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jcmarchi · 4 months

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Miniature Marvels: Wireless Millirobots Successfully Navigate Arteries - Technology Org

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Miniature Marvels: Wireless Millirobots Successfully Navigate Arteries - Technology Org

For the first time ever, wireless millirobots navigated a narrow blood vessel both along and against arterial flow.

Researchers from the University of Twente and Radboudumc inserted the screw-shaped robots in a detached aorta with kidneys where they controlled them using a robotically controlled rotating magnet. Health Holland recently awarded a grant to further develop the technology to be able to remove blood clots.

UT-researchers navigate millirobots through ex vivo aorta model. Image credit: University of Twente

Each year worldwide, one in four people die from conditions caused by blood clots. A blood clot blocks a blood vessel preventing the blood from delivering oxygen to certain areas of the body.

Surgeons can use flexible instruments to remove the blood clot therefore allowing the blood to flow again, but some regions in the body are difficult to reach. Millirobots can overcome these limitations and remove blood clots from difficult-to-reach blood vessels.

Synergistic Triumph

The researchers showed that these millirobots were able to travel through blood vessels. But to do so, the millirobots need power, to travel up- and downstream and to accurately be controlled and localised. Last but not least, they need to be biocompatible and leave no further damage to the inside of blood vessels. At the Technical Medical Centre of the University of Twente, the researchers set up their experiment with a real aorta and kidneys.

“This required an interdisciplinary approach and the collaboration of many different departments. The Robotics Lab, Laboratory of biointerface, blood lab, DesignLab, LipoCoat, and MESA+ all helped us achieve this successful outcome”, explains researcher Islam Khalil.

Guided by Precision

In the experiment, the researchers used a robotically controlled rotating magnetic field to control the millirobots wirelessly. With an X-ray machine, they were able to localise the millirobot while steering through the aorta.

The researchers maintained a maximum arterial flow of 120 ml per minute inside the aorta. But with a stronger magnetic field, the millirobots should be able to overcome a greater blood flow. The millirobots performed stable straight runs with and against the flow, and also with multiple robots at the same time.

Miniature Marvels

The robots themselves are 3D-printed, screw-shaped objects with a small permanent magnet inside.

“This tiny magnet of just one millimetre long and one millimetre in diameter is placed in such a way that it can rotate the ‘screw’ in both ways. This allows for swimming against the flow and then turning around and swimming back”, explains Khalil.

The small size makes it possible to use several robots at the same time. And the screw shape makes it possible to drill through a blood clot.

Unlocking Potential

“These millirobots have huge potential in vascular surgery”, says Michiel Warle, a vascular surgeon at Radboudumc.

“Currently, we use blood thinners and flexible tools, but a millirobot can travel to hard-to-reach arteries while they only need minimal incisions to be inserted.”

In a new collaboration with Radboudumc and Triticum Medical (Israel), the researchers will further develop the millirobots to enable them to remove blood clots wirelessly. The consortium will look at ways to exploit this technology fostering collaborative growth in medical robotics and technical medicine.

Besides breaking up the blood clots to enable the blood flow of arteries, the technology can potentially be used for other targeted interventions. “The robots can deliver drugs to very specific places in the body where the drug is needed the most. That way we have minimal side effects in the rest of the body”, explains Khalil.

Power in Collaboration

This research is a collaboration between Radboudumc and the University of Twente. It received funding from the TURBO (Twente University RadBoudumc Opportunities) programme. With the TURBO programme, research groups from both institutions can expand an innovative idea into a large research project.

The researchers extended their collaboration with Triticum Medical (Israel) to further develop the millirobots. Health Holland recently awarded them a TKI-LSH (Topconsortia for Knowledge & Innovation – Life Science & Health) grant for public-private partnerships from Health Holland

Dr. Islam Khalil is Assistant Professor in the Department of Biomechanical Engineering (BE; Faculty of ET / TechMed Centre). His research interests include the modelling and design of motion control systems for soft microrobots, biologically-inspired microrobots, mechatronic system design, and untethered magnetic micro/nanorobotics with applications to micro/nanomanipulation, micro-assembly, and targeted drug delivery.

