Karnatak Law Society’s

GOGTE INSTITUTE OF TECHNOLOGY,

Belagavi

Biomedical System Design

Unit - I Introduction to System Science

 Syllabus
• Notion of dynamic systems:
• Modeling and simulation using Simulation tool –
• Biomedical systems as dynamic systems – Compartmental
modeling of biological systems –
• Eye movement model – Muscle model – Classical system
identification.
• Moral and ethical issues in developing Biomedical Systems
Morality and ethics –
• Two moral norms: beneficence and nonmaleficence –
• Human experimentation –
• Regulation of medical device innovation –
• Ethical issues in feasibility studies - Ethical issues in
treatment use.
 Notion of dynamic systems
• Dynamical system is a system that changes over time
according to a set of fixed rules that determine how one state
of the system moves to another state.
• Dynamical system is a phase space together with a
transformation of that space
• A dynamical system has two parts a state vector, which
describes exactly the state of some real or hypothetical system
a function, which tells us, given the current state, what the
state of the system will be in the next instant of time.
• A function can be described by a single function or by a set of
functions. Entire system can be then described by a set of
differential equations
 Modeling and simulation using Simulation tool

• Modeling: Mathematical representation of a physical system

• Simulation: Procedure of solving mathematical equations that
resulted from the model development.
• Capability of the model to capture physical parameters.
• Biomedical system examples
 Biomedical systems as dynamic systems

• Dynamical systems in many cases become a base for design and

implementation of methods of investigation and computer
modeling complex processes.
• Whereas for solving direct problems we have many well-developed
methods, results for inverse problems are much more modest.
• ECG and EEG system
• Eye movement model
• Muscle model
 Compartmental modeling of biological systems

• Compartmental models are composed of sets of interconnected

mixing chambers or stirred tanks.
• Each component of the system is considered to be homogeneous,
instantly mixed, with uniform concentration.
• The state variables are concentrations or molar amounts of chemical
species.
• This fundamental simplicity makes them easy to compute since
ordinary differential equations (ODEs) are readily solved numerically
and often analytically.
• While compartmental systems have a reputation for being merely
descriptive they can be developed to levels providing realistic
mechanistic features through refining the kinetics.
• Generally, one is considering multi-compartmental systems for
realistic modeling. Compartments can be used as "black" box
operators without explicit internal structure.
Compartmental modeling of biological systems - Eye
movement model – Muscle model
• Human eye movements have the potential to be convenient,
natural, fast input modes of computers due to their
communication power.

• The visual system is our most important sensory system. It

provides a view of the world around us captured with
receptors in the eyeball that is transmitted to the central
nervous system (CNS).
• The eye movement or oculomotor system is
responsible for movement of the eyes so images are
clearly seen. The oculomotor system also responds to
auditory and vestibular sensory stimuli. A saccadic or
fast eye movement involves quickly moving the eye
from one image to another image. This type of eye
movement is very common, and it is observed most
easily while reading—that is, when the end of a line is
reached, the eyes are moved quickly to the beginning of
the next line.
• Saccades are also used to locate or acquire targets.
Smooth pursuit is a slow eye movement used to track
an object as it moves by keeping the eyes on the target.
In addition to these two movements, the eye movement
system also includes the vestibular ocular movement,
optokinetic eye movement, and vergence movement.
Vestibular ocular movements are used to maintain the
eyes on the target during head movements. Optokinetic
eye movements are reflex movements that occur when
moving through a target-filled environment or to
maintain the eyes on target during continuous head
rotation.
• Each of these four eye movements is a conjugate eye
movement—that is, movements of both eyes together driven by
a common neural source. Vergence eye movements use
nonconjugate eye movements to keep the eyes on the target. If
the target moves closer, the eyes converge, and if the target
moves farther away, they diverge. Each of these movements is
controlled by a different neural system, and all of these
controllers share the same final common pathway to the eye
muscles. Each eye can be moved within the orbit in three
directions: vertically, horizontally, and torsionally. These
movements are due to three pairs of agonist-antagonist muscles.
These muscles are called antagonistic pairs because their activity
opposes each other and follows the principle of reciprocal
innervation.
• Figure 2 shows the muscles of the eye, optic nerve, and the
eyeball. We refer to the three muscle pairs and the eyeball as the
oculomotor plant, and the oculomotor system as the oculomotor
plant and the neural system controlling the eye movement
system.

