Recent advances in Growth theories - orthodontics

Recent
advances in
Growth
theories
---
OrthodonticsDr Ravikanth Lakkakula

DIFFERENT THEORIES OF GROWTH
 Remodeling theory
 Genetic theory
 Sutural theory
 Nasal septum theory
 Functional matrix hypothesis
 van Limborgh hypothesis
 Neurotrophic control of craniofacial growth.
 Bioelectric theory
 Servosystem theory of growth
Dr Ravikanth Lakkakula

NEWER CONCEPTS
 Functional matrix revisited.
 Growth relativity
 Signal transduction
 Mao’s concepts
 Rabie’s concept
 Homeobox genes

 Growth is defined as normal changes in
amount of living substance. It is the
quantitative aspect of biologic development.
 Development: refers to all naturally
occuring unidirectional changes in life of an
individual from its existence as a single cell
to its elaboration as a multifunctional unit
terminating in death.

Growth is an increase in bulk .
Development is an adaptation of that bulk
to function. -----scott.
Growth is an increase in size.
Development is a progress towards
maturity. ---------todd.

REMODELLINGTHEORY
 Bone growth and heredity Studies by Sir John
Hunter (1771), on the growth of jaws and
eruption of dentition represent the first scientific
research on craniofacial growth.
 He observed that bones of pigs that were
occasionally fed with textile waste (ground root of
Rubia Tinctorum) were often stained, and found
out that the active agent was a dye called -
Allizarin.

 Based on this, a vital staining technique was
developed by John Hunter. In this technique
when dyes that stain mineralizing tissue are
injected into an animal, these dyes remain in
bones and teeth, and can be detected later after
sacrifice.

• Later Brash came up with an indirect method.
• First bone is deeply stained through out by
giving madder continuously from birth for
sufficient time. Then it is omitted for any period
during which growth of bone is to be
determined.
• The research by Brash (1930)provided the
foundation for development of first theory of
craniofacial growth - the remodeling theory.

Principal tenets of remodeling theory are:
 Bone grows only appositionally at surfaces,bone does
not grow grow interstitially through mitotic activity of
osteocytes.
 Growth of jaws is characterized by deposition of bone at
posterior surface of maxilla and mandible,sometimes
described as Hunterian growth of jaws.
 Calvarial growth occurs via deposition of bone on
ectocranial side and resorption endocranially.

Schematic representation of the
remodeling theory of craniofacial
growth using the cranial vault as a
model

 According to this theory all of the craniofacial
skeletal growth occurs mainly by bone
remodelling – selective addition and removal of
bone at surfaces.

Inconsistency :
 This theory created doubt about the role of
unique structures like sutures, cranial base
synchondrosis and mandibular condylar
cartilage. The doubt was that if these sites are
not essential for normal craniofacial growth
then why they were present at all ?

HERIDETARY, GENETICS AND GENE.
 Concept that morphologic traits were transmitted
between successive generations has been known
since thousands of years.
 But mechanism by which the traits were transmitted ,
nature of units of heredity and mode of action of
these units of heredity were not known till beginning
of 20th century.

 Mendel (1822-1884) was credited for
performing his benchmark research on genetics.
 He found that traits were passed between
generations in a particulate, discrete manner
from both parents according to a set of
mathematical principles.
 Weismann’s concept of germ plasm in late 19th
century was most influential among many ideas
about means of transmission of traits.

The fields of genetics was charecterised by two
principal foci,
1) Transmission genetics.
2) Nature of gene itself and mechanism of gene
action during development.

Factors in support of genetic theory:
 Genetic factors play the most important role in
early bone development. This was demonstrated
by transplantation of cartilaginous bone models
from the very early embryo into various sites
both in vivo and in vitro.

 Such transplants have the capacity to develop
for a short time into miniature replicas of adult
bone even in environment devoid of nervous,
circulatory and gross mechanical influences.
 Genetic factors affecting general size and form
of the final skeleton is clearly shown in many
familial developmental anomalies.

SUTURES
 Sutures are articulations found in the skull.
 A suture is classified as a synarthrosis which
means that bones are joined by fibrous tissue.
Biological function of sutures:
To unite bones, allowing minor movements,
To act as areas of growth,
To absorb mechanical stress, protecting
osteogenic substance.

Movements at suture sites are 2 types:
1)Displacement of bones, which together with an
intrinsic deformation of bone enables molding
of skull when head passes through birth canal
2)Displacement of bones relative to each other as
a part of skull growth.

SUTURAL THEORY
 This was put forward by Weinmann and Sicher
in 1940, two prominent whose textbooks on
skeletal growth,bone and bones,and oral
anatomy.
 According to this theory, connective tissue and
cartilaginous joints of the craniofacial joints,
like sutures and epiphysis of long bones are
principal locations at which intrinsic, genetically
regulated , primary growth of bones take place.

 Growth of cranial vault is by intrinsic pattern of
expansive, proliferative growth by sutural
connective tissue that forces bones of vault
away from each other.
 Proliferation of sutural connective tissue in
circum-maxillary sutural system forces midface
to grow downward and forward.

 Mandibular growth takes place by intrinsically
determined growth of condylar cartilage which
pushes it downward and forward.
 Role of sutural connective tissue in craniofacial
growth is identical to that of cartilage in basal
synchondrosis.

According to Sicher
sutures important in growth
of upper jaw are:
 Suture between frontal
process of maxilla and
frontal bone.
 Suture between zygomatic
bone and Maxilla.
 Suture between pyramidal
process of paltine bone and
pterygoid process of
sphenoid bone.
All these sutures are
parallel and slant
downward and backward.

 This theory also reinforced the concept that
growth of face and jaws is essentially
immutable.

sutural growth theory
also have numerous
inconsistencies, they
were:
1) A variety of major
disorders involving the
developing central
nervous system have
major effects on growth
and development of
cranial vault.
Anencephaly

2) the development of the bones of the cranial
vault and face have no direct cartilaginous
precursor, unlike bones elsewhere in the
skeletal system.

3)The histomorphology of the developing and
growing sutures according to Weinmann and
Sicher is roughly equivalent to cranial base
synchondrosis and epiphyseal growth plate.
But Scott asserted that osteologic layers within
the suture are actually continuations of the
periosteum and dura within cranial vault and of
the periosteum in facial sutures.

 Finally, Several experimental studies using vital
dyes and surgical manipulation of cranial sutures in
animal models demonstrated that although sutures
were major sites of craniofacial growth, they played
no determining role in growth.
• Rather they are permissive, secondary and
compensatory sites of bone formation and growth.

NASAL SEPTUM THEORY
Put forward by James H . Scott in 1950.
 Nasal septum is most active and important for
craniofacial growth late prenatally and early
postnatally, through approximately 3 to 4 yrs of
age in humans.

 During that time the anterio-inferior growth of
the nasal septal cartilage, which is buttressed
against the cranial base posteriorlly drives the
midface downward and forward.
This results in a separation of the midfacial suture system, which
then fills in via secondary, compensatory sutural bone growth.

 Scott asserted that the cartilage of the
mandibular condyles behaves similarly to
cranial base and nasal septal cartilages, and
directly determines the growth ofthe mandible
as its “pushes” the mandible downward and
forward.
 Instances or experiments in which the nasal
septum was manipulated or damaged, showed
that growth of mid face was hampered.

 The Studies which were done to find the role of
nasal septum cartilage involving excision or
otherwise gross disruption of the nasal septal
cartilage were thought to be relatively crude and
the detrimental effects on the growth of midface
in such studies was considered to be due to the
surgery rather than the absence of nasal septum.

FUNCTIONAL MATRIX HYPOTHESIS
 Melvin Moss.
 As stated by Moss, “bones do not grow; bones are
grown.
• According to this hypothesis, the head is a region
within which certain functions occur and every
function is carried out by a functional cranial
component. Each such component is composed of
2 parts. They are:

 functional matrix = all the soft tissues and
spaces that perform a given function.
 The skeletal unit = the bony structures
that support the functional matrix and they
are necessary or permissive for that
function

 Skeletal units include bone, cartilage or tendinous
tissues. A bone consists of a number of skeletal units
called micro skeletal units.
Eg: tuberosities, ridges .
 When adjoining portions of a number of neighboring
bones are united to function as a single cranial
component, it is called as a macroskeletal unit.
Eg: endocrinal surface of calvaria.

