Preface

Biomedical Sciences (from anatomy, physiology and molecular biology to pathology) provide the information and knowledge base for biomedical engineering and technology. Formulation of biological and physiological mechanisms and correlates of organ functions, disorders and disease states in biomedical engineering terms makes them more clearly defined in terms of equations, formulas and indices. From biophysiological disease mechanisms, we can proceed to engineering analysis and formulations of functions of physiological systems, and define normal and pathological ranges of physiological systems operations. This in turn leads to analysis of physiological systems' functional tests data or medical tests data, for carrying out medical diagnosis and prescribing medical treatments.

In this book, we start with chapter 1 on the biomedical engineering (BME) professional trail. Then, in **Section 1,** we deal with the biomedical sciences of disease pathways and mechanisms of action of treatments.

For biomedical engineering (BME) to be a professional discipline, we have addressed (in chapter 1) the professional needs of anatomy and physiology, medicine and surgery, hospital performance and management. The role of BME in Anatomy is to demonstrate how anatomical structures are intrinsically designed as optimal structures. In Physiology, the BME formulation of physiological systems functions can enable us to characterize and differentiate normal systems from dysfunctional and diseased systems. For BME in Medicine, we formulate the engineering systems analyses of physiological and organ system functions and medical tests, in the form of differential equations (Deqs), expressing the response of the organ system in terms of monitored data. The parameters of the Deq are selected to be the organ system's functional performance features. The normal and dysfunctional ranges of these parameters can enable reliable medical diagnosis, such as diagnosis of lung disease states or diagnosis of persons at risk of being diabetic. In Surgery, we can develop the criteria for candidacy for surgery, carry out pre-surgical analysis of optimal surgical approaches, and design surgical technology and implants. In Hospital management, we can develop measures of cost-effectiveness of hospital departments, budget development and allocation, such that no hospital department has a cost-effective index below a certain specific value. This chapter provides the basis of how biomedical engineering can be employed (i) to provide a new approach to the study of anatomy, (ii) in the formulation of physiological systems' functional indices and their applications in medicine, and (iii) in combination with operations research methods in hospital management. All of this can be carried out by introducing biomedical engineering courses in the MD-PhD (BME) curriculum and biomedical engineering departments in tertiary care medical centers.

**Section 1 is on Disease Pathways, Models and Treatment Mechanisms.** We start with cell signalling (in chapter 2), which is an extremely important aspect of modern biology, involving control of cellular events in response to extracellular factors. In this chapter, it is suggested that music has many parallels with the principles of cell signalling. This chapter discusses (i) signalling between organisms and the production of signals, (ii) signalling systems, receptors and degeneracy, and (iii) threshold signalling levels, with timings and phrasing.

Chemical Carcinogenes is an important concern for us. In chapter 3, we discuss: cell regulatory mechanisms and their disruptions in cancer cells caused by carcinogens; mechanism of oxidative stress and DNA damage due to micronutrient deficiency; biomarkers usage in measurement of external dose, and determination of altered structure and function of cells as a marker of chemical carcinogenesis; the bioengineering technologies associated with these processes and measurements.

We next deal, in chapter 4, with the concept of Metabolic memory, of (i) early metabolic control on longer cardiovascular outcomes, and (ii) the underlying pathophysiology of metabolic syndrome and insulin resistance. The potential mechanisms for propagating this "memory" are the non-enzymatic glycation of cellular and tissue proteins, which are conceptualized as advanced glycation endproducts (AGEs), the generation of which is implicated to be associated with increased oxidative stress and hyperglycemia. AGEs, with their receptors potentially mediate molecular and cellular pathways leading to metabolic memory. Interaction of the RAGE with AGEs leads to crucial biomedical pathway generating intracellular oxidative stress and inflammatory mediators, which could result in further amplification of the pathway involved in AGE generation. By utilizing genetically engineered mouse models, emerging evidence suggests that AGE/RAGE axis is also found to be profoundly associated with non-diabetic pathophysiological conditions, including 1) atherogenesis, 2) angiogenic response, 3) vascular injury, and 4) inflammatory response, many of which are now implicated in metabolic syndrome.

Next, in chapter 5, we present Mitochondria Function in Diabetes, on (i) various mechanisms present in mitochondria that lead to the development of diabetes, (ii) modulation of the "vicious circle" established between mitochondria, oxidative stress and hyperglycemia, and (iii) application of some agents possessing anti-glycation properties to reduce glycation phenomenon and to increase the antioxidant defense system by targeting mitochondria.

Infection by HIV and/ or TB is known to cause persistent chronic inflammation. There is evidence that patients infected with HIV and/ or TB are under chronic oxidative stress with a resultant decrease in endogenous and nutritional antioxidants as well as other micronutrients. Oxidative stress due to overproduction of free radicals and antioxidant deficiency, causes damage to vital biological macromolecules and organs and further contributes to disease complications, disease progression and morbidity. In chapter 6, we discuss the role of red palm oil from the African palm (Elaeis guinensis) in reducing oxidative stress. It is proposed that red palm oil supplementation could effectively scavenge free radicals and increase total antioxidant capacity, with the potential to (i) reduce disease progression and its complications, (ii) increase survival and (iii) improve the general wellbeing of people living with TB and HIV/AIDS.

XII Preface

(ii) in the formulation of physiological systems' functional indices and their applications in medicine, and (iii) in combination with operations research methods in hospital management. All of this can be carried out by introducing biomedical engineering courses in the MD-PhD (BME) curriculum and biomedical engineering

**Section 1 is on Disease Pathways, Models and Treatment Mechanisms.** We start with cell signalling (in chapter 2), which is an extremely important aspect of modern biology, involving control of cellular events in response to extracellular factors. In this chapter, it is suggested that music has many parallels with the principles of cell signalling. This chapter discusses (i) signalling between organisms and the production of signals, (ii) signalling systems, receptors and degeneracy, and (iii) threshold

Chemical Carcinogenes is an important concern for us. In chapter 3, we discuss: cell regulatory mechanisms and their disruptions in cancer cells caused by carcinogens; mechanism of oxidative stress and DNA damage due to micronutrient deficiency; biomarkers usage in measurement of external dose, and determination of altered structure and function of cells as a marker of chemical carcinogenesis; the bioengineering technologies associated with these processes and measurements.

We next deal, in chapter 4, with the concept of Metabolic memory, of (i) early metabolic control on longer cardiovascular outcomes, and (ii) the underlying pathophysiology of metabolic syndrome and insulin resistance. The potential mechanisms for propagating this "memory" are the non-enzymatic glycation of cellular and tissue proteins, which are conceptualized as advanced glycation endproducts (AGEs), the generation of which is implicated to be associated with increased oxidative stress and hyperglycemia. AGEs, with their receptors potentially mediate molecular and cellular pathways leading to metabolic memory. Interaction of the RAGE with AGEs leads to crucial biomedical pathway generating intracellular oxidative stress and inflammatory mediators, which could result in further amplification of the pathway involved in AGE generation. By utilizing genetically engineered mouse models, emerging evidence suggests that AGE/RAGE axis is also found to be profoundly associated with non-diabetic pathophysiological conditions, including 1) atherogenesis, 2) angiogenic response, 3) vascular injury, and 4) inflammatory response, many of which are now implicated in metabolic syndrome.

