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1. A
REVIEW OF
FUNCTIONAL
MATRIX THEORY

2. Growth is a general term
implying an increase in
magnitude. Development
is a maturational process.

3. It is important for us to know and
understand this biologic process of
growth and development because at
some point of time we manipulate
growth by intervening the course of
the control process of growth by
giving functional appliances and
orthopedic devices

4. . Morphogeneis (i.e. growth control
process) constantly tends to achieve
a balance between growing parts.
But as development progress
balance can never be actually
achieved because growth itself
creates ongoing, normal regional
imbalance

5. Facial growth operates with two
basic kinds of growth movement
a. Remodeling
b. Displacement

6. Functions of remodelling are
-Size
-Relocate
-Shape
-Fitting
-Adatation

7. Displacement: As bone
enlarges it is carried away
from other bones. This
creates space within which
bony enlargement takes place
called “Displacement” also
called translation.

8. Here is a brief selection of architectonic
factors that play into the overall issue of
craniofacial development and growth,
taken from (CGT and OT. Enlow)
Growth is a differential process of
progressive maturation.

9. Development is a process working
toward an ongoing state of aggregate
composite structural and functional
equilibrium
The “Goodness of fit” among
contiguous anatomic parts and groups
of parts is remarkable.

10. Each entire bone and all of its
regional parts participate directly and
actively in the growth of the bone.
The nature and capacity for inter-
related growth adjustments among
separate parts vary among different
tissue types

11. Displacement and remodeling are two
of the fundamental types of bone
growth activities.
Variations in head form are an
important factor in growth of facial
skeleton.

12. With regard to our phylogenetic
heritage, the factor of bipedal
posture inter-relating with the
enormous weight of human brain
and marked basicranial flexure
have imposed an inferoposterior
rotational placement of naso
maxillary complex.

13. The subject of growth
rotations associated with
the craniofacial complex
has justifiably become of
great interest.

14. In considering architectonic feedback
communication and give-and-take
regional adaptations involved in growth
control, three structures, in which
component parts play a particularly
significantly role stand out
Mandibular ramus
Periodontal connective tissue membrane
Lacrimal bone

15. Clinical intervention in the growth
control process is achieved by
either (a) use of equivalent
surgical procedures for the natural
displacement and remodeling
activities that were incomplete or
derailed

16. b) By overriding the intrinsic signals
that activate and control
morphogenesis through introduction
of clinically-induced signals that
overwhelm the intrinsic osteogenic,
chondrogenic, myogenic, and
fibrogenic architectonic systems, but
that utilize a given systems actual
operation to achieve a clinical goal.

17. Another fundamental consideration
often is conceptually by-passed.
When muscles of facial expression
contract the effect on the maxilla is a
upward and backward effective force
but the maxilla grows downward and
forward. DOES THIS CONTRADICT
THE FUNCTIONAL MATRIX
THEORY!!!!!

18. All of the above points converge to
underscore the fundamental point that
any given craniofacial component is
not entirely self-contained, is not self-
regulated and growth controlled, and
is not developmentally separate and
unrelated to other parts and the
composite of all of them.

19. Various growth theories that have been
proposed over the years
Genetic control theory (Brodie 1941)
Cartilage directed growth theory
(Scott 1953)
Sutural Theroy
Functional matrix theory (Moss 1960)
Servo system theory (Petrovic 1974)

20. FUNCTIONAL MATRIX THEORY
(MOSS 1960) PROFFIT
Moss says if neither bone
nor cartilage were
determinant or growth of
craniofacial skeleton, the
control would lie in the
adjacent soft tissues.

21. He theorizes that growth of the
face occurs as a response to
functional needs and is
mediated by the soft tissues in
which it is embedded. He
gives an example of the growth
of cranial vault.

22. Pressure exerted by the
growing brain separates the
growing bone at the cranial
sutures and new bone
passively fills in these sites, so
as the cranial vault fits the
growing brain.

