Partnerships for Progress in Medical Devices

28 February 2005 (Last Updated February 28th, 2005 18:30)

Collaboration between experts across a range of disciplines is the key to the development of new device functionality. Dr Christopher Widenhouse of Cordis Endovascular explains.

Cardiovascular or endovascular stents are highly functional. In addition to their obvious or primary function, they often incorporate improvements that enable them to perform secondary functions that increase their performance, efficacy or ease of use. These improvements in functionality are highly dependent on partnerships between experts across diverse disciplines.

At the heart of functionality improvements are the clinical indications. These can be in the form of patient needs or the functional needs of the clinician. Clinical use, materials of construction, specific geometries and other attributes collectively define functionality.

GROWING UNDERSTANDING

The standard treatment for coronary blockage at one time was bypass. Later on angioplasty became the norm, followed by stenting. Many would argue that the use of drug eluting stents is, or should be, the new standard of care. This same trend of development and improved treatments using stents is now being seen across other clinical indications. However, for this evolution to take place, an understanding of the disease state or the clinical indication is critical.

"A major challenge in the treatment of peripheral arterial disease (PAD) that needs to be addressed is diagnosis."

To this end, a major challenge in the treatment of peripheral arterial disease (PAD) that needs to be addressed is diagnosis, as a large percentage of patients with PAD are asymptomatic. The treatment of PAD based on TASC recommendations and scores indicates endovascular treatment (PTA or stenting) for TASC A lesions and surgery for TASC D.

The easiest and hardest lesions to treat are at the extremes, and there are clear guidelines and recommendations for treating these. But there is limited data to provide absolute guidance for the treatment of lesions between these extremes. However, as new technologies and methodologies are developed and implemented to advance the diagnosis and understanding of PAD, we are beginning to see the evolution of treatments and the development of devices based on this understanding.

DEVELOPMENT MODEL

Looking back at the development of the first commercialised stent, we can find a successful model for device development. After fabricating an early prototype stent with copper wire, Dr Julio Palmaz was eventually forced to find partners who had the necessary expertise to turn his concept into a viable prototype. Dr Palmaz found an unexpected patron and investor for his new technology, Johnson & Johnson.

The company possessed a critically important enabling technology: the ability to market and promote the technology. The identification and understanding of the clinical need, the development of concepts and prototypes, and the identification and development of key partnerships is a fundamental model for advances in medical devices.

The evolution of treating coronary artery blockages relied very heavily on identification of the disease, and reliable means of detecting and visualising the disease. As treatments improved, so did understanding of the problem. This allowed the identification and development of therapeutic agents such as paclitaxel and rapamycin as potential candidates for the pharmaceutical treatment of restenosis.

Collaboration with experts in polymer coatings and coating processes, in turn, allowed drug-eluting stents to be designed, manufactured, tested and proven. In short, improvements in stent designs, stent functionality and our ability to treat patients by turning technologies into successful products and advances stem directly from the process of collaboration between experts across diverse disciplines.

A wide range of materials are currently being studied for use in next-generation drug eluting stents with specific therapeutic properties – anti-inflammatory or anti-proliferative properties, for example. There are very few metallurgists, biomaterials scientists or mechanical engineers that could name all of the compounds being examined, much less suggest them as candidates for stent therapies. But they don’t have to; that isn’t their area of expertise. Pharmacologists, vascular biologists and other experts can take care of that.

What is important is recognition of the importance of developing partnerships between disciplines in enabling technological success. Focusing on a specific area of expertise in the context of a collaborative partnership is an effective means of rapidly advancing current technologies.

For many years, the medical device industry has utilised materials designed for other applications, as developers of materials focused on larger volume and commodity markets. Essentially, there was no direct partnership or link between material developers and manufacturers and the medical device industry. Recently, however, there has been a trend in materials design and development (especially in cardiovascular biomaterials) towards providing customised materials for specific applications.

This successful trend stems from the collaboration of experts in specific fields across different disciplines. A new wave of smaller material and technology development companies now exists to serve the biomaterials market.

Traditionally, the mechanical design and function of the stent dictated the selection of stent material. Now, however, materials with desirable functional properties are being used, thus placing an increased burden on the mechanical design. Similarly, new designs and mechanical structures require the selection and design of appropriate construction materials to meet functional goals.

To expand stent construction in new directions and utilise more materials with desirable functional properties, material design and selection needs to be considered alongside stent design and mechanical function. Partnerships across the materials development and stent design disciplines, similar to those described below, need to be developed.

DEGRADABILITY

If the desired improvement in stent function is that it disappears or is absorbed after it is no longer needed mechanically, one solution would be to make it out of a degradable polymeric material. Biodegradable polymers are not new, but the application of degradable materials to stents is relatively recent and is gaining interest. There are, of course, several challenges to consider when designing a mechanical device from polymers, especially a mechanical device that must undergo significant dimensional changes in use. Simple self-expanding braided structures and polymer coils are the most obvious designs for polymer stents.

