MEDICAL DESIGN & OUTSOURCING - May 2018

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www.medicaldesignandoutsourcing.com MAY 2018

THE 10 HOTTEST MEDTECH STARTUPS OF 2018

Don’t sleep on this list of the hottest medtech startups of 2018.

SEVEN WAYS TO DOOM YOUR MEDICAL DEVICE STARTUP

There are many ways a medical device startup can self-destruct.

Here are the top seven.

MINNESOTA 2.0

Can this major U.S. medical device cluster become a healthcare innovation hub?

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HERE’S WHAT WE SEE

Minnesota continues to attract medtech innovators California, especially Silicon Valley, may have a reputation as an epicenter of digital health. But while researching the health of the Minnesota medtech hub, I came to an important realization: There is actually a lot going on in the North Star State.

Here’s just a sample of the recent successes Minnesota has seen when it comes to both digital health and traditional medical device companies: • Bright Health, a Minneapolisbased health insurance startup that works closely with carefully selected “care partners,” raised $160 million last year in a Series B funding round.

• Boston Scientific announced in March a $406 million deal for NxThera (Maple Grove, Minn.) and its Rezūm benign prostatic hyperplasia device, which uses steam to ablate excess prostate tissue.

Chris Newmarker Managing Editor Medical Design & Outsourcing c newmark er@wtwhmedia.com

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• Ferring Pharmaceuticals of Switzerland recently inked a deal to acquire Rebiotix (Roseville, Minn.) and its platform of living drugs. Financial terms of the deal were not disclosed.

• Maple Grove, Minn.–based Inspire Medical Systems, a Medtronic spinout, is seeking to shake up sleep apnea treatment with a pacemaker-like system to treat obstructive sleep apnea; it has plans for an $86 million IPO. • Virtual care company Zipnosis (Minneapolis) in April announced an agreement with Allina Health, a major Twin Cities health provider, to update its online care offerings to better interact with patients.

• A Hennepin County Medical Center spinout called Hitch Health has generated attention with a proprietary software solution that integrates the Electronic Health Record and ride share services, automatically syncing ride requests with medical appointments.

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It actually shouldn’t come as a surprise that Minnesotans continue to innovate around healthcare. If we truly are going to make the U.S. healthcare system the most efficient, the most effective, the most innovative, the most humane provider of care in the world, we’re going to have to have collaboration between the hospitals and clinics, the insurers and the medtech companies.

Minnesota happens to have some of the best in all three areas. Mayo Clinic has been innovating the practice of healthcare out of Rochester, Minn., since the late 19th century. One of the largest U.S. health insurers, UnitedHealth Group, is headquartered in Minnetonka, Minn. And Medtronic, the largest medical device company in the world, is run operationally out of Fridley, Minn.

(Boston Scientific and Abbott have a major presence around the Twin Cities, too, and 3M is also based there.)

The ecosystem of consultants and contract manufacturers is also impressive. Phillips-Medisize is based just over the state line in Hudson, Wis., and Frisco, Texas–based Integer has multiple facilities in the Minneapolis-St. Paul metro. Protolabs has pioneered quick-turn manufacturing out of Maple Plain, Minn., and Heraeus is a major innovator out of St. Paul. And that’s just a small sampling of the companies serving the industry.

Some might argue that we aren’t even at Minnesota 2.0 when it comes to the device industry. Maybe it’s Minnesota 3.0 or 4.0. What matters is that the state is entering a new, exciting chapter innovating medtech.

See it for yourself at our DeviceTalks Minnesota event June 4-5 in St. Paul (https://minnesota.devicetalks.com). M

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CONTRIBUTORS

WANG

PRAKASH

DYKEMAN

BETTEN

RUBINO

CHOLETTE WILLIAMS

STANTON

LI MAXSON

BILL BETTEN is the president of Betten Systems Solutions, a product development realization consulting organization based in Minneapolis-St. Paul. Betten taps into his years of experience in the medical industry to advance device product developments into the medical and life sciences industries.

MARTIN CHOLETTE, VP of research, development & engineering for Integer, has led the development of cardiovascular, cardiac rhythm management and neuromodulation medical devices in his 20+ year tenure in the medical device industry. He is the inventor on numerous U.S. patents related to medical devices and holds degrees in both engineering and physiology from the University of Montreal.

DAVID J. DYKEMAN is a registered patent attorney with more than 20 years of experience in patent and intellectual property law, and co-chair of Greenberg Traurig’s global Life Sciences & Medical Technology Group.

WILLIAM LI is an R&D engineer at Adam Spence (formerly Fermetex Vascular Technologies) in Wall, N.J. Li works closely with sales and marketing in new business development. He has worked in the medical device industry for 22 years, 18 years of which was with W.L. Gore & Associates focusing on catheter technology and product development.

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STEVE MAXSON is VP of marketing and sales at Adam Spence (formerly Fermetex Vascular Technologies) in Wall, N.J. Prior to joining Adam Spence, Steve served in various leadership roles at American Kuhne for over 15 years, most recently as director of global business development.

DEEPAK PRAKASH is senior director of global marketing at Vancive Medical Technologies, an Avery Dennison business.

ROBERT RUBINO, director of battery research & development for Integer, is responsible for the development of battery technologies for implantable medical devices.

ROBERT STANTON is director of technology and new business development at Omnetics Connector Corp., based outside Minneapolis.

Stanton is an electrical engineer who spent the majority of his career at Tektronix in Oregon designing and developing technology for portable electronic test equipment. His graduate work at Stanford University included materials technologies applied to high-speed miniature electronics.

DAVID WANG is a global market manager for Bal Seal Engineering’s medical device business. An engineer with more than 10 years of design experience, he collaborates with OEMs and tier suppliers to create sealing, connecting, conducting and EMI shielding solutions that help set new standards for device performance.

CHRIS WILLIAMS, technical account director for Integer, serves as liaison between customers and Integer technical staff to identify and facilitate solutions for patient needs.

www.medicaldesignandoutsourcing.com

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CONTENTS

medicaldesignandoutsourcing.com ∞ May 2018 ∞ Vol4 No3

DEPARTMENTS

44

Minnesota 2.0 Can this major U.S. medical device cluster become a healthcare innovation hub?

Photo courtesy of istockphoto.com

ON THE COVER:

06

HERE’S WHAT WE SEE: Minnesota continues to attract medical device innovators

08 CONTRIBUTORS

12

IP ISSUES: Five tips to protect your medtech startup’s innovations

16 COMPONENTS: This new PTFE seal could make insulin pumps and other medical devices better 20

CONNECTORS CORNER: Protecting medical cables and connectors from electromagnetic interference

24 CONTRACT MANUFACTURING: Four ways medical device industry suppliers can save their clients money

FEATURES 44 Can Minnesota become a healthcare innovation hub?

Minnesota has the institutions and the talent to transform healthcare in the U.S. The question is whether the money will follow.

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MANUFACTURING & MACHINING: Will 3D printing replace injection molding?

58 The 10 hottest medtech startups of 2018

Don’t sleep on this list of the hottest medtech startups

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66 Seven ways to doom your medical device startup

From spending money on the wrong priorities to lacking a regulatory strategy early on, there are many ways a medical device startup can self-destruct.

MATERIALS: Making sense of your materials options in designing wearables

34

POWER SOURCES: Why new battery technology will lead to disruptive innovations

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TUBING TALKS: Exploring X-ray and MRI compatibility in braidreinforced catheter shafts

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AD INDEX

68 A public health advocate’s legacy highlights lingering questions about power morcellation

Dr. Amy Reed’s tragic case brought to light the cancer risks posed by power morcellation. Her death hasn’t stopped lingering questions about the technology.

72 Medical device product development: Here are the basics (Part 1)

The strategies for achieving medical device product development success could easily fill a book. Here’s the first in a short two-part primer on the subject.

77 Medtech veteran Mir Imran wants to replace injections with the ‘robotic pill’

Companies have tried for decades to deliver protein-based drugs orally. Can Mir Imran and his company’s robotic pill succeed where so many have failed?

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IP ISSUES

Five tips to protect your medtech startup’s innovations Building a strategic patent portfolio is crucial to success for a medtech startup.

When it comes to starting and building a medical device company, a strong patent strategy tied to business goals can be the driving force behind venture capital investment, strategic collaborations and mergers and acquisitions.

In order to safeguard its intellectual property (IP), every medtech startup should consider these five tips for protecting and leveraging its innovations.

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1. File early and file often Fundamental to a strong patent portfolio is establishing solid patent protection for a company’s core technology. First, one or a series of patent applications should be filed providing the broadest possible

5 • 2018

patent protection covering the core technology. As the core technology evolves, incremental improvements and varying applications should be patented to form a “picket fence” of protection around the core technology.

Medtech startups should file patent applications as early and as often as their budget permits. This has been particularly true since the passage of the America Invents Act in 2011, which brought the United States into conformance with the rest of the world as a first-to-file country. Thus, a key is to file patent applications before any public disclosure that

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could limit patent coverage. To ensure both U.S. and international patent coverage, a patent application should be filed before the invention is first published, disclosed, used or offered for sale. Savvy companies file patent applications early and often.

2. Proactive patenting To build a patent portfolio faster, early-stage medtech companies should consider utilizing the United States Patent & Trademark Office (USPTO) fast-track patent examination programs.

Due to the USPTO’s backlog of about 540,000 patent applications, it can take three years or more for a medtech patent application to obtain a final decision and issue as a patent. In contrast, the USPTO Track I prioritized examination program strives to achieve a final go or no-go decision within 12 months of filing. Track I prioritized patent applications are often allowed in as little as 6 months. Other ways to accelerate USPTO examination include the Patent Prosecution Highway program, based on an issued foreign patent or a favorable search report, and the age-based program which speeds examination for inventors age 65 or older.

The USPTO Track I prioritized examination program is more expensive than regular examination and accelerates costs that would normally be spread over a few years. However, early-stage medtech companies should still utilize these programs for their key patent applications to quickly obtain an issued patent with claims covering the most important features of the product. Additional patent applications with claims of different scope can be filed via regular examination to build multiple layers of patent protection around the company’s core technology.

MEDTECH STARTUPS SHOULD FILE PATENT APPLICATIONS AS EARLY AND AS OFTEN AS THEIR BUDGET PERMITS. 3. Patents attract financing Medtech startups need a strategic patent position that protects against potential competitors and entices investment from venture capitalists. In today’s innovative economy, a medtech company’s success depends on the strength and value of its patent portfolio. For early-stage medtech companies, patents are often the only way for investors to place a value on the company’s technology and judge its potential success before sales commence, which often only occurs after FDA approval. Strategic patents can also lead to joint ventures, collaborations and licenses with strategic partners.

“When evaluating whether to invest in a startup medtech company, patents are critical,” Dr. Omar Amirana, a serial entrepreneur and SVP at frequent medtech investor Allied Minds (Boston), told Medical Design & Outsourcing.

“The core technology must have solid patent protection to provide flexibility and room to operate in a desirable market,” Amirana said. www.medicaldesignandoutsourcing.com

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IP ISSUES

4. Know your competitors’ patents In addition to building their own patent portfolio, early-stage medtech companies should also become familiar with the prior art patent landscape of competitors in their technology space. Knowledge of the patent landscape can help companies further focus their product development and patent strategy.

Review of the relevant patent landscape can identify technology spaces with fewer barriers for entry due to light patent coverage. By obtaining patent coverage in a technology space with fewer competitors, a medtech company can carve out its patent niche and become a dominant player in that space. Also, filing patents covering improvements to competitors’ products can provide significant control over a competitor’s product enhancement options.

Knowledge of prior art may help companies prepare stronger patent applications that anticipate potential rejections during USPTO examination.

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5. Don’t forget about trade secrets Used in conjunction with or as an alternative to patents, trade secret protection can provide a viable option to protecting the IP of the medtech company. Trade secret protection involves protecting ideas by taking measures to keep them secret, possibly avoiding the effort and expense associated with filing patent applications. Trade secrets can provide protection for as long as the underlying technology is kept secret, but any public disclosure loses the protection. The algorithms that drive digital health and mobile medical applications are often good candidates for trade secret protection.

The path to patent success In the dynamic medtech market, a strong patent strategy is crucial for securing investment and gaining market share. Maintaining a valuable patent portfolio requires that companies periodically perform a patent audit to assess the strengths, weaknesses and gaps in the patent portfolio. By developing a strategic patent portfolio quickly and successfully, a medtech startup can navigate a path to commercial success. M

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COMPONENTS

This new PTFE seal could make insulin pumps and other medical devices better In dynamic applications requiring sealing at low-tomoderate speeds and pressures, design engineers are replacing underperforming elastomeric O-rings with spring-energized PTFE “C-ring” seals.

David Wang | Bal Seal Engineering |

When O-rings and other traditional sealing methods fail, diagnostic and drug-delivery equipment engineers are embracing a new and more cost-effective way to improve the performance of their existing hardware designs: The springenergized PTFE “C-ring” seal.

