7 January 2010 ICOD: 1 December 2009 UNCLASSIFIED/s'F8R 8FFI11Ak IJlil 8Plk?J Intelligence Acquisition Threat Support Biomaterials UNCLASSIFIED({fOll 81iiFIGI0 L P PSS CNP X UNCLASSIFIEDJs<JitJR 8SiSiI&IIL Willi 8tlbM Biomaterials Prepared by: Defense Intelligence Agency Administrative Note COPYRIGHT WARNING: Further dissemination of the photographs in this publication is not authorized. This product is one in a series of advanced technolo re orts roduced in FY 2009 under the Defense Intelligence Agency, (b)(3):10 usc 424 Advanced Aerospace Weapon System Applications (AAWSA) ro ram. ommen s or uestions pertaining to this document should be addressed to (b)(3):10 USC 424;(b)(6) AAWSA Program Manager, Defense Intelligence Agency, (b)(3):1o use 424 g 6000, Washington, UNCLASSIFIED/( rel\ err1er-L use 9HL I UNCLASSIFIEDh'FQA QFFICI t,L WEE 8tlbJJ Biomedical Silicones -Polydimethylsiloxanes .................................................... 2 Titanium -Hip and Knee Joints 11 UNCLASSIFIED//FAR OFFICIO! UNCLASSIFIEDf;'FOR 8FFIIHAL l!l!I! 8HLY Figure 1. Biomaterial Applications in Medica I Devices ............................................ vi Figure 2. Common Medical Devices That Use Biomaterials ................................... viii Figure 3. Biomaterials Such as Polycarbonates, Cellulose, and Silicones Used in Membranes for Sensors, Dialyzers, and Oxygenators .............................. 1 Figure 4. Photograph of Silicone (polydimethyllsiloxane) Biomedical Implants Figure 7. Silicone Sheets Used Under the Skin as a Physical Supporting Layer for Figure 9. Expanded PTFE (Gore-Tex or ePTFE) Used in Lip Implants ...................... 7 Figure 11. Structure of Polylactic Acid (a Biodegradable Polymer) ........................ 9 Figure 12. Biodegradable PLA as an Antiadhesion Barrier after Open-Heart Figure 13. Biodegradable Polymers Based on Copolymers of Polylactic Acid and Figure 15. Various Titanium Components Used in Hip Joint Replacement .. 11 Figure 16. Hydroxyapatite Porous Bone-Like Structure After Commercial Figure 17. Bioceramic Used in Artificial Hip Replacement Component .................. 12 Figure 18. Computer-Based Sculpted Ceramic Teeth ............................................ 13 Figure 20. Biodegradable Material CSLG Deposited in a Honeycomb Structure to Allow Infiltration by Living Cells While in a Submerged Cell Culture 15 Figure 21. Some of the More Popular Biomedical Devices and Duration of Their Figure 22. Gore Medical Teflon Foam Used in Vascular Grafts .............................. 16 Figure 23. Illustration of Treatment of an Atrial Septal Defect Using a Teflon-Based Product Manufactured by Gore, Inc ............................... 17 Figure 24. Stainless Steel and Teflon Bjork Shiley Heart Valve ............................ 18 Figure 28. Schematic Representation of Biodegradable (Bioerodible) Drug Figure 29. Photomicrograph of Titanium Metal (Appears Black in This Photo) in an Intimate Integration With Living Bone ....................................... 23 Figure 30. Illustration (Left) and Photograph (Right) of a Blood Dialyzer as Figure 31. Cuprophane Membrane Passes Blood Waste Products (Violet and Orange Dots) Through Pores and Blocks Passage of Red Blood Cells 25 UNCLASSIFIED/fl SK: err1e1-t tt9! SHE I UNCLASSIFIED/;SFQA 81iifil&IAL .. 81! OHLV Biomaterials Introduction Biomaterials are metals, ceramics, polymers, glasses, carbons, and composite materials intended to interface with biological systems. They are often used to treat, augment, or replace bodily tissues, organs, or functions. Such materials are used in various forms, including molded or machined parts, coatings, fibers, films, foams, and fabrics. Biomaterials are usually nonliving, but recent definitions also include living skin and tissues produced in culture. A biocompatible m_aterial is different from a biological material produced by a biological system, such as bone. Artificial hips, vascular stents, artificial pacemakers, and catheters are all made of biocompatible materials that typically have a synthetic origin. An extraordinarily wide range of medical devices are made from biomaterials. Figure 1 shows some representative examples of medical devices that use biomaterials. Finger joint SIIICO!lf) tutlt>el Breast implant Artificial heart polyurethane. metaJ Heart valve Intraocular lens (IOL) Figure 1. Biomaterial Applications in Medical Devices Encompassing elements of medicine, biology, chemistry, and materials science, biomaterials science has experienced steady and strong growth over its , approximately half-century history. Although biomaterials are used primarily