{"paper_id":"776f877a-1022-4491-af3e-1715dd7cad5a","body_text":"Micro/nanorobotics are one of the most\npromising alternative next-generation\nintelligent vesicles that can be used in various precision medicine\napplications, including drug, cell, and gene delivery; surgical tools\nfor biopsy; diagnostic tools such as physical and chemical biosensors\nor isolation tools; biofilm eradication; and optical, ultrasonic,\nmagnetic resonance and radionuclide imaging tools. \n − \n \n \n \n \n \n  The application of microrobots in reproductive medicine is one of\nthe emerging fields to treat and diagnose infertility, cancer, infectious\ndiseases, and other reproductive system disorders. \n −\nThe female\nreproductive system consists of the vagina, uterus,\nfallopian tubes, ovaries, and vulva, as shown in  Figure  \n .  The majority of reported female reproductive systems diseases, such\nas cervical, vaginal, endometrial, and ovarian cancer, cause significant\nmorbidity and high mortality rates. \n , \n  The most common\ndisorders of the female reproductive system can be grouped by the\nprimary organ affected. (i) Ovary: Key problems include ovulation-related\ninfertility, disorders of hormone biosynthesis, ovarian cancer, polycystic\novary syndrome, and endometriosis. (ii) Fallopian tube: Ectopic pregnancy\nis the most frequent condition, but tubal infertility and primary\ncancer of the tube are also recognized. (iii) Uterine corpus: Typical\nissues are abnormal uterine bleeding, adenomyosis, endometrial polyps,\nendometritis, and endometrial cancer. (iv) Cervix: The spectrum ranges\nfrom cervical dysplasiaoften a precancerous changeto\ninvasive cervical cancer. (v) Vagina: Common disorders include pelvic\norgan prolapse, atrophic changes (especially postmenopause), primary\nvaginal cancer, and bacterial infections.  It has been reported that these disorders can be treated by using\ndrug delivery systems such as nanoparticles (NPs), intravaginal rings\n(IVRs), microneedle patches, vaginal films and inserts, long-acting\ninjectables, and implants.\nThe diagram\nof the female reproductive system, advantages and disadvantages,\nand illustrations of microrobots. It has been shown in the literature\nthat microrobots can be used for fertility treatment and drug delivery\napplications. It allows personalized treatment, easy access to hard-to-reach\nlocations, and can be functionalized with imaging agents and/or therapeutics. \n , −\nPhysiological fluids and parameters, including\npH, temperature,\nand oxygen tension, are critical for maintaining a healthy reproductive\nsystem and equally important for developing biomedical microrobots. \n , \n  Physiological fluids such as vaginal fluid consist of epithelial\ncells, white blood cells, and various biomolecules, including acid\nphosphatase, lactic acid, citric acid, urea, vaginal peptidase, acetic\nacid, pyridine, squalene, and immunoglobulins. \n , \n  Moreover, the pH of each organ varies depending on the microbiome\nand acid–base buffering at the cellular/tissue level. For instance,\nthe vaginal pH is around 4.42 and can reach up to the pH of 7.94 in\nthe fallopian tubes. \n , , \n  Low pH in the vagina is attributed to the  Lactobacillus  dominant microbiome, which generates lactic acid and hydrogen peroxide\nthat kills the pathogen which protects the microbiome. \n ,\nMicrorobots are advanced intelligent microsystems\nthat can be moved in liquid environments with different actuation\nmodes and stimulants such as magnetic field, ultrasound, photoacoustic,\nor self-propulsions. \n − \n \n \n \n  The concept of microrobots can be linked to Richard Feynman’s\nlecture in 1959. \n , \n  The sperm-based biohybrid microrobot\nwas introduced almost 50 years later as a proof-of-concept study which\nshows that sperms can be functionalized with magnetic nanoparticles.  Afterward, microrobots have been engineered\nand utilized for assisted reproduction technology and anticancer drug\ndelivery in the female reproductive system using spermatozoa as biohybrid\nmicrorobots.  The sperm cells have evolved\nto motion devices with excellent motion properties for swimming in\na complex environment, including in viscous media, acidic pH, vaginal\nflow back, and cervical crypts. \n − \n \n  Additionally, microrobots can\nbe loaded and functionalized with bioactive molecules for therapeutic\npurposes.\nOwing to rapid changes in lifestyle, infertility is\non the rise globally, impacting 10–15% of couples worldwide. \n − \n \n  Low-cost, minimally invasive hormonal stimulation and intrauterine\ninsemination,  in vitro  fertilization (IVF), or intracytoplasmic\nsperm injection (ICSI) are the most common procedures for infertility\ntreatments. However, the success rate of these technologies falls\nbetween 42% and 47%.  