The challenge: Replacing a failed O-ring The C-ring seal was first developed for a diagnostic tool employing a piston operating in a water bath of approximately 100°F, reciprocating at a rate of 5 ft. per minute. The operating conditions were mild, but the tolerances were large. The original design called for an elastomeric O-ring to seal the piston, but the O-ring was unable to maintain a consistent seal and the equipment leaked.

With prototypes already built, engineers began looking for an alternative.

U-cups or standard lip seals, which would typically be used in a piston application, were not a viable option because of large radial tolerances. Also, installing these over a full-step groove wasn’t practical.

The installation would require too much stretching, resulting in seal deformation and premature failure.

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The successful retrofit In 2016, Foothill Ranch, Calif.-based seal designer Bal Seal Engineering proposed an experimental solution: A canted coil spring wrapped in a C-shaped PTFE ring. The seal worked exactly as intended. By combining the low-friction properties of PTFE with a streamlined jacket geometry, the “C-ring” provided reliable, consistent sealing plus smoother and quieter operation than an O-ring. In addition, the C-ring could be installed in the full-step O-ring gland, which is normally not recommended with non-elastomeric materials. As a result, the C-ring was installed with no modifications to the original hardware design and without the use of any specialized tools.

That original C-ring seal has been in use for two years, resulting in improved product performance and prolonged equipment service life – reducing downtime and maintenance costs.

One seal, many potential applications Medical imaging units, insulin pumps, ventilators and drug-delivery devices typically rely on O-rings to seal within short axial spaces. But when extreme radial deflection capability is required,

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COMPONENTS

O-rings cannot compensate – often resulting in wear, permanent deformation and leaks. Despite these shortcomings, engineers have continued to use O-rings because other solutions (e.g., U-cups, lip seals) are unable to handle radial deflection requirements and normally require more axial space than an O-ring.

The C-ring is different because it can fit into the small axial space typically afforded for O-rings, whereas standard seal configurations cannot.

In addition, the C-ring is fully customizable, based on the needs of the application. It can be configured with ultra-thin and flexible lips for cryogenic applications or with one thick lip for a dynamic application in which the seal requires more wear resistance.

Images courtesy of Bal Seal Engineering

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Rotary, reciprocating and static Because the C-ring accommodates rotary and reciprocating movements, it’s a versatile solution potentially useful in a variety of products that require slowto-moderate-speed sealing – including medical robots, portable medical equipment and probe/hose connectors.

The C-ring can accommodate an unusually large degree of radial tolerance – at least five times as much as a standard seal configuration of a similar crosssection. Tolerance ranges are dependent on ambient pressure, media type and surface finish conditions. The C-ring also functions well in static applications, where components require protection from environmental contaminants.

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PTFE density and compound options By removing PTFE material from the C-ring’s initial jacket design, engineers were able to enhance its elasticity and pliability. As a result, the C-ring has proven to be more stretchable and flexible than originally expected, making it useful for non-round applications. The C-ring is already in use in a drug-delivery pump with an oval piston. And because the seal jacket can be made with virgin or filled PTFE, the C-ring is an extremely versatile seal, compatible with hardware made from commonly-used metals and plastics.

Energizing alternatives The original C-ring developed for use in the water-based diagnostic tool included a canted coil spring inside the PTFE jacket.

But a C-ring can also be manufactured using a helical ribbon spring as the energizer. Substituting a helical ribbon spring for the canted coil spring allows the C-ring to provide very high sealing contact pressure, making it ideal for use in cryogenic or static applications.

Conclusion Citing its ability to provide longer service life in applications where clearances, surface finishes and other design characteristics vary widely, Bal Seal Engineering has called its C-ring “the perfect seal for an imperfect world.”

While no seal is perfect, the versatility and customizability of the C-ring certainly make it an interesting and potentially beneficial option in certain medical and diagnostic devices. It is a relatively lightduty seal, ideal for use in low-pressure (<500 psi), low-speed (<100 ft/min) applications that require low friction. For such environments, a C-ring may prove to be a better sealing solution than an elastomeric O-ring or other standard seal type, offering designers the opportunity to achieve more service life and quieter performance without costly hardware modifications. M

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CONNECTORS CORNER

How to protect medical cables and connectors from electromagnetic interference Cable and connector experience from military and satellite systems could help pave the way for safer electromagnetic interference control in the medical device industry.

Bob Stanton | Omnetics Connector Corp. |

Today’s medical treatment suites are crowded with increasingly complex electronic devices designed to monitor, display, assist and alarm the staff involved in patient services.

The newest generation of medical device electronics are smaller and more compact to allow more instruments into the area, causing electromagnetic noise to become an even more important concern.

The good news is that designers of military and satellite systems used in space have years of experience tackling problems around electromagnetic interference (EMI) and cable noise control in tight spaces. Cable and connector experience from that industry — including know-how at suppliers including Omnetics 20

Medical Design & Outsourcing

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— could help pave the way for safer cable EMI control within the medical industry.

Lessons learned from designing cable for military and satellite systems matter because much of the newer ICU instrumentation runs on digital signals running in gigahertz speeds while being crammed immediately close to other electronic instruments.

Often times, it helps to define if a cable being routed within a rack of instruments is going to be a victim (receiver of unwanted EMI), or if the cable may be the transmitter of EMI noise to other equipment. In either case, the EMI noise can cause poor performance or reduce accuracy of the instruments supporting practitioners.

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5/18/18 12:31 PM

If left to your own devices, this is where you hope the pumps & compressors were sourced.

There are a number of solutions for the medical cable and connector designer to control EMI noise problems in today’s medical instruments: 1. Filtering One can begin solving the EMI issue by finding the frequency of the interfering noise and adding selective filtering circuits on the instrument circuit board or by adding filters to the connectors on the cable harness. Thin film capacitor and resistor networks can drain off unwanted signal noise by grounding them near the noise source. Unfortunately, cable and connectors are required to be small, and physical size limits some of the effectiveness of in-line filter circuits within the connector shells or the cable itself.

THE NEWEST GENERATION OF MEDICAL DEVICE ELECTRONICS ARE SMALLER AND MORE COMPACT TO ALLOW MORE INSTRUMENTS INTO THE AREA, CAUSING ELECTROMAGNETIC NOISE TO BECOME AN EVEN MORE IMPORTANT CONCERN. 2. Overall shielding Braided over-shielding has been a mainstay when it comes to isolating complex cable from the outside world. Braiding is often the best shielding solution, and it easily offers up to 85 dB of isolation from outside noise.

To reduce the amount of wiring to and from systems, medical equipment devices are utilizing hybrid cables and connectors that combine power, signal and reference triggers into one connector and cable system, much like the cable pictured with this article. Note that within the connector, there are power pins on one side and signal pins on the other. More importantly, however, is the hidden braided shield over the cable from each metal circular connector to the main interface connector.

Shielding must maintain a 360-degree seal from the metal connector to each of the smaller circular connectors. If there is a gap or disconnected shield, the cable becomes an antenna at its open loop, and EMI will escape to all sections of the instrument rack in the ICU unit.

5 • 2018

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Factors including braiding thickness, metal selection, type of weave and even plating on the outer portion of the shielding can help determine EMI shield effectiveness. The system designer may want to work closely with the cable designer to select how much shielding is necessary.

3. Drain lines inside cable A number of cable designs support the highest speed digital processing systems such as live imaging or active subcutaneous inspections done by the practitioner. Cable built to IEEE 1394, similar to “fire wire” used by phone companies, has helped significantly.

Each set of high-speed digital wires are wrapped along with a “drain” wire. The twisted pair of wires handle signals in the high gigabit-per-second range, while the drain wire assists with fast return signals

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to the source as well as pulls off potential EMI noise and jitter that happens as signals run extremely fast. This method also has a lightweight overall shield underneath the overall jacketing of the medical cable. (See image with this article.)

In many cases, an aluminum foil shield is used to keep the cable small and limp but still adds to the jacket protection from EMI. 4. Conductive over-molding and shrink jackets A clever solution for some EMI cable applications is to use special jacketing made of polyolefin heat shrinkable tubing that is coated with unique silver-plated copper filled coatings from Parker Hannifin’s Chomerics division. The manufacturer’s tests show they insulate the active electronics up to 50-60 dB attenuation from 30 MHz to 18 GHz signals. Unique connector over-boots are also included.

As medical technology speeds up and is condensed, protecting cable and the systems they operate from EMI is a complex challenge, but it’s also solvable. M

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CONTRACT MANUFACTURING

Four ways medical device industry suppliers can save their clients money Medical device contract manufacturers need to be savvier than ever when it comes to saving clients money. Here are four ways that Spectrum Plastics Group has accomplished the task.

Count Spectrum Plastics Group (Alpharetta, Ga.) among the medical device industry suppliers increasing capabilities and expertise in order to add value to what they provide their customers. Long gone are the days when medtech contract manufacturers simply made orders to spec. As four recent case studies highlight, it’s all about branching out and finding ways to save medical device companies money:

Chris Newmarker | Managing Editor |

1. Taking a lead on standards A Spectrum Plastics company, formerly known as Xeridiem Medical Devices, was an early leader in the Global Enteral Device Supplier Assn.

(GEDSA) – an industry alliance seeking to address the fact that the same Luer connector was in use for several different medical tubing purposes.

The resulting ISO 80369-3 standard spurred the innovation of a new connector under the trade name ENFit that is specific for enteral feeding.

ENFit is meant to ensure that only devices intended for nutritional delivery connect with the corresponding tubing, preventing potentially deadly and costly situations.

Industry adoption for ENFit is at 25%, according to Spectrum; company officials expect full adoption by 2020.

2. Engineer-to-engineer collaboration A prominent manufacturer of negative-pressure wound therapy devices moved from manual to automated assembly, according to Spectrum.

The multi-lumen, extruded tubing components – which had a tendency to spiral, curve and stretch during manufacturing – could no longer be inspected and skillfully manipulated by the assembly team.

Spectrum Plastics engineers collaborated directly with the customer’s engineers to align tubing extrusion and automation, even though both processes occur in separate locations.

Spectrum engineers came up with a host of savings for the customer: • They created a tighter spec to remove memory from tubing, which cut waste by 5%; • Their global footprint meant they could hold inventory for an 80% savings; • Their returnable packaging reused boxes and pallets for a total savings of $70,000 per year.

3. Employing a variety of capabilities A well-known manufacturer of fluid administration sets was planning to start the manufacturing process for an upcoming product. Already a longtime supplier of medical tubing to the customer, Spectrum was able to persuade the customer that it could become the complete contract manufacturer of the fluid administration sets, from mold making to device assembly.

Spectrum Plastics Group helped the customer transition the manufacturing and assembly of finished devices to Spectrum’s facility in Reynosa, Mexico. The move helped the customer gain back 10,000 square feet of space that could be dedicated to the new device. It also reduced the overall cost of goods by a fifth.

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APOLLO’S ABILITY TO WORK FAST WITH REMARKABLE ACCURACY QUICKLY ACHIEVED THE PERFORMANCE CHARACTERISTICS REQUIRED OF THE CATHETER, AND DELIVERED UNITS READY FOR STUDIES WEEKS AHEAD OF THE OTHER TEAM.

lumen, deflectable catheter for a transcatheter mitral valve. A Spectrum Plastics company, Apollo Medical Extrusion Technologies, stepped in and got the project done within six months, according to Spectrum.

“Apollo’s ability to work fast with remarkable accuracy quickly achieved the performance characteristics required of the catheter, and delivered units ready for studies weeks ahead of the other team,” said Apollo Medical Extrusion VP & CTO Mike Schultz. “It’s a complicated delivery system that can take more than a year of development, but we were able to get them from concept to design in six months because of our expertise in

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engineering and design.”

Apollo was also small enough to be nimble, even as it was supported by the overall expertise at Spectrum Plastics Group. “We offer agility and efficiency without sacrificing quality and experience, for a dependable and repeatable solution delivered at scale,” Schultz explained.

The second generation of the catheter had an added level of complexity: The five-lumen deflectable catheter required a braided reinforcement to enhance performance. Apollo was able to draw on specialized polymers that add a certain degree of flexibility to the reinforcement offered by various braided materials, driving a 25% performance improvement and a 30% reduction in cost. M

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MANUFACTURING & MACHINING

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Image courtesy of Carbon

Will 3D printing replace injection molding?

3D printing and injection molding have their own benefits and limitations when it comes to making medical device parts, according to experts from PTI Engineered Plastics, Carbon and Protolabs.

Medical device parts makers are increasingly turning to 3D printing, but additive manufacturing has yet to reach the tipping point where it could supplant injection molding in medtech parts manufacturing, according to a panel of experts at the AD&M Cleveland show.

Whether a manufacturer uses 3D printing or injection molding depends completely on what a customer’s needs are, the experts from PTI Engineered Plastics, Carbon and Protolabs explained during the March 8 panel.

In fact, the two processes may be more of a dynamic duo.

Danielle Kirsh | Assistant Editor |

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One of the advantages of 3D printing is that a manufacturer can get their hands on a product quicker than they would be able to with injection molding, while having the ability to completely customize the product. In contrast, injection molding allows parts to be produced in mass volumes.

“3D printing allows you to get parts in your hands very quickly without an investment in your tooling and it allows you to also [make] some parts that may not be necessarily designed for injection molding, but allows you to do geometries that are unique,” said John Budreau, director of new business at PTI.