Microskeletal units of
mandible:
 Coronoid- related to
functional demands of –
temporalis muscle.
 Angular- related to
activity of masseter and
medial pterygoid.
 Basal unit- to inferior
alveolar neurovascular
triad.
 Alveolar unit – related to
presence or absence of
teeth. Dr Ravikanth Lakkakula

 To some extent , adjacent microskeletal units are
independent of each other indicating that changes
occurring in size, shape, or position of one
microskeletal unit as a result of primary changes in
its related functional matrix are relatively
independent of such changes in other microskeletal
units.

 A functional matrix includes soft tissues like
muscles, glands, vessels, nerves fat, etc.
Functional matrices are basically 2 types.
1. Periosteal matrix and
2. Capsular matrix.

Periosteal matrix:
 Corresponds to immediate local environment,
typically muscles, blood vessels, and nerves.
 example : coronoid process is a microskeletal
unit and its Periosteal matrix is temporalis
muscle.

 Studies show that
experimental removal
of the mammalian
temporalis muscle, or
its denervation
invariably results in
diminution in size
and shape or total
disappearance of
coronoid process.

 Similarly it is established that hypertrophy or
hyperactivity of temporalis muscle is productive of
increased coronoid size.
 It is also found that experimental or clinical alteration of
muscles attaching to other mandibular ramal skeletal
units can produce compensatory changes in temporalis
muscle function which will in turn equally change the
size and shape of coronoid process in proportion to
degree of muscular imbalance produced.

 The coronoid process does not grow first and
thus produce a platform upon which temporalis
muscle can then alter its function. It is quite
opposite.
 The total growth changes in all aspects of
coronoid process form (size and shape) are at all
times a direct and compensatory response to the
morphogenetically and temporally prior
demands of the temporal muscle function.

 All responses of the osseous portions of skeletal
units to Periosteal matrices are brought about by
the complementary and interrelated process of
osseous deposition and resorption.
 The resultant effect of all such skeletal unit
responses to Periosteal matrices is to alter their
size and or shape.

Capsular matrix:
 All skeletal units arise, grow, are maintained and respond
while totally embedded within their functional periosteal
matrices. At the same time all the functional cranial
component are organized in the form of cranial capsule.
 Basically functional cranial component = skeletal unit +
functional matrix
 cranial capsule = several functional cranial components

cranial capsules
1)Neurocranial
2)Orofacial
 Each capsule is an envelope which
contains a series of functional cranial
components, which as a whole are
sandwiched in between 2 covering
layers.
 In neurocranial capsule these covers
consist of skin and duramater whereas
in orofacial capsule it is the skin and
mucosa. Dr Ravikanth Lakkakula

 All spaces intervening between the functional
components themselves , and between them and
limits of capsule are filled with indifferent loose
connective tissue.
 Each capsule surrounds and protects a capsular
functional matrix.

Neurocranial capsule
The composition of this capsule (from outward
to inward) in an adult are the 5 layers of scalp,
then the bone and finally duramater.
 The calvarial bones consist of a number of
contiguous skeletal units: outer table, diploic
space and inner table. Each of these
microskeletal units has its specific Periosteal
matrix.

 As the volume of the brain increases,
secondarily expansion of the enclosed and
protected capsular matrix occurs.
 The expansion of the Neurocranial capsule is
response to the morphogenetically primary
expansion of the enclosed neural mass.

 As this capsule expands, the enclosed calvarial
skeletal tissues are passively translated in space
in response to the growth of the capsular matrix.
 At the same time , these same skeletal units
respond to the altered demands of their
functional periosteal matrices by expanding in
area and in thickness. Both occur
simultaneously.

 So the calvarial functional cranial components,
as a whole are passively and secondarily
translated in space.
 It is extremely important that this translation
occurs without selective apposition and
resorption.

 In normal growth it is difficult to find this, since
activity of Periosteal matrices on their respective
microskeletal units goes on simultaneously.
 This can be understood better from a pathologic
situation, where Periosteal matrix has been
prevented from exerting their morphogenetic
activity. Hydrocephaly is such a condition.

 Hydrocephaly is a situation in
which there is raised
intracranial pressure. This
raised intracranial pressure
causes the expansion of the
neurocranial capsule.
 But increased intracranial
pressure also effectively
decreases the blood flow within
the capsule and so prevents
periosteal deposition of bone at
sutural areas thus producing
characteristically excessively
large fontanelles. Dr Ravikanth Lakkakula

Orofacial matrices :
 All functional cranial components of the facial
skull, arise , grow and are maintained within an
orofacial capsule. This capsule surrounds and
protects the oronasopharyngeal functioning
spaces. It is the volumetric growth of these
spaces which is the primary morphogenetic
event in facial skeletal growth.

 The oronasopharyngeal functioning space is
related to the relatively dominant cranial
respiratory functional space volume. The
conception of the primacy of functional spaces
receives strong support from work of Bosma.

 The oral and pharyngeal regions are said to have
a primary function of maintaining a patent
airway. This is done by a dynamic musculo-
skeletal postural balance which is termed airway
maintenance mechanism. Bosma believes that
the related functional cranial components are so
dynamically balanced that this airway is
maintained throughout the range of motion of
head and neck.

Mandibular growth:
It is known that mandibular condylar cartilages are not
primary sites of growth, rather they are loci at which
secondary, compensatory periosteal growth occurs.
 Mandibular growth is now seen to be a combination of
morphologic effects of both capsular and Periosteal
matrices.
 The capsular matrix growth causes an expansion of the
capsule as a whole. The enclosed and embedded
macroskeletal unit (i.e mandible) accordingly is passively
and secondarily translated in space to successively new
positions.

 In normal situations the Periosteal matrices
related to the constituent mandibular
microskeletal units also respond to this
volumetric expansion.
 The change in spatial position causes changes in
their functional demands which now cause
direct alterations in size and shape of their
microskeletal units. The sum of translation plus
changes in form comprises the totality of
mandibular growth.

Cranial growth
 Cranial growth is a combination of
morphogenitically primary activity of both
types of matrix.
 Periosteal matrices act upon skeletal units in a
direct fashion by deposition and resorption.
Their net effect is to alter the form of respective
skeletal units.

 Capsular matrices act upon functional cranial
components as a whole in a secondary and
indirect manner. They do it by altering the
volume of capsules within which functional
cranial components are embedded. The effect is
to cause a passive translation of these cranial
components in space.
 So growth is accomplished by both spatial
translation and changes in form.

Primary growth of the capsular
matrix(brain) results in a stimulus
for secondary growth of the
sutures and synchondroses,leading
to overall enlargement of the
neurocranium(macroskeletal unit).
Functionof the temporalis muscle
exerts pull on theperiosteal matrix
and bone growth of the temporal
line (microskeletal unit).

VAN LIMBORGH HYPOTHESIS
According to van Limborgh (1970) craniofacial
morphogenesis is controlled by
1)Intrinsic Genetic factors: Genetics factors inherent to
the skull tissues. They exert influence within the cells
within which which they are contained and determine
the characteristics of cells and tissues.
2)Epigenetic factors: are those which are determined
genetically and are effective outside of the cells and
tissues in which they are produced.
They are 2 types.

 Local epigenetic factors- Genetically
determined influences originating from adjacent
structures(brain, Eyes etc)
 General Epigenetic factors- Genetically
determined influences originating from distant
structures (Sex and growth hormones)

3)Local environmental factors- local non genetic
influences originating from the external environment
(local external pressure, muscle forces).
4)General environment factors -General non genetic
influences originating from external environment
(food, oxygen supply).
 According to this theory, local factors as well as
genetic and general factors can cause anomalies.

NEUROTROPHIC REGULATION OF
CRANIOFACIAL GROWTH
 neurotrophism - nourishment from nerves
 Neurotrophic functions are a fundamental
expression of neurocellular activity. These
functions act homeostatically to maintain
and renew the structure and functional
capacity of body parts.

 Guth explained the process by which
neurotrophic effects work.
 He defines Neurotrophism as “an interaction
between nerves and cells which initiate or
control molecular modification in the cells”.

 The cells of posterior
pituitary are categorized as
neurosecretory cells. There
is a general consensus that
all neurons share this
fundamental property and
the axoplasmic streaming
was thought to be
intracellular transport
mechanism responsible for
trophic function of nerves.

