| Disclaimer: The information contained within the Grand Rounds Archive is intended for use by doctors and other health care professionals. These documents were prepared by resident physicians for presentation and discussion at a conference held at Baylor College of Medicine in Houston, Texas. No guarantees are made with respect to accuracy or timeliness of this material. This material should not be used as a basis for treatment decisions, and is not a substitute for professional consultation and/or peer-reviewed medical literature. Biopolymers in Otolaryngology The use of medical implants can be traced back to ancient Egypt, initially with the use of bronze plates to repair skull; and in South America, the Incas have tried the same thing with coconut shells and hem dressings. However, it really was not until the 1860s when Lister developed aseptic surgical technique that the use of synthetic medical implants really became a reality. The use of modern medical implants really came about in the 1930s, when the orthopedic implants made with stainless steel and cobalt chromium alloy were first used. During World War II, we saw a surge for the need of these synthetic material implants in reconstruction of large soft tissue defects, mostly related to war-related injuries. Interestingly, at that time it was also noted that pilots injured by fragments of the canopy, which was made of a PMMA polymer had very minimal adverse reaction when these fragments were left in for a certain period of time. In 1950, we saw further advancement in the use of medical implants, synthetic type, particularly in the use of vascular grafts in heart valve replacements. So, exactly what is an implant? As defined by the FDA, it is any device that is inserted into a surgically or naturally formed cavity of the human body that is intended to stay for more than 30 days. As you can see, this definition is quite broad and includes such things as central venous catheters and sutures, so the NIH has further narrowed this definition: implants are defined as having a minimal lifespan of at least three months, as penetrating living tissue, as having physiologic impaction, and also as being retrievable. So, while many of us may have different ideas about the ideal qualities of a spouse, there is more of a consensus on the qualities of an ideal implant. They should be clinically inert, they should not be physically modified by the tissue fluids in the body, and should elicit minimal inflammatory reaction. They should be noncarcinogenic and nonallergenic. They should be structurally stable, and easy to sculpt. They should be easy to insert and remove, sterilizable, mimic the color and consistency of the tissue they replace, and should be readily available and inexpensive. Biocompatibility is a term that is often used in describing medical implants. It is defined as acceptance of an artificial implant by the surrounding tissue and by the body as a whole. The level of biocompatibility is determined by multiple things, including the host reaction to the implanted material, the tissue site which the implant goes into, and also the surgical technique used in inserting the implant. Some of the contraindications that should be made for using implants include the host’s immunodeficiency, compromised vascular supply, such as diabetes, and also, in our situation, if the patient has had radiation to the head and neck region. The last contraindication is insufficient soft tissue coverage, as it is very important to make sure that you have enough coverage to the implant to prevent its extrusion. The biomaterial of implants can be thought of as being in two major broad categories: natural implants, which consist of autografts, allografts, meaning coming from the same species, but different individuals, and then xenografts. The synthetic implants, sometimes referred to as alloplasts, consist of metals, ceramics, such as hydroxyapatite; and polymers. As a class of material, polymers really have contributed a lot to our understanding of the interaction between hosts and implants, and from the use of IV catheters to facial implants, they have really become an essential part of our everyday practice. So, for today, I would like to particularly focus on this particular class of materials. I would like to briefly review the engineering science of polymers as biomedical implants, then look at a few case studies of specific polymers in our fields, and then look at the future direction of polymer research and applications. The word polymer really means many parts, derived from the Greek word poly, which means many, and then meros, meaning part. It is defined as a chain of small molecules that are linked through primary covalent bonding. The synthesis of a polymer is done by a couple of chemical reactions, usually either by condensation or addition through the use of chemical radicals. Polymer chains usually exist in a semi-crystalline structure because, if you think about these polymer chains, they are packed together and they usually tend to form a crystalline structure. However, these polymer chains can get very long and they can become tangled like spaghetti noodles. The side groups of the polymer chain can inhibit their complete packing. So, they do not tend to exist as a complete crystalline. Instead, they usually exist with areas of amorphous regions, which are noncrystalline regions, and then the crystalline regions. So, there are three main determinants to the physical property of a polymer. The first is degree of polymerization of a polymer, which refers to the number of repeating units, which is directly proportional to the molecular weight. When this degree of polymerization is greater than 1000, as it usually is in the medical implants, the polymer usually exists as a strong solid. The second determinant factor in the physical property of a polymer is the glass transition temperature, which can be thought of as kind of a softening temperature. This is a phase diagram that is commonly used in chemical engineering to