Next, in chapter 5, we present Mitochondria Function in Diabetes, on (i) various mechanisms present in mitochondria that lead to the development of diabetes, (ii) modulation of the "vicious circle" established between mitochondria, oxidative stress and hyperglycemia, and (iii) application of some agents possessing anti-glycation properties to reduce glycation phenomenon and to increase the antioxidant defense

Infection by HIV and/ or TB is known to cause persistent chronic inflammation. There is evidence that patients infected with HIV and/ or TB are under chronic oxidative

departments in tertiary care medical centers.

signalling levels, with timings and phrasing.

system by targeting mitochondria.

Recent researches show that medical plants have ecological functions that have potential medicinal effects for human**s.** Diabetes mellitus is the major endocrine disorder responsible for renal failure, blindness or diabetic cataract, poor metabolic control, increased risk of cardiovascular disease including atherosclerosis and AGE (advanced glycation end) products. Antioxidants play an important role to protect against damage by reactive oxygen species, and their role in diabetes has been evaluated. Many plant extracts and products are shown to possess significant antioxidant activity. Accordingly, in chapter 7, we discuss some fundamental aspects of phytomedicinal plants with an overview of those plants that have received considerable use and attention in diabetes treatment.

Atherosclerosis, causing thrombosis (atherothrombosis), is the underlying pathology of the vast majority of cardiovascular diseases. It is responsible for up to 80% of all deaths in diabetic patients. Atherothrombosis is clinically manifested as coronary artery disease (heart attacks), stroke, transient ischaemic attack, and peripheral arterial disease. The atherosclerotic process starts early in life and, in almost one-third of all people, can progress to a complicated atheromatus plaque that generates thrombosis and blockage of blood supply. These plaques preferentially develop in regions of complex blood flow, such as bifurcations and regions of curvature. Local variations in hemodynamic forces, in particular wall shear stress (WSS), have been hypothesized to cause focal endothelial cell (EDC) dysfunction leading to a pro-inflammatory environment prone to atherosclerotic lesion development. These WSS profiles can manifest morphological and phenotypical changes in EDCs through a complex pathway of mechanotransduction. In chapter 8, we provide an understanding of endothelial-leukocyte interactions in atherogenesis and plaque stability, based on 3-d culture in vitro modeling.

Now, we come to chapter 9. Osteoarthritis (OSA) is a heterogenous condition that involves not only the articular cartilage but also an adaptive response of the bone and the synovium to a variety of environmental, genetic and biomechanical stresses. This chapter deals with pain in osteoarthritis: (i) mechanisms involving activation of nociceptors (naked nerve endings close to small blood vessels and mast cells) and nociceptive stimuli causing tissue damage; (ii) pathophysiology of gradual proteolytic degradation of the joint cartilage matrix, catalysed by metalloproteinases; (iii) receptors involved in the mechanisms of action for acute pain: a-amino-3-hydroxy- 5 methyl-isoxazole-4-propionic acid (AMPA) receptors; (iv) receptors of importance in the sensation of chronic pain: N-methyl- D-aspartate (NMDA) receptors; the activation of NMDA receptors causes the release of peptide neurotransmitter SP, which amplifies the pain by causing the spinal neurons transmitting the pain to be easily stimulated; (v) modes of treatment for OA for decreasing pain and improving function through analgesics, non-steroidal anti-inflammatory drugs and joint injections, and surgery involving joint replacement with plastic, metal or ceramic implants.

**In Section 2, we deal with Biomaterials and Implants.** Among biomaterials, we have included herein: (i) non-thermal plasma surface modification of biodegrable polymers employed in sutures and biodegradable scaffolds, (ii) synthesis and surface modification of polylactic acid (PLA) based biomaterials employed in tissue engineering scaffolds and drug delivery systems, and (iii) multifunctional magnetic nanoparticles as contrast agents for magnetic resonance imaging (MRI) and as carriers for drug delivery.

During the past two decades, there has been a considerable interest in the development and production of biodegradable polymers. Besides their use as packaging materials, biodegradable polymers play a major role in biomedicine as sutures, temporary prostheses and drug delivery vehicles. Biodegradable polymers have also been studied as three-dimensional porous structures (scaffolds) in the tissue engineering domain. The ultimate goal of this technology is to generate completely biocompatible tissues that can be used to replace damaged or diseased tissues in reconstructive surgery. Ideally, the scaffold material should be able to support initial cell growth and further proliferation, and should have the ability to biologically degrade over time while leaving behind a reproduced functional tissue. The success of polymeric biodegradable scaffolds is however determined by the response it elicits from the surrounding biological environment and this response is largely governed by the surface characteristics of the scaffold. In order to obtain the desired surface properties, the use of non-thermal plasmas for selective surface modification has been a rapidly growing field. Chapter 10 presents recent advances in plasma-assisted surface modification of biodegradable polymers.

Poly(lactic acid) (PLA) has gained increasing attention as a polyester material. **C**hapter 11 deals with (i) synthesis of PLA, (ii) modification of PLA to improve its properties, and (iii) biomedical application of PLA. For PLA synthesis, different synthetic methods are described, especially direct polycondensation and ring-opening polymerization, which are presently the main synthetic methods used to obtain PLA. In order to be suitable for specific biomedical applications, PLA has been modified mainly concerning its bulk properties and surface chemistry. To achieve this, both chemical modification and physical modification have been tried, involving the incorporation of functional monomers with different molecular architectures and compositions, the tuning of crystallinity and processibility via blending and plasticization. PLA has been employed to manufacture tissue engineering scaffolds, drug delivery system materials, and bioabsorbable medical implants, due to its bioresorbability and biocompatibility in the human body.

XIV Preface

for drug delivery.

receptors involved in the mechanisms of action for acute pain: a-amino-3-hydroxy- 5 methyl-isoxazole-4-propionic acid (AMPA) receptors; (iv) receptors of importance in the sensation of chronic pain: N-methyl- D-aspartate (NMDA) receptors; the activation of NMDA receptors causes the release of peptide neurotransmitter SP, which amplifies the pain by causing the spinal neurons transmitting the pain to be easily stimulated; (v) modes of treatment for OA for decreasing pain and improving function through analgesics, non-steroidal anti-inflammatory drugs and joint injections, and surgery

**In Section 2, we deal with Biomaterials and Implants.** Among biomaterials, we have included herein: (i) non-thermal plasma surface modification of biodegrable polymers employed in sutures and biodegradable scaffolds, (ii) synthesis and surface modification of polylactic acid (PLA) based biomaterials employed in tissue engineering scaffolds and drug delivery systems, and (iii) multifunctional magnetic nanoparticles as contrast agents for magnetic resonance imaging (MRI) and as carriers

