Polymer Advances for Anatomical Repair and Exploration

• Biomimetic materials.

• Bioresponsive polymers.

• Polymer-tissue and polymer-cell interactions.

• Control of polymers' properties during exposure to biosystems.

• Self-assembling polymers.

The list of emerging medical technologies is exhaustive, and the industry is fast-paced. The developments in the areas referenced above are driven by necessity, and they lead to a trend for the creation and proliferation of designer polymers that can be used in a number of tubing and tubing-like applications, such as catheters and stents. These developments continue to present new opportunities and increase demands for intravascular exploration and deployment of these new, exciting technologies.

The Heart of the Matter

Coronary artery disease has led physicians to aggressively adopt and eagerly search for new technologies and materials to perform minimally invasive procedures (see Figure 1). Interventional cardiologists began an era of stent deployment to battle cardiovascular disease, lasers to remove lumen obstructions, and rotoblator therapy to treat diseases that afflict millions of patients.

Interventionalists faced a challenge in managing and battling multivessel disease in a single procedure. A study conducted from 1996 to 1999 compared percutaneous coronary interventions (PCI) with coronary artery bypass graft (CABG) surgery. Patients were offered an alternative to surgery for treatment using percutaneous transluminal coronary angioplasty (PTCA) with stenting.¹ The long-term outcomes seemed comparable with those observed after CABG in terms of mortality and acute myocardial infarction. The introduction of impregnated jacketed stents and drug-eluting stents (DESs) to coronary interventional procedures represents a significant therapeutic advance. Compared with bare-balloon PCI, stenting and DESs are associated with better results and lower rates of restenosis. Coronary stents are now used in approximately 80–90% of all interventional cardiology procedures.² The DES market has exceeded expectations and reached $5 billion over the last three years. Response variables, patency, and technology to treat restenosis help overcome obstacles that practitioners face.

Device Deployment

However, the choice of procedure is only one challenge that interventionalists must overcome. Navigation is another significant problem to be addressed. Albert E. Raizner, MD, described the problem of navigation: “The coronary arteries are a curving, twisting network of vessels that exist on three planes and are wrapped around a conical surface, which happens to be off-axis to any of the three planes.”³

Navigating such a network is especially difficult in patients with small-diameter vessels, tortuous arteries, or multivessel disease. Steerable catheters have opened up new territories to interventional cardiologists. However, many physicians believe there are few other improvements that are technologically feasible.³

Regardless of the technology, one of the major challenges for surgeons is deployment, and device manufacturers must be aware of this point. Delivering and deploying new and revolutionary technology is very difficult. Catheter navigation through the tortuous vasculature presents some significant problems. This has led to the recent interest in magnetic navigation of interventional devices through the vasculature. In such procedures, small magnets in the tip of a distally limp catheter are affected by an external magnetic field to steer the catheter. A key point is the difference in material properties for this distal tip. The catheter material requires different material properties, and the tubes being passed through the catheter do as well. In effect, the assembly must be maneuverable and useful when in place.⁴
Therefore, these considerations pose challenges not only to physicians, but also to the engineers of the device manufacturer. They also affect the engineers and scientists of the tubing manufacturer and the scientific staff of the resin supplier. Some of these issues go all the way back to polymer synthesis itself.

Materials Science

Polymers play a significant role in medical device development and in enabling exploration of the human body. New technologies have allowed surgeons to reach areas and perform procedures that would not have seemed possible two decades ago. New materials continue to emerge and be placed in the human body.

However, device manufacturers have struggled with limitations in the selection of polymers that are available to construct new innovative devices and delivery systems. During the last three decades, the number of new materials created via polymerization introduced into the market has been limited. This limitation has pushed device manufacturers to take on new development work themselves through internal development, university-level research, and industrial partners.

The major emphasis of raw-material suppliers has been on addressing the commercial side of the business rather than medical applications. The most significant concern for resin manufacturers supporting the medical industry is the liability associated with medical devices used for short-term exposure to the body. Implantable devices or conduits are often out of the question, because most resin producers declare the risk of liability greater than the potential rewards.

