Medical Design & Outsourcing – NOVEMBER 2023

JOHNSON & JOHNSON MEDTECH USED RWE FOR EXPANDED INDICATIONS — AND YOU CAN, TOO

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www.medicaldesignandoutsourcing.com NOVEMBER 2023

2023

How ABBOTT designed the HANDBOOK

FIRST

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JOHNSON & JOHNSON MEDTECH USED RWE FOR EXPANDED INDICATIONS — AND YOU CAN, TOO

P.76

www.medicaldesignandoutsourcing.com NOVEMBER 2023

2023

How ABBOTT designed the HANDBOOK

FIRST

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Medical Design & OUTSOURCING

November 2023 • Vol.9 No.7 • medicaldesignandoutsourcing.com

EDITORIAL

SHI

P IN M

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LEA

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N WI

HONORABLE MENTION

GOLD NATIONAL AWARD

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2023

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SILVER NATIONAL AWARD

BRONZE NATIONAL AWARD

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NATIONAL GOLD FOR OPENING FEATURE SPREAD DESIGN

R NE

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Medical Design & OUTSOURCING

DIGITAL MAGAZINE MAGAZINE OF THE OF THE YEAR YEAR

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NATIONAL GOLD FOR REGULAR DEPARTMENT

PRESENTED BY

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2023

DIGITAL MAGAZINE OF THE YEAR HONORABLE MENTION

CONGRATULATIONS 20

EDITORIAL S TA F F

2023 ASBPE AZBEE AWARD WINNER

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A

Medical Design & Outsourcing is excited to release the winners of our annual Leadership in Medical Technology program.

Since we announced the nominees in our January 2023 issue and online, our user community has voted on what companies they feel best exemplify medical technology leadership in 14 categories. We are happy to celebrate the winners here and at www.medicaldesignandoutsourcing.com.

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2014 - 2016

2014 Winner

2013 - 2017, 2021

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Medical Design & Outsourcing

11 • 2023

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These device innovations have been in the works for years, pushed forward by teams ranging from small startups to the world’s largest medtech companies — and all with help from outsourcing partners.

All of these industry players have Jim Hammerand | come together once again in our Managing Editor | Medical Design & Outsourcing | latest edition of the Medical Design & j ham hamm m e ra n d@ wtwh m e di a .c o m | Outsourcing Medical Device Handbook to offer uniquely relevant and actionable advice for device designers and engineers.

This edition includes tips and advice on components, drug delivery, manufacturing, machining, molding, materials, orthopedics, product design, development, regulatory matters, reimbursement, software, and tubing. All of these articles are also available in our online Medical Device Handbook, which includes content across all of those categories from previous handbook editions.

Learn from the teams behind Abbott’s dual-chamber, leadless pacemakers; LimFlow’s breakthrough system for saving feet from amputation; Canary Medical’s smart ortho implant; iRhythm’s next-generation cardiac monitoring patch; Medtronic’s Harmony transcatheter pulmonary valve; Insulet’s Omnipod 5 automated insulin delivery system; Stryker’s cementless knee; expanded indications for J&J MedTech products using real-world evidence; and surgical robotics systems from Intuitive and Moon Surgical.

You’ll find all this and more in our latest Medical Device Handbook. As always, I hope you enjoy this edition of Medical Design & Outsourcing — and thanks for reading.

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Medical Design & Outsourcing

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CONTRIBUTORS

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TRENT BIRKHOLZ, Intricon VP of development, leads the team that develops new and next-generation medical devices and medtech that incorporates smart, sensordriven, miniaturized electronics for efficient manufacture and delivery to new, emerging, and existing markets..

KAI LOH, applications engineer at Times Microwave Systems, has worked in the RF/ microwave industry for two decades and held various roles in engineering, marketing, and product management. His product experience ranges from microelectronic components to interconnects for technically demanding applications.

RICK LOPEZ is a senior sales engineer and project manager at binder group subsidiary binder USA.

NAJAFZADEH

WAGNER

MEHDI NAJAFZADEH, PhD., is a senior director at Medidata with experience in investigating new methods that can bridge the gap between randomized and non-randomized data sources. Before joining Medidata, he was an assistant professor of medicine in the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women’s Hospital and Harvard Medical School, and the principal investigator of NIH- and FDA-funded projects that aimed at linking randomized controlled trials to RWD. SAM PUENT, Intricon product development engineering manager, works to improve and extend people’s lives by developing advanced, sensor-driven micromedical devices. He collaborates with project team members, engineers, researchers, and customers to meet project goals through prototyping and product and process development.

PAUL PULKOWSKI is a marketing manager at binder group subsidiary binder USA and a specialist in circular connectors.

JANA WAGNER is a product manager at binder, responsible for medical-grade connectors and other customer-specific projects.

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www.medicaldesign&outsourcing.com

MD&O K-Blog_BCCR_Micro_11-23_P.indd 1

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CONTENTS

medicaldesignandoutsourcing.com • November 2023 • Vol. 9 No. 7

COLUMNS 06

HERE’S WHAT WE SEE:

10

CONTRIBUTORS COMPONENTS:

14

68

ON THE COVER

Breaking new ground in medtech

How to ensure coaxial cables and connectors for critical MRI applications are truly nonmagnetic; 4 tips for sensor miniaturization from Lura Health; Key considerations for electromagnetic sensors for surgical navigation; Connectivity is critical as the need grows for patient monitoring

24

DRUG DELIVERY:

28

MANUFACTURING, MACHINING, MOLDING:

34

MATERIALS:

38

ORTHOPEDICS:

44

PRODUCT DESIGN & DEVELOPMENT:

54

HOW ABBOTT DESIGNED THE WORLD’S FIRST DUAL-CHAMBER LEADLESS PACEMAKER SYSTEM The lead engineer on Abbott’s AVEIR project explains how his team developed a first-of-its-kind wireless pacemaker system that communicates through blood.

Why Insulet crossed the border to develop its Omnipod 5 automated insulin delivery system How Medtronic manufactures its Harmony transcatheter pulmonary valve; Medical nitinol manufacturing: How this nickeltitanium alloy is made for medical devices

76

Sticky business: Six wearable device adhesion tips from iRhythm CTO Mark Day How 3D printing and surgical robotics enable Stryker’s cementless knee implants; Tips to help device developers get paid from smart ortho implant maker Canary Medical Intuitive’s Kathryn Rieger on human factors design in surgical robotics; How Motif Neurotech designed a miniaturized neurostimulator for mental health; Braincomputer interface basics with Synchron co-founder and CEO Dr. Tom Oxley

72

FEATURES

72

MOON SURGICAL THINKS MAESTRO’S LIGHT TOUCH CAN WIN THE SURGICAL ROBOTICS ARMS RACE The Moon Surgical Maestro robotic surgery system faces some stiff competition — and the device developer plans to use that to its advantage.

REGULATORY, REIMBURSEMENT, STANDARDS AND IP:

RWE tips from Boston Scientific Peripheral Interventions CMO Dr. Michael Jaff; Why linking clinical trials to real-world data is the critical next step for medical device development

12

• • • • • THE MEDICAL DEVICE HANDBOOK

60

SOFTWARE:

64

TUBING:

80

AD INDEX

76

J&J USED RWE FOR EXPANDED INDICATIONS – AND YOU CAN, TOO

Two J&J MedTech leaders shared advice to help medical device developers use real-world evidence (RWE) in FDA submissions.

Cough-counting device developers share tips for developing algorithms How LimFlow’s foot-saving system prevents amputations in patients with no other options

Medical Design & Outsourcing

11 • 2023

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How to ensure coaxial cables and connectors for critical MRI applications are truly nonmagnetic Kai Loh Times Microwave Systems

As magnetic resonance imaging scanner fields get stronger, materials, processes and testing are crucial for nonmagnetic interconnects.

M

agnetic resonance imaging (MRI) uses powerful magnets and radio waves to generate images of the body’s internal structures. The strength of the magnetic field in MRI machines is one of the primary factors in determining the quality of the images produced. Currently, most MRI machines have a magnetic field strength between 1.5 Tesla (T) and 3T. However, there are now scanners approved for clinical use that go up to 7T and experimental systems that reach up to 11.7T. MRI machines rely on extensive arrays of radio frequency (RF) interconnects — coaxial cables and connectors — to send and receive the pulsed RF signals used to image patients. It is critical these components be nonmagnetic, as MRI machines rely on the precise and accurate alignment of magnetic fields to produce high-quality images. The presence of any magnetic material can interfere with the process and result in reduced accuracy, distorted images, and potentially even harm to patients.

The term “nonmagnetic” is often used with respect to coaxial cable assemblies.

The differences in magnetic properties among common materials used in RF interconnects can be subtle but significant in their impact, especially in potentially life-critical applications such as MRI

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Medical Design & Outsourcing

11 • 2023

machines. Therefore, careful consideration must be paid to the base materials used, material processing, component finishing, and testing of completed coaxial cable assemblies to ensure no magnetic properties are inadvertently introduced.

Material selection Although RF interconnects such as coaxial cables and connectors are integral to MRI systems, their potential to introduce magnetic materials can be easily overlooked. Therefore, when selecting coaxial cables for MRI machines, it is vital to consider the base material and to what degree it can be magnetized.

For example, ferrous materials such as iron and most types of steels should be avoided. Alternatively, nonmagnetic materials such as copper, brass, beryllium copper, aluminum alloys, and austenitic stainless steels are proven solutions in many applications.

The connectors used in MRI coaxial cable assemblies should also be made of nonmagnetic materials and designed to minimize the magnetic field they generate.

It is not uncommon for many cable assembly suppliers to use components from various sources. Key components are constructed from a number of intricate piece parts often fabricated by different vendors. Without comprehensive control www.medicaldesignandoutsourcing.com

or a vertically integrated manufacturing environment, it can be challenging for a supplier to effectively meet the critical nonmagnetic requirement for MRI machines.

Processing and surface finishing Even with careful selection of base materials and control of manufacturing processes, the extrusion process and machining of materials can introduce elements that may change magnetic properties, especially on a production line that handles a variety of materials.

Even nonmagnetic stainless steel can become magnetic after it has been machined into a connector. It is crucial to ensure the process is carefully regulated.

The finishing of components is also an essential consideration, as a nonmagnetic substrate can become magnetic if plated with the wrong material. For example, using a small amount of silver plating over a nonmagnetic substrate would typically produce an end product considered nonmagnetic.

However, with the increasing field strength of modern MRI machines, even a micro-inches-thick amount of magnetic material becomes increasingly relevant.

Therefore, it is critical to carefully select and clearly specify material for each layer of the plating stack-up. (continued on page 16)

Photo courtesy of istockphoto.com

COMPONENTS

(continued from page 14)

Testing Testing and validating the finished materials used for coaxial cables and connectors to confirm they are nonmagnetic is essential. Use an indepth test process aligned with industry standards such as ASTM F2052 or ASTM F221 to ensure the components are nonmagnetic. These standards define the requirements for materials, magnetic properties, and performance.

This can be done using a Gauss meter or a magnetometer, two tools that measure the strength and direction of magnetic fields. The cables and connectors should be tested in their final configuration, including any adapters or extensions. Thorough testing of the materials and final products can ensure they will not interfere with the MRI imaging process.

Finding the right partner Given the life-saving diagnostics provided by MRI, it is imperative to

choose a partner with a proven track record of developing solutions for mission-critical applications such as the military, spaceflight and aerospace industries. The partner should be able to leverage time-tested standards such as quality, cleanliness, and traceability from those industries.

Manufacturers must take these factors seriously and should offer not only materials but also technical expertise to solve complex problems from an industry-standard perspective.

A third party that provides engineering services in addition to coaxial cable assemblies can become a part of the design team from the beginning and collaborate on the right interconnect solutions for a specific MRI application.

Whether designing a product or helping with processing and techniques, the partner must be committed to providing technical solutions and answers to deliver highquality results.

Takeaways In conclusion, the fundamental requirement to ensure coaxial cables and connectors used in MRI applications are truly nonmagnetic is increasingly important to ensure the images produced are accurate as MRI magnetic fields strengthen.

Careful consideration of the base materials, materials processing, and component finishing ensure coaxial cable assemblies used in critical MRI applications remain nonmagnetic. Once complete, testing the assembled cables and connectors for magnetic fields and verifying compliance with industry standards confirms the assembly will not interfere with the MRI imaging process.

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Jim Hammerand Managing Editor

4 tips for sensor miniaturization from Lura Health

B

eing in China when COVID-19 hit might not seem like a stroke of good luck, but it paid off for Lura Health’s sensor miniaturization efforts.

Without a physical presence in Shenzhen, the minature sensor startup might not have been able to line up a battery supplier willing to take on the demanding needs of Lura Health’s saliva sensor, said cofounder and CEO Daniel Weinstein.

“Supply chain right now is super difficult. Vendor agreements are pretty crazy. [Just about] every PCBA house in the country is backed up with a huge backlog,” Weinstein said in an interview with Medical Design & Outsourcing.

“Our strength as a company is trying to find ways to beat the odds that are against companies — especially startups — in this industry,” he continued. “We’re on the very bottom of the food chain, and we embrace that. Yeah, it gives us a lot of headaches, but we’ve doubled down on really trying to get creative on how to navigate that to keep to timelines.”

The importance of supplier relationship-building is just one lesson Weinstein offered for other developers of miniaturized implant sensors.

Lura Health is developing a saliva sensor in a retainer.

Image courtesy of Lura Health

also promising but it’s not clear when that technology — like the watch-based glucose monitoring Apple’s been working on for more than a decade — will become reality.

Saliva testing is already a booming multbillion-dollar industry, ranging from disease diagnostics to genomics. But it’s mostly one-time testing rather than continuous monitoring.

“There’s a big market already for point-of-care salivary test with a tube sent to a lab. But we see the inevitable conclusion of this space transitioning to a wearable system,” he said.

In order to be useful and justify their cost, wearable, noninvasive monitors need to be easy to use — and easy to get on or inside patients.

“Patients with chronic conditions that need continual monitoring are dealing with a lot of challenges anyway. They don’t need medical devices to introduce even more challenges to try to address their challenges,” he said. “… Because of the universality and prevalence of existing dental devices, because of the ease of access to a dentist — maybe even more so than a doctor — because of the long-term sensor capabilities in the mouth as a long-term device rather than on the skin or something else for compliance, we

“Patients with chronic conditions that need continual monitoring are dealing with a lot of challenges anyway.

They don’t need medical devices to introduce even more challenges to try to address their challenges.”

1. Look for medtech trends and find a way in Lura Health identified three main medtech trends while developing its miniature sensor technology: noninvasive testing, wearable technology, and usability.

While blood’s long been the gold standard for testing, it still requires a skin puncture. And though sweat monitoring is showing potential, it’s difficult to obtain continual reads. Optical sensors are

www.medicaldesignandoutsourcing.com

think that saliva diagnostics in wearables are an avenue to give the patient a tool that doesn’t add any more complexity or pain points than they already have.”

2. ‘Solid state’s the future’ Weinstein is bullish on solid state battery technology for sensor miniaturization.

“I think solid state’s the future,” he said. “If anybody disagrees, I would point them to Abbott’s recent recall of 4.2 million devices where the lithium polymer cells were overheating and catching fire on some of their receivers.”

Solid-state batteries are less reactive and less prone to combustion when punctured than lithium batteries, he said.

Lura Health was among the first recipients of Ilika’s new Stereax M300 stacked batteries this year. Weinstein said Lura Health’s sensors will likely use those solid state batteries when they become available in bulk sometime next year.

3. Surface-mount technology, stacked electronics and simulations Surface-mount technology (SMT) is crucial as a standard for developers of miniaturized sensors, Weinstein said.

“Minimizing manual assembly methods and maximizing assembly that can be compatible with standard SMT machines will save a lot of costs and labor and is important to consider from the beginning,” he said. >> 11 • 2023

Medical Design & Outsourcing

17

COMPONENTS

Lura Health cofounder and CEO Daniel Weinstein

Lura Health’s saliva sensor uses a wireless charging system developed

by Resonant Link.

