This phenomenon, known as the foreign body response, can also interfere with many other types of implantable medical devices. However, a team of MIT engineers and collaborators has now devised a way to overcome this response. In a study of mice, they showed that when they incorporated mechanical actuation into a soft robotic device, the device remained functional for much longer than a typical drug-delivery implant.

The device is repeatedly inflated and deflated for five minutes every 12 hours, and this mechanical deflection prevents immune cells from accumulating around the device, the researchers found.

“We’re using this type of motion to extend the lifetime and the efficacy of these implanted reservoirs that can deliver drugs like insulin, and we think this platform can be extended beyond this application,” says Ellen Roche, the Latham Family Career Development Associate Professor of Mechanical Engineering and a member of MIT’s Institute for Medical Engineering and Science.

Among other possible applications, the researchers now plan to see if they can use the device to deliver pancreatic islet cells that could act as an “bioartificial pancreas” to help treat diabetes.

Roche is the co-senior author of the study, with Eimear Dolan, a former postdoc in her lab who is now a faculty member at the National University of Ireland at Galway. Garry Duffy, also a professor at NUI Galway, is a key collaborator on the work, which appears in Nature Communications. MIT postdocs William Whyte and Debkalpa Goswami, and visiting scholar Sophie Wang, are the lead authors of the paper.

Modulating immune cells

Most patients with type 1 diabetes, and some with type 2 diabetes, have to inject themselves with insulin on a daily basis. Some patients use wearable insulin pumps that are attached to the skin and deliver insulin through a tube inserted under the skin, or patches that can deliver insulin without a tube.

For many years, scientists have been working on insulin-delivering devices that could be implanted under the skin. However, the fibrous capsules that form around such devices can lead to device failure within weeks or months.

Researchers have tried many approaches to prevent this kind of scar tissue from forming, including local delivery of immunosuppressants. The MIT team took a different approach that does not require any drugs — instead, their implant includes a mechanically actuated soft robotic device that can be inflated and deflated. In a 2019 study, Roche and her colleagues (with Dolan as first author) showed that this kind of oscillation can modulate how nearby immune cells respond to an implanted device.

In the new study, the researchers wanted to see if that immunomodulatory effect could help improve drug delivery. They built a two-chambered device made of polyurethane, a plastic that has similar elasticity to the extracellular matrix that surrounds tissues. One of the chambers acts as a drug reservoir, and the other acts as a soft, inflatable actuator. Using an external controller, the researchers can stimulate the actuator to inflate and deflate on a specific schedule. For this study, they performed the actuation every 12 hours, for five minutes at a time.

This mechanical actuation drives away immune cells called neutrophils, the cells that initiate the process that leads to scar tissue formation. When the researchers implanted these devices in mice, they found that it took much longer for scar tissue to develop around the devices. Scar tissue did eventually form, but its structure was unusual: Instead of the tangled collagen fibers that built up around static devices, collagen fibers surrounding actuated devices were more highly aligned, which the researchers believe may help drug molecules to pass through the tissue.

“In the short term, we see that there are fewer neutrophils surrounding the device in the tissue, and then long term, we see that there are differences in collagen architecture, which may be related to why we have better drug delivery throughout the eight-week time period,” Wang says.

Sustained drug delivery

To demonstrate the potential usefulness of this device, the researchers showed that it could be used to deliver insulin in mice. The device is designed so that insulin can slowly seep out through pores in the drug reservoir or be released in a large burst controlled by the actuator.

The researchers evaluated the effectiveness of the insulin release by measuring subsequent changes in the mice’s blood glucose levels. They found that in mice with the actuated device, effective insulin delivery was maintained throughout the eight weeks of the study. However, in mice that did not receive actuation, delivery efficiency began to wane after only two weeks, and after eight weeks, almost no insulin was able to pass through the fibrous capsule.

The authors also created a human-sized version of the device, 120 millimeters by 80 millimeters, and showed that it could be successfully implanted in the abdomen of a human cadaver.

“This was a proof of concept to show that there is a minimally invasive surgical technique that could potentially be employed for a larger-scale, human-scale device,” Goswami says.