The bottleneck in\nIVF/ICSI treatments is associated with the female age, endometrial\nlining, poor oocyte activation, implantation failure, altered hormonal\nenvironment, and poor semen quality. \n , \n  The success\nrates of the treatments are measured by fertility rate, implantation\nrate, clinical pregnancy rate, and live birth rate.  However, there are some limitations to overcome critical\nbarriers for the successful translation of IVF treatment,  for instance, biocompatibility and/or biodegradability,\nthe ability to capture and secure the gametes/embryo during transport,\nthe ability to navigate through physiological conditions, access to\nthe secreted molecules either by the oviduct ciliary cells or embryo,\ndimensions must be smaller than the oviduct size (<500 μm),\nefficient movement in viscoelastic media and against the flow produced\nby peristaltic motion and cilia beating in the fallopian tube, and\npreserving the oviduct. Medical microrobots are one of the promising\nalternatives to overcome the implantation failure of current infertility\ntreatments in reproductive medicine. \n Figure  \n  illustrates the\nfemale reproductive system including advantages/disadvantages and\napplication of microrobots such as microdrillers, microhelices, sperm\ntail decorated magnetic beads, microclaws, artificial flagella, and\ninorganic membranes to transport single immotile/motile sperm for\nassisted fertility treatment. \n −\nGynecological disorders,\nin particular, ovarian, vaginal, cervical,\nand endometrial cancers, show significantly high mortality and morbidity\nrate, which require an urgent need for alternative treatment. Gynecological\ncancers are currently treated with a combination of surgical, chemotherapeutic,\nand radiotherapeutic interventions. Developing targeted locoregional\ndrug delivery systems that provide effective doses in a controlled\nway is one of the main goals in the worldwide fight against cancer. \n − \n \n  Current treatment methods are limited due to the complex tumor microenvironment,\nhigh metastatic spread, and developed multidrug resistance  which results in high cytotoxicity and low bioavailability.\nLocal delivery of therapeutics will eliminate the systemic circulation\nand hepatic clearance which will enhance the drug concentration in\nthe tumor microenvironment. Therefore, developing biomedical microrobots\nare one of the most promising alternatives which can externally be\ncontrolled and deliver the cargo to targeted regions to diagnose and\ntreat gynecological cancer.  Moreover,\nbiomedical microrobots can be tuned and bioengineered for personalized\ntreatments to minimize immunogenicity and enhance the bioavailability\nof active pharmaceutical ingredients. Competent microrobots for the\ntreatment of female reproductive system-related disease, infections,\nand assisted fertility treatment require the following properties\nincluding (i) biocompatibility, (ii) minimized immunogenicity, (iii)\nhigh maneuverability, and (iv) high stability in different pH, temperature,\nviscosity, and flow conditions. However, further studies need to be\nconducted to understand nonspecific attachment in tissues to complex\nmicroenvironments, to track microrobots using medical image guided\ntechniques, and to enhance biocompatibility for further clinical studies.\nThe microrobots can be actuated\nby external force or self-propulsion while mimicking self-organization\nand stimuli response to the environmental changes. Although there\nare many different propelling mechanisms to actuate microrobots such\nas chemically powered, light powered, ultrasound, electric field,\nand photoacoustic, most of the literature related to the microrobots\nin the female reproductive system is focused on the most promising\nphysical actuator, which is the magnetic field. The main limitations\nof photoacoustic and light-powered actuation have restricted penetration\ndepth due to the high scattering and absorption of tissues  while the magnetic field actuation showed high\ntissue penetration capacity and was proven safe under the magnetic\nfield of 8T. \n , \n  The overall speed of the microrobots\nin the reproductive tract is lower than 1 mm/s due to the viscous\nenvironment with a required penetration depth of 50 mm.\nMagnetic microrobots can be attached to\nsperm tails for external actuation.  The\nartificial microstructures’ and sperm swimming propulsive performances\ndepend on their helical shape  and viscosity\nin low Reynold numbers.  The helical shape\nshows a linear increase in the velocity as the frequency increases.\nHowever, the motion and maneuverability still need to be improved\nto implement them in real conditions. Spermatozoa and similar microorganisms\ncan move in high-viscosity mediums using cilia or rotating propellers\ncalled flagella with a corkscrew, beating, or waving motion with 10\ntimes larger bending waves than bacteria flagella. Their motion in\nsynthetic viscoelastic fluids showed higher propulsion in non-Newtonian\nfluids than Newtonian fluids of the same viscosity.  