Work by Nuutinen et al demonstrates that polymers can be fabricated into a feasible design and meet the mechanical requirements, and that the degradation mechanism and kinetics can be predicted and understood. However, the primary focus and core expertise of this group is in the material design of the absorbable material. They also need to couple this expertise with the ability to fabricate the material into a suitable mechanical design if the technology is to advance further.

Similarly, polymer and material experts at Nanyang Technological University in Singapore have developed a novel stent material and fabricated it into a coil design. The group has also demonstrated the material’s capability to load and release up to 21 different pharmaceutical compounds. However, a partnership with experts in mechanical design and pharmaceutical selection will enable this technology to be developed into a viable product to improve patient treatments and quality of life.

Polyglycolic acid (PGA), polylactid acid-based polymers and copolymers have been used in medical device applications for a number of years, but the use of these materials in stents and stent technologies is relatively recent. One advantage of these materials is that much is already known and understood about their degradation mechanisms and kinetics. Typically, poly-L-lactic acid (PLLA) and poly-D,L-lactic acid (PDLA) are mechanically stronger than PGA and PCL (poly e-caprolactone), which degrade faster.

Research and development is now focusing on understanding which combinations of material properties are most suitable for stent applications. The proper balance of copolymers, morphology, molecular weight and processing methods governs the effectiveness of these devices. A focused effort on understanding these properties, combined with an understanding of vessel dynamics and drug loading/release kinetics is necessary for ultimate success.

Amino acid-based bioanalagous (AABB) polymers are block copolymers synthesised from amino acid-based monomers and oligomers, imparting a more biologically recognisable chemistry to the polymer as a whole. The primary degradation mechanism then becomes enzymatic rather than hydrolysis, thus limiting degradation to a largely surface phenomena, as opposed to bulk degradation.

Polymers are synthesised by replacing monomer units with amino acid-based monomers. Polyester amides, polyester urethane and polylactide copolymers incorporating amino acids into the copolymer backbone have all been synthesised using a variety of synthesis technologies. The custom chemistry and synthesis of these materials allows the inclusion of specific side chain moieties allowing the direct attachment or incorporation of functionalities, whether it be for radiopacity or for targeted therapies. Upon degradation of the polymer chains, the active agents are released for site-specific therapy.

"Research and development is now focusing on understanding which combinations of material properties are most suitable for stent applications."

To enable these technologies to advance, MediVas, the developer of these materials for specific applications, has partnered with Guidant Corporation, which focuses on the development of drug eluting stent coatings. Again, partnerships across multiple disciplines, each with a focused effort on specific core competencies and areas of expertise, are enabling new technologies to drive the development of cardiovascular biomaterials and devices forward.

THE NEXT LEVEL

A recent example of taking these developments and partnerships to the next level can be found in the design and development of the Casper stent from Reva Medical. The partnerships that enabled this technology include collaborations with polymer and mechanical design experts. A specific material was designed for a degradable drug eluting stent application based on tyrosine-derived polycarbonate materials.

A basic understanding of the degradation mechanism and kinetics was developed as a function of the material composition. Altering the side chain functionality of the monomers used to create these polymers allows predictable control over the mechanical properties and the degradation kinetics. Additionally, iodinated groups can be incorporated to improve visibility under fluoroscopy and radiographic imaging.

The mechanical design is critical to enabling these novel materials to be fabricated into functional stents. The use of a ratcheting or mechanical slide-and-lock mechanism allows the stents to be expanded using a balloon with minimal deformation of the base material or stent. The size or diameter change on expansion is accommodated by the ratcheting design.

Surface functionality is also being developed. One approach is to treat the surface of the stent with antibodies to circulating endothelial progenitor cells (EPCs) to actively capture circulating EPCs, promote healing and endothelialisation, and prevent restenosis. Partnerships across the disciplines of materials science/surface modifications and vascular biology enabled this unique approach to be developed.

An example of a stent that can be used to target a specific therapy can be found in work published by Eberhart et al. The concept is to utilise microspheres – a conventional drug delivery method – loaded with the desired compound for treatment. The microspheres are made of absorbable materials, namely bovine serum albumin, and are attached to de-gradable polymer fibres (PLLA). This stent concept can be utilised for the primary thera-peutic treatment of vessel structures (although it is not limited to vascular applications).

Encapsulation or protection of therapeutic molecules within the protective structure of a micro-sphere also allows biologically derived molecules and gene therapy to be considered as treatments. The combination of different technologies (degradable polymers and drug delivery via microspheres) enables a new menu of treatment options to be realised.

There are numerous other examples of collaborative successes such as these. They all arise from partnerships between and within medical device industry companies and smaller organisations, such as academic research groups or small material technology companies. Such collaborations mean that it is becoming less and less challenging to identify materials that are suitable and approved for use in medical devices, with the result that the design options for improved medical devices are expanding all the time.