Understanding the Human Machine - A Primer for Bioengineering - Max E. Valentinuzzi

208 Understanding the Human Machine

Affer Inhibiting From

Golgi

Motor Fibers To

Muscle

Gamma Fibers To

Spindle

Figure 2.73. THE STRETCH AND THE INVERSE STRETCH REFLEXES. Simplified diagram of these two essential reflexes that play a role in posture and protection of the structures. The gamma fibers to the muscle spindle adjust its sensitivity to stretch. The triangles represent the tendons, where the Golgi sensing organ is. The central portion of the muscle is the spindle, another stretch sensing place, with its intrafusal fibers. See text.

excessive movement of a limb), the spindle also stretches generating action potentials that travel up via afferent fibers to the appropriate spinal center where they activate the efferent motor signal to the muscle to elicit its contraction and, thus, counteracting the initial stretching stimulation. Hence, it protects the muscle. However, if the stretch is too strong, it is this time also sensed by the Golgi organ, a stretch sensitive transducer set at a higher level than the muscle spindle. Its output follows afferent pathways to the same segmental spinal level where it inhibits now the motor response to the muscle. It is also a protective reflex: the stretch was too strong and it is better to yield rather to contract trying to counteract it; hence, the name of inverse stretch reflex. The constant dynamic and complex combination of these kind of responses all over the musculature help in keeping the posture, say, to maintain balance as gravity tends to pull the body down.

However, Figure 2.73 shows another neural pathway to the muscle spindle, the so-called gamma efferent system. Even though the intrafusal spindle fibers are not very contractile, they mildly do respond to stimula-

tion, and the gamma fibers are precisely motor fibers to the muscle spindle. Activation of these fibers produce contraction of the spindle and, therefore, as the structure becomes slightly shorter, it is more sensitive to the overall stretch of the whole muscle. This is a way to adjust the sensitivity to stretch or, expressed in other words, to introduce bias to the system. Since the gamma efferent neural pathways recognize their origin in the higher centers, many times psychological stress increases their outflow leading to painful muscle spasms because their spindles have been sensitized. Neck muscles are frequently the targets of these spasms. This is to be distinguished from the local and also painful muscular contracture (cramps) typically taken place in the legs. The latter may be caused by a variety of maladjustments, such as low glucose, fluid loss, electrolyte imbalance, overexertion, or fatigue. The exact physiologic mechanisms underlying cramps are not fully understood.

2.8.4. Diseases of the Neuromuscular System

The motor unit is a complex and delicate structure that, when in normal operation, performs exquisitely and with precision during a lifetime. Pablo Casals (1876–1973), Arthur Rubinstein (1886–1982) and Yehudi Menuhin (1916–1999), all three famous cellist, pianist, and violinist, re-

V. Contractile

mechanism

I. Soma in the spinal segment

II. Axon

IV. Muscle

membrane

III. Myoneural

junction

Figure 2.74. SITES OF DISEASE ALONG THE MOTOR UNIT. There are five vulnerable sites along the efferent motor unit that can be affected by serious diseases: the nerve fiber itself (soma and axon), the myoneural junction, the muscle membrane and the contractile mechanism of the muscle fibers. See text.

spectively, kept giving concerts until very old ages always capturing the audiences with their virtuosity. The finesse and dexterity of their finger movements was more than ample proof of the perfect functionality of the motor neurons involved.

However, irreversible diseases that may lead to serious crippling of the individual can hit the motor unit. Figure 2.74 marks the five vulnerable points. First, the motor fiber itself, either at the level of the cell body or soma within the spinal cord segments, or at its axon, or at both places. Poliomyelitis is the traditional and most dreaded example. Since there is peripheral nerve injury, the motor unit becomes non-operative and soon progressive muscular atrophy shows up.

First the injectable Jonas Salk’s and later on the oral Albert Sabin’s vaccines, developed and tested between 1952 and 1962, provided the effective weapon to put polio down in the United States and almost completely worldwide. In 1964, only 121 cases were reported nationally. Currently, there are typically fewer than ten new cases per year. A true-life saver, indeed.

