In today’s healthcare industry, synthetic and natural biomaterials are being introduced into the human body at an increasing rate. In the United States alone, several million biomaterial-based implants or devices are used for human patients each year. It is not uncommon to find that many of the biomaterials used today were first introduced for industrial applications other than medicine. In order to protect and promote public health, all biomaterials used by the medical device industry have to meet numerous stringent criteria required by regulatory agencies such as the Food and Drug Administration in the USA. These stringent criteria include material properties, preparation and sterilization of the materials, biocompatibility, and short-term and long-term issues related to the use of the material for a specific application. With these protections in place, reasons for the conventional use of biomaterials in clinics and hospitals include:

Metals are extensively used as materials for biomedical implants, devices, and surgical tools. Some of the implants made from metals are shown in Figure 5.1. For example, metals are used for orthopedic reconstructions (implants for artificial hip, knee, shoulder, and elbow joints), fracture fixation (plates, pins, screws, rods, and nails), oral and maxillofacial reconstructions (dental implants and mini-plates), and cardiovascular interventions (stents, heart valves, and pacemakers). In general, metals used for biomedical applications should exhibit the following properties:

Most metallic biomaterials have a stable surface oxide layer that enhances their corrosion resistance properties. It is believed that the presence of this stable surface oxide layer is key to the biocompatibility of metals. The mechanical properties of the metal are important and should satisfy the requirements of the specific application in the body. For instance, when a metal is used to augment a bone, the elastic modulus of the metal should be ideally equivalent to that of the bone. If the elastic modulus of the metal is greater than that of bone, then the load experienced by the bone is reduced due to a phenomenon known as stress shielding. This can cause the bone to remodel to adjust to the lower load and eventually result in the loss of bone quality. In another example, stainless steel is commonly used for making coronary stents due to its well-suited mechanical properties. Stainless steel has good radial strength (due to its high elastic modulus of ~190 GPa), low recoil, good expandability, and sufficient flexibility, which makes it a highly preferred metal for making stents. Several metals such as titanium, stainless steel, cobalt–chromium alloys, nitinol (nickel–titanium alloy), tantalum, and magnesium have been used for a variety of clinical applications, with titanium, stainless steel, and cobalt–chromium alloys being the most commonly used metals. This chapter describes the structure and properties of these metals.

The Rig Veda, one of the four sacred Sanskrit books of ancient India that were compiled between 3500 and 1800 BC, relates the story of a warrior queen named Vishpla, who lost a leg in battle and was fitted with an iron leg after the wound healed. There is also mention of lacerated limbs treated with sutures. Sushruta, a renowned Indian physician from circa 600 BC, wrote a very comprehensive treatise describing various ailments as well as surgical techniques. His technique for nose reconstruction using a rotated skin flap is still used in modern times. Sutures made of vegetable fibers, leather, tendons, and horse hair were commonly used in his time. There are also reports of the use of linen sutures in Egypt 4000 years ago.

These ancient records show that, since time immemorial, humans have tried to restore the function of limbs or organs that have ceased to perform adequately due to trauma or disease. Often, this was attempted through the use of materials either made or shaped by humans and used external to the body. These were the earliest form of biomaterials. Although examples of successful external prosthetic devices can be found in history, materials placed inside the body, also known as implants, were usually not viable due to infection. This changed in the 1860s with the advent of aseptic surgical techniques introduced by Dr. J. Lister. The discovery of antibiotics in the mid 1900s also reduced the incidence of infections related to surgery. Today, implants are very successful and are used in a wide variety of applications in the practice of medicine, improving the quality of life for millions and saving countless lives. However, the successes of today have come after a long history of trial and error and scientific endeavor.

Despite the advent of advanced manufacturing tools and newly developed materials with unique properties, why is the attention of biomedical scientists and engineers focused on biomaterial surfaces? Unlike the material’s bulk, which generally governs the mechanical integrity of medical devices, the material’s surface governs tissue–biomaterial interactions and these usually occur within a narrow depth of less than 1 nm on the material’s surface. Surface modification of biomaterials allows the tailoring of surface properties without affecting bulk material properties. These altered surface properties influence tissue–biomaterial interactions, which ultimately determine the success or failure of a device placed in the human body. In addition to improving tissue–biomaterial interactions, modification of biomaterial surfaces may also be performed for the purpose of improving surface mechanical properties such as wear resistance. This can be achieved through surface or subsurface alloying, or heat treatment. Enhancement of surface oxide thickness or the presence of a dense protective coating on a metallic surface can provide surface barriers which minimize the metal’s chemical reactions with its surroundings, thereby improving its corrosion resistance. Thus, through surface modification, the native surfaces of biomaterials can be physically or chemically transformed with the primary goal of engineering desired surface chemistry, topography, reactivity, biocompatibility, hydrophilicity, or charge.