describe the relationship, the physical property of a polymer as a function of temperature and molecular weight. Here, TM means melting temperature and TG means glass transition temperature. As you can see, when the material exists below TG, it usually exists as a solid or something like hard plastic. When it exists at a temperature above TG, it usually is a liquid and is kind of a soft material. So, how is this clinically relevant? It is relevant clinically because a typical polymer is stronger when it exists at a temperature below the glass transition temperature. So, if you are looking for a strong polymer implant, you generally want the glass transition temperature of a material to be above that of a body temperature, or about 37˚ Celsius. Finally, the third determinant of a physical property of a polymer is cross-linking. The cross-linking happens when the polymer chains are stabilized with each other through side groups, which makes the polymer more rigid and also stronger as well. So, I am sure this periodic table is familiar to everybody, and in evaluating a synthetic biochemical material as an implant, the chemical composition of the implant should be compared to that of the chemical composition of the body to ensure compatibility. Looking at this periodic table, as you recall, carbon is the number six element here. The next element in the same column or group is silicone. As you recall from general chemistry, the elements in the same column have the same valence structure and the same type of orbitals, and therefore they can form similar compounds with other elements. Therefore, it is no coincidence that a lot of the biocompatible materials we use today are composed of silicone and carbon. The other characteristic to consider in the use of a polymer material is its physical form. In solid and porous polymers, porosity is an important physical characteristic of the polymer to consider. When the pore size of the polymer is greater than 50 microns, it allows for tissue ingrowth and macrophage penetration. Therefore, the risk of infection of a polymer tends to be less when your pore size is greater than 50 or if it is a nonporous polymer. On the other hand, when the pore size is between 1 and 50, it allows bacteria to infiltrate into the polymer implants. However, it is too small for macrophage to pass in. The other characteristic to consider is particle size, which is particularly important in liquid polymer or injectable polymers. When the particle size is greater than 16 microns, it cannot be taken in by the phagocytes and instead, a fibrous capsule forms around these particles. When the particle size is between 20 to 60, it can potentially be taken in by the phagocytes, but eventually could cause the phagocyte to die and release intracellular enzymes, which may cause locally inflammatory reaction. Taking into account the specific demands of a polymer at the site of implantation is also another important consideration. I think this point is best illustrated by looking at the story of a Proplast, which is a material that was initially manufactured here in Houston, Texas. It was a facial implant originally composed of a polytetrafluoroethylene, PTFE, and graphite. The chemical composition of this polymer gives it excellent biocompatibility. It also is a porous polymer, and as we mentioned before, allows tissue ingrowth. It has worked really well as a facial implant. Therefore, it began to be employed by oromaxillofacial surgeons in TMJ reconstruction. However, the property of this polymer is not really able to sustain the stress of the TMJ, so the particles begin to shed once these are implanted, causing chronic inflammatory reaction, causing infection, bone resorption, and ultimately requiring the reconstruction of the joint. As a result, this material was pulled from the U.S. market in 1990. I think this illustrates how a specific polymer can be successful at a certain site, but it cannot be used other places. There are four major different types of polymers, the first of which are solid polymers — Silastic and polymethylmethacrylate are some types here — and porous polymers, Medpor, Proplast and Gortex. There is a mesh polymer, such as polyamine, which is a derivative of nylon and polyester. Finally, there are injectable polymers, including injectable silicone, Teflon, and Artecoll, which is not yet approved here in the U.S. Silicone is a polymer that is composed of interlinking repeating units of dimethylsiloxane monomers. The word ‘silicon’ refers to element number 14 on the periodic table. Silastic is the commercial name for the specific silicone polymers by Dow-Corning. Silicone was first researched by Corning Glass back in the 1930s. It was not until World War II when Corning combined with Dow Chemical that silicone began to be mass produced, initially as a high temperature and electrical insulating resin for wartime use. Silicone began to be evaluated for medical applications in the late 1940s. Again, silicone’s chemical name is polydimethylsiloxane. It is the only non-carbon-chain polymer that is used as a polymer implant today. Silicon-oxygen bonds are strong and resistant to degradation. Silastic, as we mentioned before, is a saturated vulcanized form of a silicone that has been forged with a silica powder, which increases cross-linking. As you may remember from a couple of previous slides, cross-linking gives higher strength and higher density and stiffness. In our field, it is used in various places, including malar, submalar augmentation, chin augmentation, and augmentation of the nasal dorsum. It is also used in PE tubes and thyroplasty. Silicone can be sterilized with various methods. It can be carved intraoperatively, and there is no significant tissue ingrowth into the implant. The solid silicone implant induces a mild inflammatory response with a fibrous capsule of variable thickness. The limitation of silicone lies within poor resistance to tearing. The material only goes to 50% reduction in tensile strength of the material when there is