Photo courtesy of Resonant Link

Developers of miniaturized sensors should already be thinking of how to take advantage of automated manufacturing anyhow, since machine control is going to be required for just about everything at that small scale.

Another trend gaining steam is stacking electronics. Especially in miniaturized devices and components where space is already in short supply, there’s a limited area for electronics on the horizontal plane.

“Utilizing that vertical space more is important,” Weinstein said.

And you can’t just design one part of your device in isolation anymore.

“It’s becoming more and more of a liability to design in silos,” Weinstein said.

“Ultimately you want everything to come together in one picture, from heat transfer simulations to RF simulations to flowthrough simulations. And it’s just more and more important to get that all in an integrated design stack.”

4. Build supplier relationships A physical presence in Shenzhen helped Lura Health find a battery supplier in China despite overwhelming rejection from other potential partners.

“If we reached out to 20 vendors, we got no quotes from 19 of them, and one just happened to be able to do it and give us a shot — maybe begrudgingly, but we were also in China, so we used that face-to-face relationship to do that,” Weinstein said.

Through venture capital firm SOSV’s Hax hardware accelerator, Lura Health arrived in Shenzhen just a few months before the COVID-19 pandemic.

“When we got there, none of the big manufacturers that we needed would talk to us because we were low volume, low MOQs. We were just annoying to them. We needed the best suppliers 18

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www.medicaldesignandoutsourcing.com

because they were the only ones with the capabilities we needed.”

Then the pandemic hit, and suddenly contract manufacturing managers that “previously blew us off” were showing up in their Teslas to take the team to factory tours and dinners, Weinstein said.

“For assembly and production, that was great. For the battery supplier, it was still really tough because … the parameters of the product were ridiculous.

It exceeded all of their miniaturization specs. All of them were really hesitant to even attempt to quote it, and none of them did except one company.”

They developed a hand-rolled, handsealed lithium polymer cell prototype that Lura Health will use to power the nextgeneration units for FDA review. At 10 mm by 4 mm by 0.9 mm, Weinstein said it is the smallest of its kind.

But the tradeoff of smaller batteries in sensor miniaturization is smaller capacity, and Lura Health needed a way to wirelessly recharge the batteries.

The solution came after Weinstein met the co-founder of Resonant Link through the Forbes 30 Under 30 network and learned about their latest highefficiency wireless charging technology while exchanging messages on Slack.

“We were the perfect use case. …

We need it as small as possible, no heat generation, as efficient as possible, as fast as possible,” Weinstein said.

Their collaboration resulted in the smallest charging coil Resonant Link has ever produced, and Lura Health now uses it for wireless recharging of its device.

“We’re thoroughly convinced that’s the only way in the world that we could have done it,” Weinstein said.

Relationships are more important than ever because supply challenges are greater than ever, he said.

“As a startup, it might be impossible to hit the anticipated lead times, but you should never know that there’s going to be a delay on the day that it was expected. You should know it ahead of time. And if it’s a critical supplier, you should be at their factory in person, on a plane, talking with the team. You shouldn’t be trying to get them over email.”

Go to wtwh.me/lura to read more from this interview about Lura Health’s device, its design and the potential applications.

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COMPONENTS

An electromagnetic sensor in a catheter and micro-coils on a dime for scale Illustration courtesy of Intricon

Key considerations for electromagnetic sensors for surgical navigation Tr e n t B i r k h o l z a n d Sam Puent Intricon

As clinicians increasingly rely on electromagnetic surgical navigation, strategic sensor decisions can be the difference between device failure and market success.

T

hough fluoroscopy has long been the standard in surgical navigation, it subjects clinicians and patients to undesirable X-ray exposure, has limitations for procedures with certain imaging needs (3D), and has some reliance on radiopaque material design attributes.

Electromagnetic navigation (EMN) is a proven alternative that provides precision location without radiation risks and is being considered for more widespread use.

As EMN gains traction, the importance of electromagnetic sensors in medical devices is clear. Choosing a sensor that optimizes performance, cost, and manufacturability is paramount, so manufacturers need to carefully evaluate which features their surgical navigation systems demand to achieve clinical and market success.

This article details the advantages of EMN for surgical navigation and explores considerations for optimizing sensor performance, cost, and manufacturability.

Advantages of electromagnetic navigation Fluoroscopy has limitations in the visualization of spaces and can expose patients and caregivers to relatively high doses of ionizing radiation. EMN grants access to areas inaccessible

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with conventional techniques and is considered safe as it doesn’t use ionizing radiation, but rather energy fields that are no more harmful than ultrasound.

Those advantages have driven significant growth as EMN becomes more widely adopted across clinical practice areas such as otolaryngology, oncology, urology, pulmonology, neurology, cardiology, and robotic surgery. In fact, the EMN market is projected to grow at a rate nearly three times that of fluoroscopy through 2030.

EMN sensor considerations for performance, cost, and manufacturability Sensors are integral for overall system performance, but a one-size-fits-all solution rarely works. It’s important to select the right combination of options to meet performance demands while maintaining budgets and manufacturability.

Core geometry shape: The most common core geometry shape is round.

Manufacturing gets more difficult with other core shapes as each requires a unique approach to winding. Keep an open mind around options to manipulate geometries and maximize the volume available for the sensor. Your sensor will be www.medicaldesignandoutsourcing.com

easier to manufacture if your application doesn’t demand a non-round shape.

Size: The goal is to provide the ultimate signal integrity within the smallest possible envelope size. One way to maximize signalto-noise ratio — and increase localization precision — is to increase the sensor core diameter, but that’s often impractical because it makes the sensor too large.

Other strategies include material selection to improve signal integrity — and choosing a size compatible with the application and capable of producing a quality, reliable signal.

Number of sensors: Consider how many sensors are required to visualize everything needed during a given procedure. For example, a second sensor can grant views of rotation in addition to the X, Y, and Z aspects of device position.

The number of sensors on a device ultimately affects design, manufacturing processes, and cost.

Placement and form factor: In many cases, sensors are placed within the tip of a device, such as a catheter — but that can take up a lot of real estate. Sensors can be custom-designed with form factors that fit within space constraints.

Sensor integration: Sensor components can be designed to fit into a device or, alternatively, sensors can

be constructed onto sub-components within a device, optimizing use of space.

Integrating sensors into your assembly maintains performance standards while reducing overall real estate.

Sensor design: Various design levers can be manipulated to optimize electrical performance and sensitivity for a given application. Wire size, core material, and number of wraps all affect performance. Length, diameter, shape, and core geometry can be independently adjusted to customize a sensor. Note that solid core sensors are stronger and offer greater sensitivity than hollow-core sensors. Dual-core sensors are possible, but more complicated to manufacture.

Wired versus wireless: Wireless sensors require additional consideration because they must also serve as transmitters and receivers and must be powered so those components must be included. Additional wireless considerations include latency, size, and complexity of components. There are two types of wireless sensors: standalone

sensors that incorporate all necessary components, and leaded sensors that are powered from the handle. Wireless sensors eliminate the cable, but wired sensors can be much smaller — and smaller sensors are generally better for operating rooms.

Leading: It’s important to understand how to fully integrate the sensor into the device from a connectivity standpoint, so avoid trivializing the leading of the sensors and attachments. Leading is often an afterthought but should be considered upfront. Otherwise, you’ll need to solve that problem during the design phase.

Choosing between off-the-shelf and custom sensors Off-the-shelf sensors aren’t always the best option, but in some cases, they offer advantages such as lower cost, immediate availability, and rapid turnaround. They’re ideal for prototypes, and you can often apply relatively minimal modifications to make an off-the-shelf sensor fit your design. Thus, off-the-shelf sensors can be a good choice,

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given the ubiquitous nature of cost pressures across medical devices and practices.

Custom sensors allow you to address unique challenges for specific applications.

Unlike off-the-shelf sensors, you can integrate custom sensors into an eloquent design that saves space and increases functionality. Custom sensors can also be built with specialized attachments and designed for manufacturability to accelerate time to market.

Whether your application calls for an off-the-shelf or custom sensor, choose a vendor willing to work as an extension of your design team, test your designs, and make recommendations and iterations to improve performance, manufacturability, and costs. Keep in mind that a sensor could work perfectly in a clean environment but underperform in the surgical suite. In one example, a company didn’t discover it had bad data until it entered the design validation stage, forcing a complete redesign. A good partner could have helped the company avoid the costly delay.

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COMPONENTS

Connectivity is critical as the need grows for patient monitoring Patient monitoring device connectors will need to be more compact, more durable, and able to handle higher data rates.

Rick Lopez, Paul Pulkowski and Jana Wagner binder

B

y 2050, the number of people aged 60 or older is expected to double to 2 billion worldwide. During the same period, the number of persons aged 80 and older is predicted to triple to about 430 million.

This demographic shift is already creating higher demand for a wide range of medical equipment and services.

The growing number of chronically ill patients in Western society will further increase the need for medical technology in the coming decades. An alarming 70% of deaths worldwide are caused by noncommunicable diseases such as heart failure, diabetes, and cancer. Because these are chronic conditions, patients and healthcare providers regularly monitor changes in indicators such as glucose levels and blood pressure.

Patient monitoring refers to observing, tracking, and analyzing a patient’s health and relaying that information to and between healthcare providers. In real-time, monitoring devices can detect deviations from baseline health parameters and notify healthcare providers when intervention may be necessary. On an ongoing basis, data from these devices helps medical professionals analyze patterns and detect early signs of deterioration or other developments. Patient monitoring is primarily used in clinical settings, including intensive care units, operating rooms, and post-anesthesia care units.

However, recent innovations enable remote monitoring, allowing patients to remain at home or in other non-clinical settings while staying connected to healthcare providers.

Components of patient monitoring systems Patient monitoring equipment relies on several key components. Sensors play a crucial role in measuring physiological parameters such as body temperature, blood pressure, and oxygen saturation.

Connectivity is required to transmit data

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and analysis to a monitoring station or other medical devices. This allows healthcare professionals to review the collected data on-site or remotely.

Patient monitoring systems also require enough server capacity to store electronic medical records so this data can be shared between physicians, facilities, and patients. Monitoring devices include alarm systems, which are triggered when predefined values are detected.

For example, a pacemaker may alert a caregiver when a patient’s heart rate reaches a certain level. These features enable healthcare providers to intervene quickly. Advanced patient monitoring systems incorporate trend analysis and other decision-support tools to help clinicians make treatment decisions.

Patient monitoring devices must meet extensive regulatory requirements to be approved for medical use. These include: • •

•

•

•

•

Accuracy: Equipment must be precise enough to detect even minute changes in a patient’s condition.

Reliability: A failure of function or connectivity can adversely impact patient care, making durability a crucial requirement for every component of a device.

Connectivity: Connecting to electronic health records (EHRs) and other medical devices can help streamline patient monitoring and improve patient outcomes.

Ease of use: Healthcare equipment should be easy to use, with intuitive controls and minimal setup required so a person without medical training can operate a device if needed.

Portability: Portable monitoring equipment is useful for monitoring patients in different settings, including hospitals, clinics, and homes, as well as in emergency vehicles.

Alarms and alerts: Patient monitoring equipment can be programmed to alert healthcare providers to relevant changes in a patient’s condition. www.medicaldesignandoutsourcing.com

•

•

Data analysis: Patient data should provide healthcare providers with insights that support treatment decisions.

Security: Wireless networks used in patient monitoring applications require the highest levels of security to protect patient data and privacy.

Critical requirements for medical-grade connectors in patient monitoring Connectivity is crucial in transferring data in real-time or at periodic sequences between medical devices and providers.

Medical-grade connectors must be designed for compatibility with specific devices and equipment, ensuring proper electrical and mechanical connections.

Standardization of connector types helps promote interoperability across different manufacturers and devices.

Medical-grade connectors should adhere to stringent safety standards and regulations, such as IEC 60601-1, ensuring electrical safety, insulation, and grounding. Shock vibration (DIN EN 60601-1-11) and rough handling (DIN EN 60601-1) are especially important for use in portable equipment. Medical-grade connectors should also incorporate features like locking mechanisms or color-coded coding to prevent accidental disconnections or mismating.

Medical-grade connectors must meet industry standards and regulations, such as ISO 13485, which applies to quality management systems and specific standards related to electrical safety and medical devices. Compliance with these standards ensures that connectors are manufactured and tested according to recognized best practices. Another important international standardization is ISO 10993-5, which certifies biocompatibility in medicalgrade connectors. Biocompatiblity plays a crucial role in ensuring that the material cannot cause harm to living cells.

Medical-grade connectors in patient monitoring devices need to be reliable

and robust, capable of withstanding frequent use, repeated connections, and disconnections without compromising signal integrity. They should also be resistant to environmental factors like dust, moisture, and physical stress to ensure consistent and accurate data transmission.

Regarding durability, medicalgrade connectors should be able to withstand the demands of healthcare settings. They should be resistant to wear and tear, chemical exposure, and frequent cleaning and high-temperature disinfection procedures, ensuring a long lifespan and reducing the need for frequent replacements. At the same time, medical-grade connectors must be easy to use. They should be designed for intuitive connection, disconnection, and handling. Features like ergonomic grip, tactile feedback, and clear markings or indicators help healthcare professionals to quickly and correctly connect the devices, reducing the risk of errors or delays.

These considerations are essential to ensuring seamless and reliable data transmission, patient safety, and interoperability with existing medical equipment.

Connectivity and patient monitoring For the connectivity aspect of patient monitoring, key trends are advances in materials, miniaturization of components, and increased signal transmission capabilities. Consequently, connectors will need to be more compact, more durable, and handle higher data rates allowing medical devices to perform more efficiently.

Another trend will be increased integration and changes in the design, allowing connectors to have multiple functions within a connector, such as hybrid solutions carrying different power and data transmissions.

Lastly, customer-specific solutions will play an even more significant role in meeting the specific needs of different medical devices and patient populations.

11 • 2023

Medical Design & Outsourcing

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DRUG DELIVERY

Why Insulet crossed the border to develop its Omnipod 5 automated insulin delivery system Sean Whooley Associate Editor

“The amount of work that was needed was massive,” Insulet CTO Mark Field said.

I

nsulet had to clear a series of hurdles — and cross some borders — to bring the Omnipod 5 automated insulin delivery system to those who need it.

Delivering Omnipod 5 “was one of the most important highlights of my career and also one of the most challenging,” Insulet CTO Mark Field said at DeviceTalks West 2023. “It’s probably one of the hardest jobs I’ve done in software to date.

In that process, we learned a lot.”

The Omnipod 5 system became the first tubeless, wearable automated insulin delivery system cleared for marketing in the U.S. in January 2022. Insulet fully launched Omnipod 5 in the U.S. in August 2022, and it’s now the most-prescribed insulin pump in the country, Field said.

“A product we released just a year ago completely changed the trajectory of hundreds of thousands of people’s lives,” he said. “It makes me incredibly proud to be a part of that.”

About the Insulet Omnipod 5 system Omnipod 5 is a tubeless pod enhanced with SmartAdjust technology that integrates with the Dexcom 6 continuous glucose monitor (CGM). The Omnipod 5 mobile app with an integrated SmartBolus calculator is available for compatible smartphones or with the Omnipod 5 controller, provided free with the first prescription.

SmartAdjust uses CGM data to predict where a user’s glucose level will be 60 minutes in the future. Omnipod 5 then increases, decreases, or pauses insulin delivery based on the user’s desired and customized glucose target.

The system — interoperable with G6 for automated insulin delivery — protects against high and low glucose levels.

“It’s the first version,” Field said.

“We can expect this to keep getting better and smarter to keep delivering outstanding results to our customers.”

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Insulet’s Omnipod 5 with the Dexcom G6 CGM Image courtesy of Insulet

Insulet Chief Technology Officer Mark Field Insulet is working on integrating with the Abbott FreeStyle Libre 2 to reach even more CGM users.

Starting out, COVID-19 and Mexico Field joined Insulet in May 2019, less than a year before the COVID-19 pandemic. He was CTO at Thermo Fisher when he had lunch with Eric Benjamin, who’s now Insulet’s chief product and consumer experience officer, and decided to join him.