Passive helical filaments of bacterial flagella are actuated\nby the head (body) of the rotary microrobots.\nUnique navigational\nproperties of human sperm cells make them excellent\ncandidates to deliver anticancer drugs to hard-to-reach areas in the\nfemale reproductive system, such as ovarian cancer lesions. As illustrated\nin  Figure  \n , therapeutics\nlike doxorubicin (DOX), incorporated into the sperm head, which were\nthen magnetically guided, have been reported as a potential model\nfor treating cervical and other gynecological cancers. \n , \n  Medina-Sánchez et al. reported on DOX-loaded bovine sperms\nby coincubation methods. Cell viability studies indicated that the\ntumor-killing range reached 87%, whereas the free DOX treatment group\nwas 55%. \n ,\nMagnetically controlled biohybrid sperm cells\nare possible drug\ncarrier vehicles with high encapsulation capacity, minimized cytotoxicity,\nand high stability. (a) Electron microscopy images of a tetrapod structure\nwith a tubular body and four flexible bent arms. (b) Illustration\nof sperm releasing from tetrapod microrobots. (c) Tracking the magnetic\nmotion of a tetrapod microrobots. (d) Real-time imaging of sperm release\nwhen the flexible arms are in contact with the PDMS wall. Reproduced\nfrom ref  . Copyright\n2017, American Chemical Society\nSchmidt et al. reported on human spermbots to treat\n3D cultures\nof cervical and ovarian cancer with combinatorial drug therapy with\ndoxorubicin (DOX) and camptothecin (CPT).  The study demonstrated that more than 94% of cancer cells were detached\nafter 4 days of treatment with a human spermbot loaded with DOX and\nCPT. It was also mentioned that the sperms not only promote navigation\nbut also serve as an active protective layer for the anticancer drug.\nIn summary, drug delivery application of microrobots were successfully\ndemonstrated in various applications using biohybrid microrobots to\ndeliver cancer therapautics. \n ,\nMaterial selection\nof the microrobots is highly critical to ensure biosafety and biocompatibility.\nThese microrobots can be fully degradable or retrieved from the female\nreproductive system using external forces without requiring additional\nsurgical operation. Soft scaffolds of the micromotor can be provided\nby using alginate, gelatin, gelatin methacrylate (GelMA), collagen,\nor silk while the actuation of the microrobots can be sustained by\nincorporating magnetic (superparamagnetic iron oxide nanoparticles,\nSPIONs), FePt, NdFeB, CrO 2 , and BaFe 12 O 19 ), ultrasound (SiO 2  based),  or photoacoustic (Au-decorated micromotors)  imaging. \n , , \n  Microrobots for reproductive system applications can be fabricated\nby using different methods, including template-assisted methods, 3D/4D\nprinting, ultraviolet (UV) polymerization, two-photon polymerization\n(TPP), soft lithography, stop-flow lithography (SFL), etc., in which\nsoft and smart materials are patterned in the desired geometry. \n , \n  Incorporating soft and smart materials through a two-photon lithography\nprocess enables precise control over the microcarriers’ properties\nand functionalities. The TPP method enables fabricating microrobots\nwith a uniform finish and within sub-100 nm resolution.  Although the TPP method provides fabrication\nof featured geometries, it is expensive and can be considered a slow\nmethod for clinical applications. Moreover, the biocompatible ink\noptions are limited for the TPP method such as acrylates, collagen,\nbovine serum albumin, fibrinogen, and modified ceramic and silica\nwith different photoemitters including methylene blue, rose Bengal,\neosin, and Irgacure 2959.  Schmidt et\nal. fabricated a microcarrier via the two-photon polymerization (TPP)\nmethod to address the issues of low sperm cell count and their motility\nin male infertility treatment to overcome the biological barrier for\noocyte fertilization.  Two different inks\nwere used including a nonstimuli-responsive polymer, specifically\nIPS photoresist and thermoresponsive hydrogel poly­( N -isopropylacrylamide) (PNIPAM). It has been demonstrated that the\ncombination of pH and temperature-responsive material in the microcarriers\neffect the motility of the sperm cell.  Moreover, it enhances the removal of the extracellular matrix of\nthe cumulus cell of the oocyte which facilitates sperm–oocyte\ninteraction. 3D/4D printing such as direct laser printing (DLP) and\nstereolithography (SLA) provides a broad ink type which can be printable\nincluding gelatin methacrylate-based PEGDA, composite inks with ceramics,\nlive organisms, and cells.  