Microrobots move closer to precision medicine after two decades of progress

Journal Center of Harbin Institute of Technology

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This figure illustrates a magnetic microrobot system for targeted drug delivery. A catheter or endoscope delivers a microrobotic assembly close to the target tissue, after which magnetic navigation guides the microrobots through the vasculature. The system is designed to disassemble into a microrobotic swarm, release therapeutics locally, and then undergo degradation or clearance.

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Credit: 2026 The Author(s). SmartBot published by John Wiley & Sons Australia, Ltd on behalf of Harbin Institute of Technology. Figure courtesy of Minsoo Kim, as stated in the original figure legend.

Imagine a medical machine small enough to travel through blood vessels, navigate toward diseased tissue, release a therapeutic payload, and then degrade or be cleared from the body. Microrobots, generally ranging from about a millimeter down to a few microns in size, are designed to operate in confined and complex environments that are inaccessible to conventional robotic systems. Inspired by the motility and adaptability of microorganisms, these systems are being investigated for highly localized biomedical tasks, including targeted drug delivery, minimally invasive diagnosis, microsurgery, and cell- or tissue-level therapeutic intervention. The perspective article places this development within the broader scientific foundations of microscale engineering, including early concepts of nanoscale manipulation and the physical principles governing motion at low Reynolds number.

 

A central challenge in microrobotics is that microscale motion is governed by physical rules that differ fundamentally from those at the macroscale. In low-Reynolds-number environments, viscous forces dominate while inertial effects become negligible, causing motion to stop almost immediately once external actuation is removed. Under these conditions, reciprocal motions cannot generate net propulsion, as described by Purcell’s scallop theorem. Microrobots must therefore rely on locomotion strategies that break time-reversal symmetry or exploit external fields, responsive materials, or biological propulsion mechanisms. Brownian motion, surface interactions, and limited onboard energy storage further constrain microrobot operation, making it necessary to integrate propulsion, sensing, and control through carefully designed structures and materials.

 

The article reviews several propulsion mechanisms that have shaped the field. Chemical propulsion, such as catalytic bubble-driven motion, provided early demonstrations of autonomous microscale locomotion, although biomedical translation remains limited by concerns regarding fuel toxicity and biocompatibility. Acoustic propulsion offers a noninvasive strategy for manipulating individual microrobots or swarms through ultrasonic fields, but its spatial precision may be lower than that of magnetic systems. Optical propulsion is effective in transparent or semi-transparent environments, yet its in vivo use is constrained by limited tissue penetration. Biohybrid propulsion, based on motile cells such as bacteria or sperm, offers biological adaptability but raises challenges related to immunogenicity, stability, and controllability. Among these approaches, magnetic actuation is identified as particularly promising for clinical applications because magnetic fields can penetrate biological tissues, be dynamically controlled, and integrate with existing medical imaging technologies.

 

Progress in microrobotics also depends on advances in fabrication, functional materials, and embodied intelligence. Techniques such as two-photon polymerization, microelectromechanical systems, self-assembly, and nanofabrication have enabled complex microrobot geometries, including helices, cages, artificial cilia, and other biomimetic architectures. Material selection is equally important: biodegradable polymers may reduce the need for retrieval after treatment, stimuli-responsive hydrogels can enable environment-triggered functions, and surface modifications may improve biocompatibility or reduce immune recognition. Because conventional processors, batteries, and communication modules are difficult to miniaturize, intelligence at the microscale is often encoded directly into the robot’s geometry, material composition, or collective behavior. For example, helical structures can convert rotating magnetic fields into forward propulsion, while microrobot swarms may support distributed tasks such as collective transport, broad-area sensing, or localized therapeutic delivery.

 

The most immediate and potentially transformative applications of microrobots are expected in medicine. The article highlights intravascular navigation, targeted drug delivery, tumor therapy, localized antibiotic delivery, microscale biopsy, chemical sensing, and soft microrobot navigation through tortuous biological pathways as key areas of development. Magnetic microrobots are of particular interest for delivering clot-dissolving drugs in stroke treatment and for transporting therapeutic agents directly to disease sites while reducing systemic exposure.

