This chapter will introduce the concepts underlying the use of biomaterials to deliver various types of active molecules to the body for therapeutic or preventive purposes. This starts with the premise that many traditional pharmaceutical agents have been demonstrated to be effective in certain situations but their efficacy, specificity and safety is often compromised by poor bioavailability and high systemic toxicity when delivered through the conventional oral or intravenous routes. The chapter therefore concentrates on the technologies that can be used to produce more precise, controlled and targeted delivery of these active molecules. It covers drugs, genes, vaccines and other active molecules and deals with mechanical, physical, chemical and other techniques to produce the delivery mechanism. Many of these processes are based on the details of nanobiotechnology.

Introduction to active molecule delivery

Pharmaceutical agents, or drugs, are chemical substances that are applied to the body where they are metabolized and have, or are expected to have, a beneficial effect in treating, mitigating or preventing disease or discomfort, facilitating repair of injury or otherwise beneficially altering human physiological performance. Drugs have been the mainstay of many branches of medicine for centuries and have a powerful impact on both health status and health economics around the world.

In this chapter we introduce some of the latest applications of biomaterials in medical technology. Previous chapters have concentrated on therapeutic processes, either by pharmaceutical components, regenerative medicine processes or implantable devices. All clinically successful therapeutic measures require good diagnosis of the patient’s condition. Although the doctor’s intrinsic clinical skills are extremely important, the need for very accurate, instrument-assisted, diagnosis, with good spatio-temporal resolution, is becoming increasingly significant. This is because early and precise diagnosis is essential if the doctors are able to use the most effective treatments for cancer, degenerative disease and other critical issues. Medical technologies have always played some role in diagnosis, but have rarely, until recently, involved the use of biomaterials. Most techniques are concerned with the application of some physical energy to the affected tissues and organs, using X-rays and other ionizing radiations, ultrasound and light, for example, and detecting the responses of the tissues to that energy. Conventional methods often provide relatively poor contrast between different types of tissues (and any lesions they contain), usually with restricted spatial resolution. They usually produce anatomic rather than functional information. The essential rationale for the use of biomaterials in these imaging systems is to enhance the contrast that can be seen, especially by accentuating differences between the response of different types of tissues and between different disease states. Most of these biomaterials are used in nanoparticulate form. Their applicability is controlled by their differential responses to the applied energy and by their handling within the tissues of the body.

Anatomical and functional imaging

The majority of this book so far has been concerned with the therapeutic methods that may be used to treat diseases and conditions of the human body, where those methods significantly rely on the use of biomaterials. Before any therapy can be considered, it is necessary for the clinicians involved to be aware, as accurately as possible, of the nature of the disease or condition that is affecting the patient in question. For very many years, this process of identifying what is wrong, known as diagnosis, was informed by the skilled observations of the clinicians and the measurement of some relevant physiological parameters such as temperature, heart rate and blood pressure.

In this chapter we shall address many of the practices and procedural issues that affect and control the production, supply and clinical use of biomaterials and products that are based on these materials. These are not trivial matters. They should be considered as essentials, rather than as afterthoughts or “nice-to-haves.” The reason why these issues are addressed towards the end of this book and not at the beginning is a reflection of the need for the reader to first understand the essential scientific, clinical and technological basis before coming to grips with the infrastructure issues, rather than any suggestion of lesser importance. This chapter covers the regulation of biomaterials-based health care products, the pre-clinical testing and clinical evaluation of materials and products, and the ethical, legal and economic matters that have a major influence over this industry.

Introduction

Although it could be argued that, globally, the biomaterials and medical technology industries are quite heterogeneous and fragmented, there are several facets of the industry that are highly structured. These deserve discussion in a textbook on the essentials of biomaterials science. The fundamental reason for this is that biomaterials can do harm as well as good and it is essential that they are used as safely and effectively as possible. This will not happen if each application of a medical device that incorporates biomaterials is developed in isolation, in ignorance of the relevant history of that type of device and without regard to the broader issues of patient (and doctor) safety and the ethical and legal aspects of clinical applications. That there are standards and codes of practice in industrial sectors where safety is a primary concern, such as in aerospace and nuclear industries, is no surprise. The sheer volume of medical devices used on a global scale, and the potential number of individuals that they can affect, for good or bad, suggests that there should be extensive control over these products as well.

After studying this chapter you will be able to identify all of the significant applications of biomaterials in those devices that replace the structure and/or function of tissues and organs by the use of medical devices. These may be implanted within the patients, usually for the remainder of their lives, or connected to the patient for some short-term assistance; these applications were summarized at the end of Chapter 1. This discussion covers all of the clinical disciplines. It includes implantable devices that have been in use for decades, and you will be able to understand the reasons for their success, and the reasons for failures where they have occasionally occurred. It also covers the implantable and support systems that have recently been developed and introduced into clinical practice so that you can appreciate where the technology of the twenty-first century is leading us in health care products.

As noted earlier, implantable medical devices were, for many years, the main focus of attention within biomaterials science. The rationale and performance of such devices are discussed in this chapter. Each application and each situation is different and it is not possible to deal with this in an entirely satisfactory systematic manner, but the major headings given in Chapter 1 are covered and dealt with in relation to the clinical discipline that is involved. This includes permanent (or long-term) devices, short-term devices, invasive but removable devices and artificial organs or assist devices that are attached to the body. We will conclude the chapter with an assessment of the overall performance of implantable devices and the lessons learned.

