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Clinical Laboratories and Pathology Groups

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Brigham and Women’s Hospital Researchers Develop Implantable ‘Lab in a Patient’ to Test Effectiveness of Brain Cancer Drugs

Scientists reported positive Phase 1 trial results of their “intratumoral microdevice” in patients with glioma tumors

Here is an example of new microtechnology which has the potential to greatly shorten the time and improve the ability of physicians to determine which anti-cancer drug is most effective for an individual patient’s glioblastoma. As it is further developed, this technology could give anatomic pathologists and clinical laboratories an increased role in assessing the data produced by microdevices and helping physicians determine the most appropriate anti-cancer drug for specific patients.

In a news release, researchers at Brigham and Women’s Hospital (BWH) in Boston said they have developed an implantable “intratumoral microdevice” (IMD) that functions as a “lab in a patient,” capable of gauging the effectiveness of multiple drugs that target brain tumors. In a Phase 1 clinical trial, they tested the IMD on six patients with glioma tumors.

“In order to make the greatest impact on how we treat these tumors, we need to be able to understand, early on, which drug works best for any given patient,” study co-author Pier Paolo Peruzzi, MD, PhD, told the Harvard Gazette. “The problem is that the tools that are currently available to answer this question are just not good enough. So, we came up with the idea of making each patient their own lab, by using a device which can directly interrogate the living tumor and give us the information that we need.”

Peruzzi is Principal Investigator at the Harvey Cushing Neuro-Oncology Laboratories and Assistant Professor of Neurosurgery at Harvard Medical School.

The researchers published their findings in the journal Science Translational Medicine titled, “Intratumoral Drug-Releasing Microdevices Allow In Situ High-Throughput Pharmaco Phenotyping in Patients with Gliomas.” [PHOTO OF PERUZZI HERE

“Our goal is for the placement of these devices to become an integral part of tumor surgery,” said Pier Paolo Peruzzi, MD PhD (above) of Brigham and Women’s Hospital and Harvard Medical School in an article he co-wrote for Healio. “Then, with the data that we have from these microdevices, we can choose the best systemic chemotherapy to give to that patient.” Pathologists and clinical laboratories may soon play a role in helping doctors interpret data gathered by implantable microdevices and choose the best therapies for their patients. (Photo copyright: Dana-Farber Cancer Institute.)

New Perspective on Tumor Treatments

In a news story he co-wrote for Healio, Peruzzi explained that the microdevice—about the size and shape of a grain of rice—contains up to 30 tiny reservoirs that the researchers fill with the drugs they want to test. Surgeons implant the device during a procedure to remove the tumors.

The surgery takes two to three hours to perform, and during that time, the device releases “nanodoses” of the drugs into confined areas of the tumor. Near the end of the procedure, the device is removed along with tissue specimens. The researchers can then analyze the tissue to determine the effectiveness of each drug.

“This is not in the lab, and not in a petri dish,” Peruzzi told Harvard Gazette. “It’s actually in real patients in real time, which gives us a whole new perspective on how these tumors respond to treatment.”

The Healio story notes that gliomas are “among the deadliest brain cancers and are notoriously difficult to treat.” With current approaches, testing different therapies has posed a challenge, Peruzzi wrote.

“Right now, the only way these drugs are tested in patients is through what are called window-of-opportunity studies, where we give one drug to the patient before we resect the tumor and analyze the effect of the drug,” he said. “We can only do this with one drug at a time.”

Determining Safety of Procedure

The primary goal of the Phase 1 trial was to determine the safety of the procedure, Peruzzi noted. “To be in compliance with standard clinical practice and minimize risks to the patients, we needed to integrate the placement and retrieval of the device during an otherwise standard operation.”

The trial consisted of three men and three women ranging from 27 to 86 years old, with a median age of 76. Five were diagnosed with glioblastoma and one with grade 4 astrocytoma.

“None of the six enrolled patients experienced adverse events related to the IMD, and the exposed tissue was usable for downstream analysis for 11 out of 12 retrieved specimens,” the researchers wrote in Science Translational Medicine. They noted that application of the IMD added about 32 minutes to the time required for the surgery, equating to a cost increase of $7,800.

One drug they tested was temozolomide (TMZ), “the most widely used agent in this patient population,” they wrote. “Several patients in our trial received it systemically, either before or after IMD insertion, as part of the standard of care. Thus, although our trial was not designed to choose chemotherapy agents based on IMD data, we still could compare the observed clinical-radiological response to systemic TMZ with the patient-specific response to TMZ in the IMD-exposed tissue.”

One patient, the researchers noted, had not benefited from the drug “in concordance with the poor tissue response observed in the IMD analysis.” But in another patient, a 72-year-old woman, “IMD analysis showed a marked response to TMZ,” and she survived for 20 months after receiving the treatment “with radiological evidence of tumor response. This was despite having a subtotal tumor resection, in itself an unfavorable prognostic factor. The patient expired because of an unrelated cardiovascular event, although she had remained neurologically stable.”

