Müller’s vision is ambitious but all not that far-fetched. Thousands of drugs and medical devices currently receive a free pass from the body’s dendritic gatekeepers to help debug disease: Hips, knees, ankles, teeth, heart valves, pacemakers, nails and pins routinely are implanted in our anatomies without much immunologic resistance. This impunity usually is granted on behalf of the material composition of the implants—titanium-based products almost always receive preferred guest status, while those containing chromium, nickel or cobalt often are treated as imposters (up to 13 percent of patients are “sensitive” to one or more of the latter three, rendering them less-than-ideal candidates for implantation).
Titanium 6AL4V and 6AL4V ELI, alloys composed of 6 percent aluminum and 4 percent vanadium, are the most common types of medical grade titanium. The alloys’ durability, flexibility, superb biocompatibility and high strength-to-weight ratio makes them optimal substitutes for dead roots of teeth, worn out or damaged joints, malfunctioning rib cages, deteriorated vertebrae and deformed areas of skull. Additionally, titanium is radiolucent (nearly invisible in X-rays, magnetic resonance imaging and computed tomography images), binds easily to bone and organic tissue (due to its high dielectric constant) and sports a protective oxide film that forms naturally in the presence of oxygen, even in trace amounts. That film, according to the Boulder, Colo.-based International Titanium Association, is highly adherent, insoluble and chemically non-transportable, thus preventing adverse reactions to biological tissue.
Yet for all its attributes—its remarkable repairs to nearly every body part, from the eyes, ears, mouth and heart down to the femur, tibia and ankle—titanium, surprisingly, has no real biologic purpose. Most of our 0.8-milligram daily intake of the natural element darts too quickly through our system to be absorbed or pose any significant health risks. And while it generally is harmless, large doses of titanium occasionally can lead to an adverse reaction by the body. Several studies have shown that patients with failed titanium-based prostheses are more sensitive to the metal than those with successful devices; the discovery reinforces other analyses showing a six-fold prevalence in metal allergies among recipients of failed orthopedic implants.
Müller is convinced he has found the antidote to those allergens and any other biocompatibility barrier at the bottom of the planet’s oceans. The molecular biologist regularly has scoured subaquatic rocks and reefs for sea sponges to study the chemical composition of their internal skeletons, comprised of silicium dioxide. During the course of his research, Müller and scientists from Johannes Gutenberg Universität Mainz in Mainz, Germany, encountered a new sponge protein (silicatein-α) and discovered how the soft-tissue scavengers use an organic enzyme to create an anorganic polymer (glass).“Nobody ever observed something like this,” mused Müller, head of the European Research Council’s Advanced Investigator Group at the Institute for Physiological Chemistry within the University Medical Center of Johannes Gutenberg Universität Mainz.
Inspired by the sponges’ lightweight but impenetrable defense system, experts from Johannes Gutenberg Universität (including Müller) and the Max Planck Institute for Polymer Research built a synthetic version of the creatures’ spicules (tiny, prickly splinters) using calcite and silicatein-α, a protein from siliceous sponges that catalyzes the formation of silicon dioxide (silica)—the main ingredient in Porifera spicules. These spiky structures are formed through biomineralization, a method used by most living organisms to produce minerals that turn soft tissue into stiff or hardened textures like shells or bones.
Scientists led by Wolfgang Tremel, a professor at Johannes Gutenberg Universität Mainz, built the artificial spicules by mixing silicatein-α with calcite. Each of the synthetic structures Tremel’s team created contained a multitude of calcite “nanobricks” stacked together brick chimney-style, with a matrix of the stretchy sponge protein holding them together. The process, detailed in the March 15 edition of Science, produced man-made spicules that are 10 times as flexible as their natural counterparts (the artificial structures, Tremel’s team claims, can be shaped into a U without breaking or showing any signs of stress). As a side benefit, the lab-grown spicules also can transmit light waves, even when bent.