• The eye muscles are among the fastest in the human body, with a
10 saccade taking only 50 ms.
• The saccadic system can be thought of as a targeting
system that is concerned only with accurate and
swift eye movements from one target to another
without concern for the information swept across
the retina during the eye movement. During a
saccade, the visual system is turned off. After the
saccade is complete, the system operates in a
closed-loop mode to ensure that the eyes reached
the correct destination. Information from the retina
and muscle proprioceptors is used to correct any
error between the desired and current eye position.
• The saccade system operates in a closed-loop mode to
reduce this error to zero with a corrective saccade. One
possible explanation of the operation of the neural
control of saccades is that the saccadic neural controller
is an open-loop time-optimal system using an internal
closed-loop controller. This system does not rely on
muscle proprioceptors or real time visual feedback to
ensure accuracy of movement because the eye
movements occur too fast. Instead, a complex neural
network involving the mesencephalon, cerebellum,
brainstem, and cerebrum keeps track of the eye
movement.
 Muscle model
• The force-producing properties of muscle are complex
and nonlinear. For simplicity, dimensionless muscle
models, capable of representing a range of muscles with
different architectures, are most commonly used in the
dynamic simulation of movement.
• The strategy for building a muscle model is to first
introduce the basic mechanical elements of a spring and
damper(Figure 3), and explain how series (Figure 4) and
parallel (Figure 5) arrangements can be made to
accurately model the viscoelastic behavior of soft tissues.
 Hill’s Model
• Hill-type muscle model is one of the most used models to describe
the mechanism of force production. It is composed by different
elements that describe the behaviour of the muscle (contractile,
Series Elastic (SE) and Parallel Elastic (PE) element) and tendon. –
• The three element Hill-type model (Figure 6) provides the simplest
and arguably the most widely implemented model of muscle
function that can characterize interaction between contractile and
elastic elements.
• The model includes a Contractile Element (CE) that represents the
fundamental mechanical behavior of the sarcomere, governed by
activation kinetics, force-length properties, and force-velocity
properties derived from isolated muscle studies.
• Springs in parallel with the CE and in series will influence the force,
length and speed of the entire unit. This model is useful for
exploring and describing the significance of the interaction between
these different elements, and is commonly implemented in
forward-dynamic simulations of movement.
Figure 6: Muscle model of Hill (A Hill-type model of muscle with
a Contractile Element (CE) arranged alongside a Parallel Elastic
Element (PEE) and in series with a Series Elastic Element (SEE).
Force development within the CE is a function of activation
kinetics (a), force-length (f-l) properties, and force-velocity (f-v)
properties. Force developed by the PEE depends on the CE
length, while force in the SEE is equal to the sum of PEE and CE
forces).
 Moral and ethical issues in developing Biomedical
Systems Morality and ethics - Two moral norms:
beneficence and nonmaleficence
• From the very beginning, individuals have raised concerns about
the nature of life and its significance. Many of these concerns
have been incorporated into the four fundamental questions
posed by the German philosopher Immanuel Kant (1724–1804):
What can I know? What ought I to do? What can I hope?
What is man? Evidence that early societies raised these
questions can be found in the generation of rather complex
codes of conduct embedded in the customs of the earliest human
social organization: the tribe. By 600 BC, the Greeks were
successful in reducing many primitive speculations, attitudes, and
views on these questions to some type of order or system and
integrating them into the general body of wisdom called
philosophy. Being seafarers and colonizers, the Greeks had close
contact with many different peoples and cultures.
 Moral and ethical issues in developing Biomedical
Systems Morality and ethics - Two moral norms:
beneficence and nonmaleficence
• In the process, struck by the variety of customs, laws, and
institutions that prevailed in the societies that surrounded them,
they began to examine and compare all human conduct in these
societies. This part of philosophy they called ethics. The term
ethics comes from the Greek ethos, meaning “custom.” On the
other hand, the Latin word for custom is mos, and its plural,
mores, is the equivalent of the Greek ethos and the root of the
words moral and morality.
• Although both terms (ethics and morality) are often used
interchangeably, there is a distinction between them that
should be made. Philosophers define ethics as a particular
kind of study and use morality to refer to its subject matter.
For example, customs that result from some abiding
principal human interaction are called morals.
 Moral and ethical issues in developing Biomedical
Systems Morality and ethics - Two moral norms:
beneficence and nonmaleficence
• Some examples of morals in our present society are telling the truth,
paying one’s debts, honoring one’s parents, and respecting the
rights and property of others.
• Most members of society usually consider such conduct not only
customary but also correct or right. Thus, morality encompasses
what people believe to be right and good and the reasons they give
for it.
• Most of us follow these rules of conduct and adjust our lifestyles in
accordance with the principles they represent. Many even sacrifice
life itself rather than diverge from them, applying them not only to
their own conduct but also to the behavior of others.
• Individuals who disregard these accepted codes of conduct are
considered deviants and, in many cases, are punished for engaging
in an activity that society as a whole considers unacceptable.
 Moral and ethical issues