 

Nevertheless, significant translational barriers remain, including wireless power supply, communication, real-time imaging, closed-loop control, scalable manufacturing, regulatory approval, retrieval or degradation strategies, long-term safety, and ethical acceptance. Looking ahead, the article suggests that the next stage of microrobotics will depend on combining biocompatible materials, high-resolution imaging, AI-driven control, and clinically compatible navigation systems. If these challenges can be addressed, early clinical directions are likely to focus on life-threatening conditions such as stroke and cancer, where targeted delivery and minimally invasive intervention could offer major benefits. Over time, microrobots may become practical tools of precision medicine, performing diagnostic and therapeutic tasks at scales invisible to the human eye but potentially transformative for human health.

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Journal

SmartBot

DOI

10.1002/smb2.70043 

Article Title

Microrobots: Two Decades of Progress

Article Publication Date

20-May-2026

COI Statement

The Editor-in-Chief Bradley J. Nelson is an author of this manuscript. To avoid any potential conflict of interest, he took no part in the editorial decision-making or peer-review process for this submission, which was handled entirely by an independent editor/the editorial office. The author declares no other conflicts of interest.

BEFORE NANOBOTS

 

Heat exposure during pregnancy and infancy may influence children’s brain development

New study finds an association between higher temperatures early in life and slower growth of the thalamus, a brain region involved in processing information

Barcelona Institute for Global Health (ISGlobal)

Physical activity, Exposure to high temperatures during pregnancy and early infancy is associated with slower growth of the thalamus later in childhood, according to a study led by the Barcelona Institute for Global Health (ISGlobal), a centre supported by the ”la Caixa” Foundation. The findings, published in Environment international, suggest that heat exposure during the earliest stages of life may have lasting effects on brain development.

Climate change is increasing exposure to extreme temperatures worldwide, raising concerns about its impact on children's health. Pregnancy and the first years of life are particularly important for brain development, as the brain grows rapidly and is especially sensitive to environmental factors. Although previous studies have linked heat exposure to changes in cognition and mental health, there is not much literature about its effects on brain structure.

"We wanted to examine whether exposure to heat or cold from conception to 8.5 years of age was associated with changes in brain development during late childhood and adolescence, and to identify the periods when the brain is most vulnerable," explains Laura Granés, ISGlobal and IDIAPJGol researcher and first author of the study. 

The study included 3,251 children participating in the Generation R Study, a birth cohort in the Netherlands. “We used a high-resolution climate model that provided weekly outdoor temperature estimates during pregnancy and monthly estimates from birth to 8.5 years of age at each participant's place of residence. We then analysed brain MRI scans performed at around 10 and 14 years of age”says Granés. This allowed researchers to measure how the volume of 11 brain structures changed over time and to examine whether these changes were associated with earlier exposure to heat or cold.

Why the thalamus appears especially vulnerable

Among the brain regions studied, only the thalamus showed a consistent association with early-life heat exposure. The thalamus acts as the brain's main relay centre, processing and transmitting sensory and motor information to the cerebral cortex.

The researchers believe this region may be particularly sensitive because it develops very early in pregnancy and follows a tightly regulated developmental timeline. Its rich blood supply during foetal development may also make it more vulnerable to heat-related changes affecting the placenta or blood flow to the foetus.

A critical window: from conception to the fifth month of life

The study identified a clear period of vulnerability spanning pregnancy and the first months after birth. Compared with a reference average temperature of 12.5°C, exposure to monthly mean temperaturesof 20.5°C during this period (calculated across day and night) was associated with slower thalamic growth between 9 and 15 years of age. No similar associations were found for other brain structures or for exposure to cold temperatures.

How heat could affect brain development

Although the study was not designed to identify the biological mechanisms involved, previous research suggests several possible explanations. Heat exposure during pregnancy may alter maternal stress hormone levels, affect the placenta's ability to protect the developing foetus from these hormones, or disrupt serotonin signalling, which plays an important role in the formation of connections between the thalamus and the cerebral cortex. Heat-related inflammation and oxidative stress may also contribute, although more research is needed to confirm these mechanisms.

The researchers also found that slower thalamic growth was associated with more externalising behavioural symptoms during adolescence, including aggressive and rule-breaking behaviour. However, they did not find an association with cognitive performance. "Future studies should investigate whether early-life heat exposure contributes to neurodevelopmental disorders and whether altered thalamic development could help explain these associations," says Esmée Essers, ISGlobal researcher and study co-author.