Working with Jeffrey Millman of the Washington University School of Medicine in St. Louis, the researchers now plan to adapt the device so that it could be used to deliver stem-cell-derived pancreatic cells that would sense glucose levels and secrete insulin when glucose is too high. Such an implant could eliminate the need for patients to constantly measure their glucose levels and inject insulin.

“The idea would be that the cells would be resident in the reservoir, and they would act as an insulin factory,” Roche says. “They would detect the levels of glucose in blood and then release insulin according to what was necessary.”

Other possible applications the researchers have explored for this kind of device include delivery of immunotherapy to treat ovarian cancer, and delivering drugs to the heart to prevent heart failure in patients who have had heart attacks.

“You can imagine that we can apply this technology to anything that is hindered by a foreign body response or fibrous capsule, and have a long-term effect,” Roche says. “I think any sort of implantable drug delivery device could benefit.”

The research was funded, in part, by Science Foundation Ireland, the Juvenile Diabetes Research Foundation, and the National Institutes of Health.

In an effort to include a larger and more diverse population, an international team of researchers and policymakers has written new recommendations on how to determine eligibility criteria for lung cancer clinical trials. The group was led in part by David Gerber, M.D., Associate Director for Clinical Research at UT Southwestern’s Harold C. Simmons Comprehensive Cancer Center, along with representatives from the Food and Drug Administration (FDA), National Cancer Institute, European Medicines Agency, pharmaceutical companies, and the LUNGevity Foundation.

The recommendations, published today in JAMA Oncology, offer the first publicly available outline of upcoming FDA draft guidance on lung cancer clinical trials that are expected to make it easier to include more patients.

“This paper is the public’s first look at the FDA’s proposed changes to how we determine who can participate in a lung cancer clinical trial,” said Dr. Gerber, Professor of Internal Medicine in the Hematology/Oncology Division at UTSW. “If these changes are successful, they could make clinical trials for lung cancer as well as other cancers more powerful and more representative.”

Ensuring that people from diverse backgrounds join clinical trials is key to properly evaluating how a new treatment will work among patients of all races and ethnicities. But today, only about 5% of all cancer patients enroll in a clinical trial, and only 11% of cancer clinical trial participants identify as a racial or ethnic minority.

For patients with cancer, participation in clinical trials requires not just a decision to try an experimental treatment, but time and energy spent understanding the trial, enrolling in it, and often attending extra testing or clinic appointments. Many researchers agree that complicated, inconsistent, poorly explained, and overly strict eligibility requirements to join a cancer clinical trial exacerbate this problem and are a key reason for the low number of underrepresented minorities in clinical trials.

“So many clinical trials never finish enrollment, close prematurely, or don’t recruit a population that lets researchers generalize the results,” Dr. Gerber said. “I think there’s widespread recognition that eligibility criteria have become too stringent.”

To tackle this problem in one cancer subtype — advanced non-small cell lung cancer (NSCLC) — the LUNGevity Foundation convened a roundtable discussion with experts from academia, industry, and regulatory bodies. The team assembled a prioritized list of eligibility categories that should be included in the descriptions of all NSCLC clinical trials and recommended criteria for each category. Some suggestions were more lenient than what has typically been included in previous NSCLC trial eligibility criteria; for instance, the team recommended that most patients with prior or concurrent cancers, most patients with brain metastases, and most patients with mild liver impairment — all of whom would likely have been excluded in the past — still be included in trials.

The team also suggested that these categories be clearly laid out on public websites advertising clinical trials in an easily searchable format.

The FDA will be releasing draft guidance on NSCLC clinical trials in the near future and hold a public comment period before finalizing them. Other interdisciplinary teams have already convened to standardize eligibility requirements for clinical trials of other cancer types.

If the new guidelines are effective, Dr. Gerber said clinical trials will likely be easier to fill and provide more complete and timely data on new cancer interventions.

“If you can involve more patients in clinical trials, you’re more likely to complete those trials quickly. That’s going to lead to new treatments faster,” he said.