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“I think it’s great when it’s not a part that’s actually injection-moldable,” Budreau said of 3D printing, adding that it can be costly to buy a mold up front for a unique and complex part design.

Budreau and his fellow panelists, Thomas Davis of Protolabs and Carbon’s Scott Kraemer, listed three limitations they said hold 3D printing back: 1. Machine throughput One of the shortcomings of 3D printing is machine throughput, according to Davis, an applications engineer at Protolabs.

“It’s traditionally a layering process.

The layering process has mechanical properties that fall short, from the isotropic standpoint, and the ‘Z’ when compared to the ‘X’ and ‘Y,'” Davis said.

2. Tolerancing Another limit of 3D printing is tolerancing.

Although Carbon, with its Continuous Liquid Interface Production (CLIP) process, created software that can fine-tune parts as opposed to welding or having to manually adjust things in order to make a specific part, tolerancing is still one of the biggest problems manufacturers face.

“We’re pretty close to what injectionmolded parts can do, but [tolerancy] is still the biggest hiccup or disruption in our technology,” expained Kraemer, a production development engineer at the 3D printing firm.

3. Limited materials options New and emerging materials could also change the game for 3D printing – but not yet.

That won’t happen until OEMs open up to 3D-printing-friendly materials other than polycarbonate or ABS that perform similarly to those medtech mainstays.

“Efficiency is going to increase and once we can start using 3D printing more for production, I think that the materials will follow. There will be more material choices and colors and it won’t be considered as niche and expensive,” Davis noted.

For now, there are a limited number of materials for a set number of unique 3D printing applications.

“With injection molding, we’ll probably run 1,500 different engineered materials this year of everything you can imagine, whether it’s glass fillers or other content in the materials, to achieve certain properties,” Budreau added.

“Once the 3D printing world can do that

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with their properties, that’s when you can use the process for parts that are not injection-moldable.”

“It just depends on where [customer] product development needs are and where they’re at in the project. 3D printing really does serve a purpose for a lot of our production manufacturing processes,” he said.

So when does 3D printing make sense over injection molding?

Depending on what the customer needs, injection molding might be a better fit than 3D printing, which is better suited to the product development process.

“Basically 3D printing is just another tool in the toolbox for the engineers to get their goals accomplished. It just depends on what the goal is,” Davis said, adding that the geometry and importance of a part come into play in making the choice.

price range,” he said. “When you start getting parts that are 6-by-6, somewhere around that range, that’s where it starts to lean little bit more towards injection molding” in terms of pricing.

It’s also important to recognize that each tool has its limitations.

Injection-molded parts can’t always be 3D printed, and 3D-printed parts can’t always be injection-molded, so it’s important to have engineers who can recognize the difference.

“Certainly 3D printing will take some of the injection molding market away, but I think the market will continue to grow,” Budreau said.

“Honestly, it’s not necessarily a tipping point. It’s where you’re at in your project development process. What is the value of having an injection-molded part versus a 3D-printed part? Now certainly if the design is not injection-moldable, that’s when you 3D print it.” M

CERTAINLY 3D PRINTING WILL TAKE SOME OF THE INJECTION MOLDING MARKET AWAY, BUT I THINK THE MARKET WILL CONTINUE TO GROW. “If it’s really complex, if it’s a highvalue-proposition part that’s low volume – those are great fits for 3D printing. If it’s not, higher quantities would be better for injection molding,” he said.

Part size also plays a role, Kraemer added.

“You can only make X amount of parts. So, if you look at the size of a Matchbox car and under, we can compete against injection molding in

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MATERIALS

Making sense of your materials options in designing wearables The medical device industry’s knowledge base continually evolves regarding what works — and what doesn’t — for wearable applications.

Deepak Prakash | V a n c i v e M e d i c a l Te c h n o l o g i e s |

In the dynamic wearables sector, medical device makers are searching for ways to translate their expertise into mobile, bodyworn applications. Skin-worn wearable devices are gaining traction, particularly for end uses that demand a high level of data accuracy.

Because these wearables have such intimate contact with the body, they often can pick up very subtle signals from the organs and muscles, making them ideal for some cardiac and activity monitoring applications. Their direct contact with the skin also opens possibilities for delivery of medications and supplements to patients.

Early in the wearables design process, it’s important to think about material selection and specification. Adhesive materials are a foundational component of most skin-worn wearables, so it’s wise to explore various performance characteristics, start evaluating biocompatibility and even do some preliminary wear testing during the initial stages of product development. As medical device manufacturers are all too aware, once material and component specifications are locked into regulatory documentation, it’s very difficult and time-consuming to make changes down the line.

Image courtesy of Vancive Medical Technologies

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MATERIALS

A quick review: Wearable adhesives Here are a few wearable adhesive basics to help familiarize device designers and managers with adhesive material choices. There are two primary types of adhesives used in wearable devices: •

•

Skin-contact layer adhesives – These are the materials that ultimately hold a wearable device directly to the patient’s body. They must be very comfortable and able to effectively manage different moisture and activity levels, depending on the wearable’s end use.

Construction-layer adhesives – These materials are also known as tie-layer adhesives, because they tie together the different components of the wearable device. Although construction layers usually don’t directly touch the patient’s skin, they must be compatible with the skin-contact layer. For example, if the skin-contact layer adhesive is breathable, the construction-layer material must also be breathable or it will negate the skin-contact layer’s advantages.

This figure illustrates how adhesive materials engineered for different end uses can vary in their amount of tack, moisture vapor transmission rate (MVTR), static shear and peel adhesion. Material A is a material typically used for ostomy applications, Material B is increasingly favored for wearables, and Material C is designed for wound care dressings.

Image courtesy of Vancive Medical Technologies

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There are four major material characteristics that play an important role in the performance of any wearable device adhesive: • • •

•

Static shear – The ability to hold position in the presence of shearing forces, such as bending and twisting (also known as cohesion).

Peel – The ability to resist removal by peeling (also known as level of peel adhesion).

Tack – The ability to adhere quickly. For example, some pressure-sensitive adhesives may adhere almost instantly; others may need to be held in place with light pressure for a short time to achieve optimal adhesion.

Moisture management – The ability to move moisture, such as perspiration and other bodily fluids, away from the patient’s skin to avoid discomfort and irritation.

Moisture typically is managed in one of two manners: • Fluid absorption (being absorbed and contained within the material).

• Moisture-vapor transmission (evaporating through tiny pores in the material), as measured by moisture vapor transmission rate (MVTR).

A major challenge: Achieving comfort and function Wearable devices present unique design requirements.

For one thing, they’re often designed to be attached and activated in the patient’s home, which may be many miles from the nearest healthcare provider. That means the device has to be easily self-applied, perhaps singlehandedly. Tack plays a key role here, especially for drugdelivery applications in which the patient needs a quick, secure attachment. Materials suppliers may be able to engineer adhesives for repositionability if the patient is likely to miss the ideal securement spot on first attempt.

For another, unlike hospitalized patients who may be confined to a bed or limited in their movements, most patients using wearables will be going about their usual routine at home and work. Wearables need to move with the patient through daily activities, such as exercising, showering, sleeping and dressing. An appropriate level of static shear and peel adhesion is necessary to ensure the wearable can stay secure during all of this motion.

And unlike a wound dressing, the wearable must not only stick to the patient but have the strength to hold the weight of the device itself. Even a few grams can make a big difference in terms of the demands put on the adhesive. And all the while, the skin will be exuding sweat and regenerating cells, so device materials must also manage this fluid and exudate.

Another difference entailed in the everyday nature of wearable use is that they generally must be small and unobtrusive. Within the inpatient setting there are procedures and protocols that are very familiar (e.g., taping a catheter to a patient’s arm or attaching electrodes with wires to the chest).

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This figure compares how long a wearable medical device, made with three different materials, remained adhered to the arms of 35 different human test subjects. The top line shows the results for Material B, an acrylic adhesive material ideal for wearable applications. The middle line represents how an adhesive designed for ostomy applications performed when securing a wearable device. The third line shows how an adhesive designed for advanced wound dressings performed in this wearable device test.

Image courtesy of Vancive Medical Technologies

But this approach is less acceptable in a non-medical setting. In the swirl of professional and personal life, a device usually works best when it disappears under the clothing and can be all but forgotten. For wearable device design, this means the adhesive must be long-term, requiring excellent moisture management, peel adhesion and static shear.

Another major reason for the complexity of wearable device design is the diversity of expertise required to bring these solutions to market. Consider that many wearables bear more resemblance to consumer electronics than medical devices. Depending on the device’s function, it may need to be Bluetooth-enabled or USB-compatible. Specialized software algorithms will be needed to convert the device’s digital signals into meaningful clinical information. A cloud-computing infrastructure may be required to move and store enormous amounts of data. And – as they are in so many other facets of life today, from hailing a cab to ordering pizza – user-friendly mobile apps are essential for delivering all of this data to healthcare providers and patients in a highly accessible, easy-to-digest way.

In conclusion, a strategy that nurtures multidisciplinary collaboration is the key to successful wearable design. From adhesive materials to the software code, a patient-centered approach will win the day. M

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Medical Design & Outsourcing 33

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POWER SOURCES

Why new battery technology will lead to disruptive innovations Whatâ&#x20AC;&#x2122;s the next big disruption in battery technology?

Three experts from Integer, a global leader in medical device outsourcing, weigh in.

Martin Cholette | Integer |

What new technologies in medtech are being enabled by advances in battery technology?

Chris Williams: One new technology is the leadless cardiac pacing market.

Integer has developed batteries in a cylindrical form that allows for implants through the femoral vein in a minimally invasive procedure. Applications for energy storage continue to miniaturize, driving demand for increases in energy density and also novel form factors.

This will continue to fuel the implanted sensor/recorder markets as well as less invasive therapeutic devices.

Robert Rubino | Integer |

Chris Williams | Integer |

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Rob Rubino: One potential area for big advances is in cochlear implants.

Currently, the implant is behind the ear and patients remove them when sleeping, showering and swimming. If there is a fire or emergency, they may not hear it because they took off the implant. In the future, the battery (and implant) could be inside the head, eliminating outside paraphernalia.

Martin Cholette: Still in its infancy but in a phase of accelerated development are minimally invasive diagnostics and technologies that monitor physiologic activity and vital signs.

These technologies offer information to physicians and patients that lead to more effective management of diseases. What comes to mind is implantable cardiac monitors; used 5 â&#x20AC;˘ 2018

instead of cumbersome Holter monitors with limited observation periods, these small devices are implanted under the skin in a simple procedure to provide continuous monitoring of cardiac activity and enable a level of diagnostic and arrhythmia management.

When developing new battery innovations, what are some of the challenges faced?

Martin Cholette: One of the biggest challenges is adopting new materials that drive enhanced battery performance and its related validation.

As we design and experiment with new chemistries, shapes and size formats, it will just take time.

Rob Rubino: The availability of materials can be challenging since some vendors donâ&#x20AC;&#x2122;t want to supply materials for the manufacturing of medical devices due to the liability. And, if materials get discontinued, the time needed to validate replacement materials is long and disruptive.

Are outside (non-battery) influences being brought into play that could enable battery advancement?

Rob Rubino: Improvements in how we transfer power could enable advances in recharging batteries. Today, you have limitations on how quickly batteries can be charged. If we can find a solution to

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POWER SOURCES A cut-out view of a cylindrical leadless pacemaker battery.

Image courtesy of Integer.

transfer this energy safely, and with miniature hardware, we can begin to think about shorter charge times. Shorter charge times will enable more frequent recharges, so we can store less energy in the device, which will allow the battery and device to be much smaller and less invasive.

Chris Williams: Battery heating during usage can be a concern. Our customers are working to develop more efficient pumping systems that could reduce the heating by reducing current draw. They are approaching it from the angle of less required energy, which indirectly addresses the heating concern.

Rob Rubino: With closed-loop technologies, therapy can be targeted more effectively, leading to a minimal amount of stimulation being applied to alleviate the condition. This will reduce the amount of energy needed for the therapy and smaller batteries can be used.

What’s Integer’s approach to delivering the next best power solution?

Martin Cholette: Integer’s innovations in chemistries, size reduction, complex geometries and the development of rechargeables will continue to drive improvements in battery technologies.

Rob Rubino: The battery industry is in an intense phase of investment and growth.

Integer tries to leverage that broader industry investment by picking and choosing technologies that are a good fit for our application.

Once we identify a useful piece of technology, we work to optimize it and then spend a lot of time characterizing it. The ability to predict what our products will do in various circumstances is very important to our customers and, ultimately, regulators.

Developing the technology first, then building products around it, allows us to characterize the technologies in a robust way and gather long-term data.

Chris Williams: Performance, minimally invasiveness and predictability all tie together to provide the right battery for the device and the 36

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patient. Integer’s computational and front-end modeling data lets us know exactly how the custom battery will discharge under specific usage conditions. This predictive information allows customers to incorporate accurate fuel gaging of our cells using a statistical approach to drive design elements, which ultimately leads to maximizing the longevity of a device and facilitates the regulatory process — all before any metal is cut.