23. Moss theorizes that
maxilla and mandible
grow due to enlargement
of nasal and oral cavities.

24. FUNCTIONAL MATRIX
THEORY (GRABER
AND PETROVIC)

25. Acc: to FMT regional and local
factors play a role in craniofacial
morphogenesis. It says the growth
of bone and cartilage seems to be a
compensatory response to
functional matrix growth. The
functional matrix includes muscles,
nerves, teeth, glands, blood vessels
etc.

26. Two types of functional matrix are
recognized
- Periosteal
- Capsular
The growth of functional matrix is
primary; the growth of skeletal unit
is secondary.

27. FUNCTIONAL MATRIX
HYPOTHESIS AND
EPIGENETICS

28. The hypothesis derives from a century
old work of His and Roux ad is
compatible with recent epigenetic
concepts associated with Waddington
et al.
The functional matrix hypothesis
serves as conceptual ridge between
function and epigenesis.

29. As mentioned earlier, the FMH claims
that the origin, growth and
maintenance of skeletal tissues and
organs are always secondary,
compensatory and mechanically
obligatory responses to temporally and
optionally prior events and process
occurring in non-skeletal tissues
organs and functioning spaces.

30. The term epigenetic may be used to
describe the sum of all
biomechanics, bioelectrical,
biochemical and biophysical
parameters produced by
functioning of cells, tissues, organs
and organisms.

31. These epigenetic factors serve
as an internal environment
and must be considered in
addition to the classical
external environments of
genetics.

32. Epigenetic factors are thought to act
on the genome to regulate all
developmental process. Epigenetic
views the genome as providing a set of
formal, prior, intrinsic and necessary
casual factors that when combined
with efficient, proximale, extrinsic,
and necessary epigenetic factors,
together are sufficient to account for
regulation of development.

33. What we have seen is the gross
macroscopic level of the functional
matrix theory, if we want to know
how this thesis works and the basis
for this theory, we have to see at
the microscopic and histologic
levels of what really happens.

34. FUNCTIONAL MATRIXFUNCTIONAL MATRIX
HYPOTHESISHYPOTHESIS
REVISITEDREVISITED

35. In this series of article’s we see
The mechanisms of cellular
mechanotransduction, and biologic
network theory,
mechanotransduction is a process cell
signal transfer.
Biologic network theory explains the
network of bone cells and how they
interact to the signals.

36. The several possible types of
intracellular processes of
mechanotransduction are
described in this first part.

37. The FMH postulates two types of
functional matrices: periosteal and
capsular. The former, typified by
skeletal muscles, regulates the
histologically observable active
growth processes of skeletal tissue
adaptation.

38. The molecular and cellular
processes underlying the triad
of active skeletal growth
processes: INCLUDES
deposition, resorption, and
maintenance

39. Histologic studies of actively
adapting osseous tissues
demonstrate that (1) adjacent
adaptational tissue surfaces
simultaneously show deposition,
resorption, and maintenance;

40. (2) adaptation is a tissue process.
Deposition and maintenance are
functions of relatively large groups
(cohorts, compartments) of
homologous osteoblasts, never
single cells; and

41. (3) a sharp demarcation exists
between adjacent cohorts of active,
depository, and quiescent (resting)
osteoblasts.

42. MECHANOTRANSDUCTION

43. Mechanotransduction is one type of
cellular signal transduction. There are
several mechanotransductive
processes, for example,
mechanoelectrical and
mechanochemical. Whichever are
used, bone adaptation requires the
subsequent intercellular transmission
of the transduced signals.

44. All vital cells are "irritable” and
respond to alterations in their external
environment.
Mechanosensing processes enable a
cell to sense and to respond to
extrinsic loadings by using the
processes of mechanoreception and of
mechanotransduction.

45. The former transmits an
extracellular physical stimulus into
a receptor cell; the latter
transducers or transforms the
stimulus's energetic and/or
informational content into an
intracellular signal.

46. OSSEOUS
MECHANOTRANSDUCTION

47. Static and dynamic loadings are
continuously applied to bone
tissues, tending to deform both
extracellular matrix and bone cells.