Source: University of Twente

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mit · 6 months

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Soft optical fibers block pain while moving and stretching with the body

The fibers could help with testing treatments for nerve-related pain.

Jennifer Chu | MIT News

Scientists have a new tool to precisely illuminate the roots of nerve pain.

Engineers at MIT have developed soft and implantable fibers that can deliver light to major nerves through the body. When these nerves are genetically manipulated to respond to light, the fibers can send pulses of light to the nerves to inhibit pain. The optical fibers are flexible and stretch with the body.

The new fibers are meant as an experimental tool that can be used by scientists to explore the causes and potential treatments for peripheral nerve disorders in animal models. Peripheral nerve pain can occur when nerves outside the brain and spinal cord are damaged, resulting in tingling, numbness, and pain in affected limbs. Peripheral neuropathy is estimated to affect more than 20 million people in the United States.

“Current devices used to study nerve disorders are made of stiff materials that constrain movement, so that we can’t really study spinal cord injury and recovery if pain is involved,” says Siyuan Rao, assistant professor of biomedical engineering at the University of Massachusetts at Amherst, who carried out part of the work as a postdoc at MIT. “Our fibers can adapt to natural motion and do their work while not limiting the motion of the subject. That can give us more precise information.”

“Now, people have a tool to study the diseases related to the peripheral nervous system, in very dynamic, natural, and unconstrained conditions,” adds Xinyue Liu PhD ’22, who is now an assistant professor at Michigan State University (MSU).

Details of their team’s new fibers are reported today in a study appearing in Nature Methods. Rao’s and Liu’s MIT co-authors include Atharva Sahasrabudhe, a graduate student in chemistry; Xuanhe Zhao, professor of mechanical engineering and civil and environmental engineering; and Polina Anikeeva, professor of materials science and engineering, along with others at MSU, UMass-Amherst, Harvard Medical School, and the National Institutes of Health.

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#bioengineering #biotechnology #drug delivery #pain management #research

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stephen-grey169 · 6 months

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Drug Delivery Market Analysis, Opportunities, Latest Trends

#drug delivery #pharmacy #hospital

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exorcizamus-te-dementors · 7 months

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The Important Overview to Vitamins and also Minerals: Unlocking the Power of Nourishment for Optimum Wellness

Paragraph 1: Minerals and vitamins play an essential role in maintaining our overall wellness and health. From boosting our immune system to supporting proper brain function, these essential nutrients are the foundation that our bodies need to work at their finest. In this comprehensive guide, we will certainly dive deep right into the globe of minerals and vitamins, unraveling their advantages, sources, as well as the significance of maintaining a balanced consumption for ideal health.Paragraph 2: Nutrients are not only vital for our bodily functions, however they also work as effective antioxidants, securing our cells from damage brought on by hazardous cost-free radicals. While a well-balanced diet should preferably supply us with all the necessary nutrients, certain variables such as poor dietary options, stress and anxiety, contamination, and also drugs can bring about shortages. That's where supplementation enters into play. We will certainly explore the different sorts of minerals and vitamins, their details functions, and also just how to recognize if you require to supplement your diet to ensure you're getting the right amount of these vital nutrients. Whether you're seeking to enhance your energy degrees, sustain your body immune system, or boost your skin health, comprehending the world of nutrients is the very first step towards achieving optimum wellness.

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#prescription drugs #medication errors #drug delivery

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bpod-bpod · 2 years

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Inside Job

Minuscule robots travelling along our arteries to transport drugs or fix blockages from the inside might seem like science-fiction, but progress in miniature robotics is making it increasingly plausible. Pictured on the edge of a coin, this tiny crab is the world’s smallest remote-controlled walking robot, only half a millimetre wide. Inspired by pop-up books, the robot is made from a sophisticated layered plastic sheet, cut and bent into a 3D form. Over the legs is a metal alloy, which springs back into shape when heated; precisely heating the legs with a laser beam flips them between folded and flat positions, causing the crab to quickly scuttle along in specific directions. Still a long way from versions capable of swimming in the bloodstream, more immediately achievable goals include incorporating electronic circuits, and using the robots to repair machinery in cramped spaces – small (sideways) steps towards a new form of medicine.