"With global temperatures continuing to rise, measures to reduce heat exposure during pregnancy and early infancy could play an important role in protecting children's brain development," concludes Mònica Guxens, ICREA Research Professor in ISGlobal and coordinator of the study.

 

Reference

Granés, L., Essers, E., Kusters, M. S. W., Petricola, S., Tiemeier, P. H., Soriano-Mas, P. C., Schwartz, P. J., & Guxens, P. M. (2026). Early life ambient temperature and brain volumes change throughout childhood. Environment International, 214(110385), 110385. https://doi.org/10.1016/j.envint.2026.110385

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Journal

Environment International

DOI

10.1016/j.envint.2026.110385 

Method of Research

Observational study

Subject of Research

People

COI Statement

The authors declare no competing interests.

 

Fates of famous problem-solving chimps revealed

New paper details the lives, deaths and rediscovered remains of the apes tested in Wolfgang Köhler’s landmark studies of ape intelligence

University of Auckland

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Dr Javier Virués-Ortega

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Credit: University of Auckland/Dr Javier Virués-Ortega

A University of Auckland scientist has uncovered the fates of chimpanzees who starred in seminal psychological studies of the early 20th Century.

`The Fate of Sultan’s Clan’, by psychologist Dr Javier Virués-Ortega, was published in the journal European Psychologist.

“These chimpanzees are usually remembered for what they revealed about the mind,” says Virués-Ortega. “We wanted to ask the historical question textbooks mostly leave out: what happened to the animals themselves?”

Captured in the wild as juveniles, the chimpanzees were studied by German psychologist Wolfgang Köhler on Tenerife in the Canary Islands off North Africa from 1914 to 1920.

When chimpanzee Sultan fitted two bamboo sticks together to reach a banana outside his cage, Köhler was struck by tool-making and creative problem-solving skills akin to those of humans.

Likewise, the chimpanzees would stack boxes to reach a banana too high to reach. In other experiments, they used long poles as makeshift climbing aids, carried out multi-step, goal-directed actions, and even climbed a door so they could swing closer to a piece of fruit.

In contemporary accounts, Virués-Ortega found references to some of these experiments being reenacted by the apes years later in Berlin, offering rare anecdotal evidence of long-term memory in great apes.

Köhler’s work laid a foundation for the field of comparative psychology, where scientists study the behaviour of non-human animals, and his research still features in textbooks.

Jane Goodall, the famed primatologist, described Köhler’s book The Mentality of Apes, with its close observations of the animals’ behaviour, as her Bible.

But what of the fates of the animals themselves?

When the research centre closed down, six surviving chimpanzees – females Rana, Chica, Grande, Tercera, and Tschego and a male, Sultan – were transported to Europe by steamship. After a two-week journey in individual cages, they were rehoused in the Berlin Zoological Gardens.

The animals were already celebrities because of Köhler’s research and their arrival was a much-anticipated event. According to news reports, the primates “hugged each other” on being released from their travel crates, in a touching reunion scene.

Virués-Ortega studied zoo and museum records, newspaper accounts, personal correspondence and biological samples to reconstruct what happened next.

On Tenerife, treatment of the chimpanzees had been humane by the standards of the time. They had access to an outdoors playground, interactions with humans were limited as much as possible, and the climate was suitable.

While the zoo in Berlin had agreed to avoid circus-type training, a newspaper report from 1921 described one of the female chimpanzees begging for a cigarette, then expertly puffing on it “like a woman of today”.

Born in Cameroon, the animals were totally unsuited to harsh Berlin winters and the zoo often lacked sufficient heating because of post-World War I economic hardship. During the winter of 1921 to 1922, Berlin endured more than 50 sub-zero days, including 19 days below –10C; three female chimpanzees died that winter.

Fresh fruits and vegetables were in short supply, leaving a starchy and unsuitable diet big on potatoes and bread. The chimpanzees no longer had a large space to play and interact.

One account described Sultan’s last months as “lonely and joyless”. The animals were still research subjects, but little meaningful research occurred.   

Clutching at blankets to ward off sub-zero temperatures, the animals began falling ill and within three years all were dead. The study suggests cold, inadequate diet, pregnancy, social upheaval, and illness may have converged to undermine their health. Their expected lifespans were cut short by 20 years or more.