• For example, individuals committing “criminal acts” (defined by

society) are often “outlawed” and, in many cases, severely
punished.
• These judgments regarding codes of conduct, however, are not
inflexible; they must continually be modified to fit changing
conditions and thereby avoid the trauma of revolution as the
vehicle for change.
• While morality represents the codes of conduct of a society,
ethics is the study of right and wrong, of good and evil in human
conduct.
• Ethics is not concerned with providing any judgments or specific
rules for human behavior, but rather with providing an objective
analysis about what individuals “ought to do.”
• Defined in this way, it represents the philosophical view of
morals, and, therefore, is often referred to as moral philosophy.
 Moral and ethical issues in developing Biomedical
Systems Morality and ethics - Two moral norms:
beneficence and nonmaleficence
• Consider the following three questions: “Should badly deformed
infants be kept alive?”; “Should treatment be stopped to allow
a terminally ill patient to die?”; “Should humans be used in
experiments?” Are these questions of morality or ethics?
• In terms of the definitions just provided, all three of these inquiries
are questions of moral judgment.
• Philosophers argue that all moral judgments are considered to be
“normative judgments”— that is, they can be recognized simply by
their characteristic evaluative terms such as good, bad, right, wrong,
and so on. Typical normative judgments include the following:
• Stealing is wrong.
• Everyone ought to have access to an education.
• Voluntary euthanasia should not be legalized.
 TWO MORAL NORMS: BENEFICENCE AND
NONMALEFICENCE

• Two moral norms have remained relatively constant

across the various moral codes and oaths that have been
formulated for health care providers since the beginnings
of Western medicine in classical Greek civilization.
• They are beneficence, which is the provision of benefits,
and nonmaleficence, which is the avoidance of doing
harm.
• These norms are traced back to a body of writings from
classical antiquity known as the Hippocratic Corpus.
• Although these writings are associated with the name of
Hippocrates, the acknowledged founder of Western
medicine, medical historians remain uncertain whether
any of them, including the Hippocratic Oath, were
actually his work.
 TWO MORAL NORMS: BENEFICENCE AND
NONMALEFICENCE
• Portions of the Corpus: authored during the sixth century BC.
• Nonetheless, the general injunction “As to disease, make a habit
of two things: (1) to help or, (2) at least, to do no harm” was
accepted as a fundamental medical ethical norm by at least some
ancient physicians.
• With the decline of Hellenistic civilization and the rise of
Christianity, beneficence and nonmaleficence became
increasingly accepted as the fundamental principles of morally
sound medical practice.
• Although beneficence and nonmaleficence were regarded
merely as associated to the craft of medicine in classical Greece
and Rome, the emphasis upon compassion and the brotherhood
of humankind, central to Christianity, increasingly made these
norms the only acceptable motives for medical practice.
 TWO MORAL NORMS: BENEFICENCE AND
NONMALEFICENCE

• Even today, the provision of benefits and the avoidance of doing

harm are stressed.
• Traditionally, the ethics of medical care has given greater
prominence to nonmaleficence than to beneficence.
• This priority was grounded in the fact that, historically,
medicine’s capacity to do harm far exceeded its capacity to
protect and restore health.
• Providers of health care possessed many treatments that posed
clear and genuine risks to patients and that offered little prospect
of benefit.
• Truly effective therapies were all too rare. In this context, it is
surely rational to give substantially higher priority to avoiding
harm than to providing benefits.
 TWO MORAL NORMS: BENEFICENCE AND
NONMALEFICENCE

• The advent of modern science changed matters

dramatically.
• Knowledge acquired in laboratories, tested in clinics, and
verified by statistical methods has increasingly dictated
the practice of medicine.
• This ongoing alliance between medicine and science
became a critical source of the plethora of technologies
that now pervade medical care.
• The impressive increases in therapeutic, preventive, and
rehabilitative capabilities that these technologies have
provided have pushed beneficence to the forefront of
medical morality.
 TWO MORAL NORMS: BENEFICENCE AND
NONMALEFICENCE

