications necessitates the establishment of welldefined, achievable objectives.

What Microrobotic Researchers Achieved so Far?
Over the years, the microrobotic field has achieved remarkable milestones across diverse domains. [6]Thanks to the progress in medical microrobotic research, the "magic bullet" concept has become more realistic in recent years.The researchers explored various fabrication mechanisms, enabling the intricate production of microrobots with nanometer-scale precision.Different actuation mechanisms have evolved, incorporating novel principles like magnetic, optical, and acoustic forces, allowing for precise manipulation and controlled movement at the microscale. [96]he integration of imaging technologies has resulted in realtime visualization of microrobotic behavior, facilitating a deeper understanding of their interactions within intricate environments.Additionally, the field has seen progress in the development of adaptive and responsive materials that respond to external stimuli, enabling microrobots to adapt to changing conditions. [221]urrently, several microrobotic systems could function successfully in in-vivo settings, and they promise clinical applicability in the next decade. [21,111,222]When we examine all examples of microrobots that have successfully undergone in vivo translation, we can see that all of them have long-standing collaborations for a targeted clinical application.This collaborative nature of translational research helps them to survive in the "valley of death" for biomedical innovations. [70]

Defining the Limitations for Medical Microrobotics
On the other hand, microrobotic research should be honest and realistic by defining the limitations inherent in the medical applications of microrobotics necessitates an in-depth exploration of various dimensions, including physics, actuation systems, and imaging methodologies.The locomotion on the microscale is inherently challenging, and it is even more challenging in the bodily fluids. [127]Therefore, research efforts should be directed toward systems that successfully achieve both robust fabrication and effective locomotion within complex fluids and tissues.
While microrobotic systems are investigated for efficient actuation methods in the biological media and tissues, the observation of their interactions with these complex biological environments could be used for a better understanding of human physiology. [223]Microrobotic systems that do not satisfy these criteria should be excluded from further consideration for medical applications.To achieve this, the strategic utilization of numerical simulations is essential, as well as proper experimentation to precisely predict the locomotion of various microrobotic platforms within complex fluids. [224]eyond locomotion, developing feasible and reliable actuation systems remains a pivotal concern.The integration of mechanisms that provide controlled and precise movement at the microscale necessitates concerted research efforts.For instance, the effectiveness of electromagnetic coil systems on a human scale would notably deviate from that of their laboratory-scale counterparts. [201]As a result, outcomes derived from cell culture conditions would not readily translate to in vivo experiments in terms of magnetic actuation.While chemical microrobots cannot be used in the human body due to their limited amount of onboard energy source, [225] light-based actuation of microrobots can only function on the light penetrable areas of the body, for instance, eye and skin. [17]Another concern arises in acousticbased actuation; the actuation of acoustic microrobots within laboratory confines contrasts starkly with their behavior within the human body due to the influence of human tissue on acoustic actuation. [226]All these types of considerations must be determined, and realistic actuation possibilities in the human body must be clearly demonstrated for the sake of realistic medical applications.
Similar principles about actuation systems extend to delivery, imaging, and retrieval of the microrobots as well.Both delivery and retrieval systems of microrobots should be designed for each microrobot type separately because even a precise injection of the microscale structures into the biological tissue is a significant but overlooked problem. [227]The delivery and retrieval of the microrobots should be done with the guidance of the related medical imaging system.Unfortunately, no single imaging method combines high-frequency imaging, high penetration depth, and high resolution simultaneously, which could function as a closed-loop control system for microrobots.To create the closed-loop control systems for the medical microrobots, a combination of two different physical imaging and actuation modalities can be used. [228]Consequently, careful experimentation with the microrobotic platforms within various imaging systems is needed to ascertain the potential imaging capabilities.
As a side note, given the ongoing advancements in navigating microrobots within the human body, exploring the distinctive features of microrobots in lab-on-a-chip or organ-on-a-chip applications could emerge as a noteworthy research avenue.The intricate landscapes of microfluidic environments offer a promising stage for the deployment of microrobots, capitalizing on their unique abilities for precision manipulation and controlled locomotion.][231][232][233] Despite the promising nature of microrobots in lab-on-a-chip applications, it's essential to acknowledge the current stage of development.The field is still in its early phases, with ongoing research focusing on addressing challenges and optimizing the integration of microrobotic platforms into existing microfluidic technologies.

What Should be Done for Realistic Medical Applications?
As mentioned above, despite collaborative approaches being the correct ways to build pathways to clinical applications for microrobotic researchers, these are only the beginning of the clinical translation processes.On the current clinical translational research frameworks, biomedical device development is a continuous feedback circle until achieving the success of the gold standard clinical counterparts. [69]Medical microrobotic research should establish well-defined pathways for practical medical applications by investigating the previous successful history of other biomedical innovations.In addition to the fundamental investigations concerning physics, actuation, and imaging, it is essential to discern viable medical applications that can potentially replace established gold-standard procedures by interacting and collaborating closely with clinicians.By identifying areas where microrobotics can bring transformative benefits and potentially outperform conventional procedures, the field can shift from theoretical promise to tangible impact.Through these efforts, medical microrobotic research has the potential to revolutionize healthcare practices and pave the way for a new era of precision medicine.
Medical microrobotic research requires a comprehensive foundation of knowledge from both fundamental aspects and strong collaboration with clinicians.However, the lack of robust collaboration can be attributed to the inadequate accumulation of fundamental knowledge within the field.Finding common ground between microrobotic researchers taking a bottom-up approach and clinicians approaching from a top-down perspective is challenging due to the reciprocal limited understanding.While crucial clinicians' questions often remain unanswered, investigating physical mechanisms in-depth seems to be the easier path for microrobotic researchers.Therefore, establishing a synergy between these two crucial dimensions, which includes strengthening fundamental insights and facilitating collaborative engagement, is imperative to address existing gaps and drive the field toward impactful advancements that bridge theory and practical medical applications to build new "magic bullets" to cure incurable diseases.

Figure 1 .
Figure 1.Biomedical translation concept schematics of medical microrobots from laboratory to clinics.

Figure 2 .
Figure 2. The number of research articles, reviews, citations, and patents on microrobotic research until the end of 2022.The statistics for scholarly works are collected from the Web of Science; the patent statistics are collected from lens.org."microrobot OR microrobotic OR nanorobot OR nanorobotic OR microswimmer OR microroller" is used for search queries on both websites.

Figure 4 .
Figure 4. Physiological environments in the human body and respective microrobotic challenges.