Written by Emmanuelle Briolat

Image from work by Mengdi Han, Xiaogang Guo and Xuexian Chen, and colleagues

Querrey Simpson Institute for Bioelectronics, Northwestern University, Evanston, IL, USA

Image copyright held by the original authors

Published in Science Robotics, May 2022

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#science #biomedicine #robotics #nanorobots #microrobots #drug delivery #crabs

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lupinepublishers · 2 years

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Lupine Publishers | Chemistry, Dual Use and Ethics

Abstract

When working in the area of chemistry, it is essential to have a high sense of ethics, personal and professional. In this work talk about the meaning of the term dual use, the consequences of a misinterpretation or ignorance of this concept, in the fields of drugs and chemical weapons, misuse and abuse of chemical knowledge and potential legal consequences faced when going from good to bad.

Keywords:Dual use; ethics; drugs; chemical weapons; chemical professions.

Introduction

In the practice of chemistry, an essential ethical principle must always prevail chemistry must serve to achieve the well-being of humanity, with absolute respect for the environment. It should never, never be used against either one or the other. The exercise of chemistry inevitably involves the transformation of matter, starting from one substance and arriving at another, sometimes very easily, sometimes overcoming enormous difficulties. However, the possibility that these transformations of matter result in something unwanted, or something desired but that can be used for purposes contrary to the ideal, is great, sometimes too big [1-4] .

Duality

We might think that almost all technology can have dual uses. When the primitive human discovered that he could make fire and control it, he used it to illuminate his nights and the interior of the caves, to drive away beasts and intruders, but he also learned that he could apply it to set fire to the possessions of his enemies and thus be able to subdue them [5]. And from then to today, when our civilization use fire to cook delicacies and burn villages with napalm, has the situation changed?

Louis Fieser

Using fire. During World War II, incendiary bombs were loaded with a gel formed from crude rubber. The attack on Pearl Harbor gave the Japanese control of the most important sources of natural rubber for the manufacture of bombs. Then Colonel ME Barker, from the US Army Chemical Weapons Service, met with Dr. Louis Fieser, asking him to find a substitute for natural rubber. The requirements were various: the gel should be stable between 50ºF, for operations in tropical areas and -40ºF, for operations in cold locations; withstand storage conditions and be safe in its handling to be able to adequately fill the bombs. Fieser and his team developed a gel with excellent properties, complying with what was requested by Colonel Baker and with temperature properties and destruction capacity superior to rubber gels [6]. With military optics, a great success.

Fieser was criticized for using science for destructive purposes, against humanity. Their varied answers are synthesized in a single one, supposedly published in the first issue of Time magazine of 1968, of January 5 (Science History Institute), which says: “I have no right to judge the morality of napalm, just because I invented it”. Because he never participated in attacks using napalm, nor did he order them, he considered that his only responsibility was to have invented it [7-9]. This position of Fieser contrasts with the need for scientists, particularly chemists, to carry out our activities contemplating the possible consequences of what we produce, whether they are good or not so good. And that should also apply to the corporations and companies in charge of the mass production and distribution of these products developed by chemists. The Dow Chemical company was in charge of the manufacture of the napalm used in Vietnam (and also part of the herbicides used in that war, such as the well-known Agent Orange) and this corporation could not declare itself ignorant of the use that would be given to its product; far from it, they claimed that their product brought benefits for the acts of war that were carried out, they spoke of the merits of the war and questioned whether it was really used

indiscriminately against the civilian population (Contakes, op. cit.). What a stupid way of defending themselves!