Right away, Field needed to find hundreds of engineers as the company moved forward in Omnipod 5’s development.

“The technical complexity of the system — connecting to another glucose monitor, a person’s mobile phone to be managed through the cloud — was www.medicaldesignandoutsourcing.com

huge,” Field said. “The amount of work that was needed was massive.”

Field said the company struggled to find enough engineering professionals.

He was based in San Diego, so he looked to Mexico. Insulet opened a Center of Excellence just 30 minutes away in Tijuana and tapped into a new market for talent.

While building the team and continuing to add in San Diego, the company opened another office in Sorrento Valley, a San Diego neighborhood.

“We thought, ‘Wow, what can possibly go wrong?’” Field said. “[COVID-19] came as a huge blow in early 2020.”

Fortunately, Field said, Insulet managed to stay the course with Omnipod 5 through the operations established just prior to the onset of the pandemic.

“We had a system, we could see who’s assigned what on the software side, and just pivoted,” Field said. “What was built for Mexico, these sort of operating mechanisms, suddenly became the standard operating mechanism for the whole company.”

Despite the FDA’s focus on COVIDrelated products, Insulet pushed through the regulatory process.

Approval came, followed by a limited release and then a full release, all within nine months of authorization. (continued on page 26)

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DRUG DELIVERY

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“Our wildest expectations were exceeded 10-fold,” Field said. “Omnipod 5 was such a massive hit.”

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Utilizing partnerships Once Insulet made Omnipod 5 available, Field said his company began onboarding thousands of customers per week. Pent-up demand for the product stretched the company’s cloud infrastructure to the limit and left customers waiting.

“We started noticing processing times going from seconds to tens of seconds to minutes to hours,” Field explained. “It was scary. It was all-hands-on-deck. We needed to actually improve our infrastructure. ...

We were not prepared for this.”

Partnerships across industries saved the day, Field said. Cloud experts at Wipro helped Insulet build out an architecture set to go live “in the next few months,” Field said during the October interview.

Insulet also maintains strong relations with Dexcom and Abbott, two leaders in the CGM space. Omnipod 5 launched as an integrated system with the Dexcom G6, and Field said progress is being made on integration with Abbott’s FreeStyle Libre 2. Insulet also continues to work on integrating Dexcom’s next-generation G7 CGM. “We’re working on integrating with G7 and Libre and have submitted our 510(k) for iOS, and I’m very confident that will get approved soon,” Field said. “In the meantime, our team will also have to work on the next generation of insulin delivery algorithms on Omnipod 5.”

Field lauded the Omnipod 5’s insights and capabilities for in silico testing, too. The company can now take real-world data to see what would have happened with a different algorithm, accelerating R&D. “It’s an exciting time for medtech with all the technology at our disposal,” Field said. “All of this — building the team, delivering a best-inclass product, feeling part of a winning team — just is an awesome feeling.

What’s even more profound is when our customers tell us how their experiences have changed their lives. This helps us make Omnipod 5 even better, delivering on our mission to improve the lives of people with diabetes.”

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8/21/23 1:53 PM

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How Medtronic manufactures its Harmony transcatheter pulmonary valve Each Medtronic Harmony valve is sewn by hand to attach laser-cut pig tissue to the nitinol that makes this minimally invasive heart implant possible.

M

Medical Design & Outsourcing

Medtronic’s Harmony transcatheter pulmonary valve (TPV) is made of nitinol wire, polyester and laser-cut pig tissue, all sewn together by hand.

Photo courtesy of Medtronic

edtronic’s Harmony transcatheter pulmonary valve (TPV) design is paying off after engineers solved a delivery catheter recall and relaunched the system this year.

The Harmony TPV uses pig tissue, superelastic nitinol and manufacturing techniques old and new to solve a special challenge for children and adults.

The catheter-placed Harmony valve offers a minimally invasive way to improve the flow of blood to the lungs and delay open-heart surgery for congenital heart disease. Congenital heart defects are present in about 40,000 babies born each year, making it the most common type of birth defect.

Harmony TPV is for patients with right ventricular outflow tract (RVOT) anomalies and severe pulmonary valve regurgitation. After the heart pumps deoxygenated blood into the lungs, that blood leaks back into the heart’s right lower chamber instead of being pumped out to the rest of the body.

“It can start as a small leak, but the blood starts going backward through the valve … and starts backing up within the body,” Garrett Pilcher, Medtronic VP of clinical research for Structural Heart, said in an interview with Medical Design & Outsourcing.

Patients will start feeling sluggish and face a variety of infections and other problems due to lack of oxygenated blood flow through the body.

28

Jim Hammerand Managing Editor

11 • 2023

“Harmony was the first device approved

by FDA for this indication, and before this patients were getting multiple procedures over time, ultimately open-heart surgery,” he said. “… It was a first-of-a-kind design to get into the right ventricular outflow tract for these patients that didn’t have a minimally invasive option prior to that.”

Medtronic recently released twoyear results for 86 patients with Harmony TPV implants. About half received the 22 mm valves and the other half received 25 mm valves.

The study showed 100% freedom from major stent fracture with the 25 mm valves and 98% in the 22 mm valves.

There were no vascular injuries requiring intervention, and only 3% of patients has more than mild pulmonary regurgitation.

“We’re not seeing severe backflow, which was the original issue we were trying to solve,” Pilcher said.

Though surgeons will want 10 or 15 years of durability to compare Harmony against open-heart surgery, the study shows at least two years of durability — and counting.

“We’re seeing no detriment or the valve starting to not function as well,” Pilcher said.

How Medtronic makes the Harmony valve Workers in Tijuana, Mexico, sew the Harmony valves by hand. Each valve takes 2,200 to 2,500 stitches to attach the knitted polyester and laser-cut pig www.medicaldesignandoutsourcing.com

heart tissue to each other and to six separate nitinol wire struts.

Those self-expanding wire struts are not welded together so they maintain their flexibility, allowing for a better seal on both ends of the valve to prevent blood leaks.

The thin, pericardial pig tissue used in the valve leaflets and inner wall were also selected for flexibility. Medical-grade pig tissue suppliers are owned by the parent companies of the same slaughterhouses that make sausage and pork chops; one example is Johnsonville’s Sustainable Swine Resources.

Meanwhile, Medtronic manufactures the delivery system in Massachusetts. Final assembly takes place in Galway, Ireland.

Harmony’s origins Before Harmony TPV came the Melody TPV. Melody — acquired by Medtronic from inventor Philip Bonhoeffer — was the first transcatheter valve implanted in a human in 2000 and won FDA approval in 2010.

“As we got into that space and started treating more Melody patients, what we learned was there was this analogous indication of patients that weren’t appropriate for Melody, but still didn’t have an option besides open-heart surgery,” Pilcher said. (continued on page 30)

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(continued from page 28)

a patient will face though their lifetime.

“It was actually through our Melody “The Harmony TPV provides a new experience that we learned. And a lot treatment option for adult and pediatric of it comes down to lifetime patients with certain types of management. I think what congenital heart disease,” we’re going to see in Dr. Bram Zuckerman, the future is that these director of the Office of devices will be used Cardiovascular Devices in conjunction with in the FDA’s Center each other.” for Devices and The Melody Radiological Health, implant is a said at the time. bovine jugular “It offers a lessvein valve with a invasive treatment platinum-iridium alternative to openframe. Despite heart surgery to Medtronic’s patients with a leaky experience with the native or surgicallyballoon-expandable repaired RVOT and may Melody valve, it help patients improve decided against balloon their quality of life and The supereleastic expansion for Harmony. return to their normal properties of the nitinol “Through testing, activities more quickly, wire struts in Medtronic’s we learned [balloon thus fulfilling an unmet Harmony transcatheter expansion] in the clinical need of many pulmonary valve (TPV) RVOT doesn’t always allow it to collapse down patients with congenital into a catheter for delivery. work,” he said. heart disease.”

Photo courtesy of Medtronic Instead, In March 2022, Medtronic turned to Medtronic initiated nitinol’s superelastic a recall of the catheter properties, which allow it to delivery system used to be compressed into a catheter place the Harmony implants for delivery to the heart, where it after complaints that the capsule expands back to its designed shape and at the end of the catheter could break anchors to the RVOT. during implantation. At least one injury “You’ve got a lot more flexibility was reported and the FDA designated the longer term that you need to be able to recall as Class I, the most serious level. deal with in order to anchor the device “We essentially weren’t getting the long term in these patients that may have bond that we needed [due to] a variety had prior repairs,” Pilcher said. of issues, including supplier material That flexibility is paying off as changes over time,” Pilcher said. “The Medtronic considers future congenital engineers had to work to develop a indications and its work in transcatheter aortic valve replacement (TAVR), mitral and tricuspid valves, Pilcher said.

“We’re building on experience that shows it’s better to build the right device for the patient regardless of your expertise, as opposed to trying to find one valve that you can kind of shove everywhere,” Pilcher said. “Purpose-built devices are important.”

Harmony’s launch, recall and relaunch Medtronic’s Harmony TPV won FDA breakthrough device designation for the treatment of pediatric and adult patients with severe pulmonary valve regurgitation in March 2021. Beyond delaying openheart surgery, the valve has the potential to reduce the total number of procedures 30

Medical Design & Outsourcing

11 • 2023

better bond — a polymer-molded bond.”

The fix didn’t include any changes to the Harmony valve itself, and Medtronic won approval to relaunch the system in February 2023.

“The relaunch of Harmony TPV underscores our continued commitment to advancing solutions for all people who experience heart disease,” Medtronic Structural Heart and Aortic President Nina Goodheart said at the time.

The system also won Japanese regulatory approval this year through the Harmonization by Doing (HBD) collaboration of the FDA and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA).

“They’re willing to share information about their reviews in order to hopefully expedite but better educate both groups,” Pilcher said. “Their decisions are independent, but they share information — a lot of discussion about the bench testing and the animal work in particular. The goal is to try and move reviews along consistently. We’ve seen in particular with Harmony a great partnership between PMDA and FDA.” The similar names of the HBD program and Medtronic’s Harmony valve are only a coincidence, Pilcher said, and Medtronic has advanced other products through HBD. Medtronic has since launched Harmony TPV in Japan and has a “widescale push” on training with sights set on Europe and the Middle East, Pilcher said.

“We have a massive focus right now in trying to get this into other countries, underserved countries, everywhere we can get it,” he said. “… Hopefully, we’ll span the globe, and any patient that needs this will eventually have access.”

Each Medtronic Harmony valve is sewn by hand with 2,200 to 2,500 stitches.

Photo courtesy of Medtronic

www.medicaldesignandoutsourcing.com

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Medical nitinol manufacturing: How this nickel-titanium alloy is made for medical devices Jim Hammerand Managing Editor

Titanium sponge (pictured) is a key ingredient for medical nitinol manufacturing.

Photo by Alexey Rezvykh via stock.adobe.com

N

itinol might be the hottest material in the medical device industry as manufacturers find new applications for this superelastic, shape-memory, biocompatible metal.

Nitinol — an alloy of nickel and titanium — takes a long, hot journey from the Earth’s crust to the deepest parts of the human anatomy. It starts with ore heaved from deep mines underground or stripped from the soil and refined into titanium and nickel.

To make raw nitinol, suppliers melt pure titanium — in the form of sponge or top-shelf crystal bar — with pure nickel. Titanium has a melting point around 1670°C, while nickel melts around 1453°C. Those are some of the highest melting points among metallic elements. The resulting nitinol has a melting point near 1300°C. Nickel and titanium must be combined at a roughly 1:1 atomic ratio, which comes out to around 55% nickel and 45% titanium. A nitinol at that ratio would be referred to as nitinol 55.

To be used for medical devices, the resulting nitinol should meet standards set by ASTM International, which requires nitinol to be 54.5% to 57% nickel.

Medical nitinol manufacturing with vacuum melting Because of titanium’s reactivity at high temperatures, it must be melted in a vacuum or inert atmosphere to minimize the formation of oxide inclusions (more

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on those later). The two main melting options for making nitinol are vacuum induction melting (VIM) and vacuum arc remelting (VAR). Double-melting is a process that uses both VIM and VAR. VIM and VAR both satisfy FDA guidance for nitinol and ASTM nitinol standards, so there’s little difference for medical device developers to consider.

But if you’re curious, VAR achieves uniform composition through multiple cycles of melting and remelting, while VIM achieves more uniform composition on the first melt but is only suitable for smaller quantities. For larger quantities, a double-melt process starts with VIM to reach a target composition, followed by a VAR re-melt to combine VIM batches.

Nitinol melters must measure attributes of the nitinol such as grain size, inclusions, mechanical properties, transformation temperatures and certify to nitinol processors and device makers that the nitinol satisfies FDA and ASTM requirements.

Larger oxide inclusions hurt the fatigue durability of nitinol, which could lead to a device breaking inside a patient.

“Anyone that’s worked with nitinol, you know your enemy is titanium nitride inclusions,” said Tim Laske, VP of research and business development for Medtronic‘s cardiac ablation solutions business, at DeviceTalks Boston 2023. “You can get titanium nitride crystals, which can be pretty large, and those will nucleate fractures. So when you’re choosing your www.medicaldesignandoutsourcing.com

Nitinol allows the Affera Sphere-9 mapping and ablation catheter (now owned by Medtronic) to expand inside the heart to treat atrial fibrillation.

Photo courtesy of Affera

nitinol vendor, make sure you’ve got a very reputable house and then when you’re inspecting it, look for these inclusions and be sure that they don’t exist if it’s in a highfatigue-state environment.”

To measure inclusions, nitinol melters and their customers can polish a sample and inspect the alloy using optical microscopy or scanning electron microscopy at standardized levels of magnification.

Hot forging and hot rolling nitinol ingots After melting, the molten nitinol cools in a cast to form an ingot. These nitinol ingots can weigh as much as 2,000 to 5,000 pounds.

Nitinol ingots are heated and shaped with hot forging and hot rolling into smaller shapes such as bars, rods and slabs. Making nitinol workable requires temperatures in the temperature range of 800°C to 1000°C. Go to medicaldesignandoutsourcing. com/tag/nitinol for more about this material, including supplier news and coverage of devices that use nitinol.

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MATERIALS

Sticky business: Six wearable device adhesion tips from iRhythm CTO Mark Day How to find the right balance between performance and patient comfort in wearable device adhesion.

Jim Hammerand Managing Editor

i

Rhythm’s next-generation Zio cardiac monitoring patch is smaller, lighter and thinner — three qualities that also assist the wearable device’s adhesion.

Adhesion is one of the leading challenges for wearable device developers. iRhythm Chief Technical Officer Mark Day discussed how his team designed the latest Zio patch to balance performance and patient comfort.

“So much of what we want to do is try and think about unmet needs in patient monitoring,” Day said in an interview with Medical Design & Outsourcing. “It’s really about raising the bar for performance by miniaturizing to ensure that we can get an already very compliant device even better.”

reduce the device’s size and weight. The increased energy efficiency of modern sensors and other components helped right from the start, but the iRhythm team challenged themselves further to design the latest generation with double the endurance and half the battery size — roughly one coin cell battery.

“That’s a very common, inexpensive, readily capable and very shelf-stable energy storage mechanism, but it’s not terribly energy dense. … It gives you a form factor to target,” Day said. “That’s effectively how we approached it: How do we create a medical device — a biosensor, an ECG ambulatory monitoring device — that is the size of one coin cell?

And that’s exactly what we did.”

1. Lighten the load with miniaturization “When you’re thinking about an adhesive and getting an adhesive to stick in a comfortable and compliant manner, you want to reduce the force on that adhesive, both peel and shear forces,” Day said. iRhythm reduced the size and weight of the device housing in the middle of the patch to minimize the force of gravity that’s constantly pulling on the adhesive.

“From an adhesive and performance perspective, the lower the weight, the lower shear forces and peel forces on the adhesive, the better off you’re going to be. And that’s that’s kind of just generally true,” he said.

The new device is 22% thinner and nearly 60% lighter than the last generation, aided in part by semiconductors that are smaller, more powerful and more efficient. The latest generation also has a smaller battery — more on that next.