Penetrating the veil of new medical technology development is not easy. Although it is still a critical feature, it is no longer good enough to supply tubing with close geometrical tolerances. The drive is to figure out how to manipulate a material to enhance its performance and properties. This concept goes beyond simple additives and fillers. Instead, this is where the designer polymer approach begins. Manufacturers are beginning to demand that their suppliers design a polymer to fit an intended use, rather than trying to make commercial materials work for a particular application.

Material science development will become an important business philosophy for tubing and materials suppliers targeting future medical device developments. Understanding structural property relationships, manipulation of a polymer's bulk properties, and phase domain behavior will be critical in realizing new opportunities.

Although there has been much resistance from materials suppliers, the list of polymers that are commercially used in devices is now starting to grow. Some of the more widely accepted polymers that have worked their way from a commodity world into medical usage are shown in Table I.

Biomaterials

What truly determines whether a material is classified as a biomaterial? A biomaterial is “any substance, synthetic or natural in origin, which treats, augments, or replaces any tissue, organ, or function of the body.”⁵

The majority of biomaterials in current use were originally designed for other purposes. Through investigations driven by physicians as well as device manufacturers looking to provide solutions for minimally invasive procedures, biological efficacy has gradually been proven (see Table II). As demands to explore new areas and perform new procedures increase, so do demands for new and unique materials. It is no longer as simple as the chemical inertness of a polymer. Control of the interface between the biomaterial and the host tissue is now paramount.

The field of biomaterials has evolved from simple clinical trials to an entire scientific discipline based on the interaction between tissues, cells, and polymers.

Macromolecular Manipulated Material

Polyetheretherketone (PEEK) is considered one of the highest performing thermoplastic materials, having significant mechanical properties and the ability to withstand extreme temperatures, intense pressure, and caustic fluids.⁶ A linear, semicrystalline aromatic polymer, PEEK has been taken to a new level of highly engineered performance with the development of heat-shrinkable PEEK tubing.

Controlling macromolecular crystallization and orientation is an important scientific method of crystal nucleation and the control of crystal structures. The method yields a highly crystalline material with crystal geometries of <150 nm. Driving the materials' crystallinity to 40% exceeds any published works for this material. The results of this work are found in areas of increased continuous service-temperature, 400ÞC, which is above the melt point of the polymer, and high dielectric strength.⁷ The polymer's inherent purity, lubricity, and high thermal and mechanical properties make it an ideal choice for demanding medical applications, including the following:⁸

• Radio-frequency thermal ablation (RFTA).

• High-intensity focused ultrasound (HIFU).

• Coablation technology.

• Ultrasonic coagulators.

• Microwave coagulation therapy (MCT).

• Argon plasma coagulation (APC).

The list above mentions just a few potential examples of a highly engineered material that takes PEEK to a new level. The material's performance exhibits significantly improved adhesion and wear properties over traditional PEEK and polyimide coatings.

PEEK is also available in Class VI– and implantable-grade materials, and pigments and radiopaque additives can also be incorporated.

Biodegradable Stents

Metal stents are functional in their ability to hold the vessel open, allowing restoration of blood flow. However, metal stents have several limitations, including stent thrombosis, stent-vessel size mismatch, and the fact that they are permanent. After reendothelialization, the stent serves no demonstrated purpose and may lead to late thrombosis and chronic inflammation. These limitations have driven the development of bioabsorbable stent materials and designs.⁹

The most critical requirement of a bioabsorbable stent is that it be nonpermanent. Such stents must provide an initial barrier to vessel closure and localized treatment to diseased tissue to prevent cell migration and proliferation. As the material degrades, the fragments dissolve gradually, to the point of catastrophic breakdown. The fragments should not be prothrombolytic, however. Related to this is an acceptable degradation profile. The transient material properties must be sufficient to maintain device function. Degradation rates and profiles can be controlled through use and manipulation of copolymer composition as shown in Table III for poly(DL-lactide-co-glycolide).¹⁰