The breakthrough in spicule elasticity could very well serve as inspiration for future body armor designs. Tremel’s team, however, is eyeing the silicatein-α protein for use as a biochemical agent in cultivating bone tissue or as a biosilicate sheath that will prevent the body from rejecting medical implants.
“Every day there is more information regarding the interaction of materials in contact with the human body,” said Peter Gabriele, director of emerging technology at Secant Medical Inc., a Perkasie, Pa.-based biomedical textile designer and manufacturer. “Our knowledge of tissue interaction with man-made materials has led us to the recognition that we need to know more about the cellular processes in the context of the inflammatory response and the immunologic response. Combining these cellular responses with the material engineering drives an ‘intelligent’ design approach to device process development. The ultimate goal is to develop new biomaterials that harmonize the required ‘engineering’ compliance of human tissue with the fundamental cellular bioactivity to produce a truly biocompatible implant system.”
Easier said than done. Since the dawn of civilization, mankind has searched for the consummate substitute for Mother Nature’s biological handiwork, experimenting with an assortment of substances—ancient Egyptians and Germans, for instance, fixed injured or deformed feet with wood (attached to the bone with iron nails) or a leather pouch filled with moss and hay; similarly, prehistoric Romans replaced missing hands with iron extremities. The Mayans fashioned nacre teeth from seashells in roughly 600 A.D., remarkably achieving bone integration, and Middle Age physicians used catgut sutures to close wounds.
In 1829, Mobile, Ala.-based surgeon Henry S. Levert, M.D., used a gold wire to litigate a canine artery (he later experimented with silver and platinum wire as well), and the earliest hip replacement recipients received new joints crafted from ivory, gold foil, glass and pig bladder (none of which held up very well). Lead, silver, bronze, Teflon, Dacron, nickel, stainless steel, ceramics and plastics all have been used inside the body for various purposes but none have performed to the Great Mother’s standards. And perhaps none ever will: Our bodies are a diverse concoction of gender, maturity level, genetics and chemical compositions governed by different living environments, habits and activity levels. Our faux fixes are engineered by designers and installed by doctors with varying levels of education and skill; neither group is infallible. Humans are imperfect creatures, and as such, may truly lack the ability to trump nature.
Yet we continue to try. Technological advances over the last several decades have introduced a plethora of innovative materials into the operating room, including Trabecular Metal (Warsaw, Ind.-based Zimmer Holdings Inc. initially developed the tantalum-based material to protect jet engines from birds and debris), PEEK-Optima, polylactic-glycolid acid (found in porous tissue engineering scaffolds), hydroxyapatite (a natural component of bone), Teflon (vascular grafts), bioglass (a substance that seamlessly bonds to bone), hydrogels, nitinol and more recently, glass-fiber yarns and biomedical textiles.
The yarns are manufactured by Aiken, S.C.-based AGY, a global supplier and producer of high-strength glass fiber reinforcements for the aerospace, automotive, construction, defense, electronics, industrial and recreation/consumer industries. Several years ago, the firm engineered a glass fiber biomaterial that is compatible with thermoplastic polymers like polyetheretherkeytone (PEEK), polyetherimide (PEI) and polyphenylene sulfide and can be tailored to meet specific application requirements. When it is combined with polymers, AGY’s high-performance biomaterial (HPB) produces a substance that can better withstand impact than stainless steel or titanium.
A member of the company’s S-3 glass fiber family of special grade products, the HPB features a 40 percent higher tensile strength and 20 percent higher tensile modulus than standard E-glass fibers, company executives claim. Its high tensile strength creates lighter, stiffer, and stronger implant components that are suitable for knee and hip replacements, spinal cages, dental implants and other
orthopedic products.
The advent of biomedical textiles has given device manufacturers more choice and flexibility in design than many of the traditional materials. Secant Medical’s textiles are molded from various polymers (polytetrafluoroethylene, polylactides, polycaprolactone), co-polymers, and metals through the traditional forming techniques of knitting, weaving and braiding, though 3-D weaving also is being used to fabricate orthobiologic scaffolds that promote both tissue growth and biologic integration.