Drug Duration Limitation

One limitation of the study was that testing the device during the tumor removal procedure limited the duration of the drug treatments, Peruzzi said. The Harvard Gazette noted that following their initial study, the researchers were testing a variation of the procedure in which the device is implanted three days before the main surgery in a minimally invasive technique. This gives the drugs more time to work.

Cancer researchers have theorized that common treatments for tumors can impair the immune system, Peruzzi wrote in Healio. “One thing we want to look at is which drugs can kill the tumor without killing the immune system as well,” he noted.

Future studies will determine the effectiveness of implanting microdevices into tumors to test therapies in vivo. Should they become viable, clinical laboratories and anatomic pathologists will likely be involved in receiving, interpreting, storing, and transmitting the data gathered by these devices to the patient’s doctors.

—Stephen Beale

Related Information:

Microdevices Implanted into Tumors Offer New Way to Treat Brain Cancer

Intratumoral Drug-Releasing Microdevices Allow In Situ High-Throughput Pharmaco Phenotyping in Patients with Gliomas

Microdevices Turn Brain Tumors into Tiny Labs

Devices Implanted into Brain Tumors During Surgery May Guide Treatment

Human Brain Tumor Implant Could Guide Personalized Therapies Tiny Implanted Devices Give Insights for Treating Brain Tumors

Binghamton University Scientists Develop Biobattery That Powers Ingestible Devices and Biosensors Inside the Human Small Intestine

Biobattery might one day power clinical laboratory testing devices designed to function in vivo to measure and wirelessly report certain biomarkers

Clinical laboratories may one day regularly process biomarker data sent by ingested medical devices from inside the human body, such as the colon and intestines. But powering such devices remains a challenge for developers. Now, researchers at Binghamton University in New York have developed a biobattery that derives its power based on pH reactions when it comes in contact with acids inside the gut.

The battery uses “bacteria to create low levels of electricity that can power sensors and Wi-Fi connections as part of the Internet of Things,” according to a Binghamton University news release.

The biobattery uses microbial fuel cells with spore-forming bacteria for power and it remains inactive until it reaches the small intestine.

Ingestible devices, such as wireless micro cameras, are being utilized more frequently to investigate a myriad of activities that occur in vivo. But traditional batteries that power ingestible diagnostic gadgets can be potentially harmful and are less reliable.

In addition, the small intestine in humans is typically between 10 and 18 feet in length and it folds several times to fit the abdomen. Thus, the inside area can be very difficult to reach for diagnostic purposes.

The scientists published their research in the journal Advanced Energy Materials titled, “A Biobattery Capsule for Ingestible Electronics in the Small Intestine: Biopower Production from Intestinal Fluids Activated Germination of Exoelectrogenic Bacterial Endospores.”

Seokheun “Sean” Choi, PhD

“There are some regions in the small intestine that are not reachable, and that is why ingestible cameras have been developed to solve this issue,” said Seokheun “Sean” Choi, PhD (above), Professor of Electrical and Computer Engineering at Binghamton University, in a news release. “They can do many things, such as imaging and physical sensing, even drug delivery. The problem is power. So far, the electronics are using primary batteries that have a finite energy budget and cannot function for the long term.” As these technologies develop, clinical laboratories may play a role in collecting biomarker data from these devices interpretation by physicians. (Photo copyright: Binghamton University/Jonathan Cohen.)

How Binghamton Researchers Developed Their Biobattery

To develop their new biobattery, the Binghamton researchers encased Bacillus subtilis, a bacterium found in the gastrointestinal tract of humans, in a graphene integrated hydrogel that excels at grabbing moisture from the air.

The dime-sized fuel cell assembly is then sealed with a piece of Kapton tape, which can withstand temperatures from -500 to 750 degrees Fahrenheit. When the tape is removed, moisture mixes with a chemical germinant that causes the bacteria to begin manufacturing spores. 

“We use these spores as a dormant, storable biocatalyst,” explained Seokheun “Sean” Choi, PhD, Professor of Electrical and Computer Engineering at Thomas J. Watson College of Engineering and Applied Science, Binghamton University, in the news release. “The spores can be germinated when the nutrients are available, and they can resume vegetative life and generate the power.”

The biobattery generates around 100 microwatts per square centimeter of power density, but it can take up to an hour to germinate completely. After one hour, the energy generated from the device can power an LED light, a small clock, or a digital hygrometer, as well as a micro camera for in vivo use.

“We wanted to make these bio-batteries for portable, storable, and on-demand power generation capabilities,” Choi said in the news release.