The third vulnerable point is the neuromuscular junction already referred to above. Myasthenia gravis is its disease, fortunately with a very low incidence.

Myotonia congenita is a genetic, neuromuscular disorder characterized by the slow relaxation of the muscles. It attacks the muscle membrane manifested by a failure to relax normally. Symptoms may include muscle stiffness and hypertrophy (enlargement). The disorder is caused by a genetic mutation involving the chloride channel of the muscles. The muscle stiffness, which particularly occurs in the leg muscles, may be enhanced by cold and inactivity, and is often relieved by exercise.

The last vulnerable point is the highly complex contractile machinery. Muscular dystrophy is a typical example. It refers to a group of genetic diseases too characterized by progressive weakness and degeneration of the skeletal muscles. Although some forms first become apparent in infancy or childhood, others may not appear until middle age or later.

Dermatomyositis affects also the contractile mechanism. It is one of a group of acquired muscle diseases called inflammatory myopathies and is characterized by a rash accompanying, or more often, preceding muscle weakness. The most common symptom is the latter, usually affecting those muscles that are closest to the trunk of the body (proximal mus-

cles). Eventually, patients have difficulty rising from a sitting position, climbing stairs, lifting objects, or reaching overhead. Trouble with swallowing (dysphagia) may occur. Occasionally, the muscles ache and are tender to touch. Patients may also feel fatigue and discomfort and have weight loss.

2.8.5. Closing Remarks of Section 8

In this highly partialized introduction to the muscular system, we underlined the motor unit, its myoneural junction, the basic control mechanisms involving the muscle splindle and Golgi organ actions and the diseases associated with five vulnerable points of the unit. It would be better to speak of the neuromuscular system or, perhaps, of the neuromusculoskeletal system, because it is not easy to separate them fully out.

The biomedical engineer faces a tremendous modeling task to improve the overall understanding of these inter-related systems, with non-linear mathematics and control systems as essential tools.

Artificial limbs or prostheses of different kind appear as challenging aids to the amputee. Such devices precisely intend to replace one part of the musculoskeletal system (a hand, an arm, a leg). One of them is the socalled myoelectric limb, in which the control signal is derived from surface electrodes picking up nerve or muscle action potentials still under voluntary control of the patient. The signal is processed by electronic circuitry to reach a decision as to whether a function is to be activated, usually a predetermined movement of the artificial limb.

However, for the signal to be of clinical value in controlling a prosthesis, an estimation process is required that must not take much more than one tenth of a second, otherwise, an unacceptable delay will occur between the amputees’ contraction and the action of the prosthetic. The task facing the amputee in using myoelectric prosthesis is difficult. It involves generating a myoelectric signal level corresponding to a specific target. The difference between the signal actually generated and what was intended is termed “operator’s error”. Thus, the actual behaviour of the myoelectric prosthesis results from the intent of the amputee modified by two sources of error, the system error and the operator’s error. Neither of them can be eliminated. The subject is quite a challenge for the bioengineer, for the physician and, above all, for the patient, who also generates the need of psychological support studies.

Another related subject is Functional Electrical Stimulation (FES). It is well beyond the scope of this text, but we should mention a special issue devoted to it where prostheses and the neuromusculoskeletal system are constantly dealt with (Popovic, 2003).

2.9. The Cell

As bricks are building blocks for a house, so are cells for tissues and organs.