Other authors of the paper include Harpreet Singh and Erin Larkins of the FDA; Andrea Ferris and Upal Basu Roy of LUNGevity Foundation; Patrick M. Forde of Johns Hopkins University; and Wendy Selig of WSCollaborative LLC.

Dr. Gerber holds the David Bruton, Jr. Professorship in Clinical Cancer Research.

Do you ever feel the need for a bit of fresh air to energize yourself, or to spend time in the garden to relax? Aside from clean water, food and useful raw materials, nature provides many other benefits that we might overlook or find it hard to grasp and quantify. Research into cultural ecosystem services (CESs), the nonmaterial benefits we receive from nature, aims to better understand these contributions, whether they emerge through recreation and social experiences, or nature’s spiritual value and our sense of place.

Hundreds of CESs studies have explored the connections between nature and human well-being. However, they have often used different methods and measurements, or focused on different demographics and places. This fragmentation makes it difficult to identify overarching patterns or commonalities on how these intangible contributions really affect human well-being. Better understanding them could aid real-world decision-making about the environment, which could benefit individuals and the wider society.

To try and get a “big-picture” view, graduate student Lam Huynh from the Graduate Program in Sustainability Science at the University of Tokyo and team conducted a systematic literature review of 301 academic articles. After a critical reading, they were able to identify hundreds of links. “We identified 227 unique linkages between a single CES (such as recreation or aesthetic value) and a single constituent of human well-being (such as connectedness, spirituality, or health). We knew that there are many linkages, but we were surprised to find quite so many of them,” said Huynh. “Then, through further critical reading, we could identify major commonalities.”

In particular, they identified 16 distinct underlying “mechanisms,” or types of connection, which refer to the different ways that people’s interaction with nature affects their well-being. For example, there can be positive interactions through “cohesive,” “creative” and “formative” mechanisms, but also negative interactions through “irritative” and “destructive” mechanisms. Previous studies had identified some of these mechanisms, but 10 were newly defined, including the more negative effects, clearly showing that our well-being is linked to the intangible aspects of nature in many more ways than previously thought.

According to the paper, the negative contributions to human well-being came mainly through the degradation or loss of CESs, and through ecosystem “disservices,” such as annoyance at wildlife noise, which can affect some people’s mental health in particular. However, on the other hand, the highest positive contributions of CESs were to both mental and physical health, which were generated mainly through recreation, tourism and aesthetic value.

“It is particularly interesting to note that the identified pathways and mechanisms rather than affecting human well-being independently, often interact strongly,” explained co-author Alexandros Gasparatos, associate professor at the Institute for Future Initiatives (IFI) at the University of Tokyo. “This can create negative trade-offs in some contexts, but also important positive synergies that can be leveraged to provide multiple benefits to human well-being.”

Despite the comprehensiveness of the review, the researchers acknowledge that there may still be more links that have not yet been identified, especially as the review revealed gaps in the current research landscape. “We hypothesize that missing pathways and mechanisms could be present in ecosystem-dependent communities, and especially traditional and Indigenous communities, considering their very unique relations with nature,” said Gasparatos.

“Another of the knowledge gaps we identified is that the existing literature on these nonmaterial dimensions of human-nature relationships mainly focuses on the well-being of individuals rather than on collective (community) well-being,” explained Huynh. “This significant gap hinders our capacity to identify possible synergies and trade-offs in ecosystem management research and practice.”

The team has now received a grant to explore the effects of CESs provision to human well-being in the urban spaces of Tokyo. “This project is a logical follow-up to test whether and how some of the identified pathways and mechanisms unfold in reality and intersect with human well-being,” said Gasparatos.

The researchers hope that this study and similar efforts will make it possible to apply the key findings from this complex and diverse body of knowledge to enable real-world impact. Professor Kensuke Fukushi from IFI and study co-author summarized their hope that “an improved understanding of nature’s many connections to human well-being and the underlying processes mediating them, can help policymakers to design appropriate interventions. Such coordinated action could leverage the positive contributions of these connections and become another avenue to protect and manage ecosystems sustainably.”