3. Find the right balance “One of the things we did for the first time — and this is a unique feature compared with other wearables — is to introduce a dermal adhesive structure that is not symmetric. It’s actually asymmetric,” Day said. “It has a portion of it that is a little bit more adhered upward and a portion that’s a little bit more adhered downward as you’re looking at a patient’s chest.”

2. Less power is more “For a wearable, the size of the battery is probably the biggest component for driving the overall volume of the device,” Day said.

That fact (which is also often true for other miniaturized and implantable devices) offered another opportunity to 34

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iRhythm’s nextgeneration Zio cardiac monitoring patch can be worn for up to 14 days.

Photo courtesy of iRhythm

The team designed the adhesive structure with subtle features to keep the patch in place based on what iRhythm has learned about adhesive performance and patient comfort over the years.

“That was all done with this idea of thinking about where forces, largely gravitational forces, would pull over time and where it was a little bit strategically more powerful to put in adhesive capabilities and surface area.”

4. Adapt to environmental changes No matter where you live, you’ve probably noticed hotter and hotter weather trends.

It’s not your imagination. (continued on page 36)

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(continued from page 34)

Temperatures continue to set new extreme records across the globe as carbon-emission-fueled climate change accelerates.

“We’re entering into progressively warmer and hotter summers, which we know is a time of year, for example, where patients certainly are challenged to wear adhesive devices, as they’re sweating more while living their lives,” Day said. “We want them to experience the environment and have a very good and secure and very patient-compliant experience.”

“It was a challenge even 20 years ago to figure out how to adhere things to people — not just in the summer, but any time of year,” he later continued. “…

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5. Sweat the wet stuff With 6 million Zio XT devices produced over the years, thousands of patients are wearing iRhythm devices on any day of the year. That gives the device developer plentiful experience in adhesion in countless situations, including hot, sticky days when patients sweat the most.

“The type of adhesive we use leverages some great capabilities in terms of moisture absorption,” Day said of the Zio Monitor’s hydrocolloid adhesive. “But what was happening is that the moisture was effectively getting caught between the skin of the patient and the device itself in the adhesive, and it really didn’t have anywhere to go.”

A patient’s skin can reabsorb that moisture — “The skin is really a pretty remarkable organ in that sense,” Day said — but iRhythm found a better solution.

“What we did was introduce perforations in the housing. That’s a patented design feature to allow that moisture to transpire, which is more effective and comfortable and, in fact, a more meaningful way to get moisture off and out of the device-patient interface to allow the adhesive to maintain more bond to the patient,” Day said.

Moving that sweat away from the patient and the adhesive prevents the carboxymethyl cellulose in the adhesive from absorbing the moisture, which changes the geometry of the adhesive and how it adheres to the patient.

“The intent was to make sure that the moisture could get out and ultimately not just perform better, but also be more comfortable for the patient,” Day said.

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6. Stop searching for the perfect solution “There is no perfect adhesive out there,” Day said. “And you can stop trying to find it.”

Hydrocolloid adhesive was originally designed for plasma absorption in wound dressings and, over time, has proven its adhesion capability, medical-grade utility and patient compliance, Day said.

“It’s this mixture, a very careful balance of adhesion and skin compatibility, which is always something that we’re striving to be better at,” Day said.

He encouraged device designers and engineers to experiment and be curious while thinking about the patient experience and device performance.

Silicone adhesives are “wonderfully compliant with patients but just [don’t] stick very well,” Day said. [For] a diagnostic device that you’re trying to ensure can record reliably as a patient’s living their lives and doing it naturally, whether that’s showering, exercising, sleeping, running, chasing after the

iRhythm designed its latest Zio patch with an asymmetrical adhesion surface.

Photo courtesy of iRhythm

kids or putting on their shirt … you have an obligation as an engineer to figure out a way to make the device work well. And that might mean pulling back from some of these kind of gentler adhesives because the reality is they don’t perform very well.”

On the other hand, the strongest, most secure adhesive you could design is likely going to cause irritation, allergic

reactions and other patient discomfort.

“It’s a balance you have to try and figure out, and the balance really depends on the specific application and how much you’re trying to support from a weight-wise perspective,” Day said.

“But you do have to tweak things to make sure that it all works,” he continued.

“And it’s pretty hard to get it right in one generation — so a lot of iteration.”

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ORTHOPEDICS

This rendering of Stryker’s Triathlon Tritanium tibial baseplate shows the 3D-printed surface for enhanced bone integration.

Image courtesy of Stryker

Jim Hammerand Managing Editor

How 3D printing and surgical robotics enable Stryker’s cementless knee implants

I

t’s been more than 10 years since Stryker launched its Triathlon Cementless knee implant, including the Triathlon Tritanium Baseplate and its 3D-printed surface.

Stryker designed that 3D-printed surface to encourage the patient’s bone to grow into the baseplate, securing the joint without cement. With cementless knees, surgeons and patients don’t have to worry about the potential weakening or loosening of cement over time, which could mean a patient has to go back in for another operation.

“We’re seeing an increasing adoption rate, where 50% of our overall knees are put in cementless,” Stryker Knee GM and VP Lisa Kloes said in an interview. “When we first came out with it, [people thought] we were crazy to not put cement in because that was the gold standard. We were the

Stryker Knee GM and VP Lisa Kloes

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Medical Design & Outsourcing

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first to market, and now we have over a million cementless knees implanted a decade in. It’s just great to see the success.”

She said American Joint Replacement Registry data show a statistically significant increase in survivorship with the Triathlon Cementless baseplate compared to all cemented and cementless implants.

Kloes joined the world’s largest orthopedic device developer 19 years ago and moved to its knee business in 2022. In a conversation with Medical Design & Outsourcing, she discussed how Stryker uses additive manufacturing and surgical robotics to innovate with ortho products like the titanium Triathalon Cementless knee.

“It definitely took some courage to make that leap to create this product, and 3D printing was still relatively new in med device at that point,” she said.

Today, Stryker’s manufacturing facility in Cork, Ireland, has 94,000 ft² dedicated to 3D printers.

“We are one of the largest 3D manufacturing companies in med device or otherwise,” Kloes said. “… It started with basically the Tritanium Tibial Baseplate. We now have over 10 business units within Stryker that are doing 3D-printed products.”

The following conversation has been lightly edited for space and clarity. www.medicaldesignandoutsourcing.com

How does additive manufacturing enable better ortho implants?

Kloes: “The 3D printing aspect is really about the design element and the architecture that it creates. It’s basically mimicking cancellous bone and promotes that bony ingrowth versus a flat surface that you put cement on.”

How does Stryker use laser sintering and titanium powder to create that unique design?

Kloes: “The base plate itself is a solid structure. And then we print on layer upon layer of the next design elements that create almost like a webbing, like cancellous bone. The other products are created with a foundry where you put it in a mold, and then it comes out as one piece. You can’t create the intricacy of the webbing without 3D printing. And it’s layer upon layer, 50 microns thick of each layer.”

How has 3D printing accelerated product development?

Kloes: “It has expedited our new product development process significantly, because we’ll take user need inputs from our surgeon consultants — the problem we’re trying to solve for and potential designs that meet that need — and we can get them back in a lab and give them two or three designs to try it in a lab setting. (continued on page 41)

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(continued from page 38)

Then let’s tweak this, tweak that, they go to the hotel, come back in the lab the next day, and they have the new design.

The engineers are literally right there with them, tweaking the design of their computers while they’re in the lab setting.

Before [we could do this,] they would go home, they’d come back three months later — whenever we can get their time to come back to our lab — and we have to create new CAD drawings and then send it to forging and make the product.

It’s just lightyears ahead of what we can do and how quick we can iterate design and get it in their hands, which is the most important thing to get feedback.”

helps the surgeon cut]. So we plan the case based upon a CT scan of the patient, and then in the procedure, we map the anatomy to the computer so the computer knows where the patient is in space, and then the robotic [arm] executes — with the assistance of the surgeon — that cut. It is highly precise. You don’t have any flaws in the cut. Some surgeons will say that because of the accuracy of the cuts, the fit is even better, and it increases the success of the cementless bony ingrowth.”

Do you have an example of how 3D printing has shortened those cycles?

Kloes: “Right before coming to joint replacement, I was with trauma.

We were working on what’s called the Pangea plating portfolio. … It just got 510(k) clearance.

That was the first project I’ve been involved with that used this rapid prototyping. The number of SKUs — the screws, the plates — typically would have taken us at least five years from beginning to end. And we got 510(k) clearance in half the time, twoand-a-half years. And it’s a great product. I don’t think that we sacrificed anything for that reduction in time because of the way we were able to iterate and get the new designs in front of our consultants.”

“[With robotics], we are looking at the specific anatomy of the patient and aligning the implants to their anatomy, versus some jigs that put them in the same no matter what the patient presents with.”

How does surgical robotics fit in with cementless?

Kloes: “[With robotics], we are looking at the specific anatomy of the patient and aligning the implants to their anatomy, versus some jigs that put them in the same no matter what the patient presents with.

So robotics really does go hand in hand with the cementless design, and we have a higher rate of adoption for our customers that use robotics with cementless.”

Accurate bone cutting is even more important with cementless knees, so can you explain how a robotic system like Mako helps?

Kloes: “We have what’s called AccuStop, a haptic [technology that

Have you had the opportunity to meet with patients after they’ve had a knee replaced, and what was that like?

Kloes: “It’s humbling, because of the impact you’re making on people’s lives.

What we hear both on the knee side and the hip side is, ‘I wish I would have done it sooner.’ … You see people really compromising what they love to do. It really is important to make that connection because we know what we’re doing every day is important, but when you bring a patient — at least once a year we bring in a surgeon, their patient, and somebody from the team — to talk about their experience like, ‘What was your life before you had knee pain? What was it like after? What was the procedure like? What was the recovery like? And what are you able to do now?’ That’s with our engineers, our manufacturing teams, just so everybody that’s involved with bringing it to market and keeping it on the market know the impact that they’re making. And it’s pretty remarkable to be a part of it.”

Stryker’s Mako robotic surgery systems help orthopedic surgeons perform knee and hip replacements.

Image courtesy of Stryker

www.medicaldesignandoutsourcing.com

11 • 2023

Medical Design & Outsourcing

41

ORTHOPEDICS

Tips to help device developers get paid from smart ortho implant maker Canary Medical

Jim Hammerand Managing Editor

C

anary Medical founder and CEO Dr. Bill Hunter said the smart ortho implant developer just passed a major milestone, logging a millennium’s worth of patient follow-up.

That’s 1,000 years of day-by-day follow-up on patients after they’ve had a joint replaced, Hunter said, collecting data that helps Canary Medical’s remote patient monitoring system measure and analyze post-op recovery and implant performance.

The data also helped Canary Medical secure New Technology Add-On Payment (NTAP) reimbursement this year, which Canary Medical in turn helps sell founder and CEO the technology to Dr. Bill Hunter orthopedic practices, Hunter said in a presentation at DeviceTalks West 2023 in Santa Clara, California.

“We’re starting to see a substantive inflection point,” he said. “What I think is really fascinating is… that if a practice adopts it, they tend to adopt it in its entirety.”

Sensors in the smart implant monitor from 7 a.m. to 10 p.m. daily in year one, the time period where the patient goes through the most physiologic changes. The device monitors less frequently in the years after to preserve battery life, since the battery can’t be replaced without removing the implant.

The Canary Health Implanted Reporting Processor (CHIRP)

Photo courtesy of Canary Medical

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“That’s how we got 20 years of functionality out of single battery and a single implant,” Hunter said.

These sensors measure patient activity and range of motion to track how well the patient is recovering. They can also measure — at 800 observations per second — vibration of an implant to track the implant’s stability and osseointegration.

For five seconds at 2 a.m., the implant transmits data via Bluetooth to a base station in the patient’s bedroom. But patients need to keep that base station powered up and within transmission range for the data to sync, allowing the patient and physician to review the data that next day.

The data can tell a doctor how well the patient is doing compared to their presurgery performance, and also against where they would be expected to be based on other patients’ recoveries. Traditionally, most orthopedic patients recover without problems so follow-up declines unless there’s a serious problem. But remote monitoring helps to track all patients while identifying outliers who need more attention, allowing a doctor to identify patients who need to be seen.

Patient compliance hacks “Human nature is [that] people are going to say, “I feel great. I don’t need this knee monitor anymore,’” Hunter said.

But Canary Medical has figured out a few “hacks” for ensuring compliance with its smart knee monitoring system.

Doctors can contact the patient and ask them to plug their at-home base station back in or whatever else it takes so the receiver can start pulling data from the implant again. An anniversary of the procedure might be a good excuse to reach out.

“The way I look at it is from a very clinical perspective. As long as they keep it on — honestly, for the first six months — but hopefully for the first year, that’s where most of your physiology happens,” Hunter said. “By year five and six. I’m really just looking for changes from baseline. I want to see how year six looks compared to the end of year one. And so if I get enough readings off of that it’s www.medicaldesignandoutsourcing.com

probably going to serve its clinical utility.”

Even if a patient isn’t using the base station that receives daily data from their knee implant, their doctor can download the last 30 days worth of data when the patient comes for an in-office visit.

There are other factors that motivate doctors to make that contact — not just reimbursements for annual follow-ups, but also the potential that the patient may need another knee replaced at some time.

Reimbursement tips Canary Medical won FDA breakthrough device status for its hip, knee and shoulder smart implants. Hunter said the benefits of breakthrough status boosted its reimbursement efforts for the Persona IQ knee implant it made with Zimmer Biomet, which secured FDA de novo marketing authorization in 2021.

“It really did help. We [had] an interactive review, and now that we’re launched, it’s helped a lot because it’s accelerated our reimbursement,” Hunter said.

Beyond Canary Medical’s NTAP reimbursement, Hunter said he expects Transitional Pass-Through (TPT) payment for outpatient procedures as well.

“That’s a big head start that’s going to allow us to get paid while we go about the process of building long-term value proposition,” he said.

To help physicians get paid for using the technology, Canary Medical also created a fully integrated PDF for billing.

“This goes right into the billing system, and they’re able to get paid $110 per month for doing remote patient monitoring. … It’s probably about 10 times less expensive than doing this stuff in person. But for a doc, $1,000 per patient if you’re doing 400 knees a year, it’s absolutely worth doing right. And you’re used to being paid for that anyways, but that was for in-person office visits and X-rays and MRIs and a bunch of other things. Make the same amount of money — arguably more because you don’t lose patients to follow-up — but you’re actually not costing the system more at all.”

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Surgical robotics developers must consider users beyond surgeons, like this one using a da Vinci system.

Photo courtesy of Intuitive Surgical

Intuitive’s Kathryn Rieger on human factors design in surgical robotics Jim Hammerand Managing Editor

Kathryn Rieger, head of human factors and user research at Intuitive Surgical, explains how the surgical robotics developer approaches product design.

I

ntuitive Surgical Senior Director for Human Factors and User Research Kathryn Rieger credits the Presto Hot Dogger for her career in medtech.

“If you Google it, you will see it is not a very well-designed product,” she recalls. “It was designed to cook six hotdogs in 60 seconds. Essentially, it had these big spikes that you impale the hotdogs onto [and it] was a circuit that you completed like a good old-fashioned science project to cook the hotdogs.”

So what’s the connection between meat-tech and medtech? Rieger found herself facing the frankfurter-frying contraption in her first day of “Bad Product Design,” a college course she took as an undergrad at Tufts University.

Her instructor (and future mentor) asked whether it was a good product.

“The answer is no. It’s a terrible product. It’s got these massive spikes and people can get hurt … Some of the points are very obvious about why it’s so bad. Some of them, you start thinking and getting deeper into the conversation.

The fun part and the turning point came when he said to me, “OK, so how do you fix it? How do you make it better?” And it was just the most fun exercise and got my 44

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brain kicking in a way utilizing science and art and math. And it was just amazing.”

After the class, she called her parents to let them know she had decided on a major, and would go on to graduate with a bachelor’s of science degree in human factors (HF) engineering.

