Implantable Pharmacy-On-a-Chip Now Under Fasttrack Development
By Deborah Borfitz
July 6, 2021 | A trio of universities are putting their heads together to engineer a wirelessly controlled bioelectronic implant intended to help soldiers adapt to new time zones or drastic changes in their work schedules by releasing peptide-based therapies to harmonize their central and peripheral circadian clocks. The solicitation came from the Defense Advanced Research Projects Agency (DARPA) and the timeline is ambitious, with a first-in-human safety study expected to begin by 2025, according to Jonathan Rivnay, principal investigator of the project and assistant professor of biomedical engineering at Northwestern University.
The project aims to create a Normalizing Timing of Rhythms Across Internal Networks of Circadian Clocks (aka NTRAIN) device, otherwise known as a “living pharmacy” that involves the engineering of cells that will secrete biologics based on an optoelectronic trigger and a communication signal from an external wearable device, he says. Provided the cells are alive and happy, the therapy can be produced on-site as needed or prescheduled for delivery.
Multiple engineering feats will need to happen to make this implantable pharmacy-on-a-chip feasible, notes Rivnay. The cells need to manufacture the desired biomolecules as prompted by an external optical cue, for example. Sensors for measuring biomarkers will be dependent on power transfer within budgetary constraints, and the models used to establish baseline circadian phase must be appropriate to those data types.
The project is part of the Advanced Acclimation and Protection Tool for Environmental Readiness (ADAPTER) program designed to maximize warfighter performance by giving troops control over their own physiology. Separately, research teams at Stanford will be developing an implantable device that produces and releases melatonin on demand for up to 30 days and researchers at the Massachusetts Institute of Technology will work on a swallowed device that deploys in the gut and produces compounds that kill foodborne pathogens and neutralize any toxins they may have been released.
Several investigators at Northwestern, Rice University, and Carnegie Mellon University already had the required bioelectronics expertise and the DARPA Broad Agency Announcement prompted that team to acquaint themselves with sleep experts at Northwestern's Center for Sleep and Circadian Biology (CSCB), led by Fred W. Turek. It was a “match made in heaven,” says Rivnay, enabling the team to quickly respond to the novel research opportunity.
The overall system will have several components that are being developed in parallel, he continues. Among these is the bioelectronic device using optogenetics for communication between the implant and the outside world and to interface with the engineered cells.
The device will house the engineered cells and be implanted under the skin, separated from the subcutaneous tissue of users by a membrane that prevents the body’s immune system from kicking into action, Rivnay explains. Synthetic biologists at Rice University, led by Omid Veiseh and Isaac Hilton, are tasked with genetically engineering the cells to secrete the biomolecules as triggered by a pulse of light.
Electronic components—for communication between the implant and an external wearable device, and to keep the engineered cells healthy and allow them to be triggered to deliver the biomolecule of interest—are being made by the Rice team, together with researchers at Northwestern and Carnegie Mellon, he says.
"This control system will allow us to deliver a peptide of interest on demand, directly into the bloodstream," Rivnay says. "No need to carry drugs, no need to inject therapeutics and, depending on how long we can make the device last, no need to refill the device. It's like an implantable pharmacy on a chip that never runs out."
The CSCB will test the efficacy of specific compounds the cells will deliver for shifting the circadian clock, as well as test versions of the completed device in rodent models, continues Rivnay.
The interdisciplinary project will receive up to $33 million in funding over the next 4 1/2 years, which will be doled out in phases as milestones are hit, Rivnay says. The implant will be developed during phase one, followed by integration and validation of the device, and then testing in human trials.
Another key partner in development of the NTRAIN device is Blackrock Neurotech, without which getting to the clinical trial phase in under five years would be infeasible, says Rivnay. The intent of the study is to ensure the device is safe for implantation for over a month or two—a “significant step” given that the technology has many potential applications beyond controlling circadian rhythm, including treatment of pain, diabetes, and depression.
Blackrock Neurotech has many years of experience commercializing implantable bioelectronic devices as well as working with academic groups and government agencies to shepherd them through the regulatory process. “[It] is going to help us manufacture devices that will be used for preclinical and clinical studies and make sure we are taking all the proper steps during the design process to meet the timeline [designated by] DARPA.”
As currently envisioned, the bioelectronic device could be implanted in the upper arm with a bicep wrap serving as the external hub facilitating communication between a smartphone app and the implantable device, Rivnay shares. The system would have the “biological specificity” of how pharmaceuticals typically get delivered, with the added advantage of precise dosage control and timing via bioelectronics.
If a prototype device can be successfully developed, it would open the possibility of sensing and acting on all sorts of biomarkers in a closed-loop system (implantable device, application, and wearable pump), he points out. As designed now, users control whether a dosage schedule gets initiated, but the system’s electronics could be configured to allow for engaging physicians in the approval process.
DARPA is always interested in seeing innovations it funds for the benefit of warfighters translate into useful products in the civilian sector, says Rivnay, noting that none of the work on the project is classified. As he has been learning from his colleagues at the sleep center, people who do not have a well-regulated circadian rhythm or have a work schedule that toggles between day and night shifts can experience adverse health effects, including heightened risk for cardiovascular diseases and metabolic disorders.
A device that can deliver a treatment on a regular schedule based on sensed biomarkers is going to be disruptive, Rivnay says, especially when it comes to commonplace conditions such as diabetes. Many ethical questions regarding potential abuses are also going to be openly discussed between now and then, both within the program and throughout the field, he adds.