One desirable feature will be advanced drug delivery over long periods of time. Current DES technology offers limited efficacy for elution of the pharmacologically active material (usually about one month). The prevailing degradation mechanism is hydrolytic cleavage of the backbone. During the process, water migrates into the amorphous regions of the device and cleaves chemical bonds. Because initial degradation is in the amorphous region, the greater the regions of crystalline (or, more accurately, the areas of low free volume precluding sorption, diffusion, or uptake of water), the longer mechanical properties will be maintained. Depending on the structural groups and the available enzymes, there can be a phase of enzyme attachment to the material. During water migration or enzyme attachment, molecular weight decreases and low-molecular-weight species erode. This exposes large areas of the devices to hydrolytic and enzymatic attack. The key aspects are the susceptibility of the linkages to attack (bond strength and resistance to local environment such as pH and enzymes), surface area, and solubility of low-molecular-weight species in the environment.¹⁰ A side note to the degradation behavior of the materials is on hydrolytic instability. Care must be taken in processing the materials to preclude bound moisture from degrading the material as it is processed.

Innovators behind Material Development

One of the radical innovators who pushed the polymer envelope is Robert Langer, a professor at the Massachusetts Institute of Technology. In the early 1980s, Langer designed polymers with specific functional criteria in mind. He blended natural materials and tailored the physical and mechanical properties to fit different applications. He focused his polymer designs based on engineering, chemical, and biological property requirements.

Using polyglycolic acid, which is a resorbable polymer, and other similar polymers, Langer crafted degradable and nondegradable polymer pellets into an intricate porous structure that allowed the slow diffusion of large molecules. Langer opened the world of bioresorbable polymers by working with a blend of synthetics that mimic natural materials with custom refined physiologic properties. This innovation is the foundation of much of today's controlled drug-delivery technology.

Langer joined forces with Judah Folkman of Harvard in 1983 to apply what they learned in polymer manipulation. They applied their knowledge to tissue engineering with degradable polymer scaffolds. “We design plastics from scratch that provide exactly what's needed,” Langer explains.

Conclusion

Although a host of materials are suitable for medical device manufacturing, new materials are not being generated for invasive medical device development from the resin supply chain. Device manufacturers struggle to fill the demands of physicians. This is what is driving innovators and material science companies to bring new polymer technologies targeted toward device development to fruition. The walls of isolationism will be torn down by consortia of resin manufacturers, materials processing companies, medical device manufacturers, and physicians, and a new generation of devices will be born along with new processing techniques and materials.

Robert Ballard is corporate director of research of the advanced materials and strategic business development at Zeus Inc. (Orangeburg, SC). He can be reached at [email protected]. Stephen Davis is the staff scientist directing the advanced materials group for Zeus. Reach him at [email protected].

References

1. Beatriz Villegas et al., “Triple Vessel Stenting for Triple Vessel Coronary Disease,” The Journal of Invasive Cardiology 14, no. 1 (2002): 1–5.

2. DR Holmes et al., “ACC Expert Document on Coronary Artery Stents: Document of the American College of Cardiology,” Journal of the American College of Cardiology 32 (1998): 1471–1482.

3. JA LeQuang et al., “Breakthroughs in Technology for the Assessment and Treatment of Cardiovascular Disease,” Cath Lab Digest 13, no. 6 (2005): 44–47.

4. M Faddis et al., “Magnetic Guidance System Safe and Effective in Intracardiac Mapping, Pacing, and Ablation,” Journal of the American College of Cardiology 42 (2003): 1952–1958.

5. RS Greco, Implantation Biology: The Host Response and Biomedical Devices (Boca Raton, FL: CRC Press, 1994): 418.

6. S Green, “Using Implantable-Grade PEEK for In Vivo Devices,” Medical Device & Diagnostic Industry 27, no. 5 (2005): 104–111.

7. ANSI/NEMA 1000-2003, Revision 1, “Standard Test Method Conducted by Independent Lab” (Rosslyn, VA: National Electronic Manufacturers Association, 2003).

8. L Boni et al., “Technological Advances in Minimally Invasive Surgery,” Future Drugs: Expert Review of Medical Devices 3, no. 2 (2006): 147–153.

9. R Waksman, “Biodegradable Stents: They Do Their Job and Disappear,” Journal of Invasive Cardiology 18, no. 2 (2006): 70–74.

10. E Middleton and A Tipton, “Synthetic Biodegradable Polymers as Medical Devices,” Medical Plastics and Biomaterials 5, no. 2 (1998): 30–39. n

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