Fritz Haber

Let’s talk about Fritz Haber, German chemist who won the Nobel Prize in Chemistry in 1918 , although it was awarded to him in 1919. The committee in charge of the selection of candidates agreed to recognize him “for the synthesis of ammonia from its elements ” [10]. The discovery by Haber allowed to use the most abundant gas in the planet’s atmosphere to produce in a fairly simple and economical way a compound that is of high social importance; since it allows, among other things, the synthesis of synthetic fertilizers with a high nitrogen content. Plants cannot use atmospheric nitrogen in their vital processes, but ammonia nitrogen is very easy to assimilate [11-13]. In this way, dependence on natural fertilizers (guano, manure, animal and human feces) is reduced and crops with much higher yields can be achieved. This discovery helped the world combat the specter of famine and Haber’s name was then linked to the concept of “bread from air” [6]. The curious thing about the matter is that Haber did not seek a welfare for humanity but the progress of his homeland. Before ammonia, most of the fertilizers used in Germany consisted of guano, which was imported from the distant lands of Chile. In this way, what drove Haber was a fervent nationalism; claimed that the meaning of Germanhood, (used by Haber) was something that would have to be adjusted “like everything great and eternal” [4,7]. The impetus for his development of the work on ammonia was based on the fact that in a state of belligerence although not of war per se (which would soon be declared politically), British ships blocked the importation of South American guano, affecting not only agriculture but also to the production of ammunition, which required large amounts of nitrates, available in guano. In September 1914, a group of experts, including Haber, undertook the task of solving this problem and first devoted themselves to the question of ammunition, which apparently was their primary motivation (Spleen CE,). At the outbreak of the Great War, Germany was prepared, in part thanks to Haber’s work, which had not been completed. He then began to think of a technology of war that would allow Germany to quickly rise to victory and decided to dedicate efforts in this direction. He focused on what he knew well, chemistry, developing the first chemical weapons. In April 1915, he himself appeared in the vicinity of Ypres to monitor the weather conditions, he spent several days until he considered that everything was in favor of the German army, and on the 22nd of that same month, he ordered an attack against the allied forces barricaded there. With the wind in his favor, blowing towards the enemy trenches, Haber ordered the release of about 150 tons of gaseous chlorine that was transported in 6,000 cylinders and that were opened almost simultaneously; the cylinders were placed along more than six kilometers of the German trench and a huge and dense cloud of greenish gas drifted towards the Allied lines [8]. Different authors mention different numbers of casualties due to this attack. For example, Harris and Paxman report 5,000 dead and 10,000 injured [11], while Spiers reports around 7,000 injured and 350 dead [2]. Haber bragged about the success of his strategy, adding that it caused a truly agonizing death [5]. And yet, he said that “all modern weapons ... owe their success to the vigor with which they temporarily weaken the psychological strength of the adversary” [4,10]. The point is, Haber was proud of the success of his attack, not caring that the Hague accords of 1899 had been violated. After the attack on Ypres, Haber was appointed captain of the German army. For him, humanity was not as important as the homeland, his homeland. To celebrate his appointment as captain, he held a great party at his home on May 1st, 1915 [3]. There something unexpected happened, closely related to Haber’s ethics.

Clara Immerwhar

Clara Immerwahr was an excellent chemist, in her own right. It is said that she was probably the first woman to obtain a doctorate in chemistry in Germany (Essex and Howes, op. Cit), but it was not easy at all. Her stay at the university was as observer, that is, she had to obtain authorization from all teachers to attend any of the classes, among many other obstacles. She finally obtained a doctorate degree in 1900. One of her teachers had been Fritz Haber but contact between them during Clara’s student days was short. His biggest approach was in a dance class. The couple met again after Clara’s graduation and married in 1901. Initially Clara participated in Haber’s projects, but little by little she was relegated to the role of wife and mother. To keep up to date, she translated articles from English into German for her husband to use and was responsible for the English edition of Fritz’s book, Thermodynamics of Technical Gas-Reactions. Clara never stopped thinking about going back to a laboratory, but when her son Hermann was born, she realized that this would be almost impossible, due to the delicate state of her son’s health. However, the differences between Haber and Clara grew deeper every day. The differences were clearly reflected in two statements that show two lines of thought, two views of scientific ethics; Clara thought that “scientific study was obliged to respect life”, while Haber argued that “In times of peace a scientist belongs to the world, but in times of war, he belongs to his country” [8]. In fact, it is mentioned that when the use of toxic substances as a method of warfare began, Clara publicly denounced that this “constituted a perversion of the ideals of science”, to which Haber responded by denouncing her as a traitor (Essex and Howes, op. cit.). So, disturbing the Haber’s reaction against his own wife, the mother of his child! Let’s go back to the big party on May 1st . Clara waited for the guests to leave, then took Haber’s service weapon, headed out into the garden, and shot herself in the chest. The one who heard the shot was her son Hermann, who found her still alive, but she died in a few moments. And to emphasize the tragedy, it seems that Haber’s orders were to go to the front immediately, so that his wife’s funeral was left to his son, who was then only thirteen years old (Vazquez, op. Cit.). This family conflict reflects two different visions of professional ethics: one decidedly nationalist, regardless of the consequences for humanity, and the other deeply human, always looking out for the well-being of all, regardless of borders and other differences. And paradoxically, this vision of ethics in favor of humanity, ended one life and deeply hurt another.