for medical applications, they are also used to grow cells in culture, to assay for blood proteins in the clinical UNCLASSIFIEDl;FliiGR 81iiliil&ila1Jk U&li &Sib UNCLASSIFIED//POR: 8PPll!lilit l'J!II! OHi! laboratory, in processing biomolecules in biotechnology, for fertility regulation implants in cattle, in diagnostic gene arrays, in the aquaculture of oysters, and for investigational cell-silicon "biochips." The common thread in these applications is the interaction between biological systems and synthetic or modified natural materials. Biomimetic materials, in contrast, are not made by living organisms but have compositions and properties similar to materials made by living organisms. For example, the calcium hydroxyapatite coating found on many artificial hips-used as metal-bone interface cement to make it easier to attach implants to bone-is similar to the coating found in mollusk shells. IMPORTANCE OF BIOCOMPATIBILITY Biocompatibility is an important issue in biomedical implants and sensors. A material-tissue interaction that results from implanting a foreign object in the body is a major obstacle to developing stable and long-term implantable devices and sensors. The processes that occur when sensors are placed in the complex living environment of the human body are sometimes known as biofouling. In biofouling, the physical or chemically sensitive portion of the sensor interface becomes coated with proteins, blood-formed elements, adherent immunological cells, and sometimes forms of scar tissue that tend to isolate the sensor from the rest of the body environment. This response of tissue is a foreign body reaction to any object introduced in tissue that does not express surface characteristics that identify it as pa rt of the host tissues. Experiences of many investigators (more than 600 reported studies since 1996) with the biocompatibility of biomaterials related to the function of implanted biosensors have been poor such that many companies have abandoned implantable sensor devices altogether. Rather, the recent trend in medical biosensors is toward placing them outside the body. Newer sensors are often based on optical principles in an effort to obviate the biocompatibility and biomaterial issues of placing sensors inside the human body. SCIENCE OF BIOMATERIALS The study and use of biomaterials bring together researchers from diverse academic backgrounds who must communicate clearly. Professions that intersect in the development, study, and application of biomaterials include bioengineer, chemist, chemical engineer, electrical engineer, mechanical engineer, materials scientist, biologist, microbiologist, physician, veterinarian, ethicist, nurse, lawyer, regulatory specialist, and venture capitalist. The number of medical devices used each year in humans is very large. Figure 2 estimates usage for common devices, all of which employ biomaterials. UNCLASSIFIED/J F'iUI IJffllili\l! NOi! 8HL I UNCLASSIFIEDh'EOA 9&&1&1 1L Yi& 'iflls?J Numbers of Medical Devices/yr. Worldwi9 intraocular lens contact lens vascular graft hip and knee prostheses heart valve stent (cardiovascular) breast implant dental implant renal dialyzer left ventricular assist devices Millions of lives saved. The quality of life improved for millions more. A $100 billion industry Figure 2. Common Medical Devices That Use Biomaterlals The development of biomaterials is the junction of materials science and chemistry. Medical devices may be composed of a single biomaterial or a combination of several materials. A heart valve might be fabricated from polymers, metals, and carbons. A hip joint might be fabricated from metals and polymers (and sometimes ceramics) and will be interfaced to the body through a polymeric bone cement. Biomaterials by themselves do not make a useful clinical therapy but rather have to be fabricated into devices. This is typically an engineer's role, but the engineer might work closely with synthetic chemists to optimize material properties and with physicians to ensure the device is useful in clinical applications. Biomaterials must be compatible with the body, and there are often issues that must be resolved before a product can be placed on the market and used in a clinical setting. Because of this, biomaterials are usually subjected to the same very stringent safety requirements as those of new drug therapies. UNCLASSIFIED//EAA OFFI&llal: U!!II! 8HICJ UNCLASSIFIED;<}EOl'il GFFIQI e k W&E ,a.lblC Biomaterials for Biosensors Implantable biosensors for the human body place some of the greatest functional demands on biomaterials. Biosensors monitor the physiologic state of tissues