 Such peripherally directed transport must coincide
in direction with that of impulse transmission in
motor neurons, while directed oppositely in
sensory neurons.
 The reality of axoplasmic transport has been
proved by a number of methods. A radio-isotope
labeled element was injected in a cranial nerve
nuclei and was found to accumulate peripherally
later.

Neurtrophic control of genetic activity:
 Neural control of genetic activity has been
shown in many tissues and under a number of
experimental conditions.
 Protein synthesis in oral epidermal cells and
specific enzymatic synthetases in taste bud
epithelium appear to be neurotrophically
regulated by genetic means.

Types of Neurotrophism:
1. Neuromuscular
2. Neuroepithelial
3. Neurovisceral

Neuromuscular :
 The normal contractility of skeletal muscle
depends upon ability of a neuron to transmit an
efferent impulse.
 The physiological , morphological and
biochemical parameters of skeletal muscle have
been demonstrated to depend upon neurotrophic
function.

 Embryonic myogenesis, in vivo and in vitro, is
independent of neural innervation and so of
trophic control .
 Approximately at the stage of differentiation,
neural innervation is established without which
further myogenesis usually cannot continue.

 If muscle tissue is experimentally prevented
from becoming efferently innervated, motor end
plates will never develop. Also it is
experimentally shown that muscle receptors,
muscle spindles and tendons require afferent
innervation for their development.

Neuroepeithelial :
 During early growth both oral and external epithelium
grows in spurts, which is thought to occur immediately
following repetitive sensory nerve contact.
 If such processes were absent or deficient, we can
expect orofacial hypoplasia, or malformation.
 Maxilla and mandibular hypoplasia are found associated
with a wide variety of intra oral and intra nasal sensory
defecits.

 The nerve supplying the taste bud not only
carries afferent impulses but also is
responsible for maintenance of existing
epithelial taste buds.

 The first structure to
develop in the region of
lower jaw is the
mandibular division of
trigeminal nerve.
 The prior presence of the
nerve has been postulated
as requisite for inducing
osteogenesis by production
of neurotrophic factors.

 A study was done by Behrents and Johnston to
evaluate the role of trigeminal nerve in the regulation of
facial growth.
 They have created lesions in the root, ganglion or major
sensory branch of the nerve to find out role of the nerve.
 They concluded that it may exert some trophic influence
on the craniofacial complex, but they failed to support a
major role of the nerve.

Bioelectric theory
 The most familiar form of bioelectricity is that
related to neuromuscular activity.
 But bone and other tissues like cartilage have
been shown to generate electric potential in
response to mechanical strain or deformation.
These strain generated potentials are thought to
serve as a mechanism that permits bone to be
remodeled in response to mechanical stresses.

 Basset defines piezoelectricity as electricity
resulting from pressure on certain crystals.
 In polycrystalline materials piezo-electricity
results from a summation of charges produced
by aggregation of the oriented regions within the
material.

 Direct pieizo-electric effect is generation of a
charge in response to pressure.
 Indirect piezoelectric effect is one in which the
material undergoes deformation, when it is
placed in an electric field.

 Piezo-electric properties of bone and other
biologic material were reported by Fukada and
Yasuda.
 They demonstrated Piezoelectricity in bone
caused to oscillate at a low audio frequency..
 Bassett and Becker showed that the specimen
routinely became negative on concave side and
positive on the convex.

 Frost suggested that deformation of bone surfaces
subjected to loads generates surface signals, which
causes mesenchymal cell activation.
• production of osteoclasts which subsequently undergo
transformation into osteoblasts which cause bone
depostion.
• A negative feedback mechanism neutralizes the signals
overtime so that the resultant cell activity operates to
minimize the deformation or strain which initiated the
cell activity.

Factors known about strain related potentials
 They are present in living organisms but are produced
by inanimate matrix rather than living cells.
 Exist in both dead and living bone, although they can
be modified by living cells.
 The potentials are generated only by changing loads
i.e a dynamic one.
 The potential difference reached for physiologically
meaningful stress is of order of millivolts.

Applied aspects of piezo-electric phenomena
Osteogenesis:
 Studies have demonstrated that bone formation
occurs in electronegative regions, and destruction
occurs in electropositive regions.
 Electromagnetic fields were used by
Basseett et.al.,. He found that callus formed
around the stimulated femur after 7- 14 days.
Park et al induced alveolar bone ingrowth into
porous acrylic dental implants in dogs using a
constant direct current of 7 µA.

Servo system theory
of
cybernatics

Contents
 INTRODUCTION
 CYBERNETICS
 COMPONENTS OF A SERVOSYSTEM
 PRIMARY AND SECONDARY CARTILAGES
 CONDYLAR CARTILAGE
 CONTROL OF MAXILLARY GROWTH
 CONTROL OF MANDIBULAR GROWTH
 THREE LEVEL ARBORIZATION
 BIFURCATIONS
 MODE OF ACTION OF FUNCTIONALAPPLIANCES
 CLINICAL IMPLICATIONS
 DRAWBACKS

INTRODUCTION
 In late 1960’s Petrovic & co-workers produced first
rigorous demonstration that condylar cartilage’s
growth rate & amount can be modified by using
appropriate functional & orthopedic appliances.
 Later he employed the model of cybernetics &
control theory to describe craniofacial growth
patterns & method of operation of functional &
orthopedic appliances.

 The term “CYBERNETICS” (Greek kybernetes
means steersman) was coined by mathematician
Norbert Wiener in 1948 to encompass the entire
field of control and communication theory,
whether in the machine or in the animal.
 Cybernetics is concerned with scientific
investigation of systematic processes of a highly
varied nature, including phenomenon such as
regulation, information processing, storage,
adoption, self organisation and strategic
behavior.

◦ It grew out of Shannon's information theory –
designed to optimise transmission of
information through communication channels
and the Feed back concept used in
engineering control systems.
◦ The concept of cybernetics and control theory
was put forth by Petrovic (1977,1982) to
describe craniofacial growth mechanisms and
the method of operation of functional and
orthopedic appliances.

 The theory refines orthodontic concepts by
demonstrating a qualitative and quantitative
relationship between observationally and
experimentally collected findings.
 Helps in a broader understanding of orthodontic
problems as the language of cybernetics is
compatible with the rapidly expanding use of
computers among clinicians.

WHAT IS CYBERNETICS ?

 Cybernetics is based on the communication of
information.
 Any cybernetically organized system operates
through signals that transmit information (which
may be physical, chemical or electromagnetic in
nature).
 Any cybernetic system, when provided an input
(or stimulus), processes such an input and
produces an output.The output is related to the
input by a transfer function that characterizes
the physiologic system.

Transfer functionInput Output

PHYSIOLOGIC SYSTEM
OPEN LOOP CLOSED LOOP
REGULATOR THE SERVO SYSTEM
No feedback loop
Or Comparator
Main input constant
Comparator detects
disturbances
It is –ve feedback
system
or follow up system
Main input not constant

 In an open loop, the output does not affect the input.
There are no feed back loops or comparators.
 In a closed loop system, a specific relation is maintained
between the input and output and are characterized by
a feedback loop and a comparator.

INPUT TRANSFER FUNCTION OUTPUT
INPUT COMPARATOR TRANSFER FUNCTION
OUTPUT
Feed back loop

 The input is fed into a comparator which
analyses the input and judges the degree to
which the transfer function needs to be carried
out to obtain a certain output.
 The output is fed back to the comparator
(through a feed back loop) and is analyzed for
its adequacy. If found inadequate, the transfer
function is carried out once again.
 The feed back loop can have a positive or
enhancing affect or a negative or attenuating
affect.

 A regulator type of closed loop is one in which
the input is constant. Any disturbance in the
input will cause the comparator to initiate a
regulatory feedback system, which will restore
the input to its normal state.
 Eg. The temperature regulation system of the
body-Any change in body temperature acts as
the input into the comaparator (the
hypothalamus), which causes an action
(pilorection and shivering) which ultimately
brings the body temp back to normal.

 Servosystem in this the main input is
constantly changing with time and the output is
constantly adjusted in accordance to the input.

WHY CYBERNETICS?