A male infant named Kaspar, born at the zoo in 1921, lost the use of an arm after he managed to get out of an enclosure and his mother, Rana, pulled him back in. His arm was caught between the bars and crushed, according to contemporary reports.

Orphaned by Rana’s death, Kaspar was transferred to a Berlin children’s hospital where he was bottle-fed human breast milk and cows’ milk. His stricken arm was amputated.

German psychologist Oskar Pfungst, known for debunking feats of intelligence by a horse named Clever Hans, studied Kaspar to assess the chimpanzee’s `natural’ behaviour when isolated from other chimpanzees. But what was interpreted at the time as natural primate behaviour was probably shaped by trauma and social deprivation. In 1924, Kaspar died of the same dysentery-type disease which had claimed his elders.

Virués-Ortega has rediscovered six of the chimpanzees’ remains in a Berlin museum’s storage, where they had lain for decades, unrecognised by staff, among hundreds of thousands of specimens. DNA samples extracted from the remains have been found to be viable. In the future, analysis could clarify how Sultan’s clan was related to contemporary chimpanzee populations in West Africa.

Collaborators in the research include:

Dr Clemens Maier-Wolthausen, Federal Chancellery, Berlin

Dr Alex Taylor, University of Auckland, New Zealand

David García Gonzalez, Universidad de Granada, Spain

 

Collaborators in ongoing DNA studies include:

Dr Tomas Marques-Bonet, Universitat Pompeu Fabra, Barcelona

Dr Olga Feliu, Mona Foundation, Barcelona

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Journal

European Psychologist

DOI

10.1027/1016-9040/a000582 

Method of Research

Case study

Subject of Research

Animals

Article Title

The Fate of Sultan’s Clan

 

Chimpanzee Sultan photographed in Tenerife circa 1914.

Credit

Zentrum für Geschichte der Psychologie, Julius-Maximilians-Universität Würzburg

 

Derelict research station in Tenerife, once used for studying chimpanzees

 

This skull of the chimpanzee named Rana-Loca was rediscovered in the Museum für Naturkunde Berlin.

 

Skeleton of chimpanzee named Tschego in Museum für Naturkunde Berlin.

Credit

Javier Virués-Ortega

 

Harder, longer-lasting silver plating!

KIMS develops high-hardness, low-friction silver composite plating technology based on controlled dispersion of PTFE nanoparticles

National Research Council of Science & Technology

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Schematic illustration of the controlled dispersion of PTFE nanoparticles using the FC-4 surfactant and the formation of an Ag–PTFE composite coating.

(The FC-4 surfactant suppresses the agglomeration of PTFE nanoparticles, enabling their stable dispersion in the plating bath. The uniformly dispersed PTFE particles are co-deposited with silver ions onto the electrode surface, forming an Ag–PTFE composite coating. The resulting coating exhibits finer silver grains and benefits from the solid lubricating effect of PTFE, resulting in higher hardness, a lower coefficient of friction, and improved wear resistance compared with conventional silver coatings.)

 

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Credit: Korea Institute of Materials Science (KIMS)

# Developed a technology that makes silver-plated layers on repeatedly contacting electrical components harder and more wear-resistant

# Approximately 23% higher hardness than conventional silver plating and a coefficient of friction below 0.2, offering improved durability and reliability for electrical contacts in electric vehicles and electronic devices

CHANGWON, South Korea — Korea Institute of Materials Science (KIMS), led by President Chul-jin Choi, announced that a research team led by Seil Kim of the Energy & Environmental Materials Research Division has developed an Ag–PTFE composite plating technology that produces silver coatings with greater hardness and wear resistance than conventional silver plating by stably dispersing PTFE nanoparticles in a cyanide-free acidic silver plating bath. The technology simultaneously achieves high hardness, low friction, and excellent wear resistance—properties that have traditionally been difficult to optimize together. It is expected to improve the durability and reliability of components subjected to repeated contact and friction, including electric vehicle connectors, relays, and electrical contacts in electronic devices.

Silver plating is widely used on electrical contacts found in electric vehicle connectors, automotive relays, and electronic switches because of silver's excellent electrical conductivity. However, silver is relatively soft, making plated surfaces susceptible to scratching and wear during repeated insertion and removal of connectors or continuous operation of relays and switches. Damage to the silver-plated layer can compromise electrical contact reliability, creating a need for more durable coating technologies.