Therefore,\nit is one of the promising techniques for developing personalized\nmicrorobots for translational medicine application in the female\nreproductive system. However, the resolution and scaling down of the\ngeometries are still limited.\nMicrorobots can be designed via\ndifferent approaches, including biohybrid or bioinspired approaches.\nMicroorganisms are one of the main inspirations for developing biocompatible\nself-propelled or externally propelled microrobots. Bioinspired microrobots\nmimic the natural motion and function of the biological organisms\nwhich are potential candidates for assisted reproductive technologies.  For instance, micromotors with flexible joints\nimitate human hands and provide grasping behavior which is an alternative\napproach for single cell manipulation. \n , \n  Also, the\nmicrorobot with soft segments mimics the flagellar motion of the bacteria\nand spermatozoa. \n , \n  Most of the studies were focused\non biohybrid microrobots in the female reproductive system ( Figure  \n ).\nGeneral timeline of the\ndevelopment of microrobots for the reproductive\nsystem. 2006The magnetite-coated biohybrid sperm was demonstrated\nand its ability of motility and acrosome reaction which indicates\nthe active fertility capacity was tested. Reproduced from ref  . Copyright 2006, American\nChemical Society. 2013the proof of concept magnetic microtube\nfor externally controlled motion of a single sperm was reported. Reproduced\nor adapted with permission from ref  . Copyright 2013, Wiley. 2015Artificially\nmotorized sperm cells using magnetic microhelices for transportation\nof the sperm cell to the oocyte for assisted fertility treatment was\ndeveloped couple of years later. These polymer-based microhelices\nwere prepared by using a direct laser writing method and coated with\nNi and Ti for magnetic navigation and to improve biocompatibility,\nrespectively. Overall, in vitro studies showed that the application\nof microrobots in fertility treatment is an alternative approach to\nenhancing treatment efficiency. Reproduced from ref  . Copyright 2015, American\nChemical Society. 2018a laser printed tetrapod microstructure\nwas developed to carry drug-loaded sperms in the female reproductive\ntract with using a magnetic propulsion mechanism. Reproduced from\nref  . Copyright\n2018, American Chemical Society. 2020protein (bovine serum\nalbumin, BSA)-based hyaluronic acid microflakes on magnetic helical\nshaped microcarriers were reported. Protein-based microflakes enhance\nthe binding of sperm on the micromotors, while magnetic microhelices\ndrive micromotors to the oocytes. Afterward, the protein structure\nwas hydrolyzed by a local protease enzyme. It was also demonstrated\nfor drug loading and carrying on sperm, which show there is no leakage\nnor sperm escape obtained during transportation. Reproduced from ref  . Available under a CC-BY-NC\nlicense. Copyright 2020, Wiley-VCH Verlag GmbH & Co. KGaA. There\nwas another study that was reported related to template-assisted gelatin-based\nmicrocartridges called spermbot for transportation of the sperm to\nthe oocyte for assisted fertility treatment. Reproduced from ref  . Copyright 2020, American\nChemical Society. 20224D-printed multifunctional microcarriers\nwere printed using two-photon-lithography techniques and coated with\nheparin as well to promote pH and temperature responsive release and\nmotion performance. These microcarriers were coated with gold to\nphotoacoustic imaging. Those microcarriers were designed and fabricated\nto carry around 10 sperm cells in one structure. Reproduced from ref  . Available under a CC-BY-NC\nlicense. Copyright 2022, Wiley-VCH GmbH. 2023researchers reported\nthe coupling of magnetic microparticles to spermatozoa and investigated\nthe viability, motion, and imaging using ultrasound and a photoacoustic\nmethod. Reproduced from ref  . Available under a CC-BY-NC-ND license. Copyright, 2023,\nJohn Wiley and Sons. It was shown that incorporating the magnetic\nmicroparticles did not influence the viability of the microrobots;\nmotility of the microrobots was enhanced twice compared to the microcarriers\npreviously published (ref  ).\nBiohybrid microrobots like spermbots provide high-motion\nprecision,\nhigh power-to-weight ratio, and elevated flexibility and enhance the\nbiocompatibility of microrobots. For instance, the motion behavior\nof the spermatozoa and flagellum-like bacteria has sufficient motion\nacross the low Reynold’s number regime. Among bacteria and\nalgae, sperm has additional advantages as it does not cause any immune\nresponse and has unique motion behavior regardless of fluid flow,\nwhich can move chemotaxis (chemical), thermotaxis (temperature), thigmotaxis\n(near-surface effects), and rheotaxis. \n − \n \n \n \n \n \n  Most sperm-based microrobots depend on the self-propulsive force\nof active flagellum and are sensitive to physiological conditions\n(pH, temperature, and chemicals). \n , − \n \n \n  All of these advantages promote better navigation inside the body\nfor targeted drug delivery. However, sperm-based biohybrid microrobots\nhave low coupling efficiency.  