ONE OF THE BIGGEST CHALLENGES IS ADOPTING NEW MATERIALS THAT DRIVE ENHANCED BATTERY PERFORMANCE AND ITS RELATED VALIDATION. The future — what’s next? Hype or reality?

Rob Rubino: Energy harvesting. It’s hype now, but reality in the distance. This is an active area with lots of research and potential, yet great challenges. The biggest is reliability. You have to demonstrate the harvested power will last as long as a battery. I believe sensing and pacing will be the first applications to use it.

Another reality item is miniaturization techniques. Integer is developing technologies to enable batteries that are ½ cc or less that can be targeted to certain therapeutic and diagnostic applications.

Miniaturization will lead to non-invasive solutions with minimal inconvenience for patients.

Chris Williams: Miniaturization is quickly becoming a reality. Retinal and cochlear implants are driving demand for not only smaller batteries, but also reducing the size requirements for other related components in the system. Integer is working now on micromolding, precision machining and also smaller feedthrough technologies to enable these applications. M

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TUBING TALKS

Material Matters: Exploring X-ray and MRI compatibility in braidreinforced catheter shafts To achieve stiffness in intervascular catheter shafts, manufacturers often turn to stainless or nitinol – but those materials aren’t suited for MRI. Luckily, low-cost fibers offer a viable alternative.

William Li | Adam Spence |

Intervascular catheter shafts are designed to be relatively stiff at the proximal end, to facilitate the pushing and torquing of the catheter as it advances through the body.

The proximal shaft is joined with a flexible distal end to allow passage of the catheter tip through increasingly smaller vessels.

Typically reinforced catheter shafts are constructed using a composite design consisting of a lubricious inner liner material, such as PTFE or HDPE, for guidewire tracking; and an outer sheath, usually of Pebax, polyurethane or PA12 with varying durometers, from the proximal end to the distal tip. Non-reinforced catheter shafts are generally flimsy and require a continuous braid embedded in the catheter tubing to provide torquability and pushability while retaining flexibility and kink resistance. Most commonly, the braid is a metal such as stainless steel or nitinol.

Imaging issues X-ray, including fluoroscopy and computed tomography (CT), are the common imaging methods in interventional cardiology. But fluoroscopy exposes the patient and medical personnel to ionizing radiation. This is an issue for the patient during repeat interventions (especially for children), and also for medical personnel, who must monitor their own dosage levels. In addition, fluoroscopy only generates a 2D projection.

Magnetic resonance imaging (MRI) presents several advantages over fluoroscopy in guiding cardiac interventions. MRI, which involves a complex interaction of magnetic and radiofrequency (RF) fields, does not use hazardous ionizing radiation, allowing for repeated scans. And MRI scans can be oriented in three dimensions in real time,

Tensile or elastic modulus (logarithm scale) of various polymeric fiber and metallic reinforcement.

Steve Maxson | Adam Spence |

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TUBING TALKS

providing high-resolution soft-tissue contrast compared to X-ray-based imaging.

The traditionally metallic braiding materials embedded in catheter shafts are ferro-magnetic and therefore not compatible or safe to use with MRI. These ferro-magnetic metals cause signal loss (artifacts) and result in MRI image distortion. Beyond these visibility issues, there are safety risks from the force exerted by the magnetic field on the metal in the braiding and RF-induced heating of the metallic braid reinforcement incorporated into the catheter.

In one study performed by Losey AD et al. in 2014 at UCSF’s Dept. of Radiology & Biomedical Imaging, different braid materials were analyzed during MRI scans at 1.5 Tesla and 3 Tesla.

During a 15-minute scan, nitinol braid showed a temperature increase of 0.45°C at 1.5 Tesla and 3.06°C at 3 Tesla; subsequent tests for tungsten- and PEEK-braided catheters showed no heating during scans.

Braiding requirements Braid material requirements include biocompatibility, radiopacity, tensile strength, tensile modulus and material cost. Charts with this article show the mechanical properties (tensile modulus and tensile strength), as well as the relative costs of monofilament and braid materials.

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Medical Design & Outsourcing

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Material

Tensile Modulus (Gpa)

Tensile Strength (Mpa)

Density (g/cm3)

Polyester (PBT)

2.3

52

1.31

PC

2.3

69

1.20

Polyamide 6,6

2.83

82.7

1.12

PEEK (unfilled)

3.5

93.8

1.32

LCP (unfilled)

11

100

1.45

Anneal SS Wire (SS)

134

1000

7.92

Full Hard Wire (SS)

200

2300

7.92

Nitonol

48 (martensite)

1378

6.50

Titanium (Grade 5)

114

160

4.51

Tungston (ASTM F288)

407

2450

19.29

Another important property for MRI compatibility is the braid material’s magnetic susceptibility, or the measure of the propensity of the material to become magnetized when placed in the magnetic field. This article’s final chart shows the magnetic susceptibly of common fibers and metallic braid materials.

Polymers and human tissue are MRI-compatible with very low magnetic susceptibility indices (<1x10-5, diamagnetic) and very little image distortion even if they are very close to the imaging region. MRI-incompatible stainless steel has a high magnetic susceptibility index (>1x10-2, ferromagnetic), meaning image distortion even when it is very far from the imaging region.

www.medicaldesignandoutsourcing.com

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Tensile strength (logarithm scale) of various polymeric fiber and metallic wire.

Because different modalities may be used to navigate the vasculature, itâ&#x20AC;&#x2122;s desirable to have a catheter shaft that is both radiopaque for fluoroscopy and has low magnetic susceptibility for MRI. Performance fibers Titanium and tungsten are biocompatible and X-ray- and MRIcompatible. They have relatively low magnetic susceptibility indices and only distort images if they are very close to the imaging region. Tungsten is a high-density metal (70% more dense than lead) and therefore highly radiopaque. It also boasts high tensile modulus and strength and is less expensive than other precious metals such as titanium or platinum.

Most polymer-based braid materials do not include radiopaque fillers, because the loading levels of radiopaque filler required for visibility (~20%) would likely adversely affect fiber strength. Current development studies include hybrid structures combining the superior mechanical properties of metals with MRI-compatible polymers.

Beyond the mechanical performance of tungsten wire, a catheter shaft reinforced using tungsten offers the versatility of whole-shaft X-ray and MRI visibility from the proximal end to the radiopaque distal tip at a lower price

Relative cost of various polymeric fiber and metallic reinforcement.

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compared with high-performance polymer materials such as PEEK or LCP. Lower-cost fiber such as PET, Nylon or PC can be used when the dimensions (diameter and wall thickness) of the catheter allow the fiber to have a relatively large cross section. For example, one design could include a metallic marker band and a few strands of tungsten wire to enhance radiopacity and MRI visibility.

Influence on manufacturing process Monofilament fiber and metallic wire can be braided using a Steegertype braider at speeds of up to 400 rpm. When there is a size limitation on the wall thickness of a catheter, the filament/wire size needs to be smaller. Small fiber such as 0.002-in. monofilament may need to be braided at lower speeds (175rpm to 225rpm) to avoid constant breaking and fraying.

Copper PC/PEEK/PA

Titanium Nitinol Tungsten Platinum Fiberglass

Conclusion MRI offers substantial benefits for radiationfree noninvasive visualization of reinforced catheter shafts in the vascular system. Braid materials in the form of high performance polymers and non-magnetic metals imbedded within the catheter provides the optimization of physical properties and minimized localized heating and image artifacts under MRI. Non-magnetic metallic braid materials that are both X-ray- and MRI-compatible are very good options due to their lower costs and easier processability compared to most highperformance polymer braid materials.

Metallic materials can be braided at high speeds compared to some polymer braid materials, potentially resulting in higher throughput and overall lower braiding machine capital equipment costs. M Magnetic susceptibilities of selective materials

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MINNESOTA 2.0

MINNESOTA 2 Can this major U.S. medical device cluster become a healthcare innovation hub?

CHRI S N EWMARKER | MAN AGI N G EDI TOR

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www.medicaldesignandoutsourcing.com

Image courtesy of istockphoto.com

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MINNESOTA 2.0

Minnesota has the institutions and the talent to transform healthcare in the U.S. The question is whether the money will follow.

A 2.0

R

xFunction makes wearable devices called “Walkasins” that help people with chronic health conditions prevent falls that can lead to serious injury. It took eight painstaking years, though, before the Eden Prairie, Minn.-based startup secured the $7.5 million in Series A funding it needed to prepare for the commercialization of its product: Shoe inserts that measure users’ foot pressure and enable immediate sensory cues to control balance.

Lars Oddsson, RxFunction’s president and co-founder, suspects it took so long because a wearable device that acted as a sensory prosthesis was unusual for the Minnesota market. The company eventually brought in Tom Morizio, a former Medtronic executive, as CEO; Oddsson credits Morizio with figuring out how to package data and stories from patients and clinicians into a compelling story for prospective investors.

RxFunction is just one example of how Minnesota’s large medical device community is innovating in the digital healthcare space. But it also illustrates the challenges of transforming a medical device hub that has predominantly focused on traditional medical devices like pacemakers and heart valves into one that embraces and fosters new types of cutting-edge startups.

“I think the traditional Midwest medical device investor is so used to the traditional medical technology to come out of here,” Oddsson told Medical Design & Outsourcing in reflecting on RxFunction’s long journey. “It’s cardio. It’s some orthopedics. It’s mostly implants. We’re a wearable device. We’re a sensory prosthesis. It’s unusual. It’s new.”

Minnesota will likely need to see more companies such as RxFunction raising money and doing it faster if it is to adapt and prosper in the new age of digital health. Both public and private insurers are moving away from fee-for-service and focusing on how hospitals and clinics manage the health of the populations they serve. That will require a change in how both medical device companies approach innovation – and will require creating an environment in which investors are willing and eager to fund it.

So far, funding for Minnesota medtech startups has been a mixed bag. California medical device startups raised more than $1.5 billion in venture capital last year, while their Minnesota counterparts only raised $220 million, according to the PwC and CB Insights’ MoneyTree report. Unlike the nation as a whole, quarterly medtech startup fundraising in the North Star State has yet to return to pre-Great-Recession levels.

“The funds are all in California,” said Randy Nelson, CEO of Evergreen Medical Technologies (St. Paul, Minn.), who has worked with medical device startups for more than a dozen years.

“California has a tendency for being a little more free-flowing with trying out things,” Nelson added. “I think they’re just more willing try out new things than we are in Minnesota.”

www.medicaldesignandoutsourcing.com

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MINNESOTA 2.0

Times are a changin’ The Minnesota-based Medical Alley Assn., however, points out that investment is growing when it comes to digital health. Widen the lens to include all of the life science companies in the state, and there were 26 that raised $112 million during the first three months of 2018, according to Medical Alley. More than half the companies were focused on tools and technologies related to consumer-focused healthcare.

Minneapolis-based Bind, for example, closed on a $60 million round during the first quarter to pioneer its on-demand health insurance offering.

Another digital health startup in the state, Learn to Live, raised $4.3 million for its platform to provide remote access to high-quality mental health services.

Minnesota has also seen other recent successes related to both digital health and traditional medical device companies: • Bright Health, a Minneapolis-based health insurance startup that works closely with carefully selected “care partners,” raised $160 million last year in a Series B round.

• Boston Scientific announced in March a $406 million deal for NxThera (Maple Grove, Minn.) and its Rezūm benign prostatic hyperplasia device, which uses steam to ablate excess prostate tissue.

• Ferring Pharmaceuticals of Switzerland recently inked a deal to acquire Rebiotix (Roseville, Minn.) and its platform of living drugs. Financial terms of the deal were not disclosed.

• Maple Grove, Minn.–based Inspire Medical Systems, a Medtronic spinout, is seeking to shake up sleep apnea treatment with a pacemaker-like system to treat obstructive sleep apnea; the company recently raised $108 million with its initial public offering.

• Virtual care company Zipnosis (Minneapolis) in April announced an agreement with Allina Health, a major Twin Cities healthcare provider, to update its online care offerings to better interact with patients.

• A Hennepin County Medical Center spinout called Hitch Health generated attention with a proprietary software solution that integrates electronic health record and ride share services, automatically syncing ride requests with medical appointments.

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MINNESOTA 2.0

(Check out our hottest startups feature for more examples.)

When it comes to medtech startup success, pointing out differentiation is key, according to Jodi Hubler, managing director at Lehmhi Ventures (Wayzata, Minn.), which counts Bind in its portfolio.

“There is opportunity for all sides – to stand out and to seek out innovation. It’s there for the taking.”

Back to its roots Though Minnesota may be slower than other states to embrace new medical innovation, that hasn’t always been the case. Mayo Clinic in Rochester, Minn., one of the top providers in the country, was a pioneer in integrated care – a model it started honing about 130 years ago. One of the largest private health insurers in the U.S., UnitedHealth Group, is based in Minnetonka, Minn., with its Optum subsidiary seeking to combine technology, data and expertise to improve health care delivery. And one of the world’s largest advanced manufacturing and medical device companies, 3M Co., is headquartered in Maplewood, Minn., with a history going back more than a century.