During the past two decades, there has been a considerable interest in the development and production of biodegradable polymers. Besides their use as packaging materials, biodegradable polymers play a major role in biomedicine as sutures, temporary prostheses and drug delivery vehicles. Biodegradable polymers have also been studied as three-dimensional porous structures (scaffolds) in the tissue engineering domain. The ultimate goal of this technology is to generate completely biocompatible tissues that can be used to replace damaged or diseased tissues in reconstructive surgery. Ideally, the scaffold material should be able to support initial cell growth and further proliferation, and should have the ability to biologically degrade over time while leaving behind a reproduced functional tissue. The success of polymeric biodegradable scaffolds is however determined by the response it elicits from the surrounding biological environment and this response is largely governed by the surface characteristics of the scaffold. In order to obtain the desired surface properties, the use of non-thermal plasmas for selective surface modification has been a rapidly growing field. Chapter 10 presents recent advances in plasma-assisted

Poly(lactic acid) (PLA) has gained increasing attention as a polyester material. **C**hapter 11 deals with (i) synthesis of PLA, (ii) modification of PLA to improve its properties, and (iii) biomedical application of PLA. For PLA synthesis, different synthetic methods are described, especially direct polycondensation and ring-opening polymerization, which are presently the main synthetic methods used to obtain PLA. In order to be suitable for specific biomedical applications, PLA has been modified mainly concerning its bulk properties and surface chemistry. To achieve this, both chemical modification and physical modification have been tried, involving the incorporation of functional monomers with different molecular architectures and compositions, the tuning of crystallinity and processibility via blending and plasticization. PLA has been employed to manufacture tissue engineering scaffolds,

involving joint replacement with plastic, metal or ceramic implants.

surface modification of biodegradable polymers.

Multifunctional magnetic nanoparticles (MFMNPs) possess unique magnetic properties and the ability to function at the cellular and molecular level of biological interactions, making them an attractive platform as contrast agents for magnetic resonance imaging (MRI) and as carriers for drug delivery. Nanomedical platforms, based on superparamagnetic iron oxide nanoparticles, have useful applications, for magnetic targeting, contrast enhancement in magnetic resonance imaging, and hyperthermia in response to an external alternating magnetic field. For biomedical applications, superparamagnetic iron oxide nanoparticles are usually composed of a single domain magnetic core (less than 20 nm in diameter) and a hydrophilic coating that enables the nanoparticles to be biocompatible and dispersible in water. Chapter 12 deals with: (i) a multifunctional nanoplatform of a superparamagnetic Fe3O4 core and a block copolymer (methoxy poly(ethylene glycol)-*b*-poly(methacrylic acid-*co*-*n*-butyl methacrylate)-*b*-poly(glycerol monomethacrylate), denoted MPEG-*b*-P(MAA-*con*BMA)-*b*-PGMA) shell; (ii) the loading of anticancer agent adriamycin (ADR) into the nanocarrier, release of loaded drug molecules, and enhancement of delivery efficiency and cancer specificity by anchoring folic acid (FA) onto the nanoparticles for recognition by folate receptors on surface of cancer cells; (iii) fabrication of a nanoplatform with a magnetite core, for the targeted delivery of carboxyl groupcontaining drugs using anticancer agent chlorambucil; (iv) loading of chlorambucil into the nanocarrier by a combination of ionic and hydrophobic interactions, with the release rate of loaded chlorambucil at pH 7.4, and increasing significantly at acidic pH.

In chapter 13, on drug eluting stents (DES) deployed in blocked arteries, we have discussed how the drug coating suppresses the process of smooth muscle cell migration from the medial layer of artery to the lumen to thereby mitigate vascular restenosis. This chapter (i) addresses the mechanisms and biological implications of mass transport of drugs from the stents into the arterial wall, , and (ii) provides a validated numerical model to simulate arterial drug concentrations after stent implantation and the transport of therapeutic levels of drugs within the artery wall.

In Chapter 14, we discuss how biosurfactants application on medical insertion devices (such as urethral catheters) serve as anti-adhesive coating agents against pathogens for prevention of microbial biofilm formation on these devices. The antimicrobial activity property of biosurfactants disrupts membranes, leading to cell lysis against bacterial pathogens, fungi and viruses. Biosurfactants also serve as anti-inflammatory, antitumour, immunosuppressive and immunomodulating agents. They can be employed: (i) in self-assembly, human cells stimulation and differentiation, interaction with stratum corneum lipids, cell-to-cell signalling, and hemolytic activity; (ii) in biotechnology and nanotechnology, as means of introducing foreign genes into target cells due to their high transfection efficiency, low toxicity, ease of preparation and targeted application; (iii) in the enhancement of the gene transfection efficiency of cationic liposomes, in gene therapy and drug delivery.

XVIII Preface

Contact Lens (COL) production is one of the fastest growing sectors in medical device industry. Supporting this high development trend requires non-destructive surface analysis methods on the nanometer scale, to further enhance production quality as well as therapy efficiency. The magnetic property of contact lenses (COL), as optical material, has influence on electrical and magnetic light signals properties. This multimodal research comprises measurement of intermolecular interactions on the basis of optical, mechanical, morphological and magnetic properties of contact lens material. As discussed in Chapter 15, the approach to COL structure and function analysis on the molecular level requires the usage of high precision technologies, such as atomic force microscopy (AFM) and magnetic force microscopy (MFM), in order to describe and quantitatively measure the influence of processing parameters on the final surface quality.

The introduction of an implant in a living body causes inflammation phenomena and also frequently triggers infection processes. Those problems can be overcome by using local drug delivery methods to confine pharmaceuticals, as antibiotics, antiinflammatory, and anti-carcinogens. In this context, the sol-gel process has been widely used in the preparation of organic-inorganic hybrid materials, non-linear optical materials, and mesomoporous materials. This family of organic-inorganic hybrid materials has interesting properties, such as molecular homogeneity, transparency, flexibility and durability. Such hybrids are promising materials for applications as biomaterials and contact lenses. Chapter 16 deals with synthesis and characterisation methods of organic-inorganic hybrid biomaterials to be used for controlled drug delivery applications, with a focus on the science of sol-gel processing, involving areas of physics (e.g. fractal geometry and percolation theory) and chemistry (mechanisms of hydrolysis and polycondensation) and ceramics (sintering and structural relaxation).

**Section 3 is on Biomedical Engineering.** Chapter 17 in this section is on Diabetes mechanisms, detection and monitoring. Diabetes mellitus (DIM), defined as a state chronic hyperglycaemia resulting from absolute or relative impaired insulin synthesis/secretion and/or insulin action, remains the most common endocrine disorder of carbohydrate and lipid metabolism, worldwide. This chapter develops an enquiry into diabetes from many angles: (i) the cellular and molecular mechanisms of development of diabetes and its complications; (ii) bioengineering of the glucoseinsulin regulatory system, and its employment in the modeling of the oral glucose tolerance test data, to detect diabetes as well as persons at risk of being diabetic; (iii) analysis of heart rate variability signals to depict diabetes; (iv) analysis of retinal and plantar images to characterize diabetes complications; (v) diagnosis of diabetic autonomic neuropathy complication by means of an integrated index composed of indices based on heartrate variability power spectrum plots of normal subjects, diabetic patients and ischemic heart disease patients; (v) application of the glucoseinsulin regulatory system to formulate an insulin delivery system for controlling blood sugar.