• Some have even gone so far as to hold that the old

medical ethic of “Above all, do no harm” should be
superseded by the new ethic “The patient deserves the
best.” However, the rapid advances in medical
technology capabilities have also produced great
uncertainty as to what is most beneficial or least harmful
for the patient.
• In other words, along with increases in ability to be
beneficent, medicine’s technology has generated much
debate about what actually counts as beneficent or
nonmaleficent treatment. Having reviewed some of the
fundamental concepts of ethics and morality, let us now
turn to several specific moral issues posed by the use of
medical technology.
 HUMAN EXPERIMENTATION
• Medical research has long held an glorious position in our
modern society. It has been acclaimed for its significant
achievements that range from the development of the Salk and
Sabin vaccines for polio to the development of artificial
organs.
• In order to determine their effectiveness and value, however,
these new drugs and medical devices eventually are used on
humans.
• The issue is, therefore, not only whether humans should be
involved in clinical studies designed to benefit themselves or
their fellow humans but also clarifying or defining more
precisely the conditions under which such studies are to be
permitted.
 HUMAN EXPERIMENTATION
• For example, consider the case of a 50-year-old female patient
suffering from severe coronary artery disease.
• What guidelines should be followed in the process of
experimenting with new drugs or devices that may or may not
help her? Should only those procedures viewed as potentially
beneficial to her be tried? Should experimental diagnostic
procedures or equipment be tested on this patient to evaluate
their effectiveness when compared to more accepted techniques,
even though they will not be directly beneficial to the patient?
• On the other hand, consider the situation of conducting research
on the human fetus. This type of research is possible as a result
of the legalization of abortion in the United States, as well as the
technological advances that have made fetal studies more
practical than in the past.
 HUMAN EXPERIMENTATION
• Under what conditions should medical research be
conducted on these subjects? Should potentially
hazardous drugs be given to women planning to have
abortions to determine the effect of these drugs on the
fetus? Should the fetus, once aborted, be used in any
experimental studies?
• Although these questions are difficult to answer, clinical
researchers responsible for the well-being of their
patients must face the moral issues involved in testing
new equipment and procedures and at the same time
safeguard the individual rights of their patients.
 HUMAN EXPERIMENTATION
• A human experiment must be initiated with the
following questions need to be resolved:
1. Who is responsible for proposing the conduction of
this study?
2. What should the process of approval of such a study
include?
3. What should the policy be related to informed
consent?
4. Should changes that were made in the device during
the course of the study, which would alter the nature
of the initially proposed device, be allowed
 REGULATION OF MEDICAL DEVICE
INNOVATION
• The Food and Drug Administration (FDA) is the sole federal agency
with regulating medical devices to ensure their safety and effectiveness.
• Unlike food and drugs, which have been regulated by the FDA since
1906, medical devices first became subject to FDA regulation in 1938.
At that time, the FDA’s major concern was to ensure that legitimate
medical devices were in the marketplace and were truthfully labeled,
not misbranded.
• Over time, the scope of FDA review of medical devices has evolved,
as has the technology employed by medical devices.
• The first substantive legislative attempt to address the premarket
review of all medical devices.
• This statute requires approval from the FDA before new devices are
marketed and imposes requirements for the clinical investigation of
new medical devices on human subjects. http://www.fda.gov/.
 REGULATION OF MEDICAL DEVICE
INNOVATION
• The FDA is organized into five major program centers: the Center
for Biologics Evaluation and Research, the Center for Drug
Evaluation and Research, the Center for Food Safety and Applied
Nutrition, the Center for Veterinary Medicine, and the Center for
Devices and Radiological Health (CDRH).
• Each FDA program center has primary jurisdiction over a different
subject area. According to the FDA, the CDRH is responsible for
ensuring the safety and effectiveness of medical devices and
eliminating unnecessary human exposure to man-made radiation from
medical, occupational, and consumer products.
• The CDRH has six distinct offices: the Office of Systems and
Management, the Office of Compliance, the Office of Science and
Technology, the Office of Health and Industry Programs, the Office
of Surveillance and Biometrics, and the Office of Device Evaluation
(ODE).
 REGULATION OF MEDICAL DEVICE
INNOVATION
The ODE has several principal functions, including the following:
• Advising the CDRH director on all premarket notification 510(k)
submissions, premarket approvals (PMAs), device classifications,
and investigational device exemptions (IDEs).
• Planning, conducting, and coordinating CDRH actions regarding
approval, denial, and withdrawals of 510(k)s, PMAs, and IDEs.
• Ongoing review, surveillance, and medical evaluation of the
labeling, clinical experience, and required reports submitted by
sponsors of approval applications.
• Developing and interpreting regulations and guidelines regarding
the classification of devices, 510(k)’s, PMAs, and IDEs.
• Participating in the development of national and international
consensus standards.
 REGULATION OF MEDICAL DEVICE
INNOVATION
• Everyone who develops or markets a medical device will likely have
multiple interactions with ODE before, during, and after the
development of a medical device.
• In principle, if a manufacturer makes medical claims about a product, it is
considered a device, and may be subject to FDA pre- and postmarket
regulatory controls (Figure).
• The device definition distinguishes a medical device from other
FDA-regulated products, such as drugs.
• According to the FDA, a medical device is: An instrument, apparatus,
machine, contrivance, implant, in vitro reagent, or other similar or related
article intended for use in the diagnosis of disease or other conditions, or
in the cure, mitigation, treatment, or prevention of disease in man or
other animals OR intended to affect the structure or any function of the
body of man or other animals, and which does not achieve any of its
primary intended purposes through chemical action or is not dependent
upon being metabolized.
 REGULATION OF MEDICAL DEVICE
INNOVATION
The purpose of the regulatory process is to conduct product review to ensure (1) device
safety and effectiveness, (2) quality of design, and (3) surveillance to monitor device quality.
Therefore, the review process results in verification and validation of the medical device.
 REGULATION OF MEDICAL DEVICE
INNOVATION
• In deciding whether to approve a proposed clinical investigation of a
• new device, the IRB and the FDA must determine the following:
1. That risk to subjects is minimized.
2. That risks to subjects are reasonable in relation to anticipated benefit
and knowledge to be gained.
3. That subject selection is equitable.
4. That informed consent materials and procedures are adequate.
5. That provisions for monitoring the study and protecting patient
information are acceptable.
• The FDA allows unapproved medical devices to be used without an
IDE in three types of situations: feasibility studies, emergency use, and
treatment use.
 ETHICAL ISSUES IN FEASIBILITY STUDIES