“This actually has always been a healthcare hub,” said Shaye Mandle, the Medical Alley Association’s CEO. The medtech cluster’s roots go back to the 1950s and ‘60s, when University of Minnesota surgeons including Dr. C. Walton Lillehei pioneered open heart surgery. Lillehei happened to meet Earl Bakken, who along with brotherin-law Palmer Hermundslie had started a business out of a garage repairing hospital equipment. Lillehei tasked Bakken with finding a replacement for the large, unreliable pacemakers then in use.

“Over four weeks in 1957, Bakken developed the first external, wearable, battery-powered pacemaker. It was used in the hospital on a patient the day after Bakken delivered it,” the Smithsonian Institution recounted in an article celebrating an exhibit about Minnesota’s Medical Alley.

Bakken and Hermundslie’s business eventually grew into Medtronic – now the

Even during the 1980s, Minnesota’s Medical Alley Association was touting the diversity of resources in the state.

Image courtesy of the Medical Alley Association.

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MINNESOTA 2.0

world’s largest medical device company.

Although its official headquarters moved to Dublin, Ireland, in 2015, the company is still run out of Fridley, Minn.

Manny Villafaña, a Bronx native who came to the Twin Cities decades ago, started out in the 1960s working on international sales for Medtronic. But he then took a risk and founded Cardiac Pacemakers Inc., which is now part of Boston Scientific’s Guidant business. CPI accomplished a feat that many had thought impossible: An implantable pacemaker that lasted more than a few years.

By the mid-1970s, Villafaña wanted to innovate in another area: Bileaflet mechanical heart valves. The resulting company was St. Jude Medical, which Abbott acquired for $25 billion last year.

(Villafaña, now in his 70s, remains an active entrepreneur; his latest venture, Medical 21, is developing proprietary manufacturing technology to make artificial blood vessels for bypass surgeries.)

Beyond the several well-known medical device companies with large presences in Minnesota – Medtronic, Boston Scientific and Abbott – the state also boasts a vast ecosystem of contract manufacturers, device testing outfits, designers, and regulatory and product development consultants to support the industry. The industry employed nearly 30,000 Minnesotans in 2016, according to the Minn. Dept. of Employment & Economic Development.

“We’re in the next natural evolution of a community that’s always been in the forefront of defining healthcare,” Mandle told us.

New sources of support for startups While the fundraising environment for Minnesota startups may be tough when it comes to venture capital, the big, legacy medical device companies and major institutions such as Mayo Clinic stepped in over the past decade with more resources.

“The really big device companies … they’re way more engaged, they’re way more open-minded, they’re making acquisitions that … are interesting and exciting,” Mandle said.

Corporate money has been going toward the Medical Devices Center at

RxFunction makes wearable devices called “Walkasins” — shoe inserts that measure users’ foot pressure and enable immediate sensory cues to control balance.

the University of Minnesota and similar groups, according to Frank Jaskulke, the association’s VP of intelligence.

News came out in March that Boston Scientific joined Mayo Clinic and the University of Minnesota in backing startup accelerator Gener8tor and its medtechfocused Twin Cities accelerator called gBETA Medtech.

WE’RE IN THE NEXT NATURAL EVOLUTION OF A COMMUNITY THAT’S ALWAYS BEEN IN THE FOREFRONT OF DEFINING HEALTHCARE. Next to Mayo Clinic in Rochester, work is underway on developer Mortenson’s 90,000-square-foot One Discovery Square, slated to open for occupancy next year. The biotech research, collaboration and innovation space is meant to provide companies both large and small the ability to locate close to Mayo Clinic, which will occupy a third of the building. The Mayo Clinic anchor www.medicaldesignandoutsourcing.com

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tenants will include advanced radiologic technology, advanced laboratory diagnostic medicine and regenerative medicine, according to Dr. Clark Otley, medical director of the Dept. of Business Development at Mayo.

“We hope that soon after the building is opened, another one will go up,” Otley said.

5 • 2018

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MINNESOTA 2.0

One Discovery Square rendering courtesy of Mortenson

Discovery Square is part of the 20year Destination Medical Center project, in which $585 million in state and local government infrastructure funds are expected to leverage about $5 billion of private investment in Rochester.

Overall, Mayo Clinic in recent years has sought to more efficiently commercialize its innovations. Its business development operation is now a one-stop shop for companies of all sizes seeking to collaborate with the health provider.

“We don’t ever want to feel comfortable and feel like we’ve got it figured out,” explained James Rogers III, chair of Mayo’s Business Development Department. “There’s a lot that we can learn from others. Having more people closer to us who we can learn from can only help us. We’ve got to be constantly getting better.”

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MINNESOTA 2.0

A true medtech community Nelson at Evergreen may lament that the money is in California, but he also thinks Minnesota has an impressive advantage: “The knowledge base is second to none.”

“I think it’s better than any place in the United States, actually. In California, there’s a lot of talent. In Boston and New England – there’s a lot of talent. But here, it’s so well-utilized. People work together so well. It’s a better situation,” Nelson said.

For Nelson, Minnesota feels like a “medical device neighborhood.”

It speaks to the strength of the Minnesota hub that the University of St. Thomas’ Opus College of Business in Minneapolis is launching a one-year accelerated master’s degree program in healthcare innovation. The program is targeted toward first-time supervisors in the healthcare industry, as well as people in other industries interested in innovating in healthcare. The three legs of the program are patient customer experience, innovation and lean execution.

Dr. Gwenyth Fischer, director of The Pediatric Device Innovation Consortium at the University of Minnesota, thinks the seven-year-old group’s location gives its inventors an edge. The PDIC is able to focus not only on funding but also on getting doctors and other academics with innovative ideas linked with Twin Cities experts to get their concepts commercialized.

“It’s a huge medical device community, but it’s sort of a small person community, in that I have gotten so much individual help and assistance and people connecting me to other people,” Fischer said. “Everybody knows everybody in this town, which I think is a major resource.

People are very willing to help. You don’t see a cutthroat attitude here.” M

MINNESOTA Medical Device VC (2017)

$220 million

NIH Grants (2017)

$557 million

Medical device employment (2016)

29,790

Medical device establishments (2016)

444

Medical device patents (2015)

991

Medical device patents per 1 million people (2015)

181

Percent of residents with bachelor's degree or higher (2016)

34.90%

Forbes Best States for Business Ranking

13

CALIFORNIA Medical Device VC (2017)

$1.544 billion

NIH Grants (2017)

$3.946 billion

Medical device employment (2016)

66,252

Medical device establishments (2016)

1,941

Medical device patents (2015)

3,189

Medical device patents per 1 million people (2015)

81

Percent of residents with bachelor’s degree or higher (2016)

32.90%

Forbes Best States for Business Ranking

31

MASSACHUSETTS Medical Device VC (2017)

$315 million

NIH Grants (2017)

$2.717 billion

Medical device employment (2016)

14,724

Medical device establishments (2016)

317

Medical device patents (2015)

810

Medical device patents per 1 million people (2015)

119

Percent of residents with bachelor’s degree or higher (2016)

42.70%

Forbes Best States for Business Ranking

19

Data in Minnesota, Massachusetts and California boxes from PwC MoneyTree Report, National Institutes of Health, Minnesota Department of Employment and Economic Development, and Forbes

www.medicaldesignandoutsourcing.com

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Medical Design & Outsourcing 51

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For additional session details and speaker information, please visit minnesota.devicetalks.com

DOWNLOAD THE DEVICETALKS APP! Stay up to date in real-time by downloading the DeviceTalks app. Access the schedule of events, receive important updates and enhance your networking experience by connecting with exhibitors and other attendees.

1. Download the Attendify app to your device 2. Search for “DeviceTalks” 3. Enter the access code to join the event: DT2018 Not able to download the app? You can also view the web version by visiting this site: app.minnesota.devicetalks.com

“This is a disease that exacts an enormous toll on the people who have it and the families around the people who have it.

They’re willing to go to extraordinary lengths to live better, to be safer.”

– Brewer speaking about diabetes at DeviceTalks West in December

— Jeffrey Brewer, CEO of Bigfoot Biomedical

Monday

June 4

9:00 AM 10:00 AM

11:00 AM 11:00 AM 12:00 PM 1:00 PM 2:00 PM 3:00 PM 3:00 PM 3:00 PM 3:00 PM 4:00 PM 4:00 PM 4:00 PM 4:00 PM 5:00 PM 6:00 PM

FDA Strategic Initiatives Comparing and Contrasting Global Regulatory Requirements for Clinical Evaluation Reports (CERs). Highlighting: Japan, China, Europe, Australia and ASAEN Health Economics Analyses and its Role in Medical Device Adoption Digital Health and Software as a Medical Device (SaMD) Exhibition/Luncheon Keynote: Heidi Dohse Exhibition/Networking The Changing Face of MedTech: Attracting and Keeping an Inclusive Workforce The State of R&D at the big companies Avoiding Pitfalls and Mitigating Risk Throughout a Clinical Trial Real World Evidence / Patient Preference Initiative Strategies for Today’s Funding Landscape 3D Printing: A Primer U.S. FDA Advisory Panel Meetings: Strategies to Maximize Success Novel Pathways to FDA and CMS Approval: Parallel Review in Medical Devices Exhibition/Networking Reception Dinner & Keynote: Michael J. Pederson, Abbott www.medicaldesignandoutsourcing.com

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5/18/18 9:26 AM

Behind the Scenes. Ahead of the Curve. Inside the Corner Office.

CONFERENCE OVERVIEW Tuesday

June 5

7:00 AM Exhibition/Networking Breakfast 8:00 AM Keynote: Inside Bigfoot Biomedical 9:00 AM Getting to the Exit 9:00 AM Neuromodulation 9:00 AM Transitioning from MDD to MDR: How is this REALLY rolling out?

Tips, Tricks, and Lessons Learned from Large Program Implementation.

10:00 AM Exhibition/Networking 11:00 AM Meet Your Local MedTech Reporters 11:00 AM Cybersecurity and MedTech 11:00 AM Portfolio Planning as an input to your EU MDR implementation plan.

Which devices should stay and which should go? Balancing the cost and effort of transitioning

to the EU MDR with product life cycle planning and revenue expectations.

12:00 PM The Science of Skin: Designing Wearable Medical Devices 12:00 PM From Mind to Matter: Addressing the Opioid Crisis

Through a Hands-On User-Centered Innovation Process 12:00 PM Achieving MEDDEV 2.7/1 Rev. 4 and EU MDR Compliant Clinical

Evaluation Reports (CERs): What We’ve Learned From Completing 100+.

1:00 PM Exhibition/Networking Lunch 2:00 PM Provider Perspectives: What Do Our Customers Want?

2:00 PM AI in MedTech 2:00 PM Post market surveillance under EU MDR - do I have to run a clinical study?

What other options do you have to fulfill post market

surveillance requirements; including updating CERs. 3:00 PM Closing Keynote

“This opens up the possibility of incorporating smart electronics into biomedical devices, such as brain interfaces for communicating with neurons, or optogenetic devices such as 3D printed LEDs and photodiodes to stimulate them, sensor tattoos which can directly printed onto the body, cardiac devices which can regulate beating at low power, and ‘bionic’ devices.”

– McAlpine on a method he helped invent to 3D-print semiconductors

— Michael McAlpine, associate professor of mechanical engineering at the University of Minnesota

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www.medicaldesignandoutsourcing.com

5/18/18 9:26 AM

Behind the Scenes. Ahead of the Curve. Inside the Corner Office.

EXHIBITION OVERVIEW D E D I C AT E D E X H I B I T H O U R S MONDAY, JUNE 4 12:00 PM – 1:00 PM

Exhibition/Luncheon

2:00 PM – 3:00 PM Exhibition/Networking 5:00 PM – 6:00 PM

Exhibition/Networking Reception

TUESDAY, JUNE 5 7:00 AM – 8:00 AM

Exhibition/Networking Breakfast

1 0:00 AM – 11:00 AM

Exhibition/Networking

1:00 PM – 2:00 PM

Exhibition/Networking Lunch

“I could always feel my heart beating, actually see it beating in my chest. I never considered it wasn’t normal.”

– Dohse recalling her rare and potentially deadly arrhythmia.

— Heidi Dohse, senior program manager at Google

“Twenty years ago, you’d call FDA and they wouldn’t answer and then they’d never call you. Now, they’re very interactive, with presubmission meetings and interactive reviews.”

– McKeen on how U.S. FDA is changing

— Mac McKeen, regulatory fellow at Boston Scientific and adjunct professor at the University of Minnesota 5 • 2018

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5/18/18 12:24 PM

Behind the Scenes. Ahead of the Curve. Inside the Corner Office.

EXHIBITION OVERVIEW

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“Solving the problem isn’t enough: We need to add value to the equation so that physicians, hospitals and payers can capitalize on the benefit of these therapies.

We’re still in the early innings in terms of applying information to drive efficiency.”