To address this challenge, researchers have investigated incorporating PTFE (polytetrafluoroethylene) particles into silver coatings to reduce friction. Commonly known as Teflon, PTFE provides excellent lubricating properties that enable smoother mechanical movement. However, PTFE nanoparticles tend to agglomerate in plating solutions. Increasing their concentration improves lubrication but weakens the coating, whereas lower concentrations fail to provide sufficient friction reduction. As a result, simultaneously achieving high hardness and low friction has remained a significant technical challenge. Moreover, conventional silver electroplating typically relies on cyanide-based plating baths, raising concerns regarding workplace safety and wastewater treatment.

To overcome these limitations, the KIMS research team developed a technology that precisely controls the dispersion of PTFE nanoparticles, enabling simultaneous enhancement of hardness, low-friction performance, and wear resistance in silver coatings. Using a cyanide-free acidic silver plating bath containing the fluorinated surfactant FC-4, the researchers optimized the solution's acidity, surfactant concentration, and PTFE content to prevent nanoparticle agglomeration and ensure their uniform incorporation into the silver coating. They further elucidated the stabilization mechanism through experimental analysis and molecular dynamics simulations, demonstrating how the surfactant maintains stable PTFE dispersion.

Uniformly dispersed PTFE particles function as solid lubricants within the silver coating, significantly reducing friction, while the silver grains become finer and denser, resulting in a harder coating. Compared with conventional pure silver plating, the developed Ag–PTFE composite coating exhibited approximately 23% higher hardness, a coefficient of friction below 0.2, and excellent wear resistance. These results overcome the longstanding trade-off between hardness and friction reduction, producing a coating that is simultaneously harder, smoother, and more resistant to wear.

The technology can be applied to components in which metal surfaces repeatedly come into contact and slide against each other, including electric vehicle connectors, relay contacts, switches, lead frames, and electronic terminals. As high-voltage and high-current electrical components become increasingly common in electric vehicles, technologies capable of maintaining reliable electrical contact under vibration and repeated operation are becoming increasingly important. The developed coating is expected to extend component service life, reduce maintenance and replacement costs, and improve the long-term reliability of electric vehicles and electronic products. With the global electroplating market projected to reach approximately USD 27.2 billion by 2032, the industrial value of high-reliability silver plating technologies is expected to continue growing.

The technology is also significant from an environmental perspective because it employs a cyanide-free acidic silver plating bath, improving workplace safety while reducing the burden associated with wastewater treatment and compliance with increasingly stringent environmental regulations. Its application to large-area components and mass-production processes could accelerate the commercialization of environmentally friendly, high-performance silver plating while strengthening Korea's technological independence in silver plating materials and processes and enhancing competitiveness in the high-value electrical contact component market.

“This technology is expected to enable high-performance silver coatings that offer significantly improved durability under repeated-contact conditions while eliminating the need for highly toxic cyanide,” said Seil Kim, senior researcher at Korea Institute of Materials Science. “Our next step is to validate its performance in practical components such as electric vehicle connectors and electrical contacts, and to expand the technology to large-area and mass-production processes for industrial applications.”

The research was supported by the Industrial Technology Innovation Program funded by the Ministry of Trade, Industry and Energy, as well as KIMS's institutional research program funded by the Ministry of Science and ICT. The findings were published online on June 8, 2026, in Surface and Coatings Technology (Impact Factor: 6.9), a leading international journal in materials engineering and surface engineering. A patent application related to the technology is currently pending.

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About Korea Institute of Materials Science(KIMS)

KIMS is a non-profit government-funded research institute under the Ministry of Science and ICT of the Republic of Korea. As the only institute specializing in comprehensive materials technologies in Korea, KIMS has contributed to Korean industry by carrying out a wide range of activities related to materials science including R&D, inspection, testing&evaluation, and technology support.

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Journal

Surface and Coatings Technology

DOI

10.1016/j.surfcoat.2026.133671 

Article Title

Simultaneous enhancement of hardness and wear resistance of Ag–PTFE coatings through surfactant-assisted electrodeposition

 

Combination of THC and CBD significantly reduced agitation in people with late-stage dementia

Georgetown University Medical Center

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LONDON – In a first-of-its-kind clinical trial, U.S. researchers have found that people with agitation and dementia in late life who took a special medical formulation of two active ingredients found in marijuana – THC and CBD – had significantly less agitation compared to people who received a placebo.