Clara and Fritz’s son Hermann was a chemist, worked in the patent area and committed suicide in 1946, after the death of his wife, who died of cancer. He apparently never recovered from having been in charge of his mother’s funeral and his father’s second marriage.

Back to Duality

Dual use processes are those that can be used to obtain substances for peaceful or harmful purposes. Dual-use chemical substances can have a legal, legitimate use and other illegal or illegitimate use. We can also find equipment and instruments that can be used in a double way; a knife can be used to cut meat and eat, or to assault people in the street. Large ultra-pure aluminum tubes, which can be used in rockets to put satellites into orbit, also make long-range missiles transporting explosives or weapons of mass destructions in their heads or use them in centrifuges to enrich uranium. In turn, the centrifugation of uranium to enrich it can lead to its use in nuclear power generation plants, or for the manufacture of atomic bombs [1]. Here we have examples of dualuse processes (centrifugation), dual-use equipment (rockets and missiles) and dual-use substances (aluminum).

Dual Use Substances

One example of a dual-use substance is isopropanol or isopropyl alcohol. It is widely used as a wound disinfectant (like ethanol or ethyl alcohol) and is widely used as an industrial solvent for the extraction of natural plant products, in inks and varnishes, for cleaning electrical components, in the manufacture of topical medicines, in cosmetics and in a wide variety of other applications. But it is also one of the raw materials for the manufacture of chemical weapons, specifically the neurotoxic agent called sarin, which has not only been used in warfare but has also been used in terrorist acts. And the case of chlorine is even more dramatic. Chlorine is the most used chemical for the purification of water, that is, to provide water suitable for human consumption from a microbiological point of view. In addition to this tremendously important use on its own, it has multiple industrial uses in plastics and drugs, to name a couple of them. But, as we have seen before, it was the first toxic agent used in a massive way in a war, that is to say, it is an indisputable chemical weapon. Is chlorine good or bad? Neither one nor the other. Its application is what can be questioned from the point of view of ethics. And it will depend on the type of ethics that is used to judge it. So, a chemist can face the ethical dilemma, when working with isopropanol or chlorine: do I make drugs to help people, or do I make weapons that are going to leave me more money? But this is not the only ethical dilemma someone may face in relation to these two products. Should the chemistry teacher respect the right to information of his students? Should he indiscriminately inform them of the relationship between beneficial isopropanol and chlorine and the evil chemical weapons? If they have never heard of this, now they know it. It is not necessary for the teacher to tell them how to do evil products, there are many Internet pages that describe step by step the chemical transformation of good into evil. Shouldn’t the teacher give that information to his students? What about their right to information? On the other hand, is it useful to inform young people and does it guarantee that chemistry misuse is avoided? Or is that achieved by hiding the information.

Uranium enrichment is the process by which the amount of fissile uranium (which decomposes by breaking its nucleus into smaller nuclei, emitting radioactive particles) is increased with respect to the amount of non-fissionable uranium found naturally in minerals. The fissile (U235) in nature is found in less than 1%, while the non-fissionable (U238 ) is found in more than 99%. If it is enriched to 10%, it is used for nuclear power plants; if it is enriched to 90% or more, it is used for armaments.