Hospitality

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– Pederson on the importance of medtech driving “value”

— Michael Pederson, SVP of cardiac arrhythmias and heart failure at Abbott

301 ENTRANCE

EXHIBITOR LIST COMPANY 3M Abbott The MedTech Conference powered by AdvaMeda AdvancedTek ArKco Sales, Inc. Atlas Vac B-Braun OEM Devicix by Nortech Donatelle Evergreen Medical EXB Solutions 56

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BOOTH # 207 211-213 302 400 104 401 403 205 314 209 402 5 • 2018

COMPANY Flexible Circuit Garz & Frick Green Hills Software Healthlink Europe Jama Software Jordi Labs Lin Engineering Medical Alley Medmarc Minnetronix Motion Dymanics Corporation Padilla

BOOTH # 214 309 103-105 404 312 305 304 212 304 311 215 308

COMPANY BOOTH # ProMed 113 Propel PLM 102 Qosina 202 R&Q 204-206 Revox 310 Toxikon 203 TUV Rhineland 307 Valtronic 112 Wuxi Apptec Laboratory Testing Division Medical Device Platform 306 Ximedica 208-210

www.medicaldesignandoutsourcing.com

5/18/18 9:26 AM

Behind the Scenes. Ahead of the Curve. Inside the Corner Office.

2018 CONFERENCE SPONSORS P R O D U C ED IN CO N JU N C TION WITH

HOST SPO NSO R

PL ATINUM SPONSORS

DIAM OND SPONSOR

GOL D SPONSORS

EXH IB ITO RS

M ERCHANDISE SPO NSO RS

HOSPITAL ITY SPO NSO R

MEDIA AND SUPPORTING PARTNERS A MassDevice Resource

Medical Design & OUTSOURCING

www.medicaldesignandoutsourcing.com

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Medical Design & Outsourcing 57

5/18/18 9:26 AM

HOTTEST STARTUPS

of 2018 DON’T SLEEP ON THIS LIST OF THE HOTTEST MEDTECH STARTUPS OF 2018.

C H R IS NEW M A R KER | MAN AGI N G EDI TOR

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There are truly game-changing innovations out there when it comes to medical devices – advances that could not only change the treatment of particular diseases but also enable healthcare systems to run more effectively and efficiently.

Our editors came up with a list of 20 interesting young companies. We then surveyed our readers and then whittled the list down to 10.

From neuromodulation to treat urinary and bowel dysfunction disorders and Type 2 diabetes, to new surgical robotics and drug delivery technology, here are 10 of the most exciting medtech startups.

www.medicaldesignandoutsourcing.com

5/18/18 7:32 AM

HOTTEST STARTUPS

Image courtesy of Unsplash | Ramón Salinero

Hottest Startups Feature MDO 5-18 Vs3.indd 59

www.medicaldesignandoutsourcing.com

5 • 2018

Medical Design & Outsourcing 59

5/18/18 7:32 AM

HOTTEST STARTUPS

Axonics

Brooklyn Park, Minn.

Founded: 2015 www.4cmed.com

Irvine, Calif.

Founded: 2013 axonicsmodulation.com

Big legacy medical device companies including Edwards Lifesciences, Medtronic and Abbott are seeking to move beyond transcatheter aortic valve replacement to the new frontier – transcatheter mitral valve replacement. They've spent hundreds of millions of dollars on companies in the space.

4C Medical Technologies, however, thinks it has a potentially better solution. Instead of replacing a person's mitral valve, 4C Medical's AltaValve device is positioned supraannular to the leaking native valve, preventing the leak from entering the left atrium.

By preserving the native mitral valve and left ventricle while still treating mitral regurgitation, the AltaValve provides an answer to the complications presently associated with TMVR, according to the company.

4C Medical last year raised $9 million in a round led by Canadian angel network Anges Québec. The AltaValve won first place in the Cardiovascular Research Technologies competition held March 3–6, 2018 in Washington, D.C.

Axonics Modulation Technologies is looking to challenge major players in neuromodulation. The Irvine, Calif.-based company is developing novel, implantable sacral nerve neuromodulation tech to treat patients with urinary and bowel dysfunction disorders, with hopes that the platform will be expandable into other clinical indications in the future.

With technology licensed from the Alfred Mann Foundation, the company’s Axonics r-SNM system features a miniaturized rechargeable implantable stimulator it claims will work for at least 15 years,. The system also features a charging system designed for quick charge times and a user-friendly remote control and programming interface.

Axonics has already made steps against the competition – Medtronic’s InterStim device and StimGuard – with approvals in Canada and Europe under indications for treating overactive bladder, urinary retention and fecal incontinence.

FINK DENSFORD | ASSOCIATE EDITOR Image courtesy of Axonics

Image courtesy of 4C Medical Technologies

4C Medical Technologies

CHRIS NEWMARKER | MANAGING EDITOR

Day Zero Diagnostics Allston, Mass.

Founded: 2016 www.dayzerodiagnostics.com Day Zero Diagnostics is in the process of developing a new class of diagnostic that rapidly tests patients to determine the right antibiotics to use in a given situation. The system aims to identify targeted antibiotics in five hours, rather than two to three days, enabling physicians to transition from the broad-spectrum antibiotic use behind the global health crisis of antibiotic resistance.

Image courtesy of Day Zero Diagnostics

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Unlike other molecular diagnostics that can only detect a handful of specific targets, Day Zero uses the entire genomic sequence and its proprietary Keynome algorithm to identify a comprehensive range of bacterial pathogens and their resistance characteristics within hours.

The company won the Medtech Innovator Competition in 2017. Its combination of genome sequencing and machine learning has the potential to modernize infectious disease diagnosis and treatments, as well as improve patient safety and reduce costs.

HEATHER THOMPSON | SENIOR EDITOR

www.medicaldesignandoutsourcing.com

5/18/18 7:32 AM

HOTTEST STARTUPS

Gel-E College Park, Md. Founded: 2013 gel-e.co Wound care, hemostatic devices and associated products may not have the flash of their technological competitors in medtech, but they’re just as innovative. College Park, Md.-based Gel-E is looking to make waves in the hemostatic and wound treatment fields with its platform of wound care products designed around its proprietary, self-assembling biopolymer, which it claims create rapid coagulation with inherent anti-microbial properties.

Gel-E is developing several applications using its hemostatic technology, including strips, films, bandages and gels designed for use both externally and internally.

The company touts significant improvements over commercial chitosan-based hemostatics and was featured as a top innovator in the late Stephen Hawking’s BBC series.

The company also recently won a $1.4 million grant from the U.S. Defense Dept. to develop products aimed at prolonged field care.

“Gel-E is on an arc to bring disruptive new hemostatic and wound treatment products to clinic, OR and battlefield. We rely on a programmable advanced materials platform to design products that can solve unmet clinical needs for a broad array of human bleeding events,” Larry Tiffany, the company's president, told Medical Design & Outsourcing.

“At the core, Gel-e is an advanced materials company. We're building a materials platform, and while it has found FDA-cleared applications in hemostasis and wound treatment, we view these early products as the beginning of a robust pipeline,” said chief scientific officer Matthew Dowling.

FINK DENSFORD | ASSOCIATE EDITOR 5 • 2018

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Medical Design & Outsourcing 61

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5/18/18 7:32 AM

Image courtesy of Livongo

HOTTEST STARTUPS

Livongo

Medineering Surgical Robotics

Mountain View, Calif.

Founded: 2014 www.livongo.com

Munich, Germany Founded: 2014 medineering.de

Livongo Health recently closed a $105 million round led by a group of investors including General Catalyst, Merck Global Health Innovation Fund and Echo Health Ventures.

The Mountain View, Calif.-based company has developed Livongo for Diabetes – a collection of connected devices that enable people with diabetes to interact with a virtual care team.

Livongo plans to use its newly-acquired funds to support market growth and its consumer platform. The company is also launching a disease management offering for people with hypertension.

It’s easy to picture medical robotics as large, single-purpose systems, but German medical robotics firm Medineering is hoping to develop a more diverse, procedure-focused platform of robotic tools.

The company is developing a portfolio of robotic devices designed to assist clinicians in minimally invasive surgeries, specifically focusing on surgeries in the head and neck. So far, Medineering has produced an advanced positioning arm designed for attaching instrument adapters and robotic devices.

The company already launched its first robotic solution, an endoscope positioning robot for ENT surgery called Medineering Robotic Endoscopy, which was recently used in its first clinical cases; Medineering strategic partner Brainlab also uses the arm for a navigated spinal setup called Cirq.

The seven-jointed positioning arm serves as the base for the company’s plug-and-play robotic system, and can be directly attached to an operating room table’s rail system. The system allows for exact positioning control and a mechanical interface for non-motorized instruments. The transnasal endoscope robot, which is designed to be attached to the arm, allows for robotic control of endoscope positioning.

The company is aiming to develop a number of procedure-specific attachments for the platform, and has already received support from Brainlab.

SARAH FAULKNER | ASSOCIATE EDITOR

FINK DENSFORD | ASSOCIATE EDITOR

Metavention Image courtesy of Metavention

Minneapolis Founded: 2012 www.metavention.com Metavention could potentially change the game when it comes to the treatment of Type 2 diabetes. The solution is transcatheter-based metabolic neuromodulation therapy.

The goal is to "provide improved control of elevated glucose, in a single minimally invasive procedure,"

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according to CEO Todd Berg.

The company closed a $65 million Series C round in January, with funding from New Enterprise Assoc., Sanderling Ventures and others. The money is going toward optimizing Metavention's neuromodulation therapy as the company prepares for a Phase II trial in the U.S. The goal is to "provide improved control of elevated glucose, in a single minimally invasive procedure," according to CEO Todd Berg.

CHRIS NEWMARKER | MANAGING EDITOR

www.medicaldesignandoutsourcing.com

5/18/18 7:33 AM

HOTTEST STARTUPS

Portal Instruments Cambridge, Mass.

Founded: 2012 portalinstruments.com Portal Instruments is developing a needle-free drug delivery technology designed to improve the administration of highly-viscous biologic drugs.

Companies have long sought after a needle-free injection platform as a solution to the anxiety people harbor about giving themselves shots. First-generation devices, according to Portal Instruments, all had the same problem: the jet was uncontrolled, leading to patient discomfort at the beginning of the injection and delivery challenges for high-volume drugs.

Portal’s product, which the company licensed from MIT, administers the injection in a stream the size of a strand of hair, using computer-controlled precise pressure technology to control the jet.

The company landed an exclusive $100 million deal with Takeda last year to combine Portal's needle-free delivery device with the pharmaceutical company's biologics.

"We are excited to bring this highly innovative technology from MIT to the market and help patients with the difficulty of their chronic diseases. Our first commercial relationship with Takeda will enable us to do that for patients suffering from inflammatory bowel diseases," CEO Patrick Anquetil told MDO.

Image courtesy of Portal Instruments

SARAH FAULKNER | ASSOCIATE EDITOR

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HOTTEST STARTUPS

Prellis Biologics San Francisco Founded: 2016 www.prellisbio.com

Prellis Biologics is a human tissue engineering company that’s harnessing laser-based 3D printing to create functional human organs and tissues. The technology focuses on building microvascular structures to ensure organs are properly supplied with oxygen and nutrients. Co-founders Melanie Matheu and Noelle Mullin said they can build microvasculature and additional layers of tissue at near instantaneous speeds and single-cell precision.

Organs can be built directly from CAD files, enabling the use of real human vascular and cellular data to create complex functional organs including kidneys, livers and lungs. The company estimates that the technology will provide a life-saving option for more than 90 million people in the United States who are on waitlists for donated organs.

HEATHER THOMPSON | SENIOR EDITOR

Sonex Health Rochester, Minn.

Founded: 2014 sonexhealth.com

Sonex Health touts the strong "value" argument behind its SX-One MicroKnife with Meerkat technology, designed to treat carpal tunnel syndrome with an out-patient visit.

The device performs carpal tunnel release – a procedure that once took place in an operating room – in a surgery center or office setting. The result, according to the company, is faster patient recovery and reduced costs.

The system enables surgery to take place through a single micro-incision under ultrasound guidance.

Drs. Darryl Barnes and Jay Smith of Mayo Clinic, along with business operations expert Aaron Keenan, started the company in 2014. The device has been used in more than 700 cases, with a goal of 1,000 cases by the end of 2018, Barnes told MDO. The company projects significant growth in 2019.

Barnes said the goal is for the SX-One MicroKnife to be the "least invasive and safest way to perform carpal tunnel release with the fastest recovery." He sees Sonex Health becoming a leader in micro-invasive ultrasound-guided surgery. M

The SX-One MicroKnife

Image courtesy of Sonex Health

CHRIS NEWMARKER | MANAGING EDITOR

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www.medicaldesignandoutsourcing.com

5/18/18 7:41 AM

JUNE 17-20 | BOSTON, MA

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VISIT WWW.LIVEWORX.COM TO LEARN MORE

PTC Liveworx 5-18.indd 56

5/17/18 3:36 PM

7 STARTUP FAILURE

Seven ways TODOOMYOUR

medical device STARTUP

CHRI S N EWMARKER | MAN AGI N G EDI TOR

PITFALLS RANGING FROM SPENDING ON THE WRONG PRIORITIES TO IGNORING REGULATORY STRATEGY CAN TORPEDO NASCENT MEDTECH FIRMS. HERE ARE THE TOP SEVEN.