 Craniofacial growth is an extremely complex
process involving a multitude of factors.
 The connections between constituents are
complex, although the constituents themselves
are not.
 The identification and analysis of the feed back
loops (regulation processes) is among the main
tasks in the field of craniofacial growth.

 Cybernetic language has been the best to
accurately describe the intricacy and complexity
of craniofacial morphogenesis and the means to
influence it clinically.
 The following set of approaches may be useful
in relating scientific findings and the method of
operation of orthopedic and orthodontic
appliances.

COMPONENTS OF A SERVOSYSTEM

COMMAND
Reference Input Elements
Reference Input
COMPARATOR
Performance
Analyzing
Elements
Performance
Deviation Signal
Central Comparator
(sensory engram)
Actuator, Coupling System,
Controlled System Output
(ControlledVariable)

 COMMAND :a signal established independent
of the servosystem and is not affected by the
output of the system. It tells the system what has
to be done.
 REFERENCE INPUT : is a signal established as
a standard of comparison.
 REFERENCE INPUT ELEMENTS :establish
the relationship between command and the
reference input.

 COMPARATOR (PERIPHERAL) :It is a
component that analyses the reference input and
judges the performance of the system through
performance analysing elements.
 CENTRAL COMPARATOR : the performance
judging elements then transmits a deviation
signal to the central comparator which sends a
signal to various components – the actuator,
coupling system and the controlled system.
This ultimately brings about an
output/controlled variable.

Growth of the Face
According to the
Servosystem Theory

The Face as a Servosystem
Release of
Hormones (Command)
Hormones Position of Maxillary
Dental arch (Ref Input)
OCCLUSION
(Comparator)
Periodontium,
Teeth
Musculature
Joint
Mastication
(Performance)Deviation Signal
Brain
(sensory engram)
Actuator (Motor Cortex)
Output
Actuating
signal
LPM & RDP
(Coupling system)
Growth at condyle
(Controlled System)

THE PRIMARY AND SECONDARY CARTILAGES.

Stutzman (1976) emphasized the following -
 PRIMARY CARTILAGE - dividing cells,
differentiated chondroblasts, are surrounded by
a cartilaginous matrix synthesized by them, that
isolates them from local factors able to restrain
or stimulate cartilaginous growth. Chondroblasts
undergo maturation and are later transformed
into hypertrophied chondroblasts.
 Deeper in the cartilaginous matrix, calcium is
deposited and endochondral ossification begins.

Seen in
1. Epiphysial cartilages of long bones
2. Cartilages of synchondroses of cranial bones.
3. Nasal septal cartilage.
4. Lateral cartilaginous masses of ethmoid
5. Cartilage between greater wings and body of
sphenoid

 SECONDARY CARTILAGES the dividing
cells, prechondroblasts, do not synthesize a
cartilaginous matrix, hence are not isolated
from local factor influences. Once they mature
into chondroblasts, they become surrounded
by cartilaginous matrix and do not divide.
Seen in
1. Coronoid and condylar cartilage
2. Mid palatal suture cartilage
3. Post fracture callus

Factors influencing
Growth
Primary
Cartilage
Secondary
Cartilage
Hormones Yes Yes
Local Factors No (Chondroblasts
surrounded by matrix)
Yes (Pre-
chondroblasts not
surrounded by matrix
Orthopaedic
appliances
Only Direction Direction and
Amount
Charlier, Petrovic, Stutzmann
Strasburg, FranceDr Ravikanth Lakkakula

 According to studies carried out by Chartlier,
Petrovic and Stutzmann on organ cultures-
 Dividing chondroblasts (in primary cartilages)
are more susceptible to general extrinsic factors,
especially growth hormone, stomatomedin, and
sex hormones. The cartilaginous matrix
surrounding the mature chondroblasts, isolates
them from the effects of local factors.
 Local biomechanical factors can only modify the
direction of growth and not the amount of
growth at these sites.

 In the secondary cartilages, where
prechondroblasts are the dividing cells, general
and local extrinsic factors can affect the growth.
 The amount of growth of these cartilages can
be affected by altering the local extrinsic
factors.

Condylar Cartilage
 Adaptive to both extrinsic & local
biomechanical & functional factors.
 Condylar cartilage growth is integrated into an
organized functional whole that has form of
Servosystem & able to modulate lengthening of
condyle so that lower jaw adapts to upper jaw
during growth

Specific features of condylar cartilage
1. Fibrous capsule -fibroblasts and type I
collagen.
2. Zone of growth (mitotic compartment) –
skeletoblasts and prechondroblast type II, not
surrounded by the cartilaginous matrix with
type I collagen.
3. Zone of maturation - functional and
hypertrophied chondroblasts.
4. Zone of erosion
5. Zone of endochondral ossification.

Correlation between growth direction of
condyle & sagittal distribution of dividing
cells in condylar cartilage

 Anatomic, microscopic and histologic studies
have shown that the growth direction of the
condyle coincides in general, with the axis of
individual trabeculae, located just inferior to the
central part of condylar cartilage.
 Hence the condylar growth direction can be
determined by measuring the main axis of
endochondral bone trabeculae in the condyle
and the angle it forms with the mandibular
plane.

 A histologic & radioautographic study was made
of distribution of dividing cells in a sagittal
section of condylar cartilage of juvenile rats.
 Condylar cartilage divided into 4 equal sections
from anterior to posterior & cells counted.
 Each experimental group was subjected to
specific orthopedic treatment.

 Results showed that both treatment with the
postural hyperpropulsor & with the growth
hormone produced significant increase in
growth rate of condylar cartilage compared to
control group (Charlier et al, 1968, 1969;
Petrovic et al , 1975)

 Condylar growth is not exclusively a result of
the lengthening of pre-existing endochondral
bone trabeculae under condylar cartilage but
also a result of growth of bone trabeculae
(mesenchymal cells) that are formed in parallel
& posteriorly oriented in condylar cartilage.

 Stutzmann angle- the angle formed between main
axis of endochondral bone trabeculae in condyle with
mandibular plane as viewed on lateral cephalogram.
 In anterior growth rotation there is closing of angle as
seen in treatment with growth hormone.
 In posterior growth rotation there is opening of angle
as seen in treatment with postural hyperpropulsor

1. Lateral pterygoid muscle & retrodiscal pad
tissue (blood supply ,biomechanical)
2. Effect of hormones
3. Intrinsic regulation of condylar cartilage growth
rate
4. Other hormonal & humoral factors
5. c-AMP
FACTORS AFFECTING CONDYLAR
CARTILAGE GROWTH

Retrodiscal pad

Resection of LPM & retrodiscal pad
 Experimental studies on juvenile rats were
carried out in which LPM were resected.
 The interruption of circulatory dependence on
the blood supply originating directly from LPM
& indirectly through retrodiscal pad may
contribute to inhibited differentiation of
skeletoblasts.
 It was observed that growth of condylar
cartilage & lengthening of mandible continued
but significantly decreased.

Intrinsic regulation of condylar cartilage
growth rate
 A “negative feed back signal” originates from
the proximal part of the chondroblastic zone and
exerts a restraining effect on the
prechondroblastic multiplication rate.
 This concept can help explain the effects of
some orthopedic and orthodontic appliances and
of a hormone such as thyroxine.

 The earlier commencement of chondroblastic
hypertrophy and the subsequent decrease in the
prechondroblastic division-restraining signal are
important intermediary steps in growth
stimulating effects of class II elastics,
mandibular hyperpropulsar etc.
 The acceleration of the chondroblastic
maturation rate is similarly an intermediary step
for the growth rate –stimulating effect of
thyroxine. (Stutzmann, Petrovic, 1975, 1979)

OtherTerms Related to a Servosystem
Gain = Output
Input
Attenuatation (Gain <1)Enhancement (Gain>1)
1. STH – Somatomedin
2. Small amounts of
TESTOSTERONE
3. Very small amounts of
OESTROGEN
1. Large amounts of
TESTOSTERONE
2. Small or large amounts of
OESTROGEN
3. Large amounts of
CORTISONE

Attractor Cusp to fossa relation
Repeller Cusp to cusp relation
Disturbances Abnormal tooth position
Occlusal interferences
Arthritis
Muscle Inflammation
Periodontitis, Pulpitis

CONTROL OF MAXILLARY GROWTH

Increase in length of maxilla
 Is caused by growth at the premaxillomaxillary
and maxillopalatine sutures and by subperiosteal
deposition of bone in the anterior region.
Increase in width of maxilla
 Is due to growth at the mid palatal suture and
bone deposition along lateral areas of alveolar
ridge.
 Mid palatal suture - secondary cartilage.