Conclusión

As we can see, the relationship of ethics and chemistry is a complicated matter. There are personal interpretations, nationalism, patriotism, particular interests and other ways to accommodate ourselves or accommodate the science to our particular interests. The author is left with the basic element mentioned by the OPCW: achievements in the field of chemistry must be used for the benefit of humanity and in defense of the environment

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#lupine publishers #Drug Delivery #chemical

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rachel4reading · 1 month

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The Vital Guide to Vitamins and Minerals: Unlocking the Power of Nourishment for Ideal Wellness

Paragraph 1: Nutrients play a vital duty in keeping our total health and wellness as well as health. From boosting our immune system to sustaining correct brain feature, these necessary nutrients are the building obstructs that our bodies require to operate at their finest. In this detailed overview, we will certainly dive deep right into the globe of nutrients, untangling their benefits, resources, as well as the significance of keeping a balanced consumption for optimal health.Paragraph 2: Minerals and vitamins are not just vital for our bodily features, but they also work as powerful antioxidants, safeguarding our cells from damage triggered by unsafe free radicals. While a healthy diet regimen ought to preferably supply us with all the necessary nutrients, certain elements such as inadequate dietary options, tension, contamination, and also also medicines can lead to shortages. That's where supplementation enters play. We will certainly discover the various sorts of minerals and vitamins, their particular features, and also just how to identify if you need to supplement your diet to guarantee you're obtaining the best quantity of these essential nutrients. Whether you're looking to improve your power degrees, support your immune system, or enhance your skin health and wellness, comprehending the globe of nutrients is the primary step towards attaining optimum health.

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mexicanistnet · 2 months

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A Mexican research team discovers a novel way to improve drug delivery using synthetic clay called laponite. This innovation offers controlled release, low cost, and could even replace injections.

#drug delivery #synthetic clay #laponite

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simplivia · 3 months

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Developing a groundbreaking drug is only half the battle. Delivering it effectively and safely to patients is a labyrinthine challenge in itself. With a bewildering array of drug delivery solution companies out there, each touting their unique strengths, choosing the right partner can feel like deciphering an ancient riddle. Fear not, intrepid explorer! This guide will equip you with the tools to navigate the maze and unearth the perfect drug delivery solution partner for your specific needs.

Charting Your Course:

Know thyself (and your drug): Before embarking on your quest, scrutinize your drug's unique characteristics and delivery challenges. Is it a fragile protein? Does it require targeted release? Understanding these nuances will guide your search for a company with the expertise to match.

Seek diversity, not just dragons: Don't get bewitched by the first flashy brochure. Explore a variety of companies, from established veterans to nimble startups. Each brings unique strengths and approaches to the table. Consider factors like experience with similar drugs, technological innovation, and regulatory know-how.

Follow the map of your values: Choose a partner whose ethics and business practices align with yours. Do they prioritize patient safety and responsible development? Are they transparent and collaborative in their approach? Shared values form the bedrock of a successful long-term partnership.

Demystify the jargon: Don't let scientific mumbo jumbo cloud your judgment. Ask pointed questions, demand clear explanations, and don't hesitate to seek external advice. Understanding the proposed solutions is crucial for making informed decisions.

Test the waters before diving in: Before committing to a full-fledged partnership, initiate smaller pilot projects or feasibility studies. This allows you to assess the company's capabilities, communication style, and overall fit without taking undue risks.

Remember, the ideal drug delivery solution company is not a mythical beast, but a valuable collaborator waiting to be discovered. By following these steps and remaining vigilant, you'll emerge from the maze victorious, with the perfect partner to shepherd your drug to market and, ultimately, into the hands of patients who need it most.

So, grab your map, don your questing boots, and get ready to navigate the exciting, yet challenging, world of top drug delivery solutions!