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1 • 2018

Randy Nelson has worked with medical device startups for more than a dozen years, both via his consultancy, Evergreen Medical Technologies (St. Paul, Minn.) and the University of Minnesota's Carlson School of Management.

A product development veteran of St. Jude Medical and Boston Scientific, Nelson has seen it all when it comes to medical device startups that doom themselves to failure.

Here’s his list of the top seven reasons for medtech startup failure: 1. Not managing your budget strategy Failure to plan financially for what’s expected often sets up medical device startups for failure, according to Nelson.

"They don't know how to use their money wisely," he said.

Before the Great Recession, some medtech startups would invest in space and the best office equipment. Since then, with funding increasingly difficult to come by, that doesn't happen much.

"Most startups are staying virtual and small," Nelson said. "They don't want to build up a lab with a lot of people.

Their investors aren't interested in that.

Their investors are interested in solving problems, getting the device to market and selling the company."

2. Spending money on the wrong priorities "Companies that have people who’ve never been involved in medical devices before spend money in not necessarily the right order," Nelson said.

The goal should be to "fail fast" by confronting the riskiest areas first.

"When we’re working with an earlystage startup here and they want to do an entire budget, we say, ‘Let’s take it easy and start with building a prototype,'" Nelson explained.

Create the basic prototype, and you can then conduct animal and possibly cadaver studies, to find out how much promise the technology truly holds – and reveal the most serious failings that need to be addressed as soon as possible.

www.medicaldesignandoutsourcing.com

5/18/18 7:43 AM

STARTUP FAILURE

PEOPLE DOING IT FOR THE FIRST TIME DON’T KNOW WHAT THE OBSTACLES ARE AND DON’T HAVE THE FUNDS TO PAY SOMEONE WHO’S EXPERIENCED.

"Until you do animal studies, you don’t have proofof-concept," Nelson said.

"You’ve got to understand what the risks are and address them quickly. It’s like a landmine field.

It can be anywhere."

The catch is having enough money to do the studies and arrive at a proof of concept. That's why Nelson thinks it’s so important to set spending priorities in the very earliest stages.

3. Not having a regulatory strategy at the outset Medical device startups need to quickly understand what the regulatory requirements are so that they can plan for them, according to Nelson.

"I’ve seen that hold up companies – and in one case, it killed a company," he recalled.

The startup that went under, a neurostimulation company, didn't want to talk with the FDA until it was absolutely necessary.

"By that time, it was too late to understand what the FDA required them to do,” Nelson said. “They didn't have enough money to go back and address what the FDA wanted."

People starting medtech companies can fool themselves into thinking that they understand FDA regulations.

"People try to say they have a 510(k).

Sometimes they’re right, sometimes they’re wrong,” Nelson said.

That’s why it's good to have a regulatory consultant involved at the beginning, even if they just start out by helping a bit here and there, providing input on strategy and planning, according to Nelson.

4. Lack of expertise Humility is a valuable trait for every entrepreneur, Nelson said.

"It’s more common than not to have obstacles," he noted. "People doing it for the first time don’t know what the obstacles are and don’t have the funds to pay someone who’s experienced. So they go through it themselves, and that’s where it’s easy to get tripped up."

www.medicaldesignandoutsourcing.com

Startup Failure Feature MDO 5-18 Vs4.indd 67

Get drop-in interchangeable pneumatic products

Finding a consultant or organization with the necessary chops is important – as is knowing when you don’t know enough and need outside help.

"I don’t have proof, but I think it expands the chances of success dramatically," Nelson said.

5. Small market size "When I was teaching at Carlson, one of the common obstacles was that it was a great idea, but there were so few people who would benefit, so the financing just wasn't worth it," Nelson said.

Although unfortunate for the people standing to benefit from the technology, financing simply isn’t available for devices addressing a too-small market.

That said, there are ways to get the FDA to approve a small-market device under a compassionate use designation, then develop it for a much larger market, Nelson added. It's important, though, to have a good finance person who can help you get through what could be a long journey.

6. No reimbursement plans "If you don’t have a reimbursement code, it can be very costly and take more time than you want,” Nelson cautioned. “The worst thing is to have a product ready for market and find out you don't have a reimbursement code."

7. Failure to lock down IP Medical device startups need to line up a patent attorney right away.

"I think that's one of the first things a person has to do, is have their patent application in the patent office so that they can talk to people," Nelson said.

Without intellectual property protection, there's no guarantee that investors or established legacy companies that you're talking with won't simply start working on your ideas themselves. M

5 • 2018

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We have them all.

Let us help!

Tel (352) 373-3578 • Fax (352) 375-8024 e-Mail: service@fabco-air.com

5/18/18 7:44 AM

POWER MORCELLATORS

A public health advocate's legacy highlights

lingering questions

about power morcellation

Dr. Amy Reed’s tragic case brought to light the cancer risks posed by power morcellation. Her death hasn’t stopped lingering questions about the technology.

S A R A H FA U LK NER | A S S O CI AT E EDI TOR

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Power morcellators were used for 20 years to laparoscopically remove fibroids, benign tumors of the uterus, raising not a single adverse event report with the FDA. That all changed in 2013, when Dr. Amy Reed, an attending physician at Beth Israel Deaconess Medical Center, underwent a myomectomy using power morcellation at nearby Brigham & Women's Hospital.

Reed's fibroids were not benign, but instead a malignant form of cancer called uterine sarcoma that's difficult to distinguish from benign tumors. Days after her procedure, Reed's formerly treatable condition had been upstaged to a deadly cancer.

It turned out that power morcellation, a laparoscopic procedure in which surgeons use the device to mince the tumors, can seed malignant cells throughout the abdomen, drastically accelerating the cancer's advance. Reed died last year at 44 of complications from her 2013 myomectomy, but not before she and her husband, Dr. Hooman Noorchasm, mounted a successful public health campaign to raise awareness of the risks posed by power morcellation. In 2014 the federal safety watchdog issued a black box warning for power morcellators, prompting Johnson & Johnson to pull its power morcellator from the market.

www.medicaldesignandoutsourcing.com

5/18/18 7:47 AM

Behind the Scenes. Ahead of the Curve. Inside the Corner Office.

MINNESOTA

JUNE 4-5, 2018 INTERCONTINENTAL ST. PAUL St. Paul, MN

ENGINEERING THE FUTURE OF MEDTECH IN THE TWIN CITIES WORLD-CLASS EDUCATION AND EXCLUSIVE INSIGHTS FROM THE TOP MINDS IN MEDTECH

NEW TRACKS FOR 2018

This yearâ&#x20AC;&#x2122;s DeviceTalks Minnesota will feature four tracks packed with expertly curated content created by the industry for the industry. Our ECO-SYSTEM track will focus on the issues impacting medtech companies across Minnesota; Our TECHNOLOGY track will drill down on the hottest new tech that is changing medtech: Our REGULATORY 201 and CLINICAL 201 tracks, hosted by Medical Alley, will focus on the most important trends in regulatory and clinical development.

KEYNOTE SPEAKERS

HOSTED BY

HEIDI DOHSE MICHAEL J. PEDERSON Google Abbott Tour de Heart Foundation

HON. MELVIN CARTER Mayor of St. Paul

JEFFREY BREWER Bigfoot Biomedical

Visit devicetalks.com for more information!

Save 10% with code DEVICE2018

presented by:

@DeviceTalks

Sponsorship opportunities are available for future DeviceTalks programs. For more information, contact Brian Johnson at brian@massdevice.com

DT 2018 full page ad 5-18_Vs3.indd 1

5/18/18 7:44 AM

POWER MORCELLATORS

With the devices gone, a void emerged in the market â&#x20AC;&#x201C; women who would have undergone a laparoscopic procedure with a morcellator now faced an open uterine resection. Organizations including the American College of Obstetricians & Gynecologists teamed with the Agency for Healthcare Research & Quality to lobby for the FDA to reconsider its 2014 guidance, arguing that patients need a laparoscopic option for tissue removal.

Meanwhile, some medtech entrepreneurs saw the risks posed by morcellators as an opportunity to create a device that would address the morcellator's shortcomings. Eximis Surgical, a tiny Colorado-based company, set out to do just that.

Eximis came across Noorchasm's radar after announcing that it raised $5

Power Morcellators Feature MDO 5-18 Vs3-CN-FINAL.indd 70

million from 33 investors to fund the development of its laparoscopic tissue removal system. He noticed that on their LinkedIn account, Eximis named Reed as the inspiration behind their technology.

Noorchasm penned a letter to Eximis executives and published it online, asking them to remove any reference to Reed and, among other things, acknowledge that their technology is simply a resurrected version of a power morcellator.

"What they're marketing is something that goes directly in opposition to what Amy and myself have been speaking out against," he told Medical Design & Outsourcing.

"It doesn't matter what words you use, it doesn't matter if you say morcellate, slice up, dice up, XCor out - if you take a tumor that has malignant potential and

you mince it up, you're exposing that patient to the risk of their cancer being upstaged."

Noorchashm believes that power morcellators, or any other technology that segments a potentially cancerous mass in a woman's uterus, violates a core tenet of surgery â&#x20AC;&#x201C; never disrupt a tumor with malignant potential.

The company quickly pulled down all references to Reed. But co-founder Donna Ford-Serbu pushed back against his criticism that their XCor system is just a reincarnated power morcellator. "[Reed] inspired us. Our inspiration is that we believe we can do better. I don't think she had the choice of a power morcellator being used in her procedure.

We understand that what happened to her shouldn't happen and we really want to deliver something much better to the

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POWER MORCELLATORS

marketplace. She was an inspiration to us.

I feel badly that we caused her husband anymore pain than he has already felt," Ford-Serbu said.

"Surgeons and patients want a solution that is completely laparoscopic versus having an open or a mini-lap incision where there are co-morbidities associated with having those incisions.

I believe there is a strong need for this type of innovation.

I think patients deserve an opportunity to make that choice," she added.

"Several studies have come out showing that there's no difference in outcomes or mortality [between laparoscopic and open uterine resections]," he said. "It's not like women are dropping like flies because of open uterine resections. Yes, they are staying home for an extra week or two. Yes, they are staying in the hospital for maybe a

Center for Devices & Radiological Health, said in April 2016.

"This new device does not change our position on the risks associated with power morcellation," Maisel added. "We are continuing to warn against the use of power morcellators for the vast majority of women undergoing removal of the uterus or uterine fibroids."

OUR INSPIRATION IS THAT WE BELIEVE WE CAN DO BETTER. WE UNDERSTAND THAT WHAT HAPPENED TO HER SHOULDN’T HAPPEN AND WE REALLY WANT TO DELIVER SOMETHING MUCH BETTER TO THE MARKETPLACE.

An industry-wide rift Ford-Serbu and her fellow Eximis co-founders are medtech veterans, rooted in decades of experience in the industry. When they formed the company, Ford-Serbu said they saw an area that was "hungry for innovation."

After the FDA warned against using power morcellators in gynecological procedures, some companies sought to modify the device in ways that would mitigate the risk of spreading cancerous cells around a woman's body.

Eximis executives argue that the XCor system, which combines segmenting wires and a containment bag, is distinct from power morcellators and addresses a need expressed by gynecologists and surgeons.

On the same day that the FDA released a report reaffirming its concerns with morcellation, the ACOG and the Agency for Healthcare Research and Quality published a review arguing that the risk of unexpected leiomyosarcoma is less than 1 to 13 in 10,000 surgeries.

The group has long argued that there is a need for laparoscopic tissue removal in gynecological surgeries and that the FDA should reconsider its 2014 guidance.

The FDA estimates that a hidden uterine sarcoma may be present in 1 in 225 to 1 in 580 women undergoing surgery for uterine fibroids – much higher than the ACOG estimate.

Noorchashm holds that the risk to a woman's health is too high to ethically justify a laparoscopic tissue removal procedure that threatens to disrupt a potentially cancerous tumor.

day or two longer. But in reality, what's happening now is that 1 out of 300 to 500 women, whose cancers otherwise would have been spread by a power morcellator, are now being protected from that complication."

Opportunities to innovate arise, but concerns remain Eximis is engaged in talks with the FDA about how to best move through the regulatory landscape with XCor, which is still in development. In his letter to Eximis, Noorchashm urged the company to follow a PMA pathway, which requires more stringent clinical evaluation compared to the 510(k) route.

Since it issued its 2014 guidance, the FDA has approved one device designed to address the power morcellator's faults: Olympus' tissue containment system, the PneumoLiner.

In a statement regarding that device's approval, the FDA warned that PneumoLiner has not been proven to reduce the risk of spreading cancer during laparoscopic uterine tissue removal procedures.

"The PneumoLiner is intended to contain morcellated tissue in the very limited patient population for whom power morcellation may be an appropriate therapeutic option – and only if patients have been appropriately informed of the risks," Dr. William Maisel, deputy director for science & chief scientist at the FDA's www.medicaldesignandoutsourcing.com

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Finding out if contained power morcellation reduces the risk of spreading malignant cancer cells has proven to be challenging. A proposed trial of the PneumoLiner system at the University of North Carolina was met with such criticism, including by Noorchashm, that the school announced last year that it would review the trial's design for ethical violations.