Rieger shared the story with DeviceTalks Editorial Director Tom Salemi for our IntuitiveTalks web series, describing the surgical robotics developer as “the mecca of HF.” “We get to work on every aspect of systems, from training to labeling to instructions for use, and of course the robot itself and all the interactions there,” she said. “… We’re the glue between the people who make the product and the people who use the product. And they’re not the same.”

Intuitive’s users go beyond surgeons Rieger explained how Intuitive works with surgeons to design its robotic surgery systems — and said they’re not shy about sharing their opinions as to how Intuitive can improve its product design.

“They’re very passionate about the system and about helping us,” she said. “… We listen. But they’re not always right. www.medicaldesignandoutsourcing.com

That’s just human nature. It’s not their fault.

That is, our perception doesn’t always match the reality of our performance. And so those are some of the fun moments when we get to illuminate that to some of our users who are so adamant that adding a paddle is going to be the best way to do something. And we show them an alternate way to do it, and they’re like, ‘Oh, you’re right. That was better.’ Show them the data. Those are really rewarding moments.”

And it goes beyond the surgeon.

Intuitive’s human factors team looks at the entire hospital ecosystem to make sure they’re considering all users, especially for newer digital products, but even for a relatively straightforward offering like Integrated Table Motion.

“So just moving the table and the robot moves with the table … it was a new user group to us,” Rieger said. “All of a sudden, there’s an anesthesiologist in the room who’s actually responsible for the patient and moving the table. [We] said, ‘Oh, there’s someone we’ve never talked to. We have a new user and need to understand that user and include them.’ So our user base is growing, and keeps us on our toes.” (continued on page 46)

PRODUCT DESIGN & DEVELOPMENT

said. “We’re defining and setting those expectations for what’s out there in the field. So we have to be very responsible about what interaction mental models we invoke in our users. And of course, we need to demonstrate they’re safe and effective.”

Intuitive draws inspiration from areas outside of medtech to understand how a surgeon or another user expects to interact with technology beyond the operating room, for example, while using their smartphone or driving their car.

And with more competitors entering the market, surgical robotics developers must consider the risks of negative transfer, or a surgeon’s decreased performance due to design differences when switching from one robotic platform to another.

“Things like flashing blue lights — what does that mean in robotic surgery? That does mean something to da Vinci users,” Rieger said. “And so if that da Vinci user then goes on to a different robotic platform, it could

(continued from page 44)

Intuitive conducts a “mindboggling” amount of research, she said: hundreds of studies per year, thousands of user interactions that are documented, logged and analyzed, even a truck built like a mobile operating room that goes out to surgeons.

All of that helps the human factors team find pain points where there are opportunities to make a surgeon’s job easier or help them do it better.

“Cognition is about information processing and decisionmaking. …

Social, environmental, looking at all those factors and gathering as much data as we can — it’s our job to translate that into design,” she said.

Intuitive’s human factors inspiration Rieger summed up Intuitive’s mission as creating “products that are easy to use and easy to learn.”

“Because we’re the pioneers, there’s a little bit of pressure on us,” she

have an implication of how they use it.

And thus, when that user comes back on to da Vinci, it may also impact their understanding of that blue flashing light.”

Intuitive’s human factors team also keeps negative transfer in mind across its own product line for consistency as the company develops new technology and integrates components, features or products acquired from others. As they learn what works and what doesn’t, they create design rules for the entire portfolio.

“The idea is that all of these products work seamlessly together. So much of it should be invisible to the user. … We’ve had full solutions that are ready to ship where human factors comes in and says, ‘Hey, this is breaking a fundamental principle or rule that we have established for user expectation.

We can’t do that,’” she said.

One example was Intuitive’s numbering system for the four-armed da Vinci multiport system versus a singleport system.

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“Cognition is about information processing and decisionmaking. …

Social, environmental, looking at all those factors and gathering as much data as we can — it’s our job to translate that into design.”

“That was a big debate. And we we got data to back up our final decision, which was to be consistent with the da Vinci Xi model,” she said.

Intuitive’s human factors future The Intuitive human factors team is digging in deep to cognitive load as they add new technologies like augmented reality or virtual reality.

“Surgeons are not the first adopters of technology. That is not their expertise. Their expertise is surgery. We’re asking a lot, and there’s a large potential for overload as we’re looking at layering these different technologies and potential interfaces between the human and the machine,” she said. “We have to be real careful that we are cognizant of what kind of cognitive load that we are placing on them.”

But the goal of surgical robotics isn’t simply to allow surgeons to operate on autopilot, either.

“We definitely don’t want to overload to the point where your brain is running like a slow computer because you’re you’re having to think too much and weed through too much unnecessary information,” she said. “But also, we don’t want to bore you, because we want you to be at your optimal peak performance. The whole idea behind a robot is to augment human performance, make it better.” www.medicaldesignandoutsourcing.com

Intuitive Surgical Senior Director for Human Factors and User Research Kathryn Rieger

As medical device users increasingly expect easier learning curves, Intuitive is also starting to look into ways to delight users with emotional design.

“It’s proven science that if we feel good about something, we will perform better. If we are exhibiting negative emotions towards something, our performance will decline,” Rieger said.

“We’re getting into some cool nuances in that space that I think will give us some more room to explore what we can do.”

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How Motif Neurotech designed a miniaturized neurostimulator for mental health Motif Neurotech co-founder and CEO Jacob Robinson explains how the startup’s neurostimulation system is designed to work like a pacemaker for the brain.

Sean Whooley Associate Editor

M

otif Neurotech’s small device took a large step forward in September when the device startup announced it completed the firstin-human implant of its millimeter-scale brain stimulator.

The milestone came more than a decade after Motif co-founder and CEO Jacob Robinson took a faculty position in the electrical engineering department at Rice University in 2012. There, the goal was to create neurotechnologies that were smaller, less invasive and more capable.

Since then, he’s worked to figure out new platforms and new architectures for therapeutic neurotechnologies.

In 2022, he launched Motif Neurotech with neurosurgeon and Chief Medical Officer Dr. Sameer Sheth, minimally invasive interventional neurologist Dr. Sunil Sheth and miniaturization expert Kaiyuan Yang, who leads Rice University’s Secure and Intelligent Micro-Systems Lab. Since then, Motif brought on Medtronic Neuromodulation veteran Steven Goetz as chief technology officer.

The Houston-based medtech startup developed a miniature device to precisely stimulate the brain, saying it restores healthy circuit activity to treat mental health disorders at home following a 20-minute outpatient procedure for implantation. The company designed its digitally programmable overbrain therapeutic (DOT) implant to treat treatment-resistant depression (TRD, a form of major depressive disorder) with minimal side effects compared to drugs.

Robinson sees a path to make neuromodulation therapy for mental health as common as pacemakers in cardiology, he said in an interview with Medical Design & Outsourcing.

This illustration shows the Motif DOT microstimulator device’s miniaturized components.

Image courtesy of Motif Neurotech

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“I think there’s a future in which the electronic therapies that you provide adapt to your own needs and get better over time,” Robinson said. “They get better as they learn the pattern of stimulation that works best for you. They get better as we get more data across more individuals and develop better ways to classify brain activity as signals that help us improve the therapy.

“The vision for the world that I like to imagine is where implants that you get for mental health get better over time and better as more people begin to use those devices,” he continued. “I think that part is really exciting.”

The challenge of creating the device Robinson and the Motif team set out to stimulate the brain in a way that helped people with treatment-resistant psychiatric conditions like depression. Over the past 15 years, the neurological community has learned that stimulating the prefrontal cortex can help TRD patients get better.

This method of stimulation — transcranial magnetic stimulation (TMS) — uses a large machine to create a giant magnetic field. Brainsway, Neuronetics and other device developers have made inroads in this space.

To verify that noninvasive stimulation actually stimulates the brain, practitioners first stimulate the motor cortex until the patient begins to move their finger. By proving stimulation of the motor threshold, they can then move to the prefrontal cortex and treat psychiatric conditions.

“The question we asked is, how are we building this tiny implant — about the size of a pea — and it’s supposed to replace this room-sized magnet?”

Robinson said. (continued on page 50)

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PRODUCT DESIGN & DEVELOPMENT This rendering depicts the Motif DOT microstimulator prototype used in first-in-human and large animal studies.

(continued from page 48)

“How do I know that it’s actually stimulating the brain in the same way?”

Motif recognized that it could go to the motor cortex like TMS. Working with neurosurgeons at Baylor College of Medicine, the team was able to test the device’s stimulation capabilities on a patient having a tumor resected. They placed the device on the motor cortex above the dura so it would not be in direct contact with the brain.

Robinson said surgeons used a wand to communicate with the implant, delivering energy and enabling wireless control of the tiny device.

“They pushed go and applied stimulation and that’s when we began to see finger movements,” Robinson said.

“That was our ‘aha’ moment.”

Developing the miniature Motif DOT implant The Motif DOT device measures 9 mm across, working with much less energy than a room-sized magnet to create stimulation in the way TMS does.

“What that did was that really unlocked the ability to make miniature devices and have a new way of delivering energy that will allow us to make devices smaller than anybody else can make, but still have enough power to create therapeutic neuromodulation,” Robinson said.

Motif Neurotech co-founder and CEO Jacob Robinson

When Robinson began work on this technology, he and his team looked at solving the challenge of wireless power transfer. To make the device as small as possible, they aimed to find a way to energize implants without batteries.

“The challenge is that, as you make content that is really small, the efficiencies also tend to get really small,” Robinson explained. “The amount of power that it can deliver gets really small. So we took a 50

Medical Design & Outsourcing

11 • 2023

Image courtesy of Motif Neurotech

different approach. Rather than using an antenna like a magnetic coil for magnetic induction or an antenna that you would use to capture energy from electromagnetic waves, we created a material.”

That material, he said, vibrates in the presence of a magnetic field, with the vibrational energy converting into electrical energy.

After breaking through on the wireless power transfer, the team had to find a way to get its miniaturized device close to the brain tissue. Placing the small device within a burr hole in the skull without touching the brain makes it a safer, faster and easier procedure than open-brain surgery. And it gets the Motif implant close enough to the target tissue that it eliminates the need for a lot of energy, Robinson said.

“We combined those two things to make tiny electronics, tiny energy sources and the whole thing can be really small,” Robinson said. “That allows us to get close to the brain and deliver the energy that’s required to stimulate brain activity in a way that requires a lot of energy if you’re really far away.”

The Motif Neurotech DOT as a “brain pacemaker” Motif’s leadless, batteryless DOT implant receives data and power from another device worn like a baseball cap. This werable part of the system can record data such as usage and potentially respond to individual patient needs or the activity of the brain itself.

Robinson said these closed-loop, patient-specific features break up the traditional medical device architecture of www.medicaldesignandoutsourcing.com

having an implant — and only an implant — for an extended period of time. The system can also potentially expand to other sites for stimulation and recording.

Robinson said research shows potentially better outcomes with stimulation on both sides of the brain (bilaterally). Over time, he could see adding a second, third or fourth device.

He compared the technology to cardiac pacemakers, where “people have three leads put in, but they have to route those wires all over the place.”

“We can add additional leads” with Motif’s technology, he said. “We don’t have to connect wires between them.”

The similarities to a pacemaker go beyond the leads — so far, in fact, that Robinson considers Motif’s implant a “brain pacemaker.” The technology engages a network in the brain to help people overcome the “oppressive barrier” preventing them from performing tasks like getting out of bed, taking a shower or brushing one’s teeth.

Like a pacemaker in a patient’s heart, the Motif implant delivers electrical stimulation and restores natural rhythms in the brain to help people with depression motivate themselves to perform the necessary tasks to get well, he said.

“I like the idea of being able to treat psychiatric conditions with a brain pacemaker,” Robinson said. “It’s now accepted that if you suffer from a cardiac condition and your drugs aren’t working for you, you can get an implant and it will likely save your life. The same analogy holds for mental health.”

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Synchron cofounder and CEO Dr. Tom Oxley

Brain-computer interface basics with Synchron co-founder and CEO Dr. Tom Oxley Jim Hammerand Managing Editor

B

rain-computer interface (BCI) developers are closer than ever to FDA approval of implantable devices that can restore function to patients with paralysis or amputations.

Synchron is one of those BCI developers, and in an interview with Synchron co-founder and CEO Dr. Tom Oxley, we asked him to explain some BCI basics. (Look for much more from our conversation in Medical Design & Outsourcing‘s January 2024 Leadership issue.)

What is a brain-computer interface?

“It’s pretty universally accepted that a definition of a BCI is a direct connection to the brain with an external device that enables transfer of information from the brain,” Oxley said.

But t’s important to understand that definition of a BCI is not enough when it comes to medical device regulatory approval and reimbursement, he said: “It has to do something meaningful.”

The FDA is using neuroprosthesis as a synonym for a BCI medical device.

A neuroprosthesis goes further than a BCI in that it restores a lost nervous function. Cochlear implants for hearing are examples of neuroprosthesis BCIs that are already on the market.

“The difference between a [medical] BCI and a neuroprosthesis is that the BCI has to restore a lost brain function, and you don’t necessarily achieve that with a traditional BCI definition, which is just a connection from the brain to the outside world,” Oxley said.

“I think that’s a very important distinction to make, because that piece has been missing as we contemplate how to assess the efficacy of a brain-computer interface in the clinical medical device world?”

to up until now has not been wireless — it’s been a cable coming out of the skull.”

After sensing and transmission, he said, there’s output.

“Output is the interaction with a computer that does some task,” he said. “And then you could argue task is the fourth piece.”

A BCI system must also analyze the brain signals that it’s sensing to translate or interpret them. Synchron is building a dictionary of brain signals and their corresponding actions.

Synchron developed a catheterplaced brain implant, the Stentrode, which senses neural signals from inside a blood vessel in the brain and relays them to a receiver implanted in the patient’s chest. The receiver transmits those brain signals to a decoder, and then the signals are translated into digital commands.

BCI misconceptions The biggest BCI misconception is that a BCI to treat paralysis must restore the movement of a patient’s arm or leg, Oxley said. That

might be the case one day, but for now Synchron is aiming for a simpler task.

“What we’re focused on is building a control language that can lead to control of a range of things, which may include an arm or a leg or exoskeleton or prosthesis, but actually, in the first instance, is controlling smart devices — iPhones,” he said.

“Reanimating an arm or creating a robotic limb just for the purpose of clicking on a screen is overengineering a problem,” he continued. “The way we’re thinking about it is let’s build a simplified control sequence from the brain [to] restore the control of the digital ecosystem for people whose muscles don’t work. That’s powerful.”

Another misconception, he said, is that BCI technology developers want to merge humans with computers.

“There’s this dystopian misconception around where BCI is headed, when the reality is BCI is restoring function and lost independence to people with disability,” he said.

Synchron’s braincomputer interface (BCI) system uses the Stentrode brain implant to sense brain signals and relay them to a receiver implant in a patient’s chest.

Illustration courtesy of Synchron

The basic BCI components Oxley also discussed the basic parts of a BCI system and what they do.

“There’s the implant that senses brain activity,” he said. “There’s the transmission of data, which hopefully is wireless, but up www.medicaldesignandoutsourcing.com

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REGULATORY, REIMBURSEMENT, STANDARDS AND IP

RWE tips from Boston Scientific Peripheral Interventions CMO Dr. Michael Jaff

Real-world evidence can help device developers innovate with new or improved designs.

Pictured is Boston Scientific’s EkoSonic Endovascular System (EKOS), which uses ultrasound energy combined with a thrombolytic drug to treat blood clots.

Jim Hammerand Managing Editor

Image courtesy of Boston Scientific

R

eal-world evidence (RWE) is a transformational concept for medical device design and engineering, says Dr. Michael Jaff, the chief medical officer and VP of the Boston Scientific Peripheral Interventions business.

“Every really great technological advancement in the vascular space has come from a physician’s recognition that they would like to be able to do something safely and effectively for their patients, but the technology does not exist,” Jaff said in an interview with Medical Design & Outsourcing.

“They find their way to an engineer, someone really smart takes that concept builds a prototype — off to the races. And it has time and time again transformed the way patients can be cared for.”