• In a feasibility study, or “limited investigation,” human

research involving the use of a new device would take place at
a single institution and involve no more than ten human
subjects.
• The sponsor of a limited investigation is required to submit to
the FDA a “Notice of Limited Investigation,” which includes a
description of the device, a summary of the purpose of the
investigation, the protocol, a sample of the informed consent
form, and a certification of approval by the responsible
medical board.
• In certain circumstances, the FDA could require additional
information or require the submission of a full IDE
application or suspend the investigation.
 ETHICAL ISSUES IN FEASIBILITY STUDIES
• Investigations of this kind are limited to (1) investigations of new uses for
existing devices, (2) investigations involving temporary or permanent implants
during the early developmental stages, and (3) investigations involving
modification of an existing device.
• To comprehend adequately the ethical issues posed by clinical use of
unapproved medical devices outside the context of an IDE, it is necessary to
use the distinctions among practice, non-validated practice, and research
elaborated upon in the previous pages. How do those definitions apply to
feasibility studies?
• Clearly, the goal of the feasibility study, which is a generalizable knowledge,
makes it an instance of research rather than practice.
• Manufacturers seek to determine the performance of a device with respect to
a particular patient population in an effort to gain information about its
efficacy and safety.
• Such information is important in order to determine whether further studies
(animal or human) need to be conducted, whether the device needs
modification before further use.
ETHICAL ISSUES IN TREATMENT USE

• The FDA has adopted regulations authorizing the use of

investigational new drugs in certain circumstances where a
patient has not responded to approved therapies.
• This “treatment use” of unapproved new drugs is not limited to
life-threatening emergency situations but is also available to treat
“serious” diseases or conditions.
• The FDA has not approved treatment use of unapproved
medical devices, but it is possible that a manufacturer could
obtain such approval by establishing a specific protocol for this
kind of use within the context of an IDE.
ETHICAL ISSUES IN TREATMENT USE

• The criteria for treatment use of unapproved

medical devices would be similar to criteria for
treatment use of investigational drugs: (1) the device
is intended to treat a serious or life threatening
disease or condition; (2) there is no comparable or
satisfactory alternative product available to treat that
condition; (3) the device is under an IDE or has
received an IDE exemption, or all clinical trials have
been completed and the device is awaiting approval;
and (4) the sponsor is actively pursuing marketing
approval of the investigational device.
Thank You