The study, published Aug. 2 in the Journal of Dairy Science, confirmed for the first time that heat-stressed dairy cows develop gut permeability, or leaky gut, which contributes to a reduction in milk production. Researchers also found that milk production can be partially restored by feeding the cows organic acids and pure botanicals.

“This has immediate application,” said Joseph McFadden, associate professor of dairy cattle biology in the College of Agriculture and Life Sciences and senior author of the paper. “And we hope it serves as a catalyst for the field and ignites further research into dietary approaches.”

The paper’s first author is Ananda Fontoura, a doctoral student in McFadden’s lab.

The research will help maintain the efficiency and sustainability of the dairy industry as demand and temperatures both rise. Climate change is already causing reduced production and threatened health in Holsteins, by far the dominant breed in U.S. dairy farming. McFadden said the New York state dairy industry is not safe because of its relatively cool climate — heat stress in Holsteins begins to occur at 75 degrees Fahrenheit.

“In New York state, we’re projected to have an increase in heat-stress events in the next decade, but the precipitation is supposed to stay,” McFadden said. “With major droughts and water demands in other areas of the country, there may be an increased emphasis on maintaining the strength of the Northeast dairy industry, but we’ll still have more heat-stress events, and we have to be proactive and ready.”

Heat stress causes the cows to eat less, and the drop in food intake accounts for 30 to 50% of the drop in milk production — this was known. The researchers provided evidence that the remaining decline develops with an increase in intestinal permeability, which activates the immune system.

“The general working hypothesis was that an activated immune system partitions energy away from milk production to support immune function,” McFadden said. “When the gut becomes permeable, it allows bacteria to enter the cow that activate the immune system and cause inflammation. But there had never been a study that directly confirmed that heat-stressed dairy cows developed leaky gut. Prior data only inferred this possibility.”

Researchers found that cows exposed to heat-stress conditions developed leaky gut quickly, after just three days. A control group in a thermal-neutral environment, with the same reduced food intake, experienced a delay in the development of enhanced gut permeability.

The study also found that the consumption of organic acids and pure botanicals reduced the cow’s gut permeability and increased food intake and milk production, restoring about three kilograms of milk per day. The cows showed increased nitrogen efficiency as well, which can mean less nitrogen excreted into the environment.

Currently, sprinklers and fans are used to mitigate heat stress on cows, but these strategies burn fossil fuels and only restore about 60% of milk production. Economic losses due to heat-stressed dairy cows are estimated to exceed $1.5 billion a year, more than any other domestic animal production systems — in large part because of the Holstein’s intolerance for heat.

McFadden’s team is working with surgeons at the College of Veterinary Medicine, who were able to isolate samples of the cow’s intestine, and with colleagues in the College of Engineering and at Johns Hopkins University to analyze the microbiome and metabolite profile of the cow’s GI tract. These studies will help determine why gut permeability occurs under heat stress and provide further insight into how to keep cows healthy.

“The field is really lacking in dietary approaches to improve gut health; it’s an underdeveloped area,” McFadden said. “It’s very difficult to study because you need the facilities to do the heat-stress studies and the surgeons to get those precious samples. Cornell is really unique in that we have a lot of resources at our disposal to answer these questions.”

Further research could reveal the efficacy of different additives, or even recommend changes to the staple diet of cows across the U.S., through optimization of the Cornell Net Carbohydrate and Protein System, a widely used model for determining what dairy and beef cattle should eat.

“That model helps nutritionists formulate diets for cows,” McFadden said. “If we can improve that model and understand the nutrient requirements that a cow has during a heat-stress event, we can ensure she’s getting what she needs to maintain optimum health and performance.”

This study was supported by a Northeast Sustainable Agriculture Research and Education Graduate Student Research Grant, the Foundation for Food and Agriculture Research (FFAR), and Vetagro S.p.A., a FFAR industry cosponsor. Fontoura is a FFAR Research Fellow.

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Materials provided by Cornell University. Original written by Caitlin Hayes, courtesy of the Cornell Chronicle. Note: Content may be edited for style and length.