RWE leverages modern data collection and analysis to help device developers understand limitations and opportunities from frontline data spanning many clinicians and health systems.

“Now you see how multiple physicians are taking care of patients with conditions, seeing how they’re working, how they’re not working, where the limitations are. And that automatically sheds a light on opportunity for either iterative change or full-scale change in a management strategy,” Jaff said. “I am — as a vascular doctor — very excited about the impact real-world evidence can have on developing new therapies.”

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RWE has come a long way in recent years. Because it’s based on health record coding, those records have been limited in how much they can tell device developers beyond general categories such as chronic obstructive lung disease, congestive heart failure and critical limb ischemia.

happens,” Jaff said. “So you really can link the adverse event that could be modified by a better technology by being able to scour that type of information. I think that’s the game-changer.”

He advised device developers getting started with RWE to set realistic goals from the beginning by picking a straightforward

“I am — as a vascular doctor — very excited about the impact realworld evidence can have on developing new therapies.”

“What we now have the opportunity to do is actually scour multiple electronic health record databases. Every piece of line item information that is entered into an electronic health record gets put into a central data repository that then can be queried directly,” Jaff said.

Those electronic health records offer more detail — for example, on what happens to a patient’s kidney function after a procedure that uses IV contrast, or information about a complication resulting from a procedure using a particular technology.

“That’s hard to get when you look at administrative databases. You can’t really match specific dates to events. Now I can tell dates and hours that something www.medicaldesignandoutsourcing.com

project and getting comfortable with a third-party RWE platform. (Boston Scientific works with Truveta.)

It takes some training, but Jaff said he’s had team members without formal data science backgrounds get good at querying RWE with practice.

You can start working with RWE by learning more about the patient population for specific conditions. Jaff recounted an exploration of patients with peripheral artery disease (PAD), who are traditionally thought of as being over the age of 65 with a history of tobacco use, (continued on page 56)

REGULATORY, REIMBURSEMENT, STANDARDS AND IP

(continued from page 54)

diabetes, high blood pressure and/or high cholesterol.

“We learned in this Truveta database there was a higher prevalence of younger patients with PAD than we would have imagined,” Jaff said. “That was an eyeopener to us. Then we started looking at things like gender, race, socioeconomic class, social determinants of health — these are all things that are in electronic health records. The ability to take that information and do the work that we’re doing on healthcare disparities has really been phenomenal.”

New patient insights could inform device design by exposing gaps in clinical trials. Women, for example, aren’t as commonly studied in clinical trials, so discovering a certain presentation pattern in women could lead to changes that improve patient outcomes. One example Jaff offered was if more women were found to present with disease in the distal end of the popliteal artery.

“You can’t just assume that because [your technology] works in the global population of patients with PAD that it’s always going to work in those patients,” he said. “Maybe we need a smaller diameter device, maybe we need a longer device, maybe we need to figure out a way to screen for these patients earlier to identify before they present with more advanced disease. So the the implications can be quite vast.”

He also offered advice for device designers trying to forge a path ahead in device innovation to consider the timeliness of RWE versus the longstanding ideal of randomized clinical trials.

“By the time a randomized trial is completed and published, the technology is already several years old, because those trials take a long time. They’re on a very selected patient population — not the population that’s routinely managed by physicians, but a subgroup of those patients,” Jaff said.

“So as people who are developing new

therapies are thinking about, ‘What’s my next strike opportunity? Where can I really go?’ I would urge them to think about looking into real-world evidence to help guide them.”

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Why linking clinical trials to real-world data is the critical next step for medical device development Mehdi NajafZadeh Medidata

Connecting medical device clinical trials to real-world data (RWD) helps demonstrate efficacy, safety and cost-effectiveness.

M

edical device and diagnostics manufacturers face mounting pressure from regulators, payors and providers to provide more holistic evidence to demonstrate the efficacy, safety, and cost-effectiveness of their products.

To address these increasing requirements — as well as accelerate study timelines and reduce clinical trial burden — medical device sponsors are seeking innovative solutions. Connecting clinical trials to real-world data (RWD) is an effective approach to capture the information needed and enhance evidence generation during and after a trial.

Regulators encourage the use of RWD to inform approval and market access decisions While medical device manufacturers have long relied on real-world evidence (RWE) for regulatory submissions, recent guidance from regulators around the world is accelerating the use of RWD and RWE in clinical and device development.

The U.S. regulatory push for RWD use began in 2016, when the 21st Century Cures Act required the FDA to develop guidance on the use of RWD in evidence submissions for medical devices. RWE is now prevalent in clinical development. As of mid-2021, RWE has been used in 96% of all approved new drug applications and biological license applications in the U.S. This increased acceptance has provided the investment and regulatory support for the use of RWD in medical device studies. Examples of this include: •

Accelerated investment: The FDA has established the National Evaluation System for Health Technology (NEST), a public-private collaboration to reduce the time and cost of generating evidence by linking and synthesizing data from disparate sources to support regulatory approval and postmarketing surveillance for medical devices.

•

Regulatory support: To demonstrate the value of RWE, FDA’s Center for Devices and Radiological Health (CDRH) recently published 90 examples of the successful inclusion of RWD in regulatory submissions between 2012 and 2019.

Thirteen of these examples outlined the linkage of registry data to administrative claims data, such as from the Centers for Medicare and Medicaid Services (CMS).

Linking clinical trials and RWD Linking clinical trial data to RWD at the patient level can help medical device manufacturers develop a deeper understanding of the longitudinal patient journey than ever before.

Regulators are enthusiastic to link clinical trials to RWD to reduce gaps in insights and evidence. Said FDA Commissioner Dr. Robert Califf at the 2023 J.P. Morgan Healthcare Conference: “It’s not hard to imagine that the combination of the patient’s medical record and the use of digital technologies at home would give a much better portrait of what’s going on with a human being than going to a research clinic once every three months and having a study coordinator try to figure out what happened during that intervening period.”

Sponsors are unlocking value from linked clinical trial data and real-world data in at least five ways: •

Longitudinal follow-up with minimal burden: Postauthorization surveillance is critical to fully understand the long-term effectiveness and safety of medical devices. However, the high cost and burden of clinical trials pose significant challenges for medical device manufacturers to sufficiently meet regulatory requirements for long-term tracking. Linking trial patients to RWD allows sponsors to reduce patient and site burden by

www.medicaldesignandoutsourcing.com

Medical device and diagnostics manufacturers need to build data linkage into their clinical trial planning today to remove silos and mobilize efficient use of data sources for better clinical evidence generation in the years to come.

Illustration by Djomas via stock.adobe.com

•

monitoring trial effectiveness and safety outcomes passively, even after trial completion. This capability becomes especially important for diagnostic and device trials, considering that many clinical benefits and safety signals emerge years after market authorization.

Generate evidence for patients lost to follow-up: The loss of patients to follow-up may prevent a trial from reaching the statistical significance needed for regulatory approval. Lack of insight about patients’ outcomes, especially when attrition rates are differential between treatment arms, can also result in bias and undermine the validity of findings.

Linking clinical trial participants to their RWD at the patient level helps investigators capture key outcomes like survival, disease progression and changes to treatment pathways, or to understand underlying reasons for loss to follow-up. >> 11 • 2023

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•

•

Validate and calibrate real-world endpoints in pragmatic trials: To ensure pragmatic studies using RWD are meeting regulatory standards, sponsors will need to mitigate potential data quality risks, resulting in potential biases in RWD studies. For example, to understand discrepancies between clinical trials and real-world observations, investigators can utilize patient-level linkage to validate RWD-based endpoints against trial-based adjudicated outcomes and improve measurement algorithms used in RWD. This would increase confidence in pragmatic study designs that rely on RWD as a quicker, lower-cost method of evidence generation.

Measuring healthcare resource utilization (HCRU): Medical device manufacturers can rarely collect HCRU and cost data during the trial because of practical limitations such as patient and study site burden. Although critical for coverage decisions and payor negotiations, measuring these

•

endpoints can require years of waiting for sufficient real-world evidence to accumulate post-commercialization.

By linking clinical trials to RWD such as insurance claims and payment data, manufacturers can accelerate the time to generate evidence on HCRU, cost, and cost-effectiveness of their products.

Enable adaptive trial design and reuse of trial data: Medical device manufacturers design clinical trials to evaluate pre-specified outcomes in select patient populations. After launch, however, sponsors often need to change the procedure or design based on the early clinical outcomes or physician experience during implementation and deviate from the original trial protocol.

Clinical trial data linkage can expand researchers’ flexibility in adapting to these changes by enabling them to re-use trial data and provide insight into additional outcomes and variables without increasing patient burden for active data collection.

Clinical trial data linkage can generate interconnected and reusable data assets to support these use cases. However, until recently, operational hurdles, technological limitations, and data privacy concerns have prevented sponsors from efficiently linking their clinical trials to RWD at scale.

To address these issues, commercialized technology solutions such as Medidata Link are linking clinical trials to RWD in a seamless, secure, and scalable way.

Linking medical devices and diagnostic trials to RWD can substantially enhance the depth and efficiency of evidence generation and is a technique that is being increasingly adopted by the industry. To avoid missed opportunities, obtaining essential data elements such as patient consent needs to be embedded early on in the process of trial design and implementation. Medical device and diagnostics manufacturers need to build data linkage into their clinical trial planning today to remove silos and mobilize efficient use of data sources for better clinical evidence generation in the years to come.

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SOFTWARE

Cough-counting device developers share tips for developing algorithms Jim Hammerand Managing Editor

Hyfe co-founder and Chief Product Officer Paul Rieger shares lessons learned from developing software to detect and count coughs.

Hyfe's AI-powered cough detection software runs on smartphones and smart watches, using their microphones as acoustic sensors.

Image courtesy of Hyfe

E

veryone was a bit on edge about coughs when Hyfe Chief Product Officer Paul Rieger and his cofounders launched their company in early 2020.

Hyfe has developed AI-powered acoustic software models to not only detect and track the number and frequency of coughs, but also to identify likely disease diagnoses and analyze patterns to warn of viral outbreaks.

The software-as-a-medical device (SaMD) developer has partnered with Merck & Co. The pharma giant is developing a drug for chronic cough patients, some of whom might cough up to 1,000 times in a single day.

“Cough is the most common symptom why people seek healthcare, but it is also the one that is not monitored,” Rieger said in an interview with Medical Design & Outsourcing. “You can measure your own blood pressure, 60

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your temperature, your oxygen saturation, but how do you measure your cough?

It’s not possible. Especially in your sleep, nobody knows — your spouse may know — but it’s not accurate.”

Hyfe Chief Medical Officer Dr. Peter Small has spent his entire career focused on cough-inducing disease and has firsthand experience as a chronic cougher.

“During exacerbations, when my standard 40-80 coughs per day can increase to 500-600 daily coughs, it becomes impossible to socialize or go to a movie,” he said. “Some folk’s coughs are so bad that they vomit, lose control of their bladder or even break ribs.”

Small said over-the-counter cough medicine are mostly placebos, and it’s been about six decades since the FDA approved a new antitussive.

“Fortunately, new scientific insights into the mechanisms of cough promise new and effective therapies,” he said. www.medicaldesignandoutsourcing.com

What coughs can tell us Hyfe’s algorithms run on smartphones, whose sensors are always listening for coughs. Detecting and time-stamping coughs can find patterns that could indicate changes in an individual patient’s condition.

In a larger population, those patterns could sound the alarm of an outbreak of flu or a new virus like SARS-CoV-2, offering extra time for early intervention.

“It’s less about a single cough ... and more about the patterns you can derive from continuous monitoring,” Rieger said.

“We see ourselves as a company that focuses on the continuous data stream, and then you derive continuous insights from that data stream.”

Hyfe is looking into a host of conditions, including chronic cough, refractory chronic cough, gastroesophageal reflux disease (GERD), tuberculosis, chronic obstructive pulmonary disease (COPD) and asthma.

“We see the biggest interest especially on chronic cough because there’s no treatment out there right now.

That obviously is a big pain point,” Rieger said. “And people have a hard time convincing their healthcare providers — try to go to the doctor and tell them you’re coughing 1,000 times a day.”

The sound of a cough isn’t enough to diagnose COVID-19, which doesn’t even present as a cough in all patients.

“We are a bit skeptical when it comes to these diagnostic use cases where one cough equals one diagnosis,” Rieger said.

“But we have a very positive outlook on the longitudinal one, where you can actually see disease patterns over time if you monitor for long enough and especially if you combine that with other data streams: oxygen saturation, heart rate and so on.” (continued on page 62)

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SOFTWARE

(continued from page 60)

Hyfe is looking at the different properties of a cough such as duration or whether it’s productive, but it all starts with reliably identifying a single cough — and from there, identifying coughing bouts.

“The biggest challenge is actually to have clean timestamps initially, and then from those timestamps you can derive things such as intensity of a coughing episode, who is coughing at which times and what things are happening at that time during the day,” Rieger said.

GERD patients will cough around the time when they eat, for example, while nervous-tic-based chronic coughs can be identified by nighttime relief.

“They will stop coughing the moment they fall into deep sleep, but somebody who has refractory chronic cough will not,” Rieger said. “In just the diurnal pattern of a cougher, you can see really interesting stuff.”

Sensors everywhere One of the trends Hyfe is betting on is the commoditization of hardware, something many device developers might overlook.

Smartphones are increasingly ubiquitous with a growing array of onboard sensors, powerful processors and smarter software.

“It’s just not that easy for people to wrap their heads around that because usually you think a medical device is one sensor, one device, and then you ship it,” Rieger said. “But I think there’s a big opportunity to use those existing sensors and add more capabilities on top of them instead of trying to reinvent that wheel, going bottom up with a new device and so on. That is the approach we’re taking, but I think other companies will look at it similarly just because of the costeffectiveness in go-to-market.”

The ability to collect all that data presents its own challenge. Hyfe has collected more than 600 million data points so far.

“But data can also be noise,” Rieger said. “Making sense of the data is one of the primary challenges in any AI approach, especially if you’re focused on a wide spectrum of devices.”

There are tens of thousands of different smartphone hardware combinations, with many, many different microphones of various quality collecting data.

“You have high-end and low-end phones,” Rieger said. “Working with that data, you need to start normalizing it and you need to have really good labeling pipelines. That has been one of the keys 62

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Tracking coughs can help patients identify the health conditions that may cause them — and on a larger scale, could help provide early warnings of disease outbreaks.

Image courtesy of Hyfe

as to why we’ve been able to successfully do this at scale.”

Developing algorithms for the real world Rieger distilled the process of building medical AI for sound detection into five high-level steps: 1.

2.

3.

4.

5.

Collect diverse sounds from the real world.

Label sounds using trained professionals.

Train a deep learning algorithm on these labeled sounds.

Implement the algorithm on the target platform (smartphone, medical device, etc.).

Validate the algorithm in clinical studies.

Focusing on data, cleaning it and labeling it is essential for developing algorithms that will work wherever patients and their phones are in the real world.

“It’s easy to design a really good algorithm that works in a lab setting — in a hospital, for example, that’s really easy. It’s a very clean environment, you know what the acoustic environment will look like,” Rieger said. “But the real world is noisy. It’s very noisy. People have all kinds of different environments, so you need a lot of samples.

You need not just millions, you need at least tens of millions of samples and you need to make sense of these samples. That has definitely been the biggest challenge.”

Hyfe’s using a deep learning model.

Deep learning models benefit from more www.medicaldesignandoutsourcing.com

data, but if it’s not clean data, performance deteriorates. Deep learning models are also generalizable, making it possible to run Hyfe’s software on all kinds of platforms spanning proprietary hardware to smartphones, smartwatches and computers.

“That’s only possible because of that big data set, cleaning it, and then training models on the highly accurate and cleaned subset,” Rieger said.

Labeling data The importance of labeling data is one of the biggest lessons Hyfe’s team has learned.

The average cough is between 300 and 500 milliseconds, but what happens in the moments before and after the cough is key for determining whether it was a single cough or a coughing episode. While it might be more efficient to record, review and label half-second-long audio snippets, longer chunks offer more context and quality.