“There is increasing interest in materials such as poly(glycerol-sebacate). Human soft tissue is, for the most part, elastomeric,” Secant’s Gabriele noted. “It is the Holy Grail of biomaterials to develop a new biopolymer that matches human tissue stress-strain mechanical compliance. The ability to biomimic tissue compliance is critical to supporting the appropriate expression of the regenerative process back to the normal state.”
New Exploits for Existing Materials
Material engineers are the gourmet chefs of medical device design—constantly revising, refining and altering their recipes to feed a finicky public. And like most good chefs, these couturiers are satisfying consumers’ cravings by making tweaks to existing formulas rather than creating completely new delicacies.
Cost pressures and demands for smaller, more portable, aesthetically-pleasing devices that last longer inside the body and feel more natural to patients are prompting a growing number of medtech companies to fine-tune their material ingredient lists when developing new medicinal substances.
Foster Corporation has been refining its material recipes for more than two decades, blending standard polymers with performance additives or other plastics to achieve specific properties. The Putnam, Conn.-based materials solutions firm often blends two commercially available polymers to achieve hybrid properties not found in any single resin. The combination of nylon and urethane, for instance, produces a balance of rigidity and flexibility, while high-density and low-density polyethylene achieve intermediate durometers. Foster also adds radiopaque fillers such as barium sulfate, bismuth subcarbonate, bismuth trioxide, bismuth oxychloride and tungsten to polymers to make materials that are visible during X-rays or fluoroscopy.
“In [medical] devices, where more of the traditional materials are being used, we have seen a lot more activity in innovative additives and blends. In the example of catheters, some of the traditional materials—nylons, polyurethanes—are modified through additives or blending to create a slightly different performance out of the finishing material,” observed Dan Lazas, Foster’s marketing communications consultant. “There’s a lot more innovation in compounding. In catheters, the overall diameter has been shrinking in past decades, more work is going on inside—there are fluid channels and working channels—and that produces a device with thinner walls. At the same time, [catheters] are reaching much further into the body. So we’re getting smaller catheters with thinner walls reaching into distant areas of the body, and traditional materials therefore become challenged. You still need pushability, you need to look for those things that will enhance the performance accordingly. There’s not a lot of new polymer plants being manufactured for nylons or for materials like that so we look for innovative additives like nano-reinforcements where we can add them in relatively small percentages and increase the flexural modulus, which increases pushability.”
Nano-particle-reinforced polymers incorporate particles that are less than one nanometer in thickness or diameter with aspect ratios (length: thickness) between 300:1 and 1,500:1. The nano particles approach the size of the polymer molecules and interact at the molecular level to immobilize portions of the polymer chain, creating a reinforcement effect. Small quantities of nano particles dispersed throughout the polymer matrix result in a vast number of constrained areas and leads to reinforcing effects significantly higher than traditional reinforcing agents such as glass fiber. These low loadings, according to Foster, allow the polymer to remain tough and preserve both the surface finish and weight of the blend.
Foster’s compounding screw designs and processing methods can achieve loadings up to 30 percent by weight, resulting in flexural modulus increases up to 300 percent in common medical catheter materials like thermoplastic elastomers (TPE). Previously, TPEs and nylons often were limited to 15 percent nano-reinforcement filler loading by weight to ensure dispersion of ultra-fine platelets in the polymer matrix. But by doubling the weight loading, Foster can adjust the flexural modulus of a 72 durometer of a TPE polymer from 100,000 to 400,000 psi (690 to 2,758 MPa).
“Nano reinforcing is done at such a small level that you can actually blend it in and it’s not noticeable in, say, the thin walls of a catheter,” Lazas explained. “Nano reinforcements is a very good example of using very innovative technology to increase the performance of an existing material in a compound to be able to address the smaller diameter thinner walls of a catheter.”
Material mergers also are commonplace 688 miles to the west of Foster, at Fort Wayne, Ind.-based Fort Wayne Metals Inc., a 67-year-old developer and producer of fine-grade medical wire. The company re-engineered its super alloy ASTM F562 to reduce its inclusion size, and developed composites like DFT wire, DBS (Drawn Brazed Strand) and high-performance shape-memory materials such as DPS Nitinol wire.