2.9.1. Introduction

The cell is as fundamental to biology as the atom is to chemistry. All organisms are made of cells. Behind everything we discussed up to here, there are cells, and ultimately, they supply the properties that characterize the systems of our initial general Figure 2.1. Cells are systems in themselves, with complex dynamic properties, well kept and contained in the manifold inner space. The student has probably already taken a biology course; however, a quick refreshment will help him/her out in the general understanding of this source material for the bioengineer. We will also probe into some basic concepts of molecular biology, which contains undoubtedly essential answers to the many questions about life. As a good reference to widen and improve concepts, we recommend the textbook by Campbell, Reece and Mitchell (1999), and that by Pevzner (2000) to dig into something newer and more specific. The CD by ROCHE, Genetics, of its Educational Program is another suggested reference (see www.rochegenetics.com). As always, browse the IEEE Proceedings of the Engineering in Medicine and Biology Society, say of 2002 or 2003, respectively, to find contributions on cellular engineering, cell-cell interactions in blood, stem cell engineering, molecular engineering, and molecular biomechanics, to mention just a few. INTERNET is another permanent and unavoidable source to consult because all books, without exception, are already outdated by the time they come out.

2.9.2. A Panoramic View

Robert Hooke discovered and coarsely described cells in 1665, however, a full detailed description was largely void until the last decades. Most subcellular structures are too small to be resolved by the light microscope. That was the task reserved for the electron microscope in the 1950’s and thereafter. Nowadays, imaging techniques have advanced even further with the introduction of the scanning microscope complemented with signal processing methods.

There are two types of structurally different cells: prokaryotes and eukaryotes (from Greek, pro, before, karyon, kernel or nucleus, and eu, true or correct). Only bacteria are prokaryotic cells, the rest (plants, animals) are eukaryotic.

The prokaryotic cell has no nucleus. Its genetic material is concentrated in a region called nucleoid without membrane. The eukaryotic cell, instead, is surrounded by a membrane. The region between the nuclear membrane and the cell membrane (or plasma membrane) is called cytoplasm, where the organelles are located. The latter are largely absent in prokaryotic cells.

Here, we are mainly concerned with eukaryotic cells. Their size is a general feature that strongly relates to function. Its plasma membrane acts as a selective barrier that allows sufficient passage of oxygen, nutrients, and wastes to service the entire cell. We have already referred to this membrane in the electrophysiology section and are familiar with the important ionic exchange that takes place across it. In addition to the external membrane, a eukaryotic cell has extensive and elaborately arranged internal membranes, which partition the cell into compartments. They participate in the cell’s metabolism.

2.9.3. The Nucleus

The nucleus (about 5µ in diameter), the most conspicuous organelle, contains the majority of the genes that control the eukaryotic cell. The nuclear envelope is a double membrane separated by a space in the order of 30×10–3µ. The envelope is perforated by pores of about 100×10–3µ. At the lip of each pore, the two membranes fuse. Let us remind that organelles are subcellular or intracellular structures. By and large, they are too small to be resolved by the light microscope.

Within the nucleus, the DNA (deoxyriboneucleic acid) is organized along with proteins into material called chromatin. As a cell prepares to divide (reproduce), chromatin coils up becoming thick enough to be discerned as separate structures called chromosomes (chromos means “color” in Greek, and the name originates in the staining procedures to visualize these structures when observed under the microscope). The nucleolus is the most prominent structure within the nucleus.

The nucleus controls protein synthesis in the cytoplasm by sending molecular messengers in the form of RNA (ribonucleic acid). This messenger RNA, or mRNA, is synthesized in the nucleus following instructions supplied by the DNA. Once in the cytoplasm, mRNA attaches to ribosomes, where the genetic message is translated into the primary structure of a specific protein. Ribosomes are particles whose initial components are synthesized within the nucleus, too. Such components traverse the nuclear envelope pores into the cytoplasm where they combine to form these small organelles.

DNA is the molecule which contains genetic information and makes up our genes. It consists of two complementary nucleotide chains containing the bases adenine (A), thymine (T), guanine (G) and cytosine (C), held in a double stranded helix by bonds between base-pairs. A with T and G with C.

The chromosomes are structures made up of DNA and proteins. They contain the genetic information in a linear array. The order of nucleotide bases along a DNA strand is known as the sequence. The genetic information is encoded in the precise order of the base-pairs. DNA sequencing is the laboratory process designed to precisely determine the sequence of bases in the DNA. During cell division, the entire DNA of the cell is copied.