Mechanisms controlling growth of the upper jaw
 STH-somatomedin, testosterone and estrogen
play primary roles in extrinsic control of post
natal growth of the upper jaw.
 They have direct and indirect effects.

Direct effects
 Represents almost the entire influence of the
hormones on growth of spheno-occipital
synchondrosis and nasal septal cartilage.
 Small part of the effect of hormones on growth
of cranial sutures is direct. Effects the
responsiveness of preosteoblasts to regional and
local factors, stimulating the skeletal cell
multiplication.
 In secondary cartilage - effect seen in
multiplication and responsiveness of
prechondroblasts

Indirect effect
1. Forward growth of nasal septal cartilage.
2.Thrust effect
3.Septomaxillary ligament traction effect.
4.Labionarinary muscle traction effect.

Growth in Length:
Release of
STH
Somatomedin
Growth of
Nasal Septum
Increased size
Of Tongue
Septo-
Premaxillary
ligament
Labio narinary
Muscles
Traction
Protrusion of
Lower Incisors
Protrusion of
Upper Incisors
Thrust Growth of
Maxillo
Palatine
suture
Growth of
Pre
Maxillary
extremity
Induction
Growth of
Premaxillo-
Maxillary
suture
Biomechanical
Direct Action
Anterior shift
Of premaxillary
bones
Thrust

Growth in Width:
Release of
STH
Somatomedin
Growth of
Lateral cartilaginous
masses of Ethmoid
Increased size
Of Tongue
Growth of cartilage
B/w greater wings
& body of sphenoid
Outward growth
Of maxillary
bones
Outward shift of
Alveolus and
molars Outward
Appositional
Bone
growth
Transverse
Separation of
premaxillae
Transverse
Seperation of
Horizontal
Maxilla and
Palatine plates
Growth of
inter Pre
Maxillary
suture
Growth of
mid
Palatine
suture
Direct effect Dr Ravikanth Lakkakula

CONTROL OF MANDIBULAR GROWTH

 The variation in direction and magnitude of condylar
growth is partly a quantitative response to changes in
maxillary length.
 Variation in maxillary growth can be induced through
resection of nasal septal cartilage or administration of
growth hormone or testosterone or by orthopedic
appliances.
 As long as growth alteration does not exceed a certain
limit, no significant changes in saggital relationship of
dental arches occurs.

 The physiologic adaptation of mandibular length to
maxillary length occurs through a variation in both
growth rate and direction of growth of condylar
cartilage.
 Growth hormone- somatomedin affects the lengthening
of mandible (through condylar growth) to a greater
extent than its affects on the lengthening of maxilla.
 If this hormonal effect remains within physiological
limits, the occlusion is not significantly altered, as
concomitant reduction an angle between ramus and
corpus of mandible, decreases the length of the
mandible.

 The release of somatomedin represents the
command (command to grow).
 Reference input elements are the nasal septal
cartilage, septopremaxillary frenum, labionariary
muscles and premaxillary and maxillary bones.
The position of maxillary dental arch is
constantly changing reference input of the
servosystem.
 Lower arch is controlled variable.
 The “operation of confrontation” between the
upper and lower dental arches is the “ peripheral
comparator” of the Servosystem.

 Owing to the forward and outward growth of maxilla,
there is obvious change in relation of the teeth. What
was originally a cusp to fossae relationship becomes a
cusp to cusp relationship.
 Hence the peripheral comparator (occlusion), senses
this, due to change in performance or efficiency of
mastication. Due to improper mastication there is
increases force on periodontium, teeth, muscles and
TMJ, which serve as performance analysing elements.
The performance analyzing elements send signals to the
central comparator (controller) represented by the CNS.
 The CNS is equipped with a SENSORY ENGRAM.

 The sensory engram is a collection of feedback
loops, which record the activity of masticatory
muscles corresponding to a particular habitual
mandibular position.
 It operates on the principle of OPTIMALITY
OF FUNCTION.

 Any particular muscle action or mandibular
position that gives the minimal deviation signal
is recorded in the sensory engram. i. e. when any
new mandibular position is dictated to the
patient, unless the newer position causes a
smaller deviation signal than the older position,
the CNS will tend to make the mandible relapse
to its older position, where in function was more
ideal.
 The CNS compares the present muscular
position with the ideal position stored in sensory
engram and sends a deviation signal to an
actuator-motor cortex to correct this
discrepency.

 The actuator then sends an actuating signal to the
coupling system of the lateral pterygoid muscle and
retrodiscal pad.
 The LPM positions the mandible forward and the
activity of retrodiscal pad induces mandibular growth at
the condyle.
 The resultant output or controlled variable is the
forward growth of mandible which results in an ideal
cusp to fossa relationship.
 Once growth at the condyle occurs, the posterior border
of the mandible becomes more concave in shape,
causing a negative piezoelectric effect to develop at the
posterior border of mandible and bone apposition
occurs.

 At the same time anterior border becomes more
convex, positive piezoelectric current
resorption of bone.
 Thus length of mandible increases.

THREE LEVEL ARBORIZATION

 It is a morphogeneticic classification of human
facial development.
 By Lavergne and Petrovic (1983).
 The first level, based on the quantitative
determination of the difference between
maxillary and mandibular sagittal growth, has
three main branches.

 The second level based on variations in the
direction of mandibular and maxillary growth,
relates to growth inclinations and growth
rotations of both maxilla and mandible.
 The third level, based on the occlusal
relationship that functions as the peripheral
comparator of the Servosystem, has
subdivisions representing either an aggravation
or a melioration of malocclusions resulting
from the first two arborizational levels.

BIFURCATIONS DURING FACIAL GROWTH

 Occlusal relationships play a significant role in the process
of controlling facial growth.
 The peripheral comparator has several stable positions,
each corresponding to some type of class I, II or III
intercuspations.
 Any given occlusal relationship is stable with respect to
limited fluctuations and disturbances.

 Each cusp to cusp unstable position corresponds
to a functional discontinuity-a topologic
bifurcation type instability, described by
Thom(1972)and Zeemann(1976).
 The concept of discontinuity connotes that at
critical points, the servosystem behavior goes
through some basic switch, implying the
existence of continuous quantitative variations
that appear qualitative.

 Occlusal development involves two phases.
 First phase consists of all morphogenetic process
leading to a stable occlusion, during this phase all the
parts of the servosystem are already existent and
functional, but stable occlusal relationship capable of
serving as a peripheral comparator has not yet been
achieved.
 A reference point for the development of sensory
engram is not possible
 Hence mandibular morphogenesis cannot be
regulated through information originating from
occlusal relationships.

 The beginning of the second phase coincides
with the establishment of a stable occlusion to
serve as a peripheral comparator – required for
the development of a sensory engram.
 The subsequent morphogenesis of the face is
regulated to minimize possible deviations from
achieved stable occlusal adjustment, regardless
of whether this corresponds to a class I, II or III
intercuspation.

 Depending on the relationship of maxilla to
mandible, the dentition as a whole or in part
(peripheral comparator may be located near
molars or incisors, sometimes near canines.) may
be operating as a peripheral comparator of the
servo system.
 In posterior rotating mandible - molars
In anterior rotating mandible - incisors and
canines.
 The action of the peripheral comparator is an
important part of both orthodontic and orthopedic
treatment.

Clinical implications
 Whenever a curative measure alters the position
of group of teeth operating as a part of the
peripheral comparator in a growing child
(incisor – canine group in anterior rotating
mandible, molar group in posteriorly rotating
mandible, or whole dentition in some cases), the
clinician is dealing not only with an orthodontic
treatment (moving teeth) but also with an
orthopedic one (modifying the rate, amount and
direction of growth in facial skeleton.)

MODE OF ACTION OF FUNCTIONAL
APPLIANCES

 Appropriate functional appliances that place the
mandible in forward postural position increases
condylar cartilage growth rate & amount.
 Periodic increase in thickness of postural
hyperpropulsor, produces increase in LPM
activity & of retrodiscal pad, consequently
increasing rate & amount of condylar cartilage
growth.