The DFT product combines two or more materials (including gold, silver, platinum, titanium alloys, nitinol, tantalum, platinum alloys, tungsten, stainless steel, 35N LT and MP35N) into a single wire/ribbon system, with the outer sheath providing strength, for example, and the core material offering conductivity, radiopacity, resiliency, or MRI enhancement.
Drawn Brazed Strands consist of alloy wires stranded around a core wire of a softer, highly conductive material such as silver. The wire is then brazed and drawn in a normal fashion, producing a cable that combines better fatigue life, high conductivity and improved solderability with good strength properties,
according to product literature.
Nearly two years ago, the company developed DPS nitinol for the medtech industry. The product enables device designers to achieve a high stiffness guidewire in applications operating between 1 percent and 8 percent strain within the stress-induced transformation or plateau load range. The improvement in stiffness does not sacrifice ultimate straightness, torque control or steerability, thereby potentially benefiting chronic-total-occlusion navigation. The wire is available in diameters from 0.23 mm (0.009 inches) to 0.76 mm (0.030 inches) and in lengths from 1.27 cm (0.50 inches) to 365 cm (144 inches).
“At Fort Wayne Metals, we’ve introduced what some may consider new metals but what are in fact, processing variations on existing materials,” noted Jeremy Schaffer, Ph.D., the company’s senior research and development engineer. “We’ve introduced some products within the superalloy and nitinol families that behave very differently from standard material because we’ve engineered the microstructure to achieve improved functionality.”
In some cases, the re-engineering or blending process can be quite intricate, requiring precise measurements for heat treatment and cooling, drying times, the release of gases, and injection-molding processing. The creation of a steam-resistant, high-impact polymer blend from PEI and polycarbonate (or polyester carbonate), for example, necessitates the drying of the resins for eight hours at 150 degrees Celsius. The substances need to be compounded with a 2.5-inch, 40:1 vacuum vented single screw extruder with barrel temperatures profiled and ramped from 325 degrees Celsius to 360 degrees Celsius at the feed throat and die head, respectively, a technical paper on the subject instructs. The resin blends must be processed at 160 rpm and 90A; the extrudate water is required to be cooled and then chopped into pellets for further processing by injection molding.
The modification process, however, isn’t always so complicated. Bob Myers, executive vice president and chief commercial officer at Fort Wayne Metals, recalled a decade-old instance in which the company simply removed titanium from an existing alloy to improve its fatigue durability. “In this particular application, durability was very significant because this was a material [35N LT] that today has replaced the standard MP 35N product in the market for implantable defibrillator and pacemaker leads,” he told Medical Product Outsourcing.
Fort Wayne Metals recently has installed capabilities that will enable medical-focused raw metals production, a relatively unique position within the industry. Myers said the company’s new state-of-the-art nitinol melting facility—expected to ramp up over the next few months—will enable the firm to produce medical device-targeted nitinol and Ti-alloy primary ingot. Called Advanced Materials Development and situated in Columbia City, Ind., (19 miles west-northwest of Fort Wayne’s headquarters), the facility will be able to melt heat significant amounts of material, ranging from 200 to 2,000 pounds.
Though blending still remains an option, Fort Wayne Metals’ R&D focus has shifted in recent years to the invention of truly novel materials from scratch. Schaffer described emerging custom alloy development capability within Fort Wayne’s new research and development installation on the main campus. One major project for the new R&D facility, he said, is the development of bioabsorbable metallic wire materials. Schaffer expects the firm’s ferrous (iron-containing) and magnesium bioabsorbable metal products eventually to compete against polymer-based vascular and orthopedic designs.