#Top Drug Delivery Solution Company #simplivia #drug delivery

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healthcaretrends23 · 4 months

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Drug Delivery Devices Market

Size, Share, Competitive Landscape and Trend Analysis Report by Device Type (Smart Pills, Inhalers & Nebulizers, Drug Eluting Stents, Safety Syringes, Implantable Drug Delivery Device, and Transdermal Patches, and, Others), End User (Hospitals and Diagnostic Centers, Ambulatory Surgery Centers and Clinics and Others), Global Opportunity Analysis and Industry Forecast, 2019-2026

#Drug Delivery Devices Market #Drug Delivery Devices #Drug Delivery Device #Drug Delivery #Drug Delivery Devices Market Size #Drug Delivery Devices Market Share #Drug Delivery Devices Market Trends #Drug Delivery Devices Market Growth

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jcmarchi · 2 days

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A closed-loop drug-delivery system could improve chemotherapy

New Post has been published on https://thedigitalinsider.com/a-closed-loop-drug-delivery-system-could-improve-chemotherapy/

A closed-loop drug-delivery system could improve chemotherapy

When cancer patients undergo chemotherapy, the dose of most drugs is calculated based on the patient’s body surface area. This is estimated by plugging the patient’s height and weight into an equation, dating to 1916, that was formulated from data on just nine patients.

This simplistic dosing doesn’t take into account other factors and can lead to patients receiving either too much or too little of a drug. As a result, some patients likely experience avoidable toxicity or insufficient benefit from the chemotherapy they receive.

To make chemotherapy dosing more accurate, MIT engineers have come up with an alternative approach that can enable the dose to be personalized to the patient. Their system measures how much drug is in the patient’s system, and these measurements are fed into a controller that can adjust the infusion rate accordingly.

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This approach could help to compensate for differences in drug pharmacokinetics caused by body composition, genetic makeup, chemotherapy-induced toxicity of the organs that metabolize the drugs, interactions with other medications being taken and foods consumed, and circadian fluctuations in the enzymes responsible for breaking down chemotherapy drugs, the researchers say.

“Recognizing the advances in our understanding of how drugs are metabolized, and applying engineering tools to facilitate personalized dosing, we believe, can help transform the safety and efficacy of many drugs,” says Giovanni Traverso, an associate professor of mechanical engineering at MIT, a gastroenterologist at Brigham and Women’s Hospital, and the senior author of the study.

Louis DeRidder, an MIT graduate student, is the lead author of the paper, which appears today in the journal Med.

Continuous monitoring

In this study, the researchers focused on a drug called 5-fluorouracil, which is used to treat colorectal cancers, among others. The drug is typically infused over a 46-hour period, and the dosage is determined using a formula based on the patient’s height and weight, which gives the estimated body surface area.

However, that approach doesn’t account for differences in body composition that can affect how the drug spreads through the body, or genetic variations that influence how it is metabolized. Those differences can lead to harmful side effects, if too much drug is present. If not enough drug is circulating, it may not kill the tumor as expected.

“People with the same body surface area could have very different heights and weights, could have very different muscle masses or genetics, but as long as the height and the weight plugged into this equation give the same body surface area, their dose is identical,” says DeRidder, a PhD candidate in the Medical Engineering and Medical Physics program within the Harvard-MIT Program in Health Sciences and Technology.

Another factor that can alter the amount of drug in the bloodstream at any given time is circadian fluctuations of an enzyme called dihydropyrimidine dehydrogenase (DPD), which breaks down 5-fluorouracil. DPD’s expression, like many other enzymes in the body, is regulated on a circadian rhythm. Thus, the degradation of 5-FU by DPD is not constant but changes according to the time of the day. These circadian rhythms can lead to tenfold fluctuations in the amount of 5-fluorouracil in a patient’s bloodstream over the course of an infusion.

“Using body surface area to calculate a chemotherapy dose, we know that two people can have profoundly different toxicity from 5-fluorouracil chemotherapy. Looking at one patient, they can have cycles of treatment with minimal toxicity and then have a cycle with miserable toxicity. Something changed in how that patient metabolized chemo from one cycle to the next. Our antiquated dosing fails to capture that change, and patients suffer as a result,” says Douglas Rubinson, a clinical oncologist at Dana-Farber Cancer Institute and an author of the paper.