Biocompatibility is the most critical factor that controls the success of biomaterials and those health care products that incorporate biomaterials. It is concerned with the mechanisms of interaction between biomaterials and the human body, and the consequences of these interactions. This chapter first introduces the concept of biocompatibility and then provides you with a series of scenarios that cover the whole range of situations in which biomaterials come into contact with tissues. In each case, critical mechanisms are explained and discussed, leading to the presentation of a unified framework of the sequence of events that constitute biocompatibility. This is based on the simple concept that in biocompatibility there are causative events within the biomaterial–host interactions that lead, through a variety of different but interconnected pathways, to physiological or pathological effects and then to their clinical consequences. This framework is then used to explain a variety of situations in which biocompatibility has proved to be so important.

Introduction

We discuss here a wide variety of situations in which interactions take place between biomaterials and the patients in which they are placed, and where the nature of that interaction determines both the level of satisfaction and risk that the patient receives or perceives.

In this opening chapter you will be introduced to the extent to which health care products contribute to the delivery of therapeutic and diagnostic procedures across a massive array of clinical problems and solutions. Included here are examples of long-term implantable devices, procedures of regenerative medicine, the diagnosis of disease and injury, and the specialized delivery of drugs and genes. You will then see how biomaterials science has evolved in order to optimize the performance of these products. The concepts of biomaterials science are introduced, along with a general discussion of the requirements of biomaterials and their essential characteristics.

Health care products in medical practice

You are an observer in a busy doctor’s clinic on a Monday morning during a cold wet month of the winter. This is a large polyclinic, which includes not only primary care physicians but a plethora of specialists, who deal with the diagnosis and uncomplicated treatments for a variety of conditions, ranging from dental and ophthalmological conditions, to neonatal care, trauma, geriatric complaints and common infectious diseases. A few hundred meters away is a major teaching hospital, able to deal with virtually every acute and chronic condition that is likely to be seen in this mid-size industrial city, which encompasses people of all ages and genetic background.

The military failure to resolve the war in 1914 surprised soldiers in Germany and everywhere else. It also surprised civilian leaders in all the belligerent countries, who now confronted unanticipated and unprecedented challenges. They had to redirect the productive energies of society towards the massive demands of industrial warfare. The first year and a half of the war established the framework of mobilization in all these lands. Public institutions invaded economies and societies, as vast material and moral resources were channeled to military ends.

The transition to new modes of organization for war took place everywhere by improvisation during the first months of the conflict, but some of the belligerent powers were better able than others to adjust. Imperial Germany, which in 1914 was reputed to be the most efficiently organized society on earth, faced major impediments to meeting the challenges. Deficiencies in the organization of mobilization contributed to the mounting burdens of war on the home front. They also fed the political controversies that attended the prolongation of the war.

Bureaucratic foundations

Institutions were a fundamental problem. Germany's reputation for bureaucratic efficiency was deceptive, for the country's basic administrative structures were fragmented among federal, state, and local institutions. Administrative particularism had its champions, but it posed grave obstacles to the execution of common policies in a national emergency.

The institutions of military administration, which were conceived with national emergency in mind, only compounded the difficulties. These institutions were as much geared to the wrong century as was Schlieffen's plan. They were designed to mobilize forces rapidly in the event of war (or revolution) and to provide basic services and security at home during a limited period of crisis, as they had in 1870–1. Their legal foundation was the Prussian Law of Siege, which had first been promulgated in 1851 and then taken over into the imperial constitution in 1871. Upon declaration of national emergency, this law specified that executive power passed into the hands of the corps commander in each of the country's twenty-four military districts. Because these commanders accompanied their corps into battle, however, their executive powers devolved to their seconds-in-command, the so-called deputy commanding generals.

Traditional application of thermodynamics to engineering problems involves processes that are flowing. For example, an engineer might design a refrigerator in which a refrigerant is pumped in a continuous cycle through a coil of tubing, or a generator where steam is pumped in a power cycle through several pieces of equipment. Hence, engineering has placed a lot of emphasis on balances in flowing systems. Such flow systems involve time as an independent variable. However, thermodynamics applies only to equilibrium states, and the introduction of time is strictly forbidden. The study of time-dependent processes actually falls within the domains of transport phenomena and non-equilibrium thermodynamics.

Whereas the field of transport phenomena is relatively well advanced and well understood, non-equilibrium thermodynamics is a developing field of research, and the fundamental postulates are by no means agreed upon [11, 94].

We will restrict ourselves here to the simplest of such time-dependent systems. Namely, we will assume that our system is in a local state of equilibrium. Such an assumption allows us to use the quantities derived for equilibrium systems as local variables that depend upon position and time. This simplification is usually applicable whenever the local response time of a system is much smaller than the time scale of the whole process. In this way, we can simplify many engineering flow problems to equivalent equilibrium thermodynamics problems.

For good or evil, all physical processes observed in the Universe are subject to the laws and limitations of thermodynamics. Since the fundamental laws of thermodynamics are well understood, it is unnecessary to limit your own understanding of these thermodynamic restrictions.

In this text we lay out the straightforward foundation of thermodynamics, and apply it to systems of interest to engineers and scientists. Aside from considering gases, liquids and their mixtures – traditional problems in engineering thermodynamics – we consider also the thermodynamics of DNA, proteins, polymers, and surfaces. In contrast to the approach adopted by most traditional thermodynamics texts, we begin our exposition with the fundamental postulates of thermodynamics, and rigorously derive all steps. When approximations are necessary, these are made clear. Therefore, the student will not only learn to solve some standard problems, but will also know how to approach a new problem on safe ground before making approximations.

Thermodynamics gives interrelationships between the properties of matter. Often these relationships are non-intuitive. For example, by measuring the volume and heat capacity as functions of temperature and pressure, we can find all other thermodynamic properties of a pure system. Then, we can use relations between different thermodynamic properties to estimate the temperature rise of a fluid when it is expanded in an insulated container, or, we can use such data to predict the boiling point of a liquid. In Chapter 2, we introduce the necessary variables to describe a system in thermodynamic equilibrium.