“The problem is, how can we provide the long-term storage of bacteria until used? And if that is possible, then how would you provide on-demand battery activation for rapid and easy power generation? And how would you improve the power?” Choi added.

Heating the fuel cell decreased the time it took to reach full power to 20 minutes, and increasing the humidity resulted in higher electrical output.

Potential for Long-term Power Storage

In addition, after a week of being stored at room temperature, the activated battery had only lost 2% of its power. The researchers also believe that the device could function properly in an inactivate state for up to 100 years, provided there is enough moisture to activate the bacteria after the Kapton tape is removed.

“The overall objective is to develop a microbial fuel cell that can be stored for a relatively long period without degradation of bio-catalytic activity, and also can be rapidly activated by absorbing moisture from the air,” said Choi in the news release. 

The federal Office of Naval Research funded the study.

More research and studies are needed to confirm the biobattery performs properly and is feasible for general use. This experimentation would require both animal and human testing, along with biocompatibility studies.

“I think this is a good start,” Choi added. “Hopefully, we can make a commercial product using these ideas.”

If the biobattery can power an ingestible medical device for a reasonable period of time, then this invention may be able to power a clinical laboratory testing device that could function in vivo to measure and wirelessly report certain biomarkers inside the body. 

—JP Schlingman

Related Information:

Tiny Biobattery with 100-year Shelf Life Runs on Bacteria

Capsule-Sized Ingestible Biobatteries Could Allow New View of Digestive System

Bacteria-based Biobattery Could Power Devices in the Small Intestine

A Biobattery Capsule for Ingestible Electronics in the Small Intestine: Biopower Production from Intestinal Fluids Activated Germination of Exoelectrogenic Bacterial Endospores

Spore-producing Bacteria Battery Could Last 100 Years on the Shelf

Scientists Create Stretchable Battery Made Entirely Out of Fabric

New 3D Sutures Enable Collection of Biodata In Vivo Using Thread-Based Diagnostic Devices

Engineers have designed a microfluidics and nano-scale diagnostic toolkit suitable for attaching directly to muscle and tissue to monitor biomarkers and stream results wirelessly to care providers and medical laboratories

What would change in medicine if physicians had sutures that could collect and report biomarker data, including the kinds of biomarkers that are used in clinical laboratory tests? Such a product may be feasible, based on newly-published research.

“Smart sutures” are a joint project between Tufts University, Harvard University, and Massachusetts Institute of Technology (MIT) engineers. They announced a thread-based diagnostic device (TDD) system capable of detecting biomarkers and analytes using 3D sutures composed of cotton and synthetic threads.

Processing the cotton and synthetic threads in various ways enhances their natural properties. The toolkit of different sutures developed by the team has exhibited a range of uses—including measuring physical stress at an incision, monitoring pH of tissues and fluids, and measuring glucose. (more…)

First-generation of a Clinical Laboratory-on-a-Chip Measures Multiple Bio-markers and Also Drugs in The Body

Implantable chips could change the way doctors monitor chronic conditions and administer medications, while providing pathologists with an opportunity to analyze a new stream of diagnostic data

Researchers continue to make progress on implantable diagnostic devices that are designed to monitor the same types of biomarkers used in some clinical laboratory tests. These devices are designed to provide continuous patient monitoring and can transmit data in real time to care providers and medical laboratories.

Miniature Laboratory on a Chip

Implantable medical devices have been around for quite some time. However one particular device developed by Sandro Carrara, PhD,  and Giovanni De Micheli, PhD, at the Ecole Polytechnique Federale de Lausanne (EPFL), works more like a tiny laboratory than previous generations of implantable devices.

“This is the world’s first chip capable of measuring not just pH and temperature, but also metabolism-related molecules like glucose, lactate, and cholesterol, as well as drugs,” stated Carrara in R&D Magazine. (more…)

Stanford’s New Ant-sized Radio Could Accelerate Massive Connectivity through the Internet of Things and Enable Real-time Medical Laboratory Testing

Micro-miniature intelligent radio devices are poised to revolutionize the connectivity of objects in ways that could open doors to new diagnostic devices to help pathologists detect disease

In the future, both in vitro diagnostics and in vivo diagnostics will utilize ever-smaller devices. The shrinking size of these analytical devices will give pathologists and clinical laboratory scientists new tools to detect disease earlier, while monitoring patient with chronic conditions in real-time in consultation with attending physicians.

Now comes news of a significant breakthrough that will allow researchers to shrink down the size of devices used for a wide range of applications, including medical laboratory testing. Engineers from Stanford University and the University of California, Berkeley, have created a prototype radio-on-a-chip the size of an ant.

Their invention could enable a vast assortment of gadgets to connect and communicate with each other, and with physicians, via the Internet. The new device has the potential for numerous applications for pathology and medical laboratories, and could be used in many types of diagnostic testing devices, including in vivo diagnostics. (more…)