The two-year study, which was supposed to begin last September, is not yet recruiting patients, according to ClinicalTrials.gov.

Eximis executives insist that its XCor system is different from other approved products. Instead of relying on sharp edges to cut through tissue, it uses energized wires. The system also slices tissue within a containment system and toward the surgeon's incision, to reduce the risk of slicing through the containment bag.

Noorchashm challenged those claims, saying that although Eximis is well within its rights to seek financial backing, the company's system still violates a fundamental standard of surgery.

“You can’t go and say you’re doing something different than a power morcellator – you’re not,” he told us."Yes, the tissue looks different when you cut it up, when you slice it, as opposed to grind it up, but it's the same thing. You're violating a surgical principle and you're exposing these women to the possibility of their cancers being upstaged." M 5 • 2018

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BILL BETTEN

BILL BETTEN | BETTEN SYSTEMS SOLUTIONS

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BILL BETTEN

The regulated medical device development world requires a vast level of commitment, process and demonstration of efficacy. The cost of developing a medical device ranges from $25 million to $100 million, according to a 2010 research study out of Stanford University. The cost of failure or delay is even higher.

Medical device development success simply cannot be reduced to a simple checklist or set of steps to follow.

(If it could, every entrepreneur would be successful.) The product development process is messy, at best, but still requires as much planning as possible.

With that in mind, this article – the first in a series of two – aims to provide basic guidelines for the critical elements to consider before diving into product development. We’ll focus on the definition and execution of product development activities after the idea and post-funding. The critical elements are as follows: Idea – Without it, nothing to be developed; Process – The structure for development; Plan – The blueprint; Requirements – The details; Regulatory/reimbursement – Critical to the medical device space; and • Verification/validation – The right product doing the right thing.

• • • • •

This article will cover the critical elements through requirements. Part two of the series, running in July, will go over regulatory/reimbursement and verification/ validation. Since you’ve hopefully already got the idea, let’s begin with process, the umbrella under which the other activities are conducted.

www.medicaldesignandoutsourcing.com

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Building the process The product development process is the umbrella under which all activities are conducted. Processes vary by organization and evolve over time, but still require a level of structure to accomplish the goals in a timely and efficient fashion. A product development process defines the requirements to ensure that products meet or exceed customer and business needs.

The process describes the stages, inputs, outputs and responsibilities associated with product development activities â&#x20AC;&#x201C; including post-market changes in function or intended use.

The development process also includes the Quality Management System (QMS).

Many medical device companies choose

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to implement a quality system and have it certified to ISO 13485 to ensure consistency.

For years, the FDA (and industry) adhered to the â&#x20AC;&#x153;waterfallâ&#x20AC;? process as described in the FDA Design Control guidance in 1997. The guidance viewed product development as a set of sequential activities: Requirements are developed and a device is designed to meet those requirements; the design is then evaluated and transferred to production; and the device is manufactured. However, in the mid-2000s, it was recognized that development is really an iterative process that incorporates interactions between a variety of stakeholders and the input of every group involved in the process. The

emphasis now is on sharing information throughout the product lifecycle, reflecting more realistic interactions. It also encourages the use of preventive actions over corrective actions.

The process and QMS help ensure that product development activities are conducted in a cross-functional environment. In the regulated world, where 60% to 80% of the development effort is associated with documentation in various forms, the process provides the framework for a successful effort.

Successful planning Creating a product development plan is an evolutionary effort that continues through the life of the project. It is essential to gathering and assigning

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BILL BETTEN

the appropriate resources to the effort, particularly for a startup trying to obtain funding and support for the subsequent development. It can help companies understand the complex dance of cost, schedule and resources. This initial plan is continuously refined throughout the project, reacting to the inevitable changes that occur along the way.

The plan is a formal, approved document used to guide both project execution and project control. It sets planning assumptions and decisions, defines the approved scope, cost and schedule, as well as communication

among project stakeholders. In addition, medical product development places an emphasis on quality and risk of both the product and the development process.

The plan typically comprises major phases associated with the overall quality system of the entity performing the work, with subtasks of varying levels of complexity. The phases correspond to the major segments of project development, from development of the initial concept to project launch. Project close-out should also be included because product longevity and management post-launch are critical in the tightly regulated medical environment.

High-level product development plan

During the concept phase, customer needs are gathered and translated into initial product requirements. Multiple product implementations are considered and, generally, one concept is identified for subsequent development. Phase II (planning and architecture) is where the initial project plan is refined based on the initial requirements and the basis for the subsequent development is set.

The majority of engineering design work

Image courtesy of Betten Systems Solutions

Detailed project plan

Image courtesy of Betten Systems Solutions

begins in Phase III, culminating in working hardware and software in engineering units and ultimately design verification test units. Phase IV tests those units and makes any final changes required for locking down the design and moving into production units in Phase V. The high-level phases contain detailed sub-components and deliverables associated with the entire product.

They can easily consist of hundreds or thousands of interconnected items and incorporate the tasks, schedules and resources associated with the project. They serve as a milestone tracking tool to show progress against the objectives and serve to define critical deliverables.

It is tempting to get totally in the connections and schedule charts, but remember that the project plan is a tool to accomplish your objectives.

Deviations from intermediate milestones are to be expected and, as long as the overall deviation tends to oscillate equally around the general path, the objectives are obtainable. In addition, a few additional pointers for planning and execution success include the following: • Communication by the program/ project manager to all stakeholders is critical. (Avoid late “surprises.”)

• Keep an eye on the big picture, manage to the critical path, and provide early warning for potentially late milestones. Don’t blindly schedule “boxes.”

• Do “sweat the right small stuff,” because it can derail you.

• Set priorities and make sure that the team knows what is “hot.” This is often based on a “critical path” analysis (a feature in most tools), that helps point out the tasks that must be completed on time to keep the schedule.

• Keep a sense of humor, a strong sense of team – and don’t panic when things happen, because they will.

Handling requirements Developing the product requirements is one of the most complex activities associated with product development, and one of the most important. One of the biggest challenges in developing

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good requirements is identifying and gathering input from all the stakeholders.

Much has been written on the topic, particularly regarding gathering the “voice of the customer.” Requirements are often thought of as written specifications developed by engineers after talking to marketing personnel who theoretically understand the customers’ needs. Yet in today’s development efforts, the range of inputs extends far beyond the buyer of the system, the traditional “customer.”

In medical devices, the “customer” is complex, potentially including the end user, payer, patient, clinician, caregiver, procurement organization or key opinion leader. Requirements are also driven by the regulatory, reimbursement and safety & hazard analysis constraints incumbent in the medical product development process.

FIND MORE ONLINE For a deeper dive, check out Bill Betten’s online series of articles on the product development process. https://www. medicaldesignandoutsourcing.com/ medical-device-startups-secrets-success/

There are a variety of methods for gathering information from stakeholders, such as direct questions and interviews of individuals, developing advisory boards and observational research. Devices based on a predicate often use requirements derived from the preceding device to minimize regulatory complications.

The FDA imposes additional requirements for medical devices to include human factors and usability of a device, with the intention of

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TYPICAL PRODUCT REQUIREMENT ELEMENTS Device Functions

Physical Characteristics

Performance

Safety/Risk Management

Reliability Standards Regulatory

Human Factors

Labeling & Packaging

Maintenance

Sterilization

Compatibility with other devices

Environmental Limits

Security

Representative product requirements

Image courtesy of Betten Systems Solutions

improving the probability of safety and effectiveness. These interactions involve the three major components of the device-user system: Device users, device use environments and device user interfaces. This emphasis has become so prevalent in forming design requirements that numerous consulting firms focus completely on early understanding, definition and execution of these design attributes.

The requirements form the basis not only for the product design, its features, functions and risk mitigation, but extend completely through to the verification and validation process. To that end, requirements should be clear, traceable and verifiable. Other things to keep in mind during the development of requirements include the following: • Involve all the stakeholders in the process of defining the problem and the requirements; • Complete the problem statement before defining the requirements; • Avoid stating the problem in terms of solutions; • Identify the high-level system functions; • State the requirements clearly and unambiguously; and • Identify mandatory versus tradeoff requirements, and quantify and prioritize if appropriate.

Medical manufacturers don’t have the luxury of gathering user feedback after launch or of making quick changes, unlike the consumer space, particularly softwarebased products. The medical regulatory environment requires tracing from initial requirements to demonstration that those requirements have been met. In addition, post-launch monitoring requirements ensure that product issues and deviations from desired performance are identified, tracked and resolved.

Conclusion All the activities mentioned here – as well as the ones we will cover in the next article – should be considered in parallel at the beginning of any project. Although the effort devoted to each activity ebbs and flows as you proceed through the project plan, the implications of each should form the foundation of your plan and guide your effort. For any of the topics discussed in this article, there are experts who will engage and fill in the gaps on your team. Picking good partners, a great project/manager, and keeping your sense of humor are critical to your success. M Tom Waddell, Waddell Group contributed to this article.

www.medicaldesignandoutsourcing.com

5/18/18 7:56 AM

RANI THERAPEUTICS

Medtech veteran

Mir Imran

wants to replace injections with the “robotic pill” Companies have tried for decades to orally deliver proteinbased drugs. Can Mir Imran’s robotic pill succeed where so many have failed?

SARAH FAULKN ER | ASSO CI ATE ED I TO R

Mir Imran has been building medical device companies for 40 years. Perhaps known best for his work on the first FDA-approved implantable cardioverter defibrillator, Imran’s model is to identify big, unsolved challenges and try to find solutions.

His work at Rani Therapeutics, developing an oral drug-delivery capsule to replace painful injections, is no exception. Administering biologics orally has been attempted by 100 different people over the last 50 years, with no success, Imran told Medical Design & Outsourcing.

“It’s such a compelling problem from a patient-comfort and patient-compliance standpoint. For companies, it could be a strategic, competitive edge over their competitors who are delivering drugs by injection,” he told us.

Rani Therapeutics’ investigational capsule is designed to survive the human stomach’s harsh environment thanks to a polymer coating. When it arrives in the intestine, the coating dissolves and triggers a series of reactions that transform the capsule into an auto-injector, delivering the drug directly to the intestinal wall.

“The biggest unknown right now is how well it will work in humans,” Imran said.

www.medicaldesignandoutsourcing.com

Rani Therapeutics Feature MDO 5-18 Vs4.indd 77

Developing the “robotic pill” Imran and his team have been working on the Rani Pill for the last six years, fine-tuning the chemical reactions that power the device. The company’s capsule is often described as a robot, because it appears to have a mind of its own, Imran said.

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RANI THERAPEUTICS

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Early on, the company decided that if they were going to inject a drug into the intestinal wall, they couldn’t use metal needles. Instead, they loaded a dissolvable polymer with a dry-powder drug and made needles out of it.

From there, the team had to figure out how the capsule would push the needles into a person’s intestinal wall. To resolve that challenge, Rani Therapeutics used a chemical reaction that produces carbon dioxide to inflate a small balloon.

The balloon pushes the dissolvable needles into the intestinal wall in a process that Imran describes as “painless.”

The technology has received a great deal of interest from investors and pharmaceutical companies. Rani Therapeutics raised $53 million in February this year from companies including AstraZeneca, Novartis, Shire and Alphabet’s Google Ventures.

Beyond the financial support, Rani Therapeutics has also inked strategic partnerships with the three aforementioned pharmaceutical companies. Most recently, it agreed to an exclusive deal with Shire to combine the Rani Pill with Shire’s factor VIII therapy for patients with hemophilia A. “We’re converting an intravenous drug to an oral, which is a huge leap,” Imran explained.

Rani Therapeutics has fielded interest from a number of other companies, but the company has chosen partners strategically, he added.

“In the future we might be adding more partners, but we’re a small company, so we want to make sure we do a good job for all of our partners. In a number of cases, we’ve said no mainly because of our bandwidth limitation,” Imran said.

Tackling impossible problems Throughout Imran’s lengthy career in medtech, he learned valuable lessons about innovating around previouslyunsolved challenges.

“You have to pick the right problem,” he said. “One of the challenges here is when you are doing something that is disruptive, that has never been done before, there is risk. Even for us, there is a lot of risk that we could fail. It’s generally easier to develop technologies that are incremental innovations to existing technologies.”

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With the biologics market pegged to be worth nearly $400 billion by 2025, according to Grand View Research, companies are desperate for better ways to deliver protein-based medicines. Biologics are traditionally administered via injection, since they aren’t ideal for oral delivery; enzymes and the acidic environment of the stomach chew up biologic drugs before they can be absorbed.

“Lot of companies fail because they are tackling the impossible problems,” Imran said.

Looking ahead, the medtech veteran is also hoping to solve other challenging drug-delivery problems, like getting medicines past the blood-brain barrier. In the meantime, Rani Therapeutics plans to automate and scale up its manufacturing process in preparation for first-in-man studies of the Rani Pill within the next year.

“Very few drug-delivery platforms will have such a profound impact on so many chronic diseases. I'm trying to get that message across because this could be a huge benefit to the patients, to the payers and for the doctors who are treating these patients,” Imran said. M

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