Realeve has developed the first externally powered implantable neuromod device for treating brain disorders.
By Dave Fromm, Promex
Realeve’s Pulsante implant [Photo courtesy of Realeve]
For decades, the blood-brain barrier (BBB) has been a treatment blocker in neuromedicine.
But now, design engineers at Realeve and manufacturing engineers at Promex have found their way through this obstacle, which protects the brain from microorganisms circulating in the bloodstream.
Together, we developed Pulsante, a minimally invasive, externally powered neuromodulation pain treatment implant system. It’s the first technology to deliver modulation beyond the BBB and holds extensive possibilities for brain treatment.
The team crossed clinical, regulatory and technical barriers to bring this novel neurotechnology to market. Here’s how we broke through.
The unmet need: building devices for an inaccessible organ
Realeve’s mission is to solve one of the critical barriers in brain health: the ability to bypass the brain’s natural barrier to deliver therapeutics. The BBB is the crucial immunological feature of the human central nervous system, but also prevented neuromodulation treatments for brain disorders caused by ischemic stroke, cluster headaches, age-related neurodegenerative disorders, and traumatic brain injury.
Treatments for these disorders require interventions that reach deep into brain tissue. But just as the BBB protects the brain from toxins, it also blocks more than 98% of small-molecule drugs and virtually all large-molecule biologics.
Device developers have tried to circumvent this with intrathecal pumps, ultrasound, and catheter-based approaches. Yet these methods come with safety tradeoffs, patient compliance issues, and treatment delivery variability.
The technical solution: a new paradigm for neuromodulation
Realeve’s Pulsante Micro-Neurostimulator System is a minimally invasive, externally powered neuromodulation pain treatment implant system. It’s the first technology to deliver modulation beyond the blood-brain barrier. [Image courtesy of Realeve]
The journey began when Realeve founder and Chief Medical Officer Dr. Peter Bonutti noticed an unexpected effect during due diligence on a device he was developing to treat cluster headaches. When stimulating the sphenopalatine ganglion (SPG), patients experienced changes not only in pain perception, but in neurological function. It was a signal that SPG stimulation might influence the autonomic nervous system and, perhaps, the permeability of the BBB.
In preclinical models, SPG stimulation triggered vasodilation and mechanically “stretched” tight junctions in the BBB, increasing permeability fivefold, allowing antibodies and stem cells to cross the barrier safely.
Bonutti set out to control this mechanism, trialing the delivery of neuromodulation to parts of the brain for the treatment of cluster headaches, which are so painful they are commonly referred to as “suicide headaches.” The design is a battery-free implantable device, which could be activated by patients over the long term for on-the-spot, at-home treatments.
Clinical validation of the Pulsante among more than 700 patients showed the technique was safe and effective, with 75% of patients experiencing reduced chronic cluster headache frequency and intensity within four weeks. The discovery of the increased permeability of the BBB that could enable previously impossible therapies was an adjacent discovery.
Designing Pulsante
Realeve’s Pulsante RC-200 handheld transmitter [Photo courtesy of Realeve]
At the heart of the Pulsante system is a SPG microstimulation implant, activated wirelessly via the Pulsante RC-200 handheld transmitter that patients use to trigger therapy. When patients place the transmitter on the outside of their cheek near the implant, the RC-200 powers the device and initiates precise, low-frequency stimulation, modulating BBB permeability in a controlled and reversible manner.
The design brief for the pain relief system was daunting; the team needed to design, develop, and manufacture minimally invasive implant with long-term biocompatibility, a wireless power transfer without the need to store its own energy, precision neurostimulation without onboard intelligence, seamless patient usability and experience, and scalable, cost-effective manufacturing.
Promex was tasked with converting design concepts and assembly drawings into a high-reliability, manufacturable system, particularly focused on the complex header assembly, which is sealed within a ceramic/titanium encasement.
Key manufacturing and development steps included:
While automation plays an increasingly important role in medical device manufacturing, Pulsante’s production demonstrates that human expertise remains essential to ensure precision and quality in complex, micro-scale integrations. [Photo courtesy of Promex]
Reverse engineering: Instead of redesigning from scratch, Realeve preserved historical device data and performance characteristics to accelerate technology transfer to Promex and avoid regulatory resets, once funding allowed the idea to move to prototyping and early, small production batches. Advice from the manufacturer: OEMs should carefully retain all original design drawings, especially given the increased amount of time and funding between concept and partnering with a developer/manufacturer.
Phase-gate design: Each development stage included a risk evaluation, process control assessment, and performance mapping. Advice to OEMs with first-generation devices: A phase-gate process is crucial for devices where stimulation timing and dosage directly influence neurological outcomes.
Build versus buy: The team carefully selected off-the-shelf components only when reliability and traceability met medical-grade thresholds. Otherwise, custom parts were developed in-house or by vetted suppliers. Modern devices, especially first-of-their-kind innovations, may not be able to use off-the-shelf components. Don’t resist having your production partner customize parts and don’t assume they (and the process) will be more costly than readily available inventory. In many cases, this is not true.
Surface mounting was streamlined with a “strip-snap” manufacturing technique, in which subassemblies are built in “strip” form, which enables efficient and high throughput during processing and testing. [Photo courtesy of Promex]
Hybrid assembly: The Pulsante device required a hybrid manufacturing approach that blended automation with skilled manual assembly. One example is our “strip-snap” manufacturing technique, in which subassemblies are built in strip form to streamline SMT, chip attach, and wire bonding for efficient, high-throughput processing and testing. Once these subcomponents are completed, the panels are singulated via a snap process, and the individual units are manually integrated into the final hermetic housing. This critical stage demands the precision and dexterity of highly skilled technicians, particularly when working with miniature components such as micro coils and performing intricate wire bending during final assembly. While automation plays an increasingly important role in medical device manufacturing, Pulsante’s production demonstrates that human expertise remains essential to ensure precision and quality in complex, microscale integration.
Future opportunities: a platform for BBB access
More than a neuromodulation device, Pulsante is a platform for drug and biologic delivery across the BBB. Therapeutics that have been previously blocked from entering the brain (such as monoclonal antibodies, anti-inflammatories and stem cells) will one day be administered in conjunction with Pulsante stimulation. Future iterations of the new system may integrate AI-based tracking, predictive algorithms, and closed-loop stimulation for highly individualized patient care.
Realeve is exploring expanded indications where neurostimulation has shown growing clinical relevance, including stroke recovery, neuropathic pain, sleep disorders, and anxiety.
For now, Pulsante answers a growing demand for nonpharmaceutical, minimally invasive interventions that enable home-based therapies.
Realeve’s Pulsante is a success story in bringing a new device to market, which simultaneously revealed the answer to the BBB block that had been limiting brain treatment possibilities for so long. As device complexity increases and therapeutic expectations rise, Pulsante demonstrates that even the most protected organ in the body can be reached with the right combination of insight, engineering, and execution.
Promex Chief Operations Officer Dave Fromm [Photo courtesy of Promex]
Dave Fromm is chief operations officer at Promex, a leader in microelectronic assembly for the medtech and biotechnology markets. With cutting-edge equipment, extensive material properties knowledge, and meticulous supply chain management, Promex partners with OEMs at all stages, from early prototypes to R&D development and high-volume production.
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The opinions expressed in this blog post are the author’s only and do not necessarily reflect those of Medical Design & Outsourcing or its employees.