Software engineering designs and practices differ widely among various application domains. Chapter 18 is on high performance software engineering design for bioinformatics and more specifically for diabetes mellitus study through gene and retinopathy analysis. Complex gene interaction study offers an effective control of blood glucose, blood pressure and lipids. Early detection of retinopathy is effective in minimizing the risk of irreversible vision loss and other long-term consequence associated with diabetes mellitus.

XVI Preface

final surface quality.

structural relaxation).

sugar.

Contact Lens (COL) production is one of the fastest growing sectors in medical device industry. Supporting this high development trend requires non-destructive surface analysis methods on the nanometer scale, to further enhance production quality as well as therapy efficiency. The magnetic property of contact lenses (COL), as optical material, has influence on electrical and magnetic light signals properties. This multimodal research comprises measurement of intermolecular interactions on the basis of optical, mechanical, morphological and magnetic properties of contact lens material. As discussed in Chapter 15, the approach to COL structure and function analysis on the molecular level requires the usage of high precision technologies, such as atomic force microscopy (AFM) and magnetic force microscopy (MFM), in order to describe and quantitatively measure the influence of processing parameters on the

The introduction of an implant in a living body causes inflammation phenomena and also frequently triggers infection processes. Those problems can be overcome by using local drug delivery methods to confine pharmaceuticals, as antibiotics, antiinflammatory, and anti-carcinogens. In this context, the sol-gel process has been widely used in the preparation of organic-inorganic hybrid materials, non-linear optical materials, and mesomoporous materials. This family of organic-inorganic hybrid materials has interesting properties, such as molecular homogeneity, transparency, flexibility and durability. Such hybrids are promising materials for applications as biomaterials and contact lenses. Chapter 16 deals with synthesis and characterisation methods of organic-inorganic hybrid biomaterials to be used for controlled drug delivery applications, with a focus on the science of sol-gel processing, involving areas of physics (e.g. fractal geometry and percolation theory) and chemistry (mechanisms of hydrolysis and polycondensation) and ceramics (sintering and

**Section 3 is on Biomedical Engineering.** Chapter 17 in this section is on Diabetes mechanisms, detection and monitoring. Diabetes mellitus (DIM), defined as a state chronic hyperglycaemia resulting from absolute or relative impaired insulin synthesis/secretion and/or insulin action, remains the most common endocrine disorder of carbohydrate and lipid metabolism, worldwide. This chapter develops an enquiry into diabetes from many angles: (i) the cellular and molecular mechanisms of development of diabetes and its complications; (ii) bioengineering of the glucoseinsulin regulatory system, and its employment in the modeling of the oral glucose tolerance test data, to detect diabetes as well as persons at risk of being diabetic; (iii) analysis of heart rate variability signals to depict diabetes; (iv) analysis of retinal and plantar images to characterize diabetes complications; (v) diagnosis of diabetic autonomic neuropathy complication by means of an integrated index composed of indices based on heartrate variability power spectrum plots of normal subjects, diabetic patients and ischemic heart disease patients; (v) application of the glucoseinsulin regulatory system to formulate an insulin delivery system for controlling blood The main objective of Chapter 19 is to present a method for modeling an ample variety of flows in tubes and channels, considering steady, non-steady, Newtonian and non-Newtonian flows. The method is based upon a specific shape factor that is imposed in the solution for the velocity field, thus making it possible to impose boundary conditions that determine tube or channel contour shapes. In this way, flows in tubes and channels of non-circular geometry or axially-varying cross-sections can be analyzed by means of the velocity, pressure and shear-stress fields. Knowledge of these flows is useful in the study of surgical interventions in pathological arteries and veins, and in microfluidics applications. In particular, zones of low velocity and low shear stress can be determined, which are considered risk zones related to the development of stenosis and other artery diseases. Specific applications included are (1) flow in straight tubes of constant non-circular cross-section: Newtonian unsteady, and steady plastic flows, (2) axially-varying flows in conduits: Newtonian flow in round tubes of arbitrarily axially- varying cross-section, and steady plastic flow in undulating channels.

Adrenaline and Noradrenaline changes incite changes in blood pH, buffer parameters like HCO3, lactate and blood glucose as well as electrolytes like K, Na, Ca and Mg. These parameters constitute interdependent stress-hormone effects. They can be put on organisms like a data-net, by especially designed online software, (i) to assess their workload, stress compatibility and stress duration, intensity and the kind of stress, (ii) by collecting 100 microliters of capillary blood within 3 minutes, using transportable intensive care equipment. In chapter 20 on Clinical Stress assessment, this approach is employed to: 1) determine the impact of sport training and military training units, fire fighters and others, to link changes of blood parameters not only with sportive success but also to predict success chances before competition; 2) determine mental stress as well as stress by combined psychical and physical workload; 3) determine idiosyncrasies of diabetic metabolism, namely importance of mineral deficiencies in type2 diabetics as well as new aspects of metabolic differences between hypertonic and normotonic diabetics; 4) mathematically develop "situation dependent values", to assess responses to simulated stress, and predict ability to sustain stress; 5) quantify predictions of success chances in competing animals like horses or camels, and provide stress documentations for prevention of cruelty to animals.

Neuropsychiatric disorders account for over 30% of all years lived with disability (YLD), globally. The combination of relatively easy-to-administer psychiatric assessments and emerging health information technology can aid in the treatment of psychiatric disorders. Neurotechnology, that enables psychiatric conditions to be estimated from physiological measurements and more frequent feedback on the course of therapy, would be useful for treating neuropsychiatric disorders. Also, the development of neurotechnology, that can effectively measure changes in brain function due to administration of drugs, can be very useful during the long and expensive drug testing process. If brain function and behavior are mirrors of each other, then biomarkers of mental disorders may be hidden in subtle and complex patterns of neurobiological data. A key challenge in clinical neuroscience is to discover the relationship between brain function and behavioral patterns that are indicative of mental disorders. The challenge for biomedical engineers is hence to design devices and algorithms that enable affordable measurements of brain function that can be used in clinical setting for assessing neuro-psychiatric disorders.

Chapter 21 reviews recent advances in neuroscience. The physics of complex systems and neurotechnology together may enable innovations in the diagnosis, classification and management of psychiatric disorders. Complex neurophysiological mechanisms underlying abnormal mental function cannot be understood by reduction to simple measures. Measurements of brain electrical activity with EEG has long been a valuable source of information for neuroscience research, yet underutilized for clinical and diagnostic applications. To fully exploit this data, methods for discovering nonlinear patterns and deeper understanding of the relationship between emergent complex signal features and the underlying neurophysiology are needed. Analysis of EEG signal complexity and transient synchronization may reveal information about local neural structure and long-range communication between brain regions. Research suggests that patterns in these EEG signal features may contain key biomarkers of abnormal information processing that is a central characteristic of many mental disorders. The development of novel EEG sensors, with improved resolution (together with new algorithms), promises continued improvement in the ability to measure subtle variations in brain function and yield a new window into the mind.