During the development phase of any medical devices or implants, it is essential that the biomaterials used are thoroughly characterized. The material’s surface properties are important because it is the implant’s surface where the body’s biology and the material first interact. On the other hand, the bulk properties of the material determine its mechanical and physical behavior and its long-term viability. Of course, the material’s chemical properties influence its stability, biocompatibility, and the body’s reaction to it. Since a material possesses different physical and chemical properties, the analytical instruments used for characterizing these properties can be broadly classified under the following three categories:

The use of multiple characterization techniques is essential for complete analysis of the surface and bulk properties of a biomaterial. When a material is implanted in the body, protein adsorption almost instantaneously occurs on the material surface. Hence, the cells do not directly interact with the material surface but only through the layer of proteins adsorbed on the surface. This adsorption of proteins is governed by a combination of different surface characteristics of the material including surface energy, surface chemistry, surface texture, and surface roughness. The use of contact angle measurement provides information about the material’s surface energy, whereas Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), and secondary ion mass spectrometry (SIMS) provide information on the material’s surface chemistry at different depths. Scanning electron microscopy (SEM) provides details about the material’s surface texture, whereas atomic force microscopy (AFM) allows for measurement of the material’s surface roughness. Thus, data collection using different analytical instruments provides in-depth information regarding the material’s surface and assists in predicting how surface properties would influence the biological outcome.

Therapeutic drugs play a significant role in the therapy of almost all medical problems. From the treatment of common ailments such as headaches, and colds, to the reduction of fever, fighting infection, reducing cholesterol and blood pressure, and treating cancer, drugs play a major role in medicine. The systems used for delivering drugs take on a variety of forms. These include simple oral systems such as tablets, capsules, and syrups, transdermal systems like ointments and patches, and intravenous delivery using suspensions or nanoparticles.

In order for a drug to provide a therapeutic effect, the concentration of the drug in the blood plasma has to be above the minimum effective level and below the level that may be toxic. The difference between the minimum effective level and the toxic level is called the therapeutic index. As shown in Figure 12.1a, when the drug is conventionally administered as a single dose and is metabolized quickly inside the body, the level of drug in the blood plasma immediately increases followed by an exponential decrease. In such a conventional administration of the drug, the time frame over which the drug concentration is above the minimum effective level may not be long enough to produce a significant therapeutic effect in a single dose. Although this situation can be improved by increasing the amount of dose, this quickly raises the drug level to the toxic region. The alternative is to administer doses at regular intervals (Figure 12.1b). However, this method too has limitations, such as:

In everyday life, we encounter a variety of polymers, some natural and others synthetic. The vast majority of these are carbon-based in nature. They range from synthetic polymers seen in products such as polyethylene grocery bags, polymethylmethacrylate-based window panes, and polystyrene-based eating utensils, to natural polymers such as starch, cellulose and rubber. Polymers used as biomaterials are often similar to these common materials. For example, the polymer most extensively used in total joint prostheses is ultrahigh molecular weight polyethylene – chemically identical to the material used for plastic bags, although having a much higher molecular weight. The same is true for bone cement which is used in conjunction with bone surgery and Plexiglass®, which is used for window panes. Both of these materials are polymethylmethacrylate (PMMA). Of course, any polymer that is used as an implant has to meet strict safety standards as required by governmental and other regulatory agencies and has to be virtually contaminant free.

The world around us is full of microorganisms such as bacteria, fungi, and viruses. These microorganisms are present in the atmosphere, on the surface of all objects, and even on our own skin. In the process of manufacturing an implantable medical device, there is always a possibility of contaminating the device surface with microorganisms. As required by regulatory agencies such as the Food and Drug Administration (FDA), it is mandatory to sterilize all devices prior to implantation. The goal of sterilization is to render the implant devoid of all potential infection-causing organisms, making it one of the most important steps in the manufacturing process of biomedical devices. In this chapter, the basic terminology associated with sterilization such as bioburden and sterility assurance level is explained. In addition, commonly employed sterilization methods such as steam sterilization, ethylene oxide sterilization, and gamma radiation sterilization are described along with various other new and old sterilization methods. The suitability of these methods for sterilizing different biomaterials is also discussed.