“For us, the context matters a lot and we’ve realized that makes a lot more sense to focus on continuous labeling and not explosive labeling,” Rieger said.

It’s also important to consider how to build pipelines for labeling and how to work with inter-label correlation when labelers disagree, making sure that only data where people agree on labels is included in the training set.

“We have had a lot of iterations where we realized something was wrong in the recent batch of labeling,” Rieger said. “It really messes up your performance and it costs a lot of time. It costs a lot of money.”

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How LimFlow’s foot-saving system prevents amputations in patients with no other options LimFlow’s crossing stent diverts blood from a diseased tibial artery to a tibial vein to deliver oxygen to a patient’s ischemic foot.

Jim Hammerand Managing Editor

Illustration courtesy of LimFlow

L

imFlow’s breakthrough system for treating chronic limb-threatening ischemia (CLTI) is the first of its kind approved by the FDA for this severe form of peripheral artery disease (PAD).

For CLTI patients who have lost blood flow below their knee and have no other suitable endovascular or surgical treatment options available, the LimFlow System for Transcatheter Arterialization of Deep Veins (TADV) is now the last resort to avoid amputation.

LimFlow’s TADV system won breakthrough device designation in October 2017 and secured FDA premarket approval (PMA) in September 2023.

In November 2023, Inari Medical announced and closed its acquisition of LimFlow for up to $415 million.

“A lot of technologies come out of people fiddling with technologies that already exist, and then developing unique proprietary solutions after that,” LimFlow CEO Dan Rose said in an interview with Medical Design & Outsourcing before the deal was announced. “That was kind of our journey. … We hope to break a logjam, which is the limits of [applying traditional] coronary technology below the knee by creating a new circuit that allows us to deliver the oxygenated blood these patients need.”

LimFlow’s minimally invasive procedure diverts blood around diseased arteries and into veins to restore blood flow into a patient’s ischemic foot.

TADV relieves ischemia by using veins to oxygenate tissue (essentially

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turning them into arteries), a relatively simple concept that goes back more than a century. But the risks of creating such a large surgical wound — including infection that could require amputation — have historically outweighed the benefits.

However, modern coronary and peripheral interventional medicine and the ever-growing use of catheters, wires, stents and balloons now allows surgeons to make small, precise punctures in the vasculature.

“How we actually did the first-in-man was saying, ‘How can we try to use just interventional techniques to accomplish the goal with a surgical procedure [using] off-the-shelf devices? And that was the beginning of LimFlow — using common tools to prove the principle,” Rose said.

How LimFlow’s devices restore blood flow As the LimFlow team worked on the procedure to make it simpler, faster and reproducible — figuring out how to knock out vein valves to allow reverse blood flow, avoiding vein spasms and edema and the like — they learned which tools they needed to customize.

One example is LimFLow’s proprietary technology for artery-to-vein crossing.

They designed their nitinol V-Ceiver venous catheter with radiopaque mesh to expand inside the tibial vein, providing a clear target with fluoroscopy so the nitinol needle on LimFlow’s ARC arterial catheter inside the tibial artery can puncture the www.medicaldesignandoutsourcing.com

vein and deliver a micro guidewire. The V-Ceiver’s snaring mesh captures the guidewire, which then runs out of the venous access site on the patient’s foot.

Then, an angioplasty balloon opens up the artery-vein connection. Next, the LimFlow Valvulotome cuts through vein valves at the bottom of the foot to allow the blood to flow in the opposite direction.

Self-expanding stent grafts covered with electrospun polytetrafluoroethylene (PTFE) run up the leg to keep the vein open. The last piece of the puzzle is LimFlow’s self-expanding nitinol crossing stent, which is also covered with electrospun PTFE and routes oxygenated blood from the artery into the vein, restoring a rush of blood flow to the foot. (continued on page 66)

LimFlow’s ARC arterial catheter (pictured with needle extended) and the mesh V-Ceiver venous catheter Image courtesy of LimFlow

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(continued from page 64)

“The artery is a very different diameter than the vein, and you want a stent that matches the diameter of the artery so it’s going to stay open … and the same thing in the vein, so we had to develop a conical stent graft so that we weren’t creating a mismatch of sizing,” Rose said. “We had to figure out a way to atraumatically destroy the veins endovascularly using a unique forward-cutting valvulotome because a push valvulotome didn’t exist. We invented it.”

Creating these tools wasn’t enough; they needed to be refined for speed, simplicity and dependability.

“All interventionalists have a spectrum of skills, and we have to aim for a procedure that is reproducible in the hands of the average physician. Because if you don’t, you’re building a niche technology,” Rose said.

What’s next for LimFlow CLTI is often seen in patients with diabetes, coronary artery disease, obesity or high

blood pressure. It’s estimated to affect as many as 4 million people in the U.S., causing 150,000 amputations per year in late-stage patients whose limbs can’t be saved with angioplasty or open bypass surgery.

Amputations above the ankle for vascular disease are associated with a 50% mortality rate within a year. For those who survive, losing a limb means they may never walk again.

After treatment with LimFlow’s system, Rose said, “we see these patients go from gangrene, dry, cold foot to completely healed in three to six months. And their foot is warm [and wtihout] pain.”

It’s not every patient, he said, but a significant majority save their limbs.

Now that LimFlow is able to treat the most serious cases, they’re still studying how they can expand their system to patients in less advanced stages. That includes revising their products and developing new ones. They’re already working on a new PMA submission, Rose said, though he declined to offer details.

The LimFlow Valvulotome

Image courtesy of LimFlow

“We’ve opened a new circuit, a new pathway,” Rose said. “We have to learn how to use that, we have to learn which patients it’s ideal for. That will take place over time. … I can’t speak openly about it, but we are and will be developing new technology solutions that make the procedure easier and faster and better as we go.”

“We’re passing through the first door,” he continued, “but there are many, many further doors to open, and the only way we do that is by continuing the journey.”

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ABBOTT AVEIR

How ABBOTT designed the

WORLD’S FIRST

dual-chamber leadless pacemaker system

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www.medicaldesignandoutsourcing.com

THE LEAD ENGINEER ON ABBOTT’S AVEIR PROJECT EXPLAINS HOW HIS TEAM DEVELOPED A FIRST-OF-ITS-KIND WIRELESS PACEMAKER SYSTEM THAT COMMUNICATES THROUGH BLOOD. JIM HAMMERAND MANAGING EDITOR

W

hen Abbott’s AVEIR DR leadless pacemaker system became the first approved by the FDA for dualchamber pacing this year, it expanded the benefits of leadless pacing to the majority of patients who need stimulation of both the atrium and ventricle chambers.

The lead engineer on the AVEIR project, Matthew Fishler, was working on leadless pacemaker technology at Nanostim when it was acquired by St. Jude Medical in 2013. (Abbott then purchased St. Jude Medical in 2017.) He traced the idea for a dual-chamber leadless system back to 2014 in an effort to eliminate lead failures and other complications of traditional pacemakers.

They weren’t the only ones working on leadless pacemakers. In 2016, Medtronic’s Micra became the first leadless pacemaker to win FDA approval. Instead of a

Abbot’s AVEIR AR (left) and VR (right) leadless pacemakers can communicate wirelessly with each other from different chambers of the heart.

Image courtesy of Abbott

www.medicaldesignandoutsourcing.com

pacemaker implanted beneath the skin near the collarbone and connected to the heart with leads, the 25.9 mm-long Micra is placed directly inside the heart using a catheter.

But about 80% of pacing therapy patients need dual-chamber pacing, and can now get that therapy without leads with Abbott’s AVEIR DR system.

Abbott won FDA premarket approval (PMA) for its AVEIR VR single-chamber ventricular leadless implant in 2022, and followed with an FDA PMA in June 2023 for AVEIR DR, the first dual-chamber leadless system for the atrial chamber.

The AVEIR DR system uses the AVEIR VR leadless pacemaker in a patient’s right ventricular chamber and the smaller AVEIR AR leadless pacemaker in the right atrial chamber. The two leadless implants communicate wirelessly with each other through blood and heart tissue.

How the Abbott AVEIR DR system works The AVEIR name is an acronym: AV for atrial and ventricular, E for extended longevity, I for the “i2i” implant-to-implant communication system, and R for retrievable.

The AVEIR VR right ventricle device is 38 mm long and 6.5 mm in diameter.

The AVEIR AR right atrium device is the same diameter but only 32.2 mm long.

The team designed AVEIR AR with a shorter length to avoid interference with the tricuspid valve that connects the right atrium with the right ventricle.

The catheter-delivered implants anchor into the heart tissue using a corkscrew-like helix. Inside the helix is a small tip electrode for sensing and pacing stimulation. A return electrode is at the opposite end of the device. The pacemakers generate electrical pulses to correct slow or irregular heartbeats and communicate with each other to coordinate their pacing. >>

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ABBOTT AVEIR

Abbott’s AVEIR leadless pacemakers have a helix at one end to anchor to tissue inside the heart’s chambers.

Image courtesy of Abbott

The ‘solve-it-or-go-home’ challenge The biggest design decision at the very beginning was how to independently position the two devices in separate chambers and have them operate as well as a conventional, dual-chamber system with leads.

“That was a huge challenge that we needed to tackle,” Fishler said in an interview with Medical Design & Outsourcing. “Way back in 2014 when we first started, that was our primary target: Solve this, or we’re going home.”

The two devices needed to wirelessly communicate with each other with every heartbeat. Potential options like Bluetooth low energy (BLE), inductive or radiofrequency required more power than batteries inside the heart could provide.

The team spent six months brainstorming ideas and fast-failing to evaluate and eliminate options. Some of the “wacky” ideas included light pulses between the devices, but again the constraint was power.

“Through this iterative fast-fail process, we were able to relatively quickly home in on what worked and what didn’t,” Fishler said. “And [over] multiple refinement cycles, we came up with this approach that we now use.”

That approach is their new i2i conductive communication protocol, which uses the conductive properties of the heart’s blood and tissue to relay very small packets of information electronically between the devices.

With each heartbeat, the devices send a 32-bit message with a header indicating whether the device sensed or paced and a payload with other key information.

The idea looked good on paper, so they modeled the technology with computers, built test chips and 70

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developed crude dummy devices they called submarines for testing in a fish tank filled with saline.

“Blood is very much a salt solution. … You can titrate out a saline solution to be very equivalent to what blood would be in terms of conductivity, so that’s exactly what we did,” Fishler said.

They used the longstanding C computer programming language for the device code and C++ for the software and the programmer.

“Especially for the software that’s in the device, the compilers for C are so effective and efficient, it generates very efficient code. It’s all about the efficiency, reducing the number of cycles that the micro has to run,” Fishler said.

That first evidence of feasibility in the fish tank was what Fishler called the “aha moment.”

Dual-chamber leadless lessons learned When the AVEIR team set out to adapt their ventricular chamber device for the atrium, the thinner atrial wall and more dynamic motion inside the chamber presented other design hurdles.

“We started by just taking what we learned, what we knew and loved in the ventricle, and applying it in the atrium. And then we quickly learned it was a little bit more challenging. … We had to essentially reinvent how the system engaged with the tissue in the atrium. It didn’t take a lot, but they were critically important. We made subtle changes to the fixation helix. And then we also changed the tip electrode from a passive or a dome tip electrode in the ventricle to an active inner helix for the atrial device. That was key to getting the stability in the atrial chamber so that we would get good, stable chronic threshold and chronic engagement in the tissue over time.”

The team also learned through development the importance of a protective sleeve over the entirety of the pacemaker as the device travels to a patient’s heart from their groin and up through their vasculature, helix-endfirst. When the device reaches the site of implantation, the physician pulls the sleeve back.

“That’s really an important feature to mitigate against potential harm to the patient or potential damage to the device,” Fishler said. “The sleeve doesn’t

“You can’t believe how much we celebrated. It was a huge moment. All of the dual-chamber function, all of the standard features that a clinician would expect to see out of a dualchamber pacemaker system is built on top of our i2i protocol.”

“You can’t believe how much we celebrated. It was a huge moment,” he said. “All of the dual-chamber function, all of the standard features that a clinician would expect to see out of a dual-chamber pacemaker system is built on top of our i2i protocol.

Without that, we wouldn’t have a [leadless] dual-chamber system, and we certainly wouldn’t have a realtime [leadless] dual-chamber system that could maintain this beat-to-beat synchronization across all different scenarios.” www.medicaldesignandoutsourcing.com

open or close, it’s just extended to go past it, like a very flexible, very compliant cylinder. That’s sufficient. … We generally want to keep that open because we’re constantly flushing saline through the system to keep it open, keep it fresh and make sure no blood clots can form on the system.”

With the helix exposed for placement, a mapping feature built into the AVEIR device and catheter allows the physician to use fluoroscopy for visualization

ABBOTT AVEIR

of the endocardial chamber. Radiopaque markers allow the physician to navigate the pacemaker to target locations, where the device can take measurements by touch but before being screwed in. Those measurements — such as impedance or sense amplitude — help the physician determine the best spots to anchor the device, which they do by rotating the entire device to screw the helix into the heart tissue.

“Then they can confirm that their measurements are still good — and if not, for whatever reason, they can unscrew it and go back to another location,” Fishler said. “We give them a lot of flexibility to dynamically evaluate and reevaluate locations across the entire process of implantation.”

The AVEIR pacemakers are retrievable not only to adjust placement right away, but in case they need to be removed and replaced sometime after the procedure.

Custom lithium-carbon monofluoride batteries from Integer power the implants — and take up a majority of the device’s volume to maximize capacity. The team

optimized not only the physical electronics package, but also the functional aspects: minimizing background current just to keep the system on without pacing.

“We focused a lot on making it so much more efficient than a conventional system. We are generally about 10 times smaller in size than a conventional pacemaker, and about 10 times more efficient in background current as a conventional pacemaker,” Fishler said.

While Abbott hasn’t yet shared AVEIR longevity data from its clinical trial, Fishler said the average longevity is more than 17 years for Abbott’s other singlechamber devices.

“This is a first-in-human, first-in-theworld system, so we learned a lot through the trial. For the engineers, we are taking all that knowledge and feeding it back into finding improvements, making improvements, and we will continue to iterate,” Fishler said.

And keep an eye out for other applications from Abbott for the i2i

Abbott’s chief engineer for leadless pacemakers Matthew Fishler

communication protocol. Fishler said his team is already exploring other opportunities to use it.

“We’re not in a position yet to really say where we’re going, but we’re using our imagination,” Fishler said. “We’re trying to see how we can leverage it because we really do think the concept of interbody communication between implanted medical devices has a lot of potential benefits beyond just this dualchamber pacing system.”

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“We’ve built a collaborative robot, which is not necessarily what you typically see out there in the market.”

Moon Surgical thinks Maestro’s light touch can win the surgical robotics arms race

JIM HAMMERAND MANAGING EDITOR

(ABOVE) A surgeon using the Moon Surgical Maestro surgical robotics system Photo courtesy of Moon Surgical

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THE MOON SURGICAL MAESTRO robotic surgery system faces some stiff competition — and the device developer plans to use that to its advantage.

In an interview with Medical Design & Outsourcing, Moon Surgical CEO Anne Osdoit and Chief Technology Officer David Noonan discussed the technology behind what they described as their system’s key benefit: the ability to collaborate with surgeons.

“We’ve built a collaborative robot, which is not necessarily what you typically see out there in the market,” Noonan said. “[Most] robot arms are extremely stiff. If you want to try and grab a hold of that and use it to manipulate it, you can’t because the payload and the stiffness is what’s needed to execute the task.”

But Maestro is designed to let surgeons directly move the laparoscopic instruments attached to its robotic arms and hold them in place. That reduces strain on surgeons and frees up assistants, increasing www.medicaldesignandoutsourcing.com

procedure efficiency and effectiveness.

“When a user attaches an instrument to our system, they still manipulate the instrument in the way that they used to before, via its handle if it’s a grasper or via the camera head if it’s a laparoscope,” Noonan said.