Mars manned mission requires resolution of problems on the ground with test subjects, related to crew life-support and psychological stability. In chapter 22, we deal with life support system virtual simulators for Mars-500 Ground-based experiment. In order to make interplanetary missions a reality, it is necessary to provide special crew's trainings. However use of full-scale systems at first phases of ground simulation of spaceflight to Mars is extremely complicated and economically unprofitable. A more rational approach is (i) the application of standard system virtual simulators interacting with simulation models for both environment and crew as a load component, and (ii) integrated in a single Hardware/Software Complex for Serving Operational Systems (HSCSOS) by crew, intended for system functioning in normal, off-normal, emergency situations in systems and deviation of environment controllable parameters from specified values. An additional biomedico-engineering system can be incorporated in the HSCSOS hardware architecture to perform psychophysiological tests. This chapter provides analysis of all possible approaches to development of such complexes based on simulation of long-duration space missions. The results can be used in development of similar hardware/software complexes to analyze complicated human-machine interaction and specialist training for variouspurpose Man-Made Ecosystems (MMES).The final chapter 23 in this section describes the traditions and the present status of medical physics and biomedical engineering education in Poland. A detailed history of the development of these specializations is provided with the example of the Multidisciplinary School of Engineering in Biomedicine founded in 2005 at the Akademia Gorniczo-Hutnicza (AGH) University of Science and Technology in Krakow. This program of studies incorporates a single 7 semester track leading to the First (Undergraduate) Degree (Bachelor's/Engineer's); five domain-oriented 4-semester tracks leading to the Second (Graduate) Degree (Master's), and a single 8-semester track leading to the Third Degree (Doctor's). The program provides special adaptation mechanisms to develop students' connection to prospective workplaces. Considerable emphasis is placed on specific characteristics of BME-related corporate culture that requires mutual understanding and good cooperation within multidisciplinary teams striving for technical excellence. The chapter also describes opportunities and perspectives of all BME-teaching institutions in Poland. The syllabi and curricula of the degree programs are included in the Appendix.

### Now we start the next **Section 4 on Biotechnology.**

XVIII Preface

psychiatric disorders. Neurotechnology, that enables psychiatric conditions to be estimated from physiological measurements and more frequent feedback on the course of therapy, would be useful for treating neuropsychiatric disorders. Also, the development of neurotechnology, that can effectively measure changes in brain function due to administration of drugs, can be very useful during the long and expensive drug testing process. If brain function and behavior are mirrors of each other, then biomarkers of mental disorders may be hidden in subtle and complex patterns of neurobiological data. A key challenge in clinical neuroscience is to discover the relationship between brain function and behavioral patterns that are indicative of mental disorders. The challenge for biomedical engineers is hence to design devices and algorithms that enable affordable measurements of brain function that can be used

Chapter 21 reviews recent advances in neuroscience. The physics of complex systems and neurotechnology together may enable innovations in the diagnosis, classification and management of psychiatric disorders. Complex neurophysiological mechanisms underlying abnormal mental function cannot be understood by reduction to simple measures. Measurements of brain electrical activity with EEG has long been a valuable source of information for neuroscience research, yet underutilized for clinical and diagnostic applications. To fully exploit this data, methods for discovering nonlinear patterns and deeper understanding of the relationship between emergent complex signal features and the underlying neurophysiology are needed. Analysis of EEG signal complexity and transient synchronization may reveal information about local neural structure and long-range communication between brain regions. Research suggests that patterns in these EEG signal features may contain key biomarkers of abnormal information processing that is a central characteristic of many mental disorders. The development of novel EEG sensors, with improved resolution (together with new algorithms), promises continued improvement in the ability to measure subtle variations in brain function and yield a new window into the mind.

Mars manned mission requires resolution of problems on the ground with test subjects, related to crew life-support and psychological stability. In chapter 22, we deal with life support system virtual simulators for Mars-500 Ground-based experiment. In order to make interplanetary missions a reality, it is necessary to provide special crew's trainings. However use of full-scale systems at first phases of ground simulation of spaceflight to Mars is extremely complicated and economically unprofitable. A more rational approach is (i) the application of standard system virtual simulators interacting with simulation models for both environment and crew as a load component, and (ii) integrated in a single Hardware/Software Complex for Serving Operational Systems (HSCSOS) by crew, intended for system functioning in normal, off-normal, emergency situations in systems and deviation of environment controllable parameters from specified values. An additional biomedico-engineering system can be incorporated in the HSCSOS hardware architecture to perform psychophysiological tests. This chapter provides analysis of all possible approaches to

in clinical setting for assessing neuro-psychiatric disorders.

The preparation of polymer-anticancer drug conjugates is an effective way to improve the efficacy and decrease the toxicity of anticancer drugs. Chapter 24 deals with polymer-drug conjugates, which are made by combining a suitable polymeric carrier, a biodegradable linker and a bioactive anticancer agent, to form the basis of a new generation of anticancer agents. Poly (L-glutamic acid)-paclitaxel conjugate is a polymer-drug conjugate that links anticancer agent paclitaxel (PTX) to poly (Lglutamic acid) (PG). PG-PTX conjugate can improve the anticancer activity and the pharmacokinetic properties of PTX.

Hydrophobic interaction chromatography (HIC) is a powerful technique used for separating homologous proteins, receptors, antibodies, recombinant proteins and nucleic acids. Macromolecule retention in HIC is promoted by hydrophobic interactions between the HIC support and the macromolecule, and it is governed by an entropy change. The thermodynamics fundamentals of protein retention in HIC are discussed in this chapter 25. The strength of the interaction depends mainly on the properties of the HIC support and on the macromolecule hydrophobicity, which can be defined by different approaches. The hydrophobic interaction is weakened by a decrease in the ionic strength in the mobile phase, thus producing the elution of the macromolecule. The effect of the type and concentration of salt has been modeled through a thermodynamic model that considers macromolecule retention due to electrostatic and hydrophobic interactions. The outcome of a HIC process is a chromatogram, which can be described by the dimensionless retention time (DRT) of a macromolecule. HIC constitutes a purification tool suitable for biomedical applications, such as purification of vaccines, therapeutic proteins, plasmids and antibodies. In addition, the use of chromatography in high-throughput studies, such as proteomics and protein interactomics, is increasing.

Protein scaffolds have been employed as frameworks for innovative peptide drug development. New functions can be introduced to protein scaffolds through engineering processes. The antibody scaffold is one of the most extensively studied scaffolds. Although it is widespread in biomedical applications, the disadvantages of antibody stagnate its development in biomedical applications. In recent years, there is an urgent demand for new promising protein scaffolds in biomedical applications. The cysteine-knot scaffold demonstrates a rigid structure and ultra-stable characteristics. The proteins containing the scaffold usually serve as the defender in the innate immunity of their host. These proteins exhibit low sequence identity, but share a common three-dimensional structure. The structure is stabilized and sealed with two to four disulfide bridges. The scaffold has been reported to be engineered and to exhibit new functions. For its excellent properties, it is believed that the scaffold can fit the required criteria and serve as a fundamental building block for peptide drug development. Proteins with CSαb motif widely exist in crops and vegetables; they affect physiological regulations, and have been employed as remedies in traditional Chinese therapies. In chapter 26, we discuss the possible stratagem and the bottlenecks to engineer the CSαb motif for biomedical applications.