There are\nvarious strategies to decorate sperm of bacteria-based biohybrid microrobots\nwith nanoparticles to enhance imaging and enable external actuation\nand cargo delivery. These are (i) electrostatic interactions between\nnegatively charged sperm or bacteria membranes and positively charged\nnanoparticles, (ii) noncovalent bonding of nanoparticles on sperm\nto maintain sperm motility (for instance, biotin–streptavidin\ninteractions are well-known noncovalent ligand protein interactions),\nand (iii) covalent surface functionalization such as amide, thiol–maleimide,\nor click-chemistry reactions. \n , , , \n  There were reported motorized\nsperm cells with magnetic microhelices to transport immotile but functional\nsperm to the oocyte for infertility treatment.  The microcartridges were prepared with stimuli-responsive\nbehavior in order to release the sperm by pH change via heparin coating\non gelatin-based microcartridges.\nMicrorobot motility can be\nenhanced by the addition of caffeine\nin the medium of the sperm bots. In addition, biofunctionalization\nof the microtubes with fibronectin or hyaluronic acid to improve the\ncoupling efficiency results in enhancement of spermbot performance.  Magnetically driven microtubes and a synthesized\nprotein-based hyaluronic acid (HA) microflake (MC3) are utilized to\ntransport multiple motile sperm cells. The motion behavior was monitored\nin different viscosity ranges, simulating oviduct fluid, saliva, and\nblood.  It has also been reported that\nthe length of the microtubes affects the performance of the spermbots.\nAs the microtubes were shorter, spermbots moved faster.\nTranslational\nstudies of biohybrid and bioinspired microrobots in the female reproductive\nsystem have been getting attention and are promising to treat disease\nand assist fertility treatment ( Figure  \n ). Several microrobots are under evaluation for minimal\nto noninvasive anticancer interventions.  However, to date, none have been explored to diagnose or treat issues\nwith the female reproductive system at the clinical level. Similarly,\nmicrorobots can be a promising approach to treating infectious diseases\nin the female reproductive system, particularly as an effective alternative\nfor high doses of antibiotic treatment. The microrobots can deliver\nantibiotic drugs locally, which might enhance biodistribution and\nincrease treatment efficiency to tackle issues related to bacterial\ninfections, such as bacterial vaginosis (BV).\nScheme of perspective\nin the translational application of microrobots\nin precision medicine and personalized diagnostic and treatment applications.\n(A) Illustration of the most common female reproductive system disorders,\nrequired characteristics, possible application of microrobots, and\nincorporating therapeutics with microrobots. (B) Schematic of diagnostic,\nmotion control of microrobots that can be possible with ultrasound\nand photoacoustic methods. (C) Microrobots can be remotely monitored\nwith real-time imaging techniques by medical professionals. (D) Implementation\nof artificial intelligence technology offers a great opportunity to\nimprove the minimal invasive diagnostics methods including biopsy\nand controlled motion behavior.\nCharacterization of endometrial microbiota and\ntissue sampling\nis critical for early diagnostics of female-specific cancers and for\npredicting fertility issues. \n , \n  Microrobots can also\nbe utilized for tissue or liquid biopsy in the female reproductive\nsystem.  Unlike large scale robotic biopsy\ntools, microrobots can move inside the body with minimal invasion\nand high precision.  In addition, microrobots\ncan collect liquid samples. Moreover, specific DNA mutations associated\nwith ovarian or endometrial cancer can be detected with an on-the-fly\nmode microrobot sensor.\nThe microrobots\ncan be used in medical image-guided locoregional\ndrug delivery with ultrasound, X-ray fluoroscopy, magnetic resonance\nimaging (MRI), and computer tomography (CT). Incorporating clinically\nused contrast agents with microrobots allows one to monitor the locomotion\nusing X-ray fluoroscopy. This application will enhance the efficiency\nof cancer treatment as it allows precise control and monitoring of\ndrug delivery in the female reproductive system for precision medicine.\nAlternatively, ultrasound and photoacoustic manipulations can be\nfeasible approachs to image and navigate the microrobots since the\nultrasound transducers have already been FDA approved and already\nbeen used in clinical applications.  