Postural Hyperpropulsor
 If appliance removed after growth completed –
little or no relapse.
 If removed before growth completed- no relapse
if good intercuspation.
 If good intercuspation has not been achieved
before the growth is completed - then the
comparator of Servosystem imposes an
increased or decreased growth rate until state of
good intercuspation achieved.

Class II elastics
 Class II elastics not only move teeth but act also
act as a functional appliance capable of
stimulating the growth rate & amount of
condylar cartilage.
 The stimulating effect of the Class II elastics on
the lengthening of the condyle appears to be
mediated primarily through the retrodiscal pad.

HERREN (L.S.U) ACTIVATOR (Louisiana state
university)
 It opens the construction bite beyond the
postural rest position.
 According to Herren (1953) & Auf der maur
(1978) the wearing of appliance does not bring
about any increased activity of LPM as no free
movement of mandible possible.

TWO STEP ACTION
• When appliance is worn-
Forward positioning of mandible is the cause
of reduced increase in length of LPM.
New sensory engram
• When appliance is not worn-
Mandible functioning in more forward position
More stimulation of retrodiscal pad activity

 Repetitive activity of pad leads to earlier onset
of condylar chondroblasts hypertrophy.
 Decrease in no of functional chondroblasts.
 Decrease in prechondroblasts multiplication
restraining signal.
 Increase in condylar cartilage growth.

FRANKEL LATERAL VESTIBULAR SHIELD
 The appliance acts by stimulating midpalatal suture
growth & to lesser extent by increasing bone
apposition on external subperiosteal layer of maxilla.
 Buccal shield --- eruptive pathway of teeth at the
critical time in their development.
 The relief of pressure from the cheeks in the
dentoalveolar area seems to allow a more downward
and outward eruptive path at a time of maximal
variability, permitting horizontal and vertical
adjustment of osseous tissues involved.

Summary of method of operation of functional
appliances
 Class II elastics, postural hyperpropulsar, Frankel
regulator, Balters bionator, Clark twin block all
exert effects mainly through movement of
mandible. Their stimulating effects are produced
mainly during wearing of appliance.
 Herren & L.S.U activators & extraoral forward
traction on mandible seem to exert their effects
mostly through sagittal repositioning of mandible.

 Regardless of differences in mode of action, the
following causal chain is involved-
Functional appliance
Increase contractile activity of LPM
Intensification of repetitive activity of retrodiscal
pad

Increase in growth stimulating factors
Enhancement of local mediators
Reduction of local mediators (factors causing negative feedback
effects)
Additional growth of condylar cartilage
Additional subperiosteal ossification of posterior border of
mandible
Supplementary lengthening of mandible

CLINICAL IMPLICATIONS

 According to the principle of optimality of function,
a condition which results in maximum efficiency is
one that is instilled in the brain. Hence the tendency
for relapse will be less if we achieve an optimal
functional situation.
 Functional appliance therapy should be extended
until growth is completed, or should achieve a good
intercuspal relation, if growth is not completed.
 If Treatment ends with teeth in poor occlusion,
during growth phase, relapse is more likely to occur.

 The sensory engram is poorly developed in
children. Hence they respond better to
functional appliance therapy.
 Hormonal activity is highest during pubertal
growth spurt. As hormones are very important
for growth, one must take full advantage of the
increased hormonal activity if any growth
modulation is required.
 Proper functioning of LPM-RDP, is essential for
growth. (Petrovic and Stutzmann)

Drawbacks
1) Lot of importance on condyle:
Fracture ?
2)Peripheral comparator (occlusion)
discrepancies may be overcome by
Dentoalveolar
changes.

3) Occurrence of Class II end on relation is
seen often ?
4) Action of reverse pull headgear on maxilla
(primary cartilage)

FUNCTIONAL MATRIX REVISITED
 Advances in biomedical, bioengineering and
computer sciences made Moss to do a
comprehensive revision of functional matrix
hypothesis.

 One incompleteness with functional matrix
hypothesis was that it did not describe how
extrinsic, functional stimuli are converted
into controlling signals by individual bone
cells, and how individual cells communicate to
produce coordinated multicellular responses.

 In his old functional matrix hypothesis, Moss
described that all growth changes in size, shape
of the skeletal unit (bone) are always secondary
to changes in their specific functional matrices
(soft tissues).
 But he did not describe how
changes in functional matrix
growth changes in bone ?????

Old functional matrix hypothesis had a
Hierarchical constraint:
Initial explanations did not extend
"downward" to processes occuring at the
cellular, subcellular, or molecular level, or
extend "upwards" to the multicellular processes
by which bone tissues respond to lower level
signals.

Mechanotransduction:
 It is a process by which a
cell converts an
external stimuli in the
form of a load into an
intracellular signal.
 All vital cells are
"irritable" or perturbed by
and respond to alterations
in their external
environment.

Osseous Mechanotransduction:
 Static and dynamic loadings are continuously
applied to bone tissues. They tend to deform
both extracellular matrix and bone cells.
 When an appropriate stimulus exceeds
threshold values, the loaded tissue responds by
the triad of bone cell adaptation processes which
are deposition, resorption and maintenance.

 Osseous Mechanotransduction translates the
information content of a Periosteal functional
matrix stimulus into a skeletal unit cell signal,
i.e., it moves information hierarchically
downward to the osteocytes.

 Both osteocytes and osteoblasts are capable of
intracellular stimulus reception and transduction
and for subsequent intercellular signal
transmission.
 Osteoblasts directly regulate bone deposition
and maintenance and indirectly regulate
osteoclastic resorption.

 There are two, osseous mechano
transductive processes:
1.Ionic and
2.Mechanical

Ionic or electrical process :
This involves ionic transport through the
osteocytic plasma membrane. It occurs by means
of stretch activated channels. These channels are
found in plasma membrane of bone cells, and
significantly in fibroblasts.
Upon loading, several types of deformation can
occur in strained bone tissue. One of these is the
activation (stretch) of stretch-activated ion
channels, found in plasma membrane.

 When activated, the stretch activated channels of
the strained osteocytes permit passage of a
certain ions, like K+, Ca2+ and Na+.
The ionic flow may in turn, initiate intracellular
electrical events like change in membrane
potential.
This results in formation of an electric signal.

There is a subsequent intercellular transmission
of the created electrical signals that, in turn, is
analyzed by the operation of an osseous
connected cellular network. The network's
output regulates the multicellular bone cell
responses.

Mechanical processes:
The mechanical properties of the extracellular
matrix also can influence cell behavior.
This is explained by findings from recent studies
that show that, series of connections exist, capable
of transmitting information from the strained
extracellularmatrix to the bone cell nuclear
membrane.

The basis of this mechanism is the physical
continuity of the transmembrane molecule
integrin. This molecule is connected
extracellularly with collagen of the organic
matrix and intracellularly with the cytoskeletal
actin.

The molecules of the actin, are connected to the
nuclear membrane, at which site the action of
the mechanical lever chain initiates a series of
intranuclear processes capable of controlling
genomic activity.

Such a cytoskeletal lever chain, connecting to the
nuclear membrane, can provide a physical
stimulus able to activate the osteocytic genome.
It is by such an interconnected physical chain of
molecular levers that periosteal functional matrix
activity may regulate the genomic activity of its
strained skeletal unit bone cells.

BONE AS AN OSSEOUS CONNECTED CELLULAR NETWORK
 Just like human beings even
cells communicate with each
other.
 The bone cells also
communicate with each other.
All bone cells, except
osteoclasts, are extensively
interconnected by gap
junctions that form an
osseous connected cellular
network.
Compact bone

 Each osteocyte, enclosed
within its mineralized
lacuna, has many (n = ± 80)
cytoplasmic processes, 15
mm long and arranged
three-dimensionally.
 These interconnect with
similar processes of up to 12
neighboring cells. They lie
within mineralized bone
matrix channels - canaliculi.

 Gap junctions are found where the plasma
membranes of a pair of markedly overlapping
canalicular processes meet.

Gap junctions
 permit the intercellular transmission of ions and
small molecules,
 exhibit both electrical and fluorescent dye
transmission.
 They also permit bidirectional signal traffic,
 In these junctions, connexin 43 is the major
protein.