Liposomes represent ideal carrier/delivery systems for the components of synthetic vaccines, due to their biodegradability and ability to retain and incorporate a variety of essential vaccine components simultaneously. Different synthetic vaccine components can be encapsulated within the aqueous cavities of liposomes (if hydrophilic) or associated with liposome bilayers (if at least partially hydrophobic in character). Furthermore, essential components can be attached to either internal or external outer leaflet membrane by electrostatic, covalent or metallochelation interactions. The most diverse synthetic vaccine components are typically adjuvants needed to provoke innate immune reactions (e.g. monophosphoryl lipid A [MPL A], CpG oligonucleotides, muramyl dipeptide [MDP] and analogues). In addition, these can be combined with antigens needed to provoke specific immunity such as soluble or membrane proteins, synthetic peptides and oligosacharide antigens. Finally, liposomes may present ligands to assist functional delivery of antigens and adjuvants to antigen-presenting cells necessary to invoke immunostimulation. Chapter 27 discusses applications of Liposomes for construction of vaccines. Owing to biodegradability and safety, liposomes are compatible with various routes of application (intranasal, intramuscular, intradermal, peroral, sublingual, etc.). This is the main advantage of liposomes over other adjuvants. Many new synthetic components like cationic lipids, neoglycolipids, activated lipids and metallochelating lipids are now available for construction of liposomal carriers tailored for specific antigen. New synthetic adjuvants are being designed and tested, e.g. compounds based on muramyl or norAbu-muramyl peptides, CpG oligonucleotides and MPL-A. The potential for the participation of liposome-based recombinant vaccines in the human and veterinary vaccine market is very promising.

XX Preface

applications, such as purification of vaccines, therapeutic proteins, plasmids and antibodies. In addition, the use of chromatography in high-throughput studies, such as

Protein scaffolds have been employed as frameworks for innovative peptide drug development. New functions can be introduced to protein scaffolds through engineering processes. The antibody scaffold is one of the most extensively studied scaffolds. Although it is widespread in biomedical applications, the disadvantages of antibody stagnate its development in biomedical applications. In recent years, there is an urgent demand for new promising protein scaffolds in biomedical applications. The cysteine-knot scaffold demonstrates a rigid structure and ultra-stable characteristics. The proteins containing the scaffold usually serve as the defender in the innate immunity of their host. These proteins exhibit low sequence identity, but share a common three-dimensional structure. The structure is stabilized and sealed with two to four disulfide bridges. The scaffold has been reported to be engineered and to exhibit new functions. For its excellent properties, it is believed that the scaffold can fit the required criteria and serve as a fundamental building block for peptide drug development. Proteins with CSαb motif widely exist in crops and vegetables; they affect physiological regulations, and have been employed as remedies in traditional Chinese therapies. In chapter 26, we discuss the possible stratagem and the bottle-

Liposomes represent ideal carrier/delivery systems for the components of synthetic vaccines, due to their biodegradability and ability to retain and incorporate a variety of essential vaccine components simultaneously. Different synthetic vaccine components can be encapsulated within the aqueous cavities of liposomes (if hydrophilic) or associated with liposome bilayers (if at least partially hydrophobic in character). Furthermore, essential components can be attached to either internal or external outer leaflet membrane by electrostatic, covalent or metallochelation interactions. The most diverse synthetic vaccine components are typically adjuvants needed to provoke innate immune reactions (e.g. monophosphoryl lipid A [MPL A], CpG oligonucleotides, muramyl dipeptide [MDP] and analogues). In addition, these can be combined with antigens needed to provoke specific immunity such as soluble or membrane proteins, synthetic peptides and oligosacharide antigens. Finally, liposomes may present ligands to assist functional delivery of antigens and adjuvants to antigen-presenting cells necessary to invoke immunostimulation. Chapter 27 discusses applications of Liposomes for construction of vaccines. Owing to biodegradability and safety, liposomes are compatible with various routes of application (intranasal, intramuscular, intradermal, peroral, sublingual, etc.). This is the main advantage of liposomes over other adjuvants. Many new synthetic components like cationic lipids, neoglycolipids, activated lipids and metallochelating lipids are now available for construction of liposomal carriers tailored for specific antigen. New synthetic adjuvants are being designed and tested, e.g. compounds based on muramyl or norAbu-muramyl peptides, CpG oligonucleotides and MPL-A.

proteomics and protein interactomics, is increasing.

necks to engineer the CSαb motif for biomedical applications.

Embryonic Stem Cells (ESCs), the topic of chapter 28, have been a focus of biomedical research in regenerative medicine and tissue engineering for more than ten years, because of their potential to give rise to cells of all three germ layers, a property termed pluripotency. However, progress to clinical translation in this field faces significant obstacles that include immune incompatibility and ethical concerns surrounding the use of human blastocyst embryos and therapeutic cloning, which have led to several high- profile legal challenges to continued funding. It has been recently discovered that adult somatic cells, including easily-obtained fibroblasts and lymphocytes, can be directly reprogrammed back to a primordial state of being functionally identical to ESCs. These Induced Pluripotent Stem Cells (iPSCs) not only circumvent ethical obstacles to clinical use of ESCs, but also are isogenic and negate concerns of immune complications in patients. Additional iPSCs also provide optimal substrate for gene-specific targeting to fix the genetic defects and subsequently treat these diseases using regenerative approaches. Induced pluripotency has therefore significantly improved the potential of cell and tissue engineering and is poised to take it closer to translational regenerative medicine.

Chapter 29 is on Genetic modification of Domestic animals for Agriculture and Biomedical applications The production of genetically modified animals greatly improves their utility in agriculture, as biomedical research models of human diseases, for the production of recombinant pharmaceutical proteins, and for making organs with greater potential for xenotransplantation. While numerous strategies have been used in the production of transgenic large animals, cell-based transgenesis followed by somatic cell nuclear transfer (SCNT) is currently the most widely applied method. Novel strategies for making specific modifications to somatic cells are rapidly being developed that allow targeted, conditional and tissue specific modifications to the mammalian genome. Continued utilization of cell-based transgenesis followed by SCNT will require improvements in efficiency, particularly in the areas of making targeted genetic modifications and in SCNT. This chapter discusses current and expanding applications for transgenic domestic species, emerging strategies to improve targeted genetic modification frequency of somatic cells, and methods to improve the efficiency of SCNT.

Angiogenesis and lymphangiogenesis are involved in regulation of tissue growth during development, regeneration, and in adults. Furthermore, deregulated angiogenesis/lymphangiogenesis may result in the onset and progression of cancer, cardiovascular disease, obesity, diabetes, ophthalmological diseases and chronic inflammation. Knowledge of the fundamental mechanisms of angiogenesis and lymphangiogenesis can therefore assist us in identifying new molecular targets for therapeutic intervention against such pathologies. In vivo animal models are essential for the study of angiogenesis and lymphangiogenesis, and are employed to study vascular formation, remodeling, permeability, maturation, and stability. Chapter 30 provides methodological tools and fundamental information about the most commonly used animal models of angiogenesis and lymphangiogenesis, employed in angiogenesis research.