“There are not many companies developing new metals right now,” Myers said. “What we’re attempting to do with our new melt facility is advance the design of new materials for the medical device industry. A lot of the materials being developed are basically enhancements to existing materials—they might be tweaks, they might add cobalt or chromium to a nitinol alloy to increase the stiffness or strength. But we are hoping that we will be in a position to help the industry design totally new materials. There’s an absolute need for that right now.”
There also is a need for better collaboration between the device industry and academic research of new materials. Schaffer contends that the melt facility and newly installed research and development capacity can help enhance this often-overlooked partnership.
“There are not many corporations that are developing new materials,” he noted. “In the university labs, there’s a lot going on, but most of these won’t reach commercial fruition unless an industry partner steps in. To a large degree we’re acting to foster that connection. We certainly collaborate with industry and device customers in order to help realize some of these newer, more promising technologies. And invariably we have a clinical focus in mind. We like to understand where the technology is going to be applied in the body so that we may help guide development and profit physicians and ultimately the patient recipients.”
The (Healing) Power of Plastic Ray Kurzweil and his futurist comrades envision quite an interesting fate for the human race. Where climatologists foresee rising temperatures and sea levels, and doomsdayers fret over nuclear apocalypse, Kurzweil forecasts artificial intelligence (by 2029), machine dominance, economics overhaul and longevity bordering on immortality. It may sound like pure fantasy novel fodder, but to Kurzweil’s credit, society slowly is drifting in that direction. It might be a while, if ever, before mankind finds his Fountain of Youth but many of the inventive health remedies purported in 20th-century science fiction tales now are coming true (think synthetic muscles, telemedicine and artificially grown organs) and many more are right around the corner. The following list is just a small sampling of the medicinal marvels (all involving polymers) soon to befall the sick and injured: Resorbable heart stent:Abbott Laboratories has enrolled roughly 2,250 patients in a clinical trial to compare the performance of its Absorb Bioresorbable Vascular Scaffold device to another drug-eluting stent system made of metal. Made of polylactide, Absorb opens a clogged vessel, restoring blood flow to the heart, and then dissolves into the blood vessel. This resorbable plastic could eliminate the need for another invasive procedure to remove the stent as well as reduce the likelihood of blood clots and scarring. The polymer drug eluting stent currently is sold in Europe and parts of Latin America and Asia. Lifesaving plastic foam:Arsenal Medical of Watertown, Mass., has developed a polyurethane plastic foam to stabilize patients with severe internal injuries from combat. The foam expands inside the body, conforms to the shape of injured tissue and reduces blood loss before being removed in one piece in less than a minute by a surgeon. The foam is injected into the abdominal cavity and can expand to about 30 times its original volume while conforming to the surfaces of injured tissue. The foam then becomes solid, enabling it to resist intra-abdominal blood loss. The foam can expand through pooled and clotted blood and withstand the hydrostatic force of an active hemorrhage. Artificial muscle:Engineers at Duke University in Durham, N.C., are layering atom-thick lattices of carbon with polymers to create a unique material with numerous applications, the most interesting being artificial muscles. The lattice, known as graphene, is made of pure carbon and resembles chicken wire under magnification. The engineers layered the graphene with different polymer films to make a “soft” material that can act like muscle tissues by contracting and expanding on demand. When electricity is applied to the graphene, the artificial muscle expands in area; when electricity is cut off, it relaxes. Varying the voltage controls the degree of contraction and relaxation. Self-healing prosthetics:Researchers are developing a new plastic “skin” that recognizes when it has been damaged and responds by healing itself. The plastic skin mimics the flexibility and sensitivity of human skin—it becomes electrically conducive by adding a bit of nickel. The artificial skin also restores its mechanical and electrical properties after being cut, and can repeat the cycle. Bacteria-resistant plastics:Several newly discovered plastics with “non-stick” surfaces potentially could be used to make catheters or medical equipment that help reduce infections and ward off preventable disease. The material composition of these plastics makes them unsuitable environments for bacterial communities (also known as biofilms) because they resist biofilm formation. Since the body’s immune system can more easily attack free-floating bacteria than the films, devices coated in the biofilm Teflon might help the body ward off infections on its own.— M.B. |