It\nhas been shown that ultrasound microswimmers are fabricated by a 3D-nanoprinted\ntechnique using Nanoscribe. The 3D-nanoprinted microrobotic swimmers\nwere propelled and manipulated using a single ultrasound transducer\nby oscillating air bubbles inside the microrobotic swimmers’\ncavity.\nAlthough, the ultrasound-based microrobots have been\nreported in\nthe literature, they have not yet been fully understood regarding\ntheir motion and real-time imaging in the female reproductive system\nyet. Therefore, there is still a need to discover precise control\ninside the physiological environment. The ultrasound-based microrobots\ncan move autonomously by taking advantage of high energy density\nand low attenuation, which may help to move the hard-to-reach point\nin the female reproductive system. Physiochemical conditions including\nbubble generation, oscillation, and expansion and mechanical vibration\nof the fluid causes microstreaming which results in enhancing the\nultrasound actuation of microrobots.  Compares\nto ultrasound-based microrobots, magnetically controlled microrobots\nhave main advantages, including that they are relatively easy to use\nand can be controlled precisely in complex physiological conditions.\nHowever, it is a costly method that requires a magnetic field generator\nand controller.\nArtificial intelligence (AI) offers a promising\nsolution to control\nand analyze the motion of the microrobots, particularly in biomedical\napplications such as female reproductive health.  Incorporation of AI technology into microrobots can enhance\ntheir precision, autonomy, and ability to respond dynamically to complex\nbiological environments. In female reproductive health, AI-powered\nmicrorobots have great potential to transform diagnostics, treatment,\nand drug delivery. For instance, microrobots could be used to navigate\ninside the reproductive system with high accuracy, targeting specific\nareas to treat conditions, such as endometriosis, uterine fibroids,\nor certain gynecological cancers. AI can help these microrobots analyze\nreal-time data, adjust their movements, and optimize their therapeutic\nactions based on each patient’s specific needs.  Additionally, AI algorithms can assist in monitoring\nreproductive health by analyzing patterns in data collected from microrobots.\nThis could lead to early diagnostics and a better understanding of\nreproductive system disorders and personalized treatment plans. For\nfertility treatments, AI-enhanced microrobots might assist in more\nprecise sperm or egg delivery, potentially improving success rates\nin procedures such as in vitro fertilization (IVF). Incorporating\nAI into microrobots offers a future where minimally invasive, precise\ninterventions in female reproductive health become more effective,\nreducing side effects and enhancing patient outcomes. Implementation\nof artificial intelligence and deep learning-based approaches to navigate\nand perform the predecided tasks using predefined algorithms can be\nanother approach to monitor and control the collective behavior of\nuntethered microrobots in the female reproductive system. \n ,\n\nMicrorobots can be adopted as\nan advanced technology for translational\nmedicine applications, including drug delivery, IVF treatments, biopsy,\nminimally invasive medical imaging, and treating bacterial infections\nin the female reproductive system. The ability to fine-tune size,\nstructure, and biocompatibility makes them an ideal candidate for\npersonalized medicine applications.  As\nadvanced intelligent drug delivery platforms, the untethered microrobots\nminimize systemic and cytotoxicity and enhance bioavailability during\nlocoregional administration. Moreover, recent studies show microrobots\ndesigned and engineered for X-ray, ultrasound, magnetic resonance,\nand acoustic imaging.  However, clinical\nand regulatory evaluations are essential before adoption of these\ntechnologies. Achieving this will require seamless collaboration among\nacademic, pharmaceutical, and biomedical sectors and swift translation\nof research into practice. Although the microrobots physical, mechanical,\nand in vitro drug release tests can be conducted according to the\nFDA device guidelines for drug eluent stents and in vitro vaginal\nrings, there are still regulatory approvals of the microrobots for\nclinical applications that remain a significant challenge due to the\nnovelty of the materials, reproducible fabrication method, in vivo\ndegradation, precise drug-release kinetics, actuation mechanism, real-time\nimaging, in vitro–in vivo correlation, large-scale manufacturing,\nlong-term biosafety, and patient-specific variability requirements.","source_license":"CC-BY-4.0","license_restricted":false}