Chapter 31 describes the legal and ethical issues which surround the practice of biobanking human clinical materials. The storing of human tissues has long stimulated public debate due to a series of recent and historical scandals which have stimulated new legislation to regulate the practice. Examples of important criminal cases which have resulted in new legal requirements or clarification of ethical principles are highlighted in this chapter. Particular issues covered include issues of informed consent, which in modern history were described in the Nuremberg code and more recently in the Helsinki Declaration. These ethical and legislative aspects of biobanking in the UK are addressed in theory and in practice. We also describe the working practice of the Infectious Diseases BioBank in London (UK), as a model system which has the aim of facilitating and expediting medical research into infectious agents whilst meeting and often exceeding current day requirements.

The last Section 5 is on Physiological systems engineering in Medical assessment. It deals with formulation and analysis of physiological systems, identification of parameters representing systems performance, and combining these parameters into a system index which can be employed in medical assessment.

In Chapter 32 , we study the course (i) of cardiomyopathy diseased LVs (with myocardial infarcts) progressing to heart failure (HF) through LV remodeling and decreased LV contractility, and (ii) their recovery through surgical therapeutic interventions of CABG and Surgical ventricular restoration (SVR), by restoration of myocardial ischemic segments, reversal of LV remodeling and improvement in LV contractility. For this purpose, we first provide the methodology for detecting myocardial infarcts. Then, we characterize LV remodeling of cardiomyopathy diseased LVs (with myocardial infarcts) in terms of reduced change in curvedness from end-diastole to end-systole. In these LVs, there is also reduced contractility; so we provide an index for cardiac contractility, in terms of maximal rate-of-change of normalized wall stress, dσ\*/dtmax, and its decrease in an infarcted LV progressing to heart failure. We provide clinical studies of remodelled cardiomyopathy diseased LVs, in terms of reduced values of their curvedness index and contractility index. By way of CABG surgical intervention, we have presented the hemodynamic flow simulation of the CABG, and pointed out certain factors and sites of wall shear stresses that cause intimal damage of vessels and hyperplasia, as potential causes for decreased graft patency. We have shown that surgical ventricular restoration (SVR), in conjunction with CABG, is seen to benefit the ischemic-infarcted heart, by (i) restoration of cardiac remodeling index of 'end-diastolic to end-systolic curvedness change', (ii) reduction of regional wall stresses, and (iii) augmentation of the cardiac contractility index value.

In Chapter 33 , we present how the renal system is intrinsically designed as a functionally optimal system for filtration and regulation of urine concentration as well as renal clearance of unwanted metabolic substrates such as creatinine. This chapter analyses how the kidney performs its urine concentration ability, through various mechanisms, focussing on the countercurrent multiplier mechanism operating in the loop of Henle and its medullary vicinity. This mechanism is physiologically engineered to increase and critically maintain at steady-state the hyperosmolality of the renal medullary interstitium to as high as 4 times normal blood osmolality, so as to produce a highly concentrated urine in the interest of conserving needed water. The linear coupled system model of the Loop of Henle is seen to account for the salient physiological features of this mechanism quantitatively. Analysis of the way the kidney optimally handles waste metabolites, specifically creatinine (one of its most important functions) is carried out by using a single-compartment kinetic model, with continuous input of metabolic substrate. The continuous input case is aimed at reproducing the in-vivo physiological conditions under which the kidney functions within the body. The analytical solutions for the continuous input case are obtained, and predict that the body waste metabolite creatinine level in the blood varies with renal clearance as an inverse rectangular hyperbolic function. The kinetics of the kidney's handling of the metabolic waste product creatinine, shown by convolution analysis on the single-compartment model, demonstrates how the blood creatinine is bounded, and stabilizes to an asymptotically steady-state concentration. The analysis predicts reasonable estimates for the actual serum creatinine levels in the body, based on empirical renal clearance and creatinine substrate input parameters.

XXII Preface

angiogenesis research.

provides methodological tools and fundamental information about the most commonly used animal models of angiogenesis and lymphangiogenesis, employed in

Chapter 31 describes the legal and ethical issues which surround the practice of biobanking human clinical materials. The storing of human tissues has long stimulated public debate due to a series of recent and historical scandals which have stimulated new legislation to regulate the practice. Examples of important criminal cases which have resulted in new legal requirements or clarification of ethical principles are highlighted in this chapter. Particular issues covered include issues of informed consent, which in modern history were described in the Nuremberg code and more recently in the Helsinki Declaration. These ethical and legislative aspects of biobanking in the UK are addressed in theory and in practice. We also describe the working practice of the Infectious Diseases BioBank in London (UK), as a model system which has the aim of facilitating and expediting medical research into

infectious agents whilst meeting and often exceeding current day requirements.

system index which can be employed in medical assessment.

The last Section 5 is on Physiological systems engineering in Medical assessment. It deals with formulation and analysis of physiological systems, identification of parameters representing systems performance, and combining these parameters into a

In Chapter 32 , we study the course (i) of cardiomyopathy diseased LVs (with myocardial infarcts) progressing to heart failure (HF) through LV remodeling and decreased LV contractility, and (ii) their recovery through surgical therapeutic interventions of CABG and Surgical ventricular restoration (SVR), by restoration of myocardial ischemic segments, reversal of LV remodeling and improvement in LV contractility. For this purpose, we first provide the methodology for detecting myocardial infarcts. Then, we characterize LV remodeling of cardiomyopathy diseased LVs (with myocardial infarcts) in terms of reduced change in curvedness from end-diastole to end-systole. In these LVs, there is also reduced contractility; so we provide an index for cardiac contractility, in terms of maximal rate-of-change of normalized wall stress, dσ\*/dtmax, and its decrease in an infarcted LV progressing to heart failure. We provide clinical studies of remodelled cardiomyopathy diseased LVs, in terms of reduced values of their curvedness index and contractility index. By way of CABG surgical intervention, we have presented the hemodynamic flow simulation of the CABG, and pointed out certain factors and sites of wall shear stresses that cause intimal damage of vessels and hyperplasia, as potential causes for decreased graft patency. We have shown that surgical ventricular restoration (SVR), in conjunction with CABG, is seen to benefit the ischemic-infarcted heart, by (i) restoration of cardiac remodeling index of 'end-diastolic to end-systolic curvedness change', (ii) reduction of regional wall stresses, and (iii) augmentation of the cardiac contractility index value.

In Chapter 33 , we present how the renal system is intrinsically designed as a functionally optimal system for filtration and regulation of urine concentration as well Next we present, in chapter 34 , Lung ventilation modeling for assessment of lung status, for detection of lung diseases and for prescribing an index for weaning of COPD patients on mechanical ventilation. In pulmonary medicine, it is important to detect lung diseases, such as chronic obstructive pulmonary disease (COPD), emphysema, lung fibrosis and asthma. These diseases are characterized in terms of lung compliance and resistance-to-airflow parameters. Another important endeavour of pulmonary medicine is mechanical ventilation of COPD patients and determining when to wean off these patients from the mechanical ventilator. In both these medical domains, lung ventilation dynamics plays a key role. So in this chapter, we develop the lung ventilation dynamics model in terms of monitored lung volume (*V*) and driving pressure (*PN*), in the form of a differential equation with parameters of lung compliance (*C*) and resistance-to-airflow (*R*). Now, *PN = PL – Pel0* (elastic *recoil p*ressure @ end-expiration) = *Pm* (pressure at mouth) - *Pp* (pleural pressure) – *Pel0* (= *PL @* endexpiration)*.* We obtain the solution of this equation in the forms of lung volume (*V*) function of *PN*, *C* and *R*. For the monitored lung volume *V* and pressure *PN* data, we can evaluate *C* and *R* by matching the model solution expression with the monitored lung volume V and driving pressure *PN* data. So what we have done here is to develop the method for determining the average values of *C* and *R* during the ventilation cycle. A more convenient way for detecting lung disease is to combine *R* and *C* along with some ventilator data (such as tidal volume and breathing rate) into a non-dimensional lung ventilator index (LVI). Then, we can determine the ranges of LVI for normal and disease states, and thereby employ the patient's computed values of LVI to designate a specific lung disease for the patient.