a crack of 0.1mm. Also, when it is in the body, it undergoes deterioration with liquid absorption, free radical oxidation, and calcium deposition. In a review of 240 solid silicone implants inserted, the most common complications included displacement, infection, and exposure and extrusion. There has been a lot of bad press about the use of silicone specifically related to breast augmentation. However, there is really little conclusive medical data to substantiate these claims. In a report by the Institute of Medicine in 1999, which reviewed all available scientific evidence, they concluded that there is really no evidence to support the conclusion that silicone causes major disease. In general, solid silicone implants are very well-tolerated. On the other hand, injectable silicone and silicone gel-filled implants have been shown to cause giant cell formation and chronic foreign body response based on leakage of the silicone oil. These inflammatory reactions tend to be quite limited. However, the extent is unpredictable. Some of the systemic adverse reactions associated with leaking of silicone gel include soft tissue induration, lymphadenopathy, arthralgias, hepatitis, and also silicone pneumonitis. In 1991, the FDA banned the use of silicone injectable liquid for use in the U.S.; however, it is still used a little bit outside the U.S. Polyethylene as a class of material is very stable and is very well-tolerated. There are three main grades: low density, high density, and ultra high molecular weight. The low density polyethylenes were first used for chin and malar implants in the 1940s. The high density polyethylene is what is mostly used today and represents improvement both in the production process of the polymer, as well as the property of the polymer. The use of a sterile-specific catalyst in the production of high density polyethylene allows it to be produced at a relatively low pressure of 10 mega paschals, which is about the same pressure that water comes out of the dishwasher. So, it allows for minimal branching, and the better packing of material gives it increased density and strength. It is relatively noncompressible and can be carved with a little bit of effort. High density polyethylene used in our field is marketed under the name Medpor. It gives high tensile strength and is malleable when soaked in hot water. Again, this is a porous implant with a pore of 125 to 250 microns in size. As you recall from the previous slide, the pore size allows soft tissue ingrowth, and according to some studies, may allow some limited osseous integration as well. It is a nonresorbable polymer and has low reactivity with a minimal foreign body response. It has been used in malar, genio, and nasal dorsum augmentation. Reconstruction-wise, it has been used orbital blowout fracture, orbital implants, and thyroplasty. It needs to be inserted into a subperiosteal pocket for optimal fixation, and should be in areas that do not have stress-bearing properties, because it could potentially delaminate when it is under stress-bearing conditions. Polytetrafluoroethylene (PTFE) is a class of fluorocarbon polymers, and as shown here, is based on carbon backbone with fluorene side groups. The carbon fluorene bond is very strong and is responsible for its thermal and chemical stability. It comes in various forms, including the porous and the pace form. It is inert and has excellent biocompatibility and has a very low friction coefficient. It has a very low tensile strength, about 14 mega paschals, and therefore PTFE as a class of material has sometimes difficulties in maintaining shape and providing the structure support under stress - most of the time it is reinforced with other materials. The pace form of PTFE is marketed under the name Teflon. It was introduced in the late 1940s. It was first used for true vocal cord paralysis back in 1962. PTFE, as you are aware, also has some migration issues because of low friction coefficient of the material. It was never approved for facial augmentation. However, even when it is used in the enclosed space of the larynx, there is some issue with migration into surrounding muscles, as shown in an animal study. The particle size of the material is about 20 to 60 microns. As you remember from the previous slide, the particle size between 20 to 60 allows microphage to take in the particles and can eventually cause microphage death and inflammatory reaction, which is what happened in this case. It can also cause granuloma formation as well, as shown in this figure. The removal of Teflon can be quite difficult and often may requires resection of the entire area that is involved. The expanded form of PTFE is marketed in the name of Gortex, which is not foreign to us, and the expanded here means that it comes in a sheeting form that is formed by nodes of solid PTFE interconnected by these thin PTFE fibers, as shown in this electromicrograph of the material. It was first introduced in 1971. It comes in sheets of various sizes. The pore sizes range from 10 to 30 microns, which average about 22 microns. As I mentioned before, pore size greater than 50 microns will allow for significant tissue ingrowth, and the fact that it is 22 microns allows some limited tissue ingrowth, but not tremendously. It is used in vascular grafts. There have been greater than two million used to date. Malar augmentation, nasal dorsum augmentation, genioaugmentation, and thyroplasty are some of the other uses for Gortex. In animal studies, Gortex has shown some limited fibrous tissue ingrowth, as I mentioned earlier, and also has limited inflammatory reaction and capsule formation. However, because of its microporosity, there has been some concern about the stability of Gortex once it is inserted into the site, and therefore there has been ongoing research to try to improve the stabilization of Gortex once inserted. There is an interesting study that showed if you actually form the Gortex into a tubular form, it actually gives better stability when inserted. Here are stains