New ‘FRRB’ packaging technology may solve an ingestible capsule challenge

Fig 6 from the paper. [Click to enlarge.] (a) A schematic of the internal flex actuator (left) before and (right) after deployment via thermal actuation. (b) An uncoated actuator packaged capsule before (left) and after (right) firing of the actuator. (t=0 min) (c) An image of the microneedles fired into agar showing dye diffusion from the microneedle patch. (t=20 min) (d) The 5x FRRB coated preloaded capsule before (left) and after (right) translation and deployment of the GI simulator. (e) Images of the capsule during translation across the small intestinal phantom showing the microneedle patch left behind as the capsule translates.

A new University of Maryland technology is advancing the development of ingestible devices to diagnose and treat diseases of the gastrointestinal (GI) tract. This work by the MEMS Sensors and Actuators Laboratory (MSAL) has been published in the Nature journal Microsystems & Nanoengineering.

IBD—inflammatory bowel disease—is just one of many auto-immune conditions affecting or originating in the GI tract. Like many diseases in this genre, detection, diagnosis and treatment is complicated and takes time. Typically it involves repeated blood and stool lab work; many clinician visits; biopsies, colonoscopies and endoscopies; and x-ray, CT scan and MRI imaging.

Ingestible capsules could soon be an attractive alternative to these traditional ways GI diseases are diagnosed and treated. A new generation of ingestibles under development is incorporating components that can interact with the GI environment. They will be able to perform complex diagnostic and therapeutic tasks like sensing, monitoring and drug delivery. Overall, these devices will be less invasive to the patient and promise fast and accurate diagnosis.

To work well, the components inside ingestible capsules must be protected from the acidic fluids and solids they encounter as they journey through the GI tract on their way to their intended destination in the intestines. This is a “packaging” challenge, to which there are a number of possible solutions. A pH-responsive surface coating can be applied to ingestible capsules. Commonly known as an “enteric” coating, this is similar to those used to delay pharmaceutical drug delivery, like the daily 81mg enteric-coated aspirin many people take for heart health. However, its usefulness is limited, especially when the capsule needs to perform complex tasks.

Another idea that has been tried is adding an active mechanical opening mechanism to the capsule. However, such mechanisms can be bulky and add complexity and weight to the device. They also may require stimulus from beyond the capsule, through high-powered equipment.

Now, the MEMS Sensors and Actuators Laboratory (MSAL), a University of Maryland research group with a long history of groundbreaking research into ingestible capsules, has developed a new solution: a hybrid, passive, freestanding packaging technology that can be used to cover, then expose, a capsule’s mm-scale components. It’s something pH-responsive polymer coatings cannot do on their own.

The new research has just been published in Microsystems & Nanoengineering. “Freestanding Region Responsive Bilayer for Functional Packaging of Ingestible Devices” introduces FRRB (freestanding region responsive bilayer), which can be readily applied to various functional ingestible capsule components. The paper was written by Bioengineering Ph.D. student Michael Straker, Materials Science and Engineering Ph.D. student Joshua Levy, Electrical and Computer Engineering Ph.D. candidate Justin Stine, alum Vivian Borbash (ECE BS 2022), UMD Research Associate Luke Beardslee and Professor Reza Ghodssi (ECE/ISR), who directs the MSAL lab. Ghodssi is the advisor to the student and alumni authors.

In creating FRRB, the researchers have combined pH-responsive and water-soluble materials to achieve versatile, easy-to-use freestanding structures for capsules. It is a big step in proving the potential of passively activated functional packaging components.

“Ingestible capsule devices are the next frontier of medical technology,” said first author Michael Straker. “The FRRB is a simple yet elegant solution to one of the major challenges of developing these devices. It can be used to develop creative new designs, allowing sensitive actuators and sensors to reach targeted regions of the GI tract unscathed.”

The FRRB bilayer is made from a rigid polyethylene glycol (PEG) under a flexible pH responsive Eudragit® FL 30 D 55. This bilayer protects the contents of an ingestible capsule as the capsule transits through the GI tract to its target environment in the intestines. The PEG support allows the FRRB to protect underlying components without contacting them, while facilitating exposure in response to pH-specific regions along the GI tract. The bilayer eliminates the need for complex space- and energy-intensive opening mechanisms.

FRRB can be fabricated into a number of shapes useful for functional packaging mechanisms. The PEG support, formed by melt processing, provides a conformable substrate to enable previously unattainable geometries. The paper illustrates a number of these configurations and their potential functions.

It can be customized to cover any portion of an ingestible capsule and to form packaging that passively serves a role in capsule operation. This could include operations such as depositing drug payloads and exposing sensors with large surface areas. In addition, FRRB operates sequentially, offering versatility for various functions. The Eudragit layer is removed in the small intestine target environment via a combination of dissolution and abrasion from the intestinal wall. Next, the PEG layer dissolves in the surrounding aqueous media to reveal the underlying components of the capsule. In the paper, the authors demonstrate a capsule design where—in a simulated environment—exposure to the pH and abrasive forces of the small intestine successfully caused halves of a capsule to separate, which could be useful for drug delivery.

FRRB can protect large areas of a capsule, establishing a gap between itself and internal capsule components. This ability to protect large surface areas without direct contact with underlying components could provide a simple packaging solution for sensors that have been functionalized with fragile surface modifications.

Overall, FRRB provides a versatile packaging solution that can be readily applied to any ingestible capsule platform. It can protect fragile capsule components within the GI tract until they reach their intended destination, then dissolve away so they can perform the functions for which they were designed.

“For many years, pH-responsive materials have been used by pharmaceutical companies for drug delivery,” says Reza Ghodssi. “Our group has demonstrated an integrative hybrid version of this packaging concept towards the promise of ingestible capsules. It is our expectation that this manufacturing approach will widen the design paradigm of developing minimally invasive micro/nano/bio devices and systems for health care monitoring, treatment, and prevention applications.”

Ingestible capsule devices are the next frontier of medical technology.

Michael Straker, Bioengineering Ph.D. student and first author

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