 All osteoblasts are interconnected laterally.
Vertically, gap junctions connect periosteal
osteoblasts with preosteoblastic cells, and these,
in turn, are similarly interconnected.

 With so many interconnections do they all
perform a similar type of function (deposition or
resorption) ?
 No. The gap junctions close at the boundary
between groups of cells creating a histologic
discontinuity to prevent flow of information.

 Effectively, each closed cell network is a true
syncytium. As bone cells are electrically active,
bone tissue can be called as "hard-wired”.
 The osseous connected cellular network
computationally processes the intercellular signals
created by mechanotransduction of periosteal
functional matrix stimuli.

 Subsequently the output
informational signals
move hierarchically
"upward" to regulate the
skeletal unit adaptational
responses of the
osteoblasts.

 Moss also revisited the earlier analysis of the
perennial genomic or epigenetic controversy.
 The newer functional matrix hypothesis
reconsidered the relative roles of genomic and of
epigenetic processes in the regulation of
craniofacial growth and development.
 A genomic thesis, an epigenetic antithesis and a
resolving synthesis were done by Moss.

 An example of genomic/epigenetic dichotomy:
odontogenesis.
 Vertebrate dental coronal morphology in zoology,
is thought to be under rigid genomic control of
odontogenesis and is so used for diagnostic use
in forensic odontology and vertebrate
paleontology.
 But data exists strongly supportive of epigenetic
regulation of odontogenesis.

He reasons this with 2 postulates:
 Mechanical forces, due to differential diet
hardness generate epigenetic signals,
mechanotransductively processed by dental
papilla cells.
 These signals control the expression of genomic
products related to development of differential
tooth form, such as size and shape.

GENOMIC
THESIS
Morphogenesis is
predetermined
reading out of an
inherited genomic
blueprint.
EPIGENETIC
ANTITHESIS
Many different
extrinsic stimuli are
capable of
modifying DNA.
Mechanical loading
is known to
influence gene
expression.

Genes control the
mechanism by which a
fertilized egg divides
and progresses through
various decision points,
to result in a group of
cells that are first
determined to become
and then differentiate ,
to become specialized
tissue of right
dimension and in proper
location.
Tissue loading can
alter cell shape. This
deforms the
cytoskeleton. The
epigenetic processes
of changing cell shape
stimulate epigenetic
mechanism of
mechanotransduction
of forces into genomic
and
morphogenetically
regulatory signals.

 The resolving synthesis suggests that both
genomic and epigenetic factors are necessary
causes , that neither alone is sufficient cause,
and that only the two, interacting together,
furnish both the necessary and sufficient causes
of ontogenesis.

GROWTH RELATIVITY HYPOTHESIS
 Several theories have emerged attempting to shed
light on condylar growth.
 An early hypothesis, based on electromyographic
(EMG) monitoring technique, suggested that
hyperactivity of the lateral pterygoid muscle
promotes condylar growth. This was put forward
by Charlie, Petrovic and later supported by
McNamara.

The lateral pterygoid muscle arises by 2 heads.
1. Superior head: arises from infratemporal crest and
infratemporal surface of greater wing of sphenoid
bone.
2. Inferior head: arises from lateral surface of lateral
pterygoid plate.
Insertion: both are inserted into pterygoid fovea.
But a part of upper head is found attached to capsule
and to anterior and medial border of articular disc.

Retrodiscal tissues
Articular disc
Fibro cartilage layer
Sup. Head of
lateral pterygoid

Three-dimensional illustration of
human TMJ which shows minimal
attachment of superior head of the
lateral pterygoid muscle to
articular disk.

 Studies done using permanently implanted
muscle monitoring techniques have found that
the condylar growth is actually related to
decreased postural and functional lateral
pterygoid activity.
 This was supported in human studies by Auf
der Maur, Pancherz and Anehus-Pancherz.

 The concept of Growth relativity was put
forward by John Voudoris.
 Growth relativity refers to growth that is
relative to the displaced condyles from actively
relocating fossae.
 In his hypothesis, growth is discussed relative
to long-term retention results, rather than short-
term treatment outcomes that are different.

The glenoid fossa promoting condylar growth
during orthopedic mandibular advancement
therapy is based on three Main foundations.
They are:
1. Displacement affects the fibrocartilaginous
lining in the glenoid fossa to induce bone
formation locally.
2. Stretch of nonmuscular viscoelastic tissues.

3. New bone formation occuring at a distance
from the retrodiskal tissue attachments in the
fossa. Both the displaced condyle and glenoid
fossa are influenced by articular disc, fibrous
capsule and synovium, which are contiguous
anatomically and functionally.

Viscoelasticity is conventionally applied to
elastic tissue, primarily muscles but according to
Voudoris viscoelasticity refers to all
noncalcified tissues like:
 the viscosity and flow of the synovial fluids,
 the elasticity of the retrodiskal tissues,
 the fibrous capsule and other nonmuscular
tissues including lateral pterygoid muscle
perimysium, TMJ tendons and ligaments.

 Microscopic examination of TMJ sections have
revealed direct connective tissue attachments of
the retrodiskal tissues into the
fibrocartilaginous layer of the condylar head.
These distinct attachments to the condylar head
use the articular disk and fibrocartilage to
communicate between the glenoid fossa and the
condyle.

 Condylar growth is affected by viscoelastic tissue
forces via attachment of the fibro-cartilage that
blankets the head of the condyle.

During orthopedic mandibular advancement:
 there is an influx of nutrients and other
biodynamic factors into the condylar region
through the engorged blood vessels of the
stretched retrodiskal tissues that feed into the
fibrocartilage of the condyle.

 The expulsion of these factors occurs during
reseating of the displaced condyles in the fossa
during relapse. The result is a metabolic pump-
like action of the retrodiskal tissues.

 Another thing is alteration of synovial fluid
dynamics. Nitzan using disoccluding
appliances in human beings found low
subatmospheric intra-articular pressures within
the TMJ in the open position.

 The low intra-articular pressures significantly
alter the flow of synovial fluid. It was observed
surgically that these negative pressures shift
synovial fluid in a posterior direction.

 The shift of synovial fluid in a posterior direction
acts like a suction cup placed directly on the
displaced condylar head to activate growth.
 The negative pressures, which are initially below
capillary perfusion pressures, permit greater flow
of blood into the condyle - glenoid fossa region .

Three factors influence growth modification.
1. Displacement,
2. Viscoelasticity, and
3. Referred force.

 An analogy was put forward by Voudouris
where, the condyle appears to act like a light
bulb on a dimmer switch. It lights up during
advancement, dimming back down to near
normal levels in retention.

Retention Relapse Of Condylar Modification:
The active return of the condyles to the fossae
during post-treatment appears to deactivate the
modifications occurred by compressing the
condyle against the proliferated retrodiskal
tissues.

SIGNAL TRANSDUCTION
 Regulation of growth and development is
controlled by the interactions of cells with each
other and the extracellular environment through
signal transduction pathways that control
differentiation process by stimulating
proliferation or causing cell death.

 Intracellular signaling is usually triggered by a cell
surface event such as a specific protein (ligand)
binding to a cell surface receptor to form a receptor-
ligand interaction.

Interactions of cells with other cells or the
extracellular matrix can stimulate many
reactions, like:
1. Increased cell division,
2. Cell movement,
3. Differentiation, and even programmed cell
death (apoptosis).

 Interaction of the cells with other cells and
extracellular matrix occurs by means of receptors
located on the cell surface in the plasma
membrane.
 The receptors are classified by the protein structure
and ligand characteristics.

Receptor parts:
 Part of the protein located outside the cell to interact
with the ligand - extracellular ligand binding
domain.
 Part of the protein that traverse through the
membrane - membrane spanning domain,
 Part of the protein inside the cell - cytoplasmic
domain.

 There are different types of cell surface receptors
The classic growth factor receptors belong to the
class tyrosine kinases, or receptor
serine/threonine kinases.
 In addition to these classic receptor classes, cells
can respond to their extra cellular matrix
environment through integrin receptors.

Intracellular signaling proteins:
 One basic principle of signal transduction is that
the proteins exist in at least two states: activated
and inactivated.
There are several methods to turn the signals on
and off, including
1. Phosphorylation,
2. Dephosphorylation,
3. Intracellular location
4. Calcium ion levels .

