When the founders of Merlin MD set out to develop and launch a new product for the endovascular treatment of intracranial aneurysms, they recognized the need for a highly innovative and cost-effective approach to product design, development, and business strategy. Selecting the best manufacturing location was a critical part of the business strategy, with Singapore and Switzerland becoming the front-runners. Singapore won out because its government agencies offered the best overall support for start-ups.
For example, the Singapore Economic Development Board (EDB) provided a research and development grant and equity-based funding. And enterprise-development agency SPRING Singapore provided a development grant, while International Enterprise (IE) Singapore helped Merlin MD enter the Brazilian and Mexican markets. The Singapore location also made it possible to tap qualified engineering talent through educational institutes such as Nanyang Technological Univ, the National Univ of Singapore, and Nanyang Polytechnic.
Without the help of the Singapore governmental agencies, developing our X*Calibur Aneurysm Occlusion Device (AOD) would have been more difficult. The device is placed across the neck of an aneurysm to induce thrombosis of the aneurysm sac by altering the blood flow between the artery and the aneurysm. The stent-like device, which is covered in a semi-permeable, biocompatible membrane, seals the neck of the aneurysm, while still maintaining blood flow to nearby vessels.
The primary advantage of this method is it isolates the intracranial aneurysm from blood circulation with a minimally-invasive endovascular approach. AOD thereby combines the best of surgical clipping and endovascular coiling, the two currently available technologies. A balloon expandable AOD — rather than a self-expandable flow diverter — provides a more-precise fit to vessel diameters, greater radial strength to resist stent closure, and lower porosity, which results in a higher percentage of material covering the vessel.
Key design challenges
The AOD design entailed a number of challenges. The device needed to be both biocompatible and biostable. Because the device would be delivered through intracranial blood vessels, it had to easily slide through tight spaces and curvatures. Thus, the stent portion had to be much more flexible than a coronary stent, while the coating had to be durable as well as lubricious so there would be no risk of damage to the vessel wall during delivery. Also, a high precision was needed to inflate and deploy the device so it would locate properly against the vessel wall. In addition, it became evident that laser drilling the stents was necessary for the required porosity.
The design solution comprised a balloon-expandable AOD pre-mounted on the balloon of a 0.032 to 0.036-in.-diameter delivery catheter. With the AOD implant mounted on the catheter, the total diameter is less than 0.055 in.
The catheter is a rapid-exchange (RX) type, co-axial design, with a balloon located at the distal end where the AOD mounts. The catheter safely carries the AOD through the neurovasculature over a 0.014 in. guide wire to the target vessel. The distal portion of the catheter, excluding the balloon, is hydrophilic-coated for enhanced trackability. The balloon expands the AOD to a given diameter at a specified pressure. The supporting frame for the AOD is fabricated from 316L stainless-steel tubing laser-cut into a special strut and ring pattern that enhances flexibility, allows low inflation pressures, and maintains radial strength. Radiopaque markers are embedded in the proximal and distal struts for accurate placement. An ultra-thin, porous polymeric film covers the frame such that the interstices of the struts are webbed. When the device is placed and expanded in the parent vessel, the webbing permanently occludes the neck of the aneurysm. This lets the aneurysm heal while eliminating the potential for rupture. The optimal porosity allows for the flow of blood to neighboring vessels.
Supply and manufacturing strategy
Not only does the Singapore government encourage companies to locate there, it also helps firms explore other global markets and suppliers. For instance, we use a California-based company to cut and electro polish the stents. We had IP concerns for other parts of Asia. And because the process is highly automated, any cost differences between Asian suppliers and our U.S. supplier are negligible.
The polymer used to coat the stent was exclusively licensed from a group in California. The design required a very thin polymer with specific mechanical characteristics that are durable enough to withstand expansion and the harsh environment of the human body. Raw polymer is shipped to the Singapore manufacturing facility, where it is processed and applied to the stent. Once the stents are coated, the solvents are extracted using an internally developed process. A U.S.-based subcontractor then laser drills the coated devices. Optimal porosity comes from photo ablation of the polymer, which basically evaporates the polymer using multiple beam pulses. Laser drilling preserves the polymer’s mechanical properties by minimizing heat effects.
Last, the drilled devices return to the Singapore facility for testing, hydrophilic coating, assembly, packaging, and sterilization. A qualified contractor in Singapore performs sterilization.
The design team had to both anticipate and react to issues identified during animal studies and pre-clinical workups. Studies can take a significant amount of time, so it was important to develop several design variations through design of experiments which could be simultaneously tested. Bench testing per applicable requirements of ISO 14630:2005, EN 14299:2004, and EN 12006:3:2007 also helped fine-tune options. We tested to confirm sterility per ISO 11135 and ISO 10993-7; packaging and shelf life per ISO 11607; magnetic resonance imaging (MRI) compatibility; radiopacity; corrosion resistance per ASTM 2129 and ASTM G71; fatigue; and biocompatibility per ISO 10993-1:2003. We also performed a battery of bench testing.
The first feasibility study in animals, done in June 2005, identified several needed design changes. More rounds of animal testing were done in November 2005 and March 2006 to dial-in the optimized porosity. Four and nine-month follow-ups and histological exams led to the first human studies in September 2006.
The implant performed well during the human trials, but it became evident that the delivery catheter needed improvement, which was completed prior to the start of our clinical trials. Other enhancements included automating the polymer-coating process and improving the crimping of the AOD on the catheter to ensure device integrity as it goes through tight anatomical curves. Merlin MD is presently conducting clinical trials in Spain and Germany and is awaiting approval to begin in Mexico this summer. The Singapore agencies were instrumental in opening these potential markets to us.