for medical therapeutics or for assessing human performance. Sensors for glucose, oxygen, blood pH, adrenal hormones, nervous activity, heart performance, and blood pressure monitors are all of interest. Blood biochemistry sensors are the most difficult sensors to keep functioning over time primarily because the sensor interface materials provoke low-level foreign-body reactions in tissues. These types of responses are not specifically important to implantable devices that have structural rather than sensing functions such as heart valves, but they can completely render a biosensor for blood glucose, for example, useless aher a few days. Chemically sensitive biosensor interfaces to tissue and body environments employ membranes in an effort to protect the biosensor active-sensing surface from possible body reactions. The membrane allows small molecules of interest to pass through its pores while excluding larger proteins, blood-formed elements, and cells like macrophages that would engulf the sensor. The membrane's biomaterial composition, pore size, and long-term physical integrity are critical components in the functioning of the sensor. If the biomaterial chosen retards the adhesion of proteins and does not provoke a biological response improves sensor longevity. Figure 3 shows some representative biomembranes. No one biomaterial is best for all sensor applications, primarily because different biomaterials behave differently relative to the substance being sensed. Membranes that pass glucose, for example, may not pass oxygen that is needed for a sensor to function. Membrane biofouling starts immediately upon contact of the sensor with the body cells. Proteins and other biological components adhere to the sensor surface, and in some cases, impregnate the pores of the material. This process retards diffusion of the molecules of interest to the sensor surface and either slows the sensor's response to changes in concentration or reduces the overall response to the point where the sensor falls out of calibration. Figure 3. Biomaterials Such as Polycarbonates, Cellulose, and Silicones Used in Membranes for Sensors, Dialyzers, and Oxygenators The design of sensor membrane materials has been found to be critically dependent on subtle features of the membrane's chemistry, material thickness, and porosity, as well as, more generally, where in the human body the sensor is located. The blood stream is UNCLASSIFIED/ /EAR QliliHll/21! Y91! 8Ht i UNCLASSIFIED;'/F8R. IPPIIJ,at '-tOE 8HL'f the most hostile location both for sensor performance and in terms of the potential for danger to the patient through the provocation of blood clotting. The most successful biomembrane materials have been porous forms of Teflon, polyurethanes, and cellulose-based materials such as cellulose acetate. As important as the material composition is for sensors, so are aspects of a membrane's structure and mechanical properties, such as its ability resist abrasion and adhere to sensor surfaces. Biomaterials for Biomedicine In this review, we look at representative biomaterials as well as representative applications. These biomaterials are among the most popular of those used in medicine today, and the applications in some cases represent multibillion-dollar-a-year markets. Some of the best known of the biomaterials are: Silicone Biodegradable polymers Hydrogels Titanium alloys Ceramics Tissue constructs Some of the largest applications are: Cardiovascular - stents, synthetic blood vessels, heart valves Hip and knee joints Contact I en ses Drug delivery devices Kidney dialysis BIOMEDICAL SILICONES-POLYDlMETHYLSILOXANES Perhaps the most well known of all biomaterials are the silicones-soft, pliable, and semitransparent materials that are used in many different applications in modern society, ranging from water sealants to fibrous insulations. Silicone is often mistakenly called "silicon." Although silicones contain silicon atoms, they are an organic material of greater complexity and are not made up exclusively of silicon. Silicone is used in an exceptionally large number of biomedical applications. It is blood compatible, sterilizable, rugged, and strong but flexible. Its mechanical properties UNCLASSIFIED//509 OSEJCJCP UNCLASSIFIED,) P:OR. OP:P:IC!l!illt fJ:!11! Olt I can be tailored to varying degrees of hardness and strength for stiffness in catheter applications. Biomedical silicones attracted notoriety in 1995 when a class-action lawsuit against Dow Corning, Inc., brought a huge settlement resulting from the supposed dangers of silicone breast implants. After reviewing years of evidence and research c