Human cells have 23 pairs of chromosomes, one of each pair inherited from each parent. The basic unit of heredity is the gene; they are ordered sequences of DNA base-pairs, located in specific positions on chromosomes. Genes contain the information for producing proteins or functional RNA molecules, which make up the structure of cells, and control their functions.

The complete genetic material of an organism conforms the genome. The haploid human genome contains 3 billion base-pairs of DNA organized

into 23 chromosomes. Diploid is the state of having two copies of each chromosome. Most human cells, except the gametes, are diploid with 46 chromosomes (23 pairs), including the sex chromosomes. Conversely, haploid is the state of having one copy of each chromosome. The reproductive cells are haploid, with 23 chromosomes in human egg and sperm cells.

In short, genes are sequences of base-pairs that encode information for proteins. They can range in size from less than 100 base-pairs to several million base-pairs. A diploid genome of 6x109 bases, if stretched, would measure about 1.8 meters long. Chromosomes are relatively large structures made up of DNA and proteins that contain genes, that is, the genetic information. The nucleus acts as a master station.

2.9.4. Closing Remarks of Section 9

Cell anatomy and cell physiology are inter-related disciplines of basic biology standing on their own feet. This section is a mere refreshment of some concepts or just a bare preliminary set. We should briefly mention the remaining parts.

The different membranes of an eukaryotic cell form the endomembrane system. It includes the nuclear envelope, the endoplasmic reticulum, the

Golgi apparatus (not related at all to the Golgi tendon organ already described before), lysosomes, and different types of vacuoles. Although the plasma membrane is the cellular boundary, it is part of the system because it strongly interacts with the endoplasmic reticulum and other internal membranes. Functions of this system are many, complex and important. The student is invited to dig deeper, even though it is not fully necessary for the time being.

Another cellular system is the cytoskeleton. Its most obvious unction is to provide mechanical support to the cell and maintain its shape. Mitochondrion is the singular form of mitochondria. Their major role is synthesis of substances from sugars, fats, and other fuels with the help of oxygen to supply energy to the cellular metabolic processes. These are mobile and flexible organelles, although in some cells they tend to stay in a fixed position (as for example in muscle fibers). Mitochondria are also self-reproducing, they have their own circular DNA.

Cells of multi-cellular organisms also receive signals from other cells, including signals for cell division and differentiation. The majority of

cells in our bodies must constantly receive signals that keep them alive and functioning. The key concept is that the many signaling systems of biology have very similar or related steps. The same signaling system can lead to very different responses in different cells or different organisms. Studies of the mechanisms of cell signaling are leading to new understanding of many diseases, and to new strategies for therapy.

Chapter 3

Signals: What They Are

“Observe, think, and observe again”, used to say Dr. J.J. Izquierdo, an old well-reputed professor of physiology at the Universidad Nacional Autónoma de México (UNAM), in Mexico City, back in the 1960’s ... “and physiological signals are one way to observe”, we may add.

3.1. Introduction

The biological source of information has been already reviewed in the preceding chapter. Now it is the time to consider the signals it generates. Researchers always struggled to somehow “see” the physiological events they were dealing with, so that some kind of visualization means (such as records on paper, records on an oscilloscope, records on a monitor, or records as images) became mandatory, for the first processing of that graphic information is made by eye, using the observer's knowledge and experience.

This chapter deals with the nature of the biological/physiological signals always or mostly presented as experimental functions of time (even though something was already anticipated in the preceding chapter, especially when describing the cardiovascular system). The explicit mathematical relationship is rarely known, if ever; at most it is an empirical approximation. They contain the information to be interpreted later on and, thus, their true shape, timing and location are essential characteristics to preserve. Hence, the first objective is to give an overview of them. A second objective is to glance into their fields, showing how bioengineering unexpectedly projects out when, by sheer necessity, new techniques must be developed in order to recover information otherwise hid-

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