of tubular Gortex with a lot of the fibrous tissue ingrowth versus the conventional strip Gortex design, which you can see is not as closely opposed by the fibrous tissue. Some of the complications associated with the Gortex include infection, inflammation, and extrusion. Generally, they are quite low. Finally, I would like to just briefly mention a fairly new class of polymers, absorbable polymers. It serves a certain function, and then becomes degraded inside the body, and then metabolizes, and eventually is eliminated from the body. The polyglycolic acid, PGA, and polylactic acid, PLA, are the most commonly used today and are mostly found in sutures. The degradable polymers undergo a two-phase degradation, the first of which is hydrolysis. These polymers undergo degradation by water and then break into these short chains. The second phase is phagocytosis by the surrounding microphages. I think the mechanical properties of these polymers are both very interesting and instructive to a certain extent. The figure here shows three generic absorption curves, the first of which is the molecular weight of the material, the second of which is the strength of the material, and the last of which is mass. This is illustrated as a function of time. So, as you can see, as time progresses, the molecular weight decreases as the water breaks down the polymers. When the molecular weight decreases to a certain extent, the strength begins to decrease as well. However, I think the point I want to show here is the relationship between the strength curve and the mass curve. As you can see here, you lose a significant amount of strength, and therefore its biomechanical usefulness, before a significant amount of mass is lost of the polymer. The degradable polymer is used already today in ORIF hardware and is continuing to be improved. One of the exciting potential applications of this classic polymer, I think, is its role as a potential to support cellular migration and to guide axonal growth across anerve lesion, which has shown some promising data on some initial research. So, the majority of the polymers that we discussed today are considered first generation polymers, in that their goal is to achieve a suitable combination of physical properties to match those of the replaced tissue with minimal toxic response to the host. Second generation polymers are what we think of as resorbable polymers, in that it undergoes controlled action and reaction inside the body and integrates into the physiological environment. The improvement in these two-generation materials is limited, in that ultimately they represent materials with the goal of replacing the body tissue. However, what characterizes living tissue is its ability to respond and adapt to the physiological and biochemical stimuli, which these two classes of materials cannot do. The third-generation materials are being developed with the goal of stimulating specific molecular and cellular response inside the body. Examples of these new materials include resorbable polymers that as they break down release substances such as neurotrophins that stimulate cell proliferation and differentiation. So, as a result, instead of implanting an entire biomaterial, you could potentially implant only the ingredients of these polymers and only minimally invasive surgery will be needed to implant these molecular scaffolds to stimulate the body to regenerate. Finally, to summarize, polymer again is only one type of alloplast that is available in your armamentarium as implants. There is no universally good biomaterial, as illustrated by the example of Proplast. There are only good implant applications for biocompatible materials. The selection of the biomaterial depends on the chemical composition of the polymer, the physical form, and also the site of implantation. The success of polymer implants is based on scientific and surgical knowledge. The traditional polymers and first generation polymers include the solid types, porous types, mesh types, and injectable types. I think the future of polymers is exciting, in that it may represent engineered polymeric scaffolds that can potentially respond and adapt into the host environment and represent active biological entities. Case Presentation: His past medical history is also significant for diabetes, hypertension, allergic rhinitis, hypercholesterolemia, peripheral vascular disease, and chronic low back pain. On review of systems he reports that he feels his dyspnea on exertion has improved somewhat since excision of retrosternal goiter. He is allergic to penicillin. His medications includes ASA, nasal steroids, HCTZ, levothyroxine, lisinopril, loratadine, KCl, rosiglitazone, simvastatin, and verapamil On physical exam patient was not in any respiratory distress. His voice is breathy in quality and can only sustain his voice for 5 – 6 seconds. Tympanic membrane was clear bilaterally. There was a right septal deviation. Oral cavity and oropharynx were clear to inspection and palpation. No lymphadenopathy or masses were palpated in the neck. On flexible nasolaryngoscopy in the clinic a left true vocal cord paralysis was noted with a 2 – 3mm glottic gap. The right true vocal cord was mobile and normal in appearance. No other laryngeal masses or lesions were noted. Treatment options for true vocal cord paralysis were discussed with patient, and he wished to pursue thyroplasty. Elective Isshiki type I thyroplasty was performed. Intraoperatively a Silastic ® block was carved into a 6 x 4 mm boat-shaped implant and inserted into the surgically-created left thyroid cartilage window achieving medialization of the paralyzed left true vocal cord. Position was verified intraoperatively with fiberoptic nasolaryngoscopy and elimination of glottic gap noted. Patient tolerated the procedure well without complications. During his 1-month post-operative follow-up clinic visit, G. B. was satisfied with his voice improvement despite some residual raspiness in his voice. 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