The technology convinced Dr. Fred Moll — co-founder of surgical robotics leader Intuitive Surgical — to join Moon Surgical first as an advisor and now as board chair.

“His first reaction was somewhat skeptical, and until we really had something to show him and put into his hands, it was hard for him to picture what we would be doing,” Osdoit said. “That’s something we’re also experiencing with surgeons that we have to solve. Until they can touch and feel it, what we’re doing is so different from the other surgical robotic approaches that people have a hard time even understanding how it’s possible and representing it in their minds.” (continued on page 74)

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MOON SURGICAL MAESTRO

a new pricing and new terms. Otherwise, I’m not sure our historical investors would have been supportive.”

The latest round will fund development and commercialization with a limited market release before a full commercial launch in 2025.

Moon Surgical is improving Maestro’s design from the first version that won FDA and EU approval.

“It’s not a version of the device that we felt we could scale from,” Osdoit said. “We have basically translated all our learnings into a commercial embodiment that not only looks a lot nicer — it looks amazing — but has the same core architecture and functionalities and incorporates some of the learnings from our initial feasibility study where we’ve treated 50 patients.”

To scale for manufacturing, Moon Surgical is working to stabilize the design and assemble the necessary infrastructure and resources, particularly Moon Surgical’s components for the arms Maestro surgical robotics that set Maestro apart. system has two arms that can hold the same laparoscopic instruments that surgeons already use.

Maestro’s light touch in the surgical robotics arms race Photo courtesy of Moon Intuitive Surgical’s da Surgical Vinci system remains the leader to beat in soft tissue surgical robotics. (continued from page 72) But Osdoit thinks one reason Landing Moll is surgical robotics haven’t snatched a just one of Moon Surgical’s larger share of total procedure volume accomplishments this year. After winning — besides the cost — is that surgeons its first FDA clearance for Maestro in aren’t comfortable operating on a December 2022, the device developer patient from a surgical system console in followed up with European Union CE the corner of the room. mark approval in April 2023. Then came “What we wanted to do when we a $55.4 million funding round in May and started Moon was provide a solution the addition of Chief Financial Officer that would deliver the benefits of robotic Anne Renevot and Commercial Strategy surgery — the things that surgeons love VP Lisa Jacobs to the leadership team.

— maybe not with the complete degree Moon Surgical closed that Series B of sophistication that you could have in funding round less than a year after its $31.3 million Series A round — and about a da Vinci system, but something that would be appropriate to cover the vast a year-and-a-half sooner than Osdoit majority of surgical procedures, maybe previously anticipated. even 70%, 80% of what you would do “Since we announced the A round with the da Vinci,” she said. we’ve had constant inbound interest Maestro’s disposable couplers allow from investors, and at the end of last surgeons to use the same laparoscopic year we realized there might be people tools as they did before, except they can out there willing to give us some money do the same procedures with one fewer and in the current environment it would person in the room. be foolish not to take it,” she said. “We “The surgeon is his or her own had also reached a number of significant assistant using our system,” Osdoit said. milestones that justified a new round with 74

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www.medicaldesignandoutsourcing.com

“The concept is it’s the robot that adapts to the surgeon and not the surgeon who adapts to the robots. For patients, we are hoping to increase throughput, reduce anesthesia time and give the surgeon better control and confidence over what’s done during the procedure, which ultimately should turn into better care for patients.”

To do that, Maestro allows surgeons to use their own hands to manipulate instruments, but holds them perfectly still when the surgeon releases them.

“Our architecture is very different to that more traditional serial manipulator with stiff joints all the way along the degrees of freedom,” Noonan said.

“Our design actually started as a haptic interface, in this case an impedance control device which is mechanically transparent.”

While traditional robots are mechanically rigid, a surgeon can grab Maestro’s arms and move them around, with the robotic arms making themselves feel light by compensating for their own mass and the mass of the attached instrument.

And while a more traditional robot has a motor and a gearbox to provide torque amplification, Maestro’s system has no gearboxes.

“Our torque amplification comes from the combination of a capstan with a pre-tensioned tendon that wraps around and then goes to a larger capstan, so we get a gear ratio by taking a capstan wrapped around a smaller diameter pulley to a larger diameter pulley,” Noonan said. “And that approach allows you to basically amplify the torque while having very little backlash and no friction between gear teeth, which is what you get on a more traditional gearbox.”

The system senses motor current on the motor side to infer the force being applied to a joint, detecting when a surgeon is trying to move the arm in order to assist that movement.

“We’ve got multiple modes,” Noonan said. “The arm can act as a robot and it can move our laparoscope in order to track the surgeon’s tools to be able to reposition in a hands-free manner, but also can guide the surgeon to a certain place, it can hold perfectly still, or provide feedback to the surgeon regarding what sort of force it’s experiencing elsewhere.”

The tendons are made of stainless steel, and the system also has a series of springs for passive compensation. While

MOON SURGICAL MAESTRO

the bulk of the system’s weight is in its base, the team is trying to drive down the mass and inertia of the linkages and transmission mechanisms that extend to the distal joints.

“You can algorithmically compensate for a lot of stuff, but there’s some things you can’t,” Noonan said. “We’re trying to minimize that perceived mass because ultimately transparency of the system is really what we’re fighting for: it’s easy for the surgeon to move it, he or she doesn’t feel like it’s there, and it becomes the best possible assistant for that surgeon as opposed to a clunky or complicated tool they have to adapt to.”

What’s next for Moon Surgical As Moon Surgical builds more Maestro systems, it will have to solve shortages of critical sensors like encoders.

“That’s been a real pain point,” Noonan said, with lead times of up to 40 weeks.

The Maestro system uses at least two encoders to measure joint angles at each motorized axis. All of the encoders are redundant, and the system compares the sensors on each joint to make sure each joint is working as needed — and that all the sensors are working as well.

“In surgical robotics, one of the things from a design perspective you’re always looking for is to make sure you never can have uncontrolled motion.

That’s the big no-no,” Noonan said. “All our joints have redundant encoders, and you’re constantly looking to detect a failure of one of those by constantly measuring the two of them.”

Moon Surgical is constantly scouring the internet for available encoders, and for early prototypes even resorted to buying products containing encoders solely for the encoders.

“In that case, you need to only have two of everything or, you know, 2X of everything. And then as we go through our verification and validation cycle and now we’ve got six units, we need to make sure you’ve got 6X of everything,” Noonan said. “As [you] go toward commercialization ... you’re actually often making decisions based on what’s available as opposed to what you might prefer.”

At the time of this interview earlier this year, Moon Surgical was assembling almost everything in the Maestro system except for the arms, with plans for final testing of the arms in 2023 before internalizing manufacturing. The

company’s arm supplier is based in France, so internalization of the arm was to be done there and the rest of the work planned for San Carlos, California.

“Our overall strategy is to keep a relatively lean and efficient manufacturing team,” Osdoit said, “which means that as the sub-components of our system get really stable over time, we would be able to outsource them to OEM partners and then just keep the final assembly and testing in-house and leverage our infrastructure and team more and more to get more throughput. … We’re at the beginning.”

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JOHNSON & JOHNSON RWE

and you can, too TWO J&J MEDTECH LEADERS SHARED ADVICE TO HELP MEDICAL DEVICE DEVELOPERS USE REALWORLD EVIDENCE (RWE) IN FDA SUBMISSIONS. JIM HAMMERAND MANAGING EDITOR

R

eal-world evidence (RWE) took a big step forward recently when the FDA approved expanded indications for Johnson & Johnson MedTech ablation catheters.

For the first time, the federal medical device safety regulator approved a label expansion based on RWE from a retrospective study of health records documenting off-label use by physicians.

“The clinical evidence used to support the expansion of indications was based solely on an analysis of a dataset comprised of electronic health records from two hospital systems,” the agency said. “The FDA worked closely with the study sponsor to ensure that the RWE resulting from the analysis was both relevant and reliable.”

Two J&J MedTech executives who led the project — Anthony “Tony” Hong, VP of preclinical and clinical research and medical affairs for the cardiovascular and specialty solutions group, and Paul Coplan, VP and global head of medical

device epidemiology — discussed their experience to help other device developers use RWE in the same way.

The study was a test case for the National Evaluation System for Health Technology (NEST), which coordinated the FDA and J&J MedTech project to evaluate the use of RWE in regulatory decisions.

J&J MedTech won approval of one expanded indication after a six-month FDA review period, though this included a stop in the review clock for Mercy Health and Mayo Clinic, the research partners in the study, to reanalyze their data to address FDA’s additional data requests.

It would normally take nine to 12 months for a traditional premarket approval (PMA) process, including investigational device exemption (IDE) review.

J&J MedTech’s Biosense Webster ThermoCool SmartTouch ablation catheter was already approved for paroxysmal atrial fibrillation (AFib), but cardiologists were also using the device to treat persistent AFib. The J&J MedTech team compared their device against another ablation catheter already approved for persistent AFib — the ThermoCool SmartTouch SF

(ABOVE) J&J MedTech’s Biosense Webster ThermoCool SmartTouch Image courtesy of J&J MedTech 76

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www.medicaldesignandoutsourcing.com

(STSF) — in an analysis of records for 1,450 patients treated with either of the devices at Mayo Clinic and Mercy Health.

RWE also secured expanded indications for both catheters and other devices to be used for ablation to treat AFib without fluoroscopy, sparing patients and physicians from potential X-ray radiation exposure.

“There’s a lot of interest in using RWE more,” Coplan said. “The FDA has been particularly interested because there are often gaps in evidence, and sometimes I think that they see a medical need to get the label to be more consistent with what’s happening in clinical practice or what could be done to benefit patients. But they can’t get the evidence because it’s just too much of a hurdle to do a large clinical trial. So in that case, the RWE can actually help FDA, informing its public health role to provide patients and physicians with information that can guide the good practice of medicine.”

The folllowing quotes have been lightly edited for space and clarity.

Which devices are good candidates for RWE? Hong: “We’re looking at how physicians are using existing products that don’t have a pediatric label, for example, and understanding how that usage is safe and effective. This can be done for Class II — even for Class III PMA devices, it can be done. 510(k) Class II devices seem to be the most obvious. (continued on page 78)

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JOHNSON & JOHNSON RWE

(continued from page 76)

You don’t need to run a large, multicenter 500-patient study, but that doesn’t mean that the evidence isn’t needed from a product adoption perspective. So certainly for Class II devices, as the product is rolled out and it is being used in the real world, gathering that data is very powerful for demonstrating the utility of that device.

With Class III, you’re already running large IDE trials to demonstrate the safety, effectiveness, efficiency — but with RWE, I always say if I ran a 500-patient IDE but if I can gather 2,000 patients’ worth of data in a real-world setting that corroborates this, the data becomes more powerful. And it is that usage and standard of care that ultimately will change guidelines.”

Coplan: “For the 510(k) pathway, getting approval using clinical or nonclinical data has a lower hurdle with the FDA than reimbursement approval by the U.S. Centers for Medicare & Medicaid Services (CMS).

In contrast, for the PMA pathway, getting approval using clinical or nonclinical data has a high hurdle with the FDA and that data tends to be sufficient for reimbursement approvals by CMS. Often, the RWE is most useful where the hurdle is highest: for devices using the 510(k) pathway, RWE is useful for CMS reimbursement decisions and for devices using the PMA pathway, RWE is useful for FDA approvals.

J&J MedTech Cardiovascular and Specialty Solutions VP of Preclinical and Clinical Research and Medical Affairs Anthony "Tony" Hong

J&J MedTech VP and Global Head of Medical Device Epidemiology Paul Coplan

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Make sure to define your goal Hong: “You’ve got to start with the end in mind. What is it that you are really trying to achieve and why? That finish line allowed us to think about the evidentiary hurdles and the evidence channels that we can use. We can run company-sponsored IDE studies, but we started pushing the boundaries in terms of leveraging real-world evidence and asking how the usage of a product in the real world corroborates the IDEs that we run, and is that an alternative channel of evidence that can be used to cross that finish line? That’s when we started partnering with Paul and his team and saying, ‘Hey, let’s think way outside the box here.’ We knew that physicians are using our product for persistent cases — that’s not onlabel. For STSF, we actually ran a persistent study and got the label, but given the fact that ST is similar to STSF, is there a way in which we can do this? Data is king, and it is the power of the data that’s going to help convince the FDA that the RWE is valid in making label changes. It’s going to be very important to think about that finish line and what type of data do you need and why.”

Coplan: “The evidence strategy needs to be developed for the key questions or key themes that need to be demonstrated for the product to get approved by FDA and approved by CMS and approved globally.

Once the key research questions are identified, then the question is do you need to use clinical data or can you use RWE? If it would be feasible to use RWE because the product has been used in the real world, then the next step is to assess the data sources that capture product usage and have the data quality to meet the rigor that FDA requires. Once the availability of sample size and data quality questions have been addressed, then the next step is to identify the best study methodology to address the research question using that particular data source? That’s the logical flow I use to get to a fit-for-purpose study using RWE.” How to pick your RWE partners Hong: “Internally, it goes back to the alignment on what that finish line is and what are the internal capabilities and functions that need to be a part of this. And it’s not just clinical medical, but you have epidemiology, you have health economics and market access, and all of these groups need to be aligned. Internal alignment and partnership are absolutely critical.” www.medicaldesignandoutsourcing.com

J&J MedTech’s Biosense Webster ThermoCool SmartTouch SF Image courtesy of J&J MedTech

Coplan: “We submitted a proposal to the coordinating center of NEST. NEST has a network of about 21 partners that are probably the best institutions for medical device RWE research. The initial selection of NEST’s partners came through involvement in PCORnet (the National Patient-Centered Clinical Research Network). When we submitted our proposal to NEST, NEST then approached the 21 partners and asked who was interested in partnering on the study we had proposed. One of the criteria that the research partners had to affirm in order to be a partner was that they had to have use of that medical device in their healthcare system, because if they didn’t there wouldn’t be any relevant data.”

Ensuring RWE data integrity Coplan: “We got some excellent research partnerships with very good academic researchers and well-established databases that were fit-for-purpose for our research.

The first step was to validate each of the data sets according to a number of criteria that FDA required. Some of them were data quality steps, and then we submitted that to FDA, and they had additional requests for data quality validation. The feasibility and validation work was done through NEST funding and support, which I think

JOHNSON & JOHNSON RWE

is important because that data quality and validation work takes quite a bit of time.

Once we finished the data quality work and the feasibility work, we went to the actual hypothesis testing stage of the study, all the time staying in touch with FDA.” Coplan: “A key part of success in RWE is making sure you have good algorithms to identify your study outcomes, your cohort identification, your safety endpoints. Say if you’re doing a registry study, you typically can collect the data elements that you want from more proactively from within the study.

If you’re using a retrospective analysis of secondary data — data that was collected for the conduct of a clinical practice, information that was either used for billing purposes or electronic health records to help with the coding for reimbursement or so the next time the patient comes in there’s a clear record of what the problem was and how it was treated — you rely a lot on the codes. The first thing is you really have to understand the codes and spend time on the codes to make sure that you have the codes —we have ICD-9 codes, ICD-10 codes and soon to be ICD-11 codes — you have to be familiar with all of those codes.

The next thing we did was a chart review for 10 or 15 people. We had a specific code. One of the endpoints was stroke. So then we identify 15 people with stroke: 15 at Mercy, 15 at Mayo Clinic, and then do a chart review to see if they really did have a stroke. If not, what was the problem? Then we’d create a positive predictive value to compare. With stroke, it had a positive predictive value around 50%, which is too low. Normally you need around about 80%.

The problem was that a lot of people who had a code for stroke, they had previously had a stroke and were coming in for poststroke care. So we then had to figure out through a series of codes to differentiate between a past stroke and a current stroke.”

Hong: “The consistency of data is absolutely critical. Garbage in gives you garbage out. When you are gathering RWE, every physician’s usage of a device can be very different. As we think about partners we’re working with and the data that’s out there, understanding of how the data was collected and what was collected really ensures that your analysis is going to be meaningful. Otherwise, the heterogeneity of the data will be such that it will be very difficult to make heads or tails out of it.”

11• 2023

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