One way to try to counteract the variability in chemotherapy pharmacokinetics is a strategy called therapeutic drug monitoring, in which the patient gives a blood sample at the end of one treatment cycle. After this sample is analyzed for the drug concentration, the dosage can be adjusted, if needed, at the beginning of the next cycle (usually two weeks later for 5-fluorouracil). This approach has been shown to result in better outcomes for patients, but it is not widely used for chemotherapies such as 5-fluorouracil.

The MIT researchers wanted to develop a similar type of monitoring, but in a manner that is automated and enables real-time drug personalization, which could result in better outcomes for patients. In their “closed-loop” system, drug concentrations can be continually monitored, and that information is used to automatically adjust the infusion rate of the chemotherapy drug and keep the dose within the target range. Such a closed-loop system enables personalization of the drug dose in a manner that considers circadian rhythm changes in the levels of drug-metabolizing enzymes, as well as any changes in the patient’s pharmacokinetics since their last treatment, such as chemotherapy-induced toxicity of the organs that metabolize the drugs.

The new system they designed, known as CLAUDIA (Closed-Loop AUtomated Drug Infusion regulAtor), makes use of commercially available equipment for each step. Blood samples are taken every five minutes and rapidly prepared for analysis. The concentration of 5-fluorouracil in the blood is measured and compared to the target range. The difference between the target and measured concentration is input to a control algorithm, which then adjusts the infusion rate if necessary, to keep the dose within the range of concentrations between which the drug is effective and nontoxic.

“What we’ve developed is a system where you can constantly measure the concentration of drug and adjust the infusion rate accordingly, to keep the drug concentration within the therapeutic window,” DeRidder says.

Rapid adjustment

In tests in animals, the researchers found that using CLAUDIA, they could keep the amount of drug circulating in the body within the target range around 45 percent of the time. Drug levels in animals that received chemotherapy without CLAUDIA remained in the target range only 13 percent of the time, on average. In this study, the researchers did not do any tests of the effectiveness of the drug levels, but keeping the concentration within the target window is believed to lead to better outcomes and less toxicity.

CLAUDIA was also able to keep the dose of 5-fluorouracil within the target range even when the researchers administered a drug that inhibits the DPD enzyme. In animals that received this inhibitor without continuous monitoring and adjustment, levels of 5-fluorouracil increased by up to eightfold.

For this demonstration, the researchers manually performed each step of the process, using off-the-shelf equipment, but they now plan to work on automating each step so that the monitoring and dose adjustment can be done without any human intervention.

To measure drug concentrations, the researchers used high-performance liquid chromatography mass spectroscopy (HPLC-MS), a technique that could be adapted to detect nearly any type of drug.

“We foresee a future where we’re able to use CLAUDIA for any drug that has the right pharmacokinetic properties and is detectable with HPLC-MS, thereby enabling the personalization of dosing for many different drugs,” DeRidder says.

The research was funded by the National Science Foundation Graduate Research Fellowship Program, a MathWorks Fellowship, MIT’s Karl van Tassel Career Development Professorship, the MIT Department of Mechanical Engineering, and the Bridge Project, a partnership between the Koch Institute for Integrative Cancer Research at MIT and the Dana-Farber/Harvard Cancer Center.

Other authors of the paper include Kyle A. Hare, Aaron Lopes, Josh Jenkins, Nina Fitzgerald, Emmeline MacPherson, Niora Fabian, Josh Morimoto, Jacqueline N. Chu, Ameya R. Kirtane, Wiam Madani, Keiko Ishida, Johannes L. P. Kuosmanen, Naomi Zecharias, Christopher M. Colangelo, Hen-Wei Huang, Makaya Chilekwa, Nikhil B. Lal, Shriya S. Srinivasan, Alison M Hayward, Brian M. Wolpin, David Trumper, Troy Quast, and Robert Langer.

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