 There is a signal transduction pathway that is
important in craniofacial development termed
Epithelial Mesenchymal Transformation,
which is employed during gastrulation, cranial
neural crest migration, and secondary palate
formation.

Epithelial Mesenchymal Transformation :
 It is a process in which an epithelial cell changes
into a mesenchymal cell. It is found that not
only epithelial-mesenchymal transformation,
also mesenchymal – epithelial cell
transformation occurs and is important in
embryonic development, wound healing, and
tumor metastasis.

 Epithelial mesenchymal transformation occurs
during gastrulation, one of the early developmental
events that change the two layered embryonic disc
into a three layered embryo.
 This process involves the invagination of the epiblast
cells (top layer) to form the mesoderm and endoderm
germ layers.

 They serve as the boundary between the external
environment and the remainder of organs.
 Their barrier function is partly supported by firm
cell-cell junctions, such as tight junctions and
desmosomes.
Characteristics of epithelial cells:

 They have an intact basal lamina
 They normally have basal polarity and attach to
basal lamina by hemidesmosomes.

 They are found in the connective tissue
compartment. They are more mobile and are
surrounded by extracellular matrix.
 They form only temporary contacts with their
neighboring cells..
Characteristics of mesenchymal cells:

During Epithelial mesenchymal transformation:
 epithelial cells lose expression of cell adhesion proteins,
like E-cadherin,
 lose cell-cell attachment and become mobile,
 and increase expression of enzymes that break down
the basal lamina and then expresses mesenchymal
proteins.

Regulation of Epithelial mesenchymal
transformation:
 The control of Epithelial mesenchymal
transformation is critical during dynamic
developmental processes and postnatal homeostasis.
 According to Hay master genes that get turned on in
epithelia by changes in the environment, initiate
Epithelial mesenchymal transformation (master gene
theory).

 Recently several molecules have been identified as
possible master genes including the transcription
factors.
The changes in the environment that may initiate
Epithelial mesenchymal transformation are:
1. Growth factors,
2. Cell adhesion molecules,
3. Extracellular matrix, and
4. The surface receptors and downstream signal
transduction events and transcription factors.

 Growth Factors Important in Epithelial
Mesenchymal transformation - members of the
transforming growth factor β (TGF- β) family and
fibroblast growth factor.
 Studies have shown that TGFβ-2 mediates initial
cell-cell separation and TGFβ-3 is required for the
cell morphological change that enables the migration
of cells into the underlying extracellular matrix.

 TGF- family members are essential for Epithelial
mesenchymal transformation during development.
 A recent study showed that the removal of the
transforming growth factor β receptor II (TβrII)
gene in only the cranial neural crest lineage resulted
in clefting of secondary palate and calvaria defects.

Palatal development:
 It is recently shown that sonic hedge hog (shh) and
the Fgfr2b were expressed in the early palatal
epithelium and appear to be induced by Fgf10.
 When this pathway was disrupted in animals, the
palatal processes failed to grow.

 The normal palatal shelves elevate and grow toward
the midline where they fuse and some of the medial
edge epithelial cells move into the mesenchyme
through the EMT process.

 During mammalian palate development TGF-
isoforms 1, 2, 3, TβRII, and TβRIII were detected
in the medial edge epithelium.
 Studies found out that that TGF-β3 is an essential
growth factor inducing Epithelial mesenchymal
transformation during palatal fusion.

Craniofacial growth and development is a
complex and closely regulated process.
 The actions of growth factors are very complex, with
each growth factor having both multiple and different
effects on various tissues.
 Further studies are required to determine how these
factors can be manipulated within a clinical
environment to augment treatment.

 Cells are influenced by genes and environmental
stimuli to migrate, proliferate, and differentiate to
ultimately result in shapes such as the nose and chin.
 Mechanical forces are the most studied
environmental influences.
MAO’S CONCEPTS

 A force propagating through biological tissue is
transduced as tissue borne mechanical stresses which
induce interstitial fluid flow.
 Interstitial fluid flow causes deformation of
extracellular matrix molecules, trans-membrane
channels and cytoskeleton resulting in strain.

 Exogenous forces are transmitted in biological
tissues as strain before cellular and genetic
responses are elicited via a series of
mechanotransduction events.

 So mechanical strain becomes the common thread of
all mechanical forces acting on tissues, cells and
genes.
 All characteristics of mechanical signals (force)
including magnitude and duration have been
examined in experiments and clinical practice of
craniofacial orthopedics except force frequency.

 MAO states that “Multiple cycles of change in force
magnitude are effective in that bone and cartilage cells
respond more readily to rapid oscillation in force
magnitude than to a constant force”.
 Cyclic forces with sinusoidal wave forms induce
accelerated growth of not only craniofacial sutures, but
also chondrogenesis of cranial base cartilage spheno-
occipital synchondrosis.

 Growth cartilage of cranial base is generally
regarded as growth center with growth potential
predetermined by genes and with little
influence from environment.
 It was hypothesized that mechanical stimuli
enhance growth of sphenooccipital
synchondrosis.

 To test the hypothesis a study was done on rabbits, in
which they were treated with no force, 2 N static
force for 20 mins per day over 12 days, and 2 N
cyclic forces for same duration.
 Cells kinetics experiments showed that, chondrocytes
treated with cyclic forces had significant increase in
proliferating zone of sphenooccipital synchondrosis.

RABIE’S CONCEPT
 With his studies Rabie found out that condylar
growth follows a sequence of transitory stages
caused by molecules synthesized by
undifferentiated mesenchymal cells and by
differentiating chondrocytes.

The sequence he found out was:
 The cells in the proliferative layer of condylar cartilage
express Sox 9 transcription factor.
 Differentiation of mesenchymal cells into chondrocytes
which synthesize type II collagen which forms matrix of
cartilage.
 Chondrocytes become mature and they hypertrophy and
start secreting type X collagen.
 Cells in upper zone of hypertrophic cartilage secrete
vacular endothelial growth factor (VEGF).

 VEGF causes neovacularization (new blood vessel
formation) of hypertrophic cartilage and influences
removal of the cartilage matrix.
 Invading blood vessels bring osteogenic progenitor
mesenchymal cells that differentiate into osteoblasts
resulting in osteogenesis.

 The critical role of VEGF, which stimulates
neovascularization and marks the onset of endochondral
ossification, made Rabie to think of its applications in
craniofacial anomalies like micrognathia and hemifacial
microsomia.
 With rapid development of recombinant DNA
technology using specific gene encoding the proteins, we
are now able to synthesize large quantities of the
therapeutic proteins for treatment purposes.

 Most recently, a delivery vehicle has been
constructed using which potential therapeutic genes
could be delivered to the condyle.
 Recombinant adeno-associated virus was chosen as a
vehicle for delivery of VEGF.
 Studies have found that local recombinant adeno-
associated virus mediated VEGF transfer leads to
mandibular condyle growth.

HOMEOBOX GENES
 Cell proliferation and differentiation are important
events in growth and development. Along with this,
cell migration and apoptosis (programmed cell
death), which helps in localized removal of tissue and
shaping of organs are also needed.
 With so many complex things happening during
growth, a mechanism should exist that regulates
gene expression.

 With revolution in molecular biology it was found
that 2 special groups of molecules namely homeobox-
containing transcription factors and growth factors
play this important role.
 Transcription factors: are nuclear proteins that regulate
the expression of genes by binding to DNA.

 A specific group of transcription factors that
bind to DNA by the so called homeodomain
have a key role in developmental regulation.
 Homeobox containing genes: the genes of
these special group of transcription factors have
a 180 base pair sequence that encodes DNA-
binding homeodomain

 Important feature of hox genes is that some of them
encode positional information during
embryogenesis.
 They were first detected in fruitfly in which they
were called major pattern formation genes.
 An example of importance of hox genes in
regulating position, is a fly in which the mutation in
homeobox containing Antennapedia gene causes
development of legs in the place of antennae.

 Vertebrates including humans have homeobox
genes and they specify positional information.
 In man and most vertebrates there are 4 hox gene
clusters containing total of 39 hox genes.
 Combination of different homeobox genes
expressed in specific locations, form hox codes
which specify the position of cells.

 With increased understanding of craniofacial
growth and development we can develop better
mechanotherapies.

Thank you

Recent advances in Growth theories - orthodontics

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