The primary findings of the study were presented July 14, 2026, at the Alzheimer’s Association International Conference in London by Jacobo Mintzer, MD, of the and Medical University of South Carolina and Georgetown University’s Brigid Reynolds, MSN, APRN, ANP-BC.          

The study, dubbed the LiBBY trial (Life’s end Benefits of cannaBidiol and tetrahYdrocannabinol), enrolled 120 participants with Alzheimer’s disease or other types of dementia who were hospice-eligible and experiencing agitation. Ten medical centers nationwide conducted the LiBBY study visits at participants' homes or places of residence. Close to 90% of study participants who received the treatment showed overall improvement after 12 weeks.

“These trial results were extremely impressive and showed a level of response not seen before in clinical trials related to dementia. Rarely do we see close to 90% of patients in a trial respond positively to a new medication,” said Mintzer, the co-lead investigator.

“Agitation affects many people with late-stage dementia, causing symptoms such as restlessness, aggression, and emotional distress that can profoundly impact patients and their caregivers,” explained Reynolds, the co-lead investigator. “Current treatment options are limited and often carry significant side effects, underscoring the need for safer, more effective therapies.”

Medications such as morphine, Valium and Haldol have had limited effectiveness in treating dementia-related agitation and can cause undesirable side effects.

The study was designed to evaluate the effectiveness, safety, and tolerability of a combination of purified tetrahydrocannabinol (THC) and cannabidiol (CBD) given orally in a rapid-acting digestible oil suspension. Participants were randomly assigned to receive either the active combination or placebo. To ensure unbiased results, neither the participants, their caregivers, nor the clinicians knew who received the active treatment. The mean age of participants was 80 years old.

Using a 29-factor agitation assessment survey, the Cohen-Mansfield Agitation Inventory, the researchers compared participants who received the THC/CBD mixture to those receiving a placebo at 2 weeks, the primary outcome due to the fast-acting nature of the drug, and then at 12 weeks.

Each factor related to agitation was rated on a 7-point scale from “never” to “several times per hour” by the caregivers, who were also responsible for giving the medications. After 2 weeks, there was a 6.27-point reduction in mean agitation scores in the THC/CBD group compared with the placebo group; at 12 weeks, there was a significant, sustained reduction in agitation.

A key secondary measurement was the Clinical Global Impression of Change in Behavior assessment. This analysis showed that the THC/CBD group was much less agitated at 2 weeks (83.9% vs 30.5%) and 12 weeks (87.2% vs 23.6%) compared to the placebo group. Adverse event rates, such as infections and gastrointestinal disorders, were comparable between groups (46.7% vs 42.4%) and were expected occurrences in this patient population.

Laura, whose mother participated in the LiBBY trial, said taking part in the study gave her hope that new treatment options may one day improve quality of life for families living with dementia. Although she did not know whether her mother received the study medication or a placebo, she noticed what she described as meaningful changes during visits with her. "She seemed happier," Laura said. "We experienced joy. There were still moments of connection."

Although researchers say the results of this trial are encouraging, they caution that the treatment evaluated in the trial differs significantly from commercially available THC and CBD products.

"People should not assume that products available at dispensaries or online are equivalent to what was studied in this trial," Reynolds said. "The medication used in this research was carefully formulated, manufactured, and administered under close medical supervision. Over-the-counter or commercially available THC and CBD products may vary widely in their composition, quality, and dosing, making them potentially ineffective or even harmful."

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The study authors wish to express their gratitude to the LiBBY study participants, their caregivers, and families who generously volunteered their time to make this study possible.      

This trial was supported by an National Institutes of Health cooperative agreement grant #R01AG068324-01 and by the Alzheimer’s Association. It is being conducted by the NIH-funded Alzheimer’s Clinical Trial Consortium and coordinated by the University of Southern California’s Epstein Family Alzheimer’s Therapeutic Research Institute, the Medical University of South Carolina, and Georgetown University. The ClinicalTrials.gov ID is NCT05644262.

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Method of Research

Randomized controlled/clinical trial

Subject of Research

People

Article Title

The Life’s End Benefits Of Cannabidiol And Tetrahydrocannabinol (LiBBY) Study Topline Results

COI Statement

The authors report having no personal financial interests related to the study.