XXVI Preface

Now, in this methodology, we need to monitor (i) lung volume, by means of a spirometer, and (ii) lung pressure (*PN*) equal to *Pm* (pressure at mouth) minus pleural pressure (*Pp*). The pleural pressure measurement involves placing a balloon catheter transducer through the nose into the esophagus, whereby the esophageal tube pressure is assumed to be equal to the pressure in the pleural space surrounding it. This procedure cannot be carried out non-traumatically and routinely in patients. Hence, for routine and noninvasive assessment of lung ventilation for detection of lung disease states, it is necessary to have a method for determining *R* and *C* from only lung volume data. So, then, we have shown how we can compute *R*, *C* and lung pressure values non-invasively from just lung volume measurement. Finally, we have presented how the lung ventilation modeling can be applied to study the lung ventilation dynamics of COPD patients on mechanical ventilation. We have shown how a COPD patient's lung *C* and *R* can be evaluated in terms of the monitored lung volume and applied ventilatory pressure. We have also formulated a lung ventilator index to study and assess the lung status improvement of COPD patients on mechanical ventilation, and to decide when they can be weaned off mechanical ventilation.

Now we finally arrive at an epochal concept of nondimensional physiological indices or physiological numbers. In medicine, for making diagnosis, many tests are needed. It may so happen that some tests results may be in the normal range, while some test results may be abnormal. So how is the doctor going to precisely decide how "sick" is the patient: is s/he at risk, or marginal, or very sick?

Hence, in the last chapter 35, we have presented a new concept of a Nondimensional Physiological Index (NDPI). This NDPI is made up a number of parameters characterizing an organ function and dysfunction or a physiological system function and disorder or an anatomical structure's property and pathology, in the format of a medical assessment test; the NDPI combines these parameters into one nondimensional number. Thus, the NDPI enables the doctor to integrate all the parameters' values from the medical test into one non-dimensional index value or number. Then, by examining a large number of patients, we can determine the statistical distribution of that particular NDPI into normal and abnormal categories. This makes it convenient for the doctor to make the medical assessment or diagnosis.

Now for an organ or physiological system assessment test (such as a Treadmill test or Glucose tolerance test) or for an anatomical structure's property and pathology determination (such as for determining mitral valve calcification and pathology), the method of formulating and evaluating the NDPI (from the medical test) entails developing its bioengineering model's differential equation incorporating the parameters characterising the organ state or physiological system function or the anatomical structural constitutive property. These parameters are adroitly combined into a NDPI, so that the NDPI unambiguously conveys the normal and abnormal state of the organ or physiological system or the anatomical structure.

This bioengineering model's governing equation or its solution (involving the model parameters) is then applied to fit or simulate the monitored Test data of the physiological system or the anatomical structure. The model parameters are then evaluated (from the simulated solution to the Test data), and their ranges are determined for normal and abnormal states of the organ or physiological system or anatomical structure. Then, the NDPI (composed of the parameters of the organ function or physiological system function or the anatomical structural constitutive property) is also evaluated for normal and abnormal states of the patient's organ or physiological system or anatomical structure. In this way, we can apply these NDPIs to reliably diagnose the patient's health state, from preferably noninvasive medical assessment tests. In this chapter, we have developed a number of noninvasive medical tests involving NDPIs, based on biomedical engineering formulations of organ function, physiological system functional performance and anatomical structural constitutive property, to provide the means for reliable medical assessment and diagnosis. These tests include (i) some conventional tests, such as Treadmill and Glucose tolerance tests, as well as (ii) some of our newly formulated tests, to detect arteriosclerosis, aortic pathology, mitral valve calcification, and osteoporosis. Indeed, the development of NDPls for physiological systems and their clinical employment can revolutionise medical diagnosis and assessment.

XXIV Preface

ventilation.

diagnosis.

Now, in this methodology, we need to monitor (i) lung volume, by means of a spirometer, and (ii) lung pressure (*PN*) equal to *Pm* (pressure at mouth) minus pleural pressure (*Pp*). The pleural pressure measurement involves placing a balloon catheter transducer through the nose into the esophagus, whereby the esophageal tube pressure is assumed to be equal to the pressure in the pleural space surrounding it. This procedure cannot be carried out non-traumatically and routinely in patients. Hence, for routine and noninvasive assessment of lung ventilation for detection of lung disease states, it is necessary to have a method for determining *R* and *C* from only lung volume data. So, then, we have shown how we can compute *R*, *C* and lung pressure values non-invasively from just lung volume measurement. Finally, we have presented how the lung ventilation modeling can be applied to study the lung ventilation dynamics of COPD patients on mechanical ventilation. We have shown how a COPD patient's lung *C* and *R* can be evaluated in terms of the monitored lung volume and applied ventilatory pressure. We have also formulated a lung ventilator index to study and assess the lung status improvement of COPD patients on mechanical ventilation, and to decide when they can be weaned off mechanical

Now we finally arrive at an epochal concept of nondimensional physiological indices or physiological numbers. In medicine, for making diagnosis, many tests are needed. It may so happen that some tests results may be in the normal range, while some test results may be abnormal. So how is the doctor going to precisely decide how "sick" is

Hence, in the last chapter 35, we have presented a new concept of a Nondimensional Physiological Index (NDPI). This NDPI is made up a number of parameters characterizing an organ function and dysfunction or a physiological system function and disorder or an anatomical structure's property and pathology, in the format of a medical assessment test; the NDPI combines these parameters into one nondimensional number. Thus, the NDPI enables the doctor to integrate all the parameters' values from the medical test into one non-dimensional index value or number. Then, by examining a large number of patients, we can determine the statistical distribution of that particular NDPI into normal and abnormal categories. This makes it convenient for the doctor to make the medical assessment or

Now for an organ or physiological system assessment test (such as a Treadmill test or Glucose tolerance test) or for an anatomical structure's property and pathology determination (such as for determining mitral valve calcification and pathology), the method of formulating and evaluating the NDPI (from the medical test) entails developing its bioengineering model's differential equation incorporating the parameters characterising the organ state or physiological system function or the anatomical structural constitutive property. These parameters are adroitly combined into a NDPI, so that the NDPI unambiguously conveys the normal and abnormal state

of the organ or physiological system or the anatomical structure.

the patient: is s/he at risk, or marginal, or very sick?

**Prof. Dhanjoo N. Ghista** Consultant, Department of Graduate and Continuing Education Framingham University Massachusetts, USA