In everyday life, we often define materials using relative terms such as soft or hard, flexible or rigid, strong or weak, tough or brittle, and in a variety of other qualitative ways. What do these terms really mean in the world of engineering? Is such qualitative categorization sufficient for the design and manufacture of a product? The answer is definitely a no, especially when human health or lives may depend on the product. For example, you certainly would not want engineers who are building bridges to pick materials based on such relative and qualitative descriptions! Choices based on much more rigorous, scientific, and quantitative characterization would be expected. The same is true when selecting biomaterials.

Material properties can be characterized quantitatively using standardized tests under defined conditions. Once characterized, these properties can be used in conjunction with engineering design techniques to predict the behavior of the engineered product under the expected operating conditions and to ensure that it would function safely. This is important because properties may change based on independent variables such as temperature or rate of application of force. Often a variety of material properties need to be considered for each product.

The biological environment

One of the most basic principles of systems biology is the concept of reductionism where behavior of a “whole” can be explained by the corresponding behavior of its “parts.” By successively deconstructing the organism and studying its components, biologists can explain the function of the body in terms of its organ systems, cells, subcellular organelles, macro- and biochemicals, and so forth until we reach fundamental particles. This concept of reductionism is among the most common techniques used to study biomaterials as we explore their influence at the biochemical, protein, cellular, and whole-organism levels. However, great care must be taken as reductionism leads to more and more missing information with each step taken. As an example, in vitro experimentation often lacks the cellular complexity and hormonal control of in vivo behavior and can lead to false or contradictory conclusions. Despite the limitations of reductionism, it is among our best tools for understanding and testing biomaterials when care is taken to identify the assumptions of each experiment and result. In this chapter, we will focus on the communication systems at the cellular level and its implications for biomaterials.

What makes natural materials unique and piques the interest of biomaterials scientists, engineers and clinicians? There is a belief that all aspects of materials created naturally have a useful purpose or function. Utilization of such materials thus allows these materials to perform a combination of diverse functions such as intracellular communications and storage. In general, the properties of natural materials are dependent on their composition. For example, the physical–chemical properties of monomers and their sequences determine the properties of polymeric natural biomaterials. Like synthetic materials used for biomedical applications, it is expected that the natural biomaterials should satisfy requirements such as

Natural biomaterials possess most of the above properties because they are found in biological systems and work well within their respective environments. Favorable characteristics of natural materials include facilitating cell attachment, enhancing the mechanical properties of synthetic biomaterials, and their ability to bind and deliver macromolecules. These desirable characteristics allow natural materials to be used in various biomedical applications including tissue engineering and regenerative medicine. With the exception of corals, which are deposits of calcium carbonates, most of the common natural materials are polymeric in nature and are either protein-based or polysaccharide-based materials. Examples of protein-based natural polymers include collagen, gelatin, silk fibroin, fibrin, and elastin, whereas examples of polysaccharide-based natural polymers include chitosan, starch, alginate, hyaluronan, chondroitin sulfate, and dextran. In this chapter, we will discuss some of the natural biomaterials that are commonly used today in the fabrication of medical devices.

How do cells, containing the same genetic information, diversify and give rise to so many types of tissue? This fundamental question of cell biology has a surprisingly simple answer: environment. Despite the incredible complexity of internal genetic control, cells rely equally on their surroundings to define their form and function. In the study of cell biology, the plasma membrane traditionally defines the boundary between the functional unit of the cell and its environment. The interactions that occur at this interface represent an exceedingly complex and highly organized series of reactions that permits the cell to send and receive biochemical signals across the membrane. Most eukaryotic cells define their structure and function based on these signals. Even for those cells that are not substrate bound, such as those of the circulating immune system, it is essential to sense and respond to biochemical gradients and interactions in the body. The availability, intensity, and duration of these gradients are the signals which direct cells into their most common activities, that is, migration, division, and differentiation. These activities provide the complexity of all cell response in the body and can specifically define the reaction to any material implanted.