48. When the level exceeds threshold
values, the loaded tissue responds
by the triad of bone cell adaptation
processes.

49. Osseous mechanotransduction is
unique in four ways: (1) Most
other mechanosensory cells are
cytologically specialized, but bone
cells are not; (2) one bone-loading
stimulus can evoke three
adaptational responses, whereas
nonosseous processes generally
evoke one;

50. (3) osseous signal transmission is
aneural, whereas all other
mechanosensational signals use
some afferent neural pathways
and, (4) the evoked bone
adaptational responses are
confined within each "bone
organ" independently,

51. There are two, possibly
complementary, skeletal
cellular mechanotransductive
processes: ionic and
mechanical.

52. IONIC OR ELECTRICAL
PROCESS

53. This involves some process (es) of
ionic transport through the bone
cell (osteocytic) plasma membrane.
This signal in turn is computed to
an osseous connected cellular
network.
The output of this network
regulates the multicellular bone
cell responses.

54. Stretch activated channel

55. Several types of deformation may
occur in strained bone tissue. One
of these involves the plasma
membrane stretch-activated (S-A)
ion channels, a structure found in
bone cells,

56. When activated in strained
osteocytes, they permit passage of a
certain sized ion or set of ions,
including K+, Ca2+, Na+

57. Such ionic flow may, in turn,
initiate intracellular electrical
events, for example, bone cell S-A
channels may modulate membrane
potential as well as Ca2+ ion flux.

58. Electrical processes. These include
several, nonexclusive
mechanotransductive processes
Electromechanical.
Electro kinetic
Electric field strength.

59. MECHANICAL PROCESS

60. The mechanical properties of the
extracellular matrix influence cell
behavior. Loaded mineralized bone
matrix tissue is deformed or strained.
Data indicate that a series of
extracellular macromolecular
mechanical levers exist, capable of
transmitting information from the
strained matrix to the bone cell
nuclear membrane.

61. The basis of this mechanism is the
physical continuity of the
transmembrane molecule integrin.
This molecule is connected
extracellularly with the
macromolecular collagen of the
organic matrix and intracellular with
the cytoskekeletal actin.

62. These cytoskekeletal actins are
connected to the nuclear
membrane, where a subsequent
series of intranuclear processes
regulatory of genomic activity takes
place.

63. 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,

64. BONE AS AN OSSEOUS
CONNECTED
CELLULAR NETWORK
(CCN)

65. All bone cells, except
osteoclasts, are extensively
interconnected by gap
junctions that form an osseous
CCN. In these junctions,
connexin is the major protein.

66. Each osteocyte, enclosed within its
mineralized lacuna, has many
cytoplasmic (canalicular)
processes, 15 mm long and arrayed
three-dimensionally, that
interconnect with similar processes
of up to 12 neighboring cells.
These processes lie within
mineralized bone matrix channels
(canaliculi)

67. Gap junctions are found where the
plasma membranes of a pair of
markedly overlapping canalicular
processes meet. In compact bone,
the canaliculi cross "cement
lines," and they form extensive
communications between osteons
and interstitial regions.

68. Gap junctions also connect
superficial osteocytes to periosteal
and endosteal osteoblasts. All
osteoblasts are similarly
interconnected

69. Effectively, each CCN is a true
syncytium. Bone cells are
electrically active. In a very real
sense, bone tissue is "hard-wired."

70. In addition to permitting the
intercellular transmission of ions
and small molecules, gap junctions
exhibit both electrical and
fluorescent dye transmission.

71. Gap junctions are electrical
synapses, in contradistinction to
interneuronal, chemical synapses,
and, significantly, they permit
bidirectional signal traffic, e.g.,
biochemical, ionic.

72. Mechanotransductively activated
bone cells, e.g., osteocytes, can
initiate membrane action potentials
capable of transmission through
interconnecting gap junctions

73. CCN is operationally analogous to
an "artificial neural network," in
which massively parallel or
parallel-distributed signal
processing occurs.

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

75. In network theory, these cells are
organized into "layers": an initial
input, a final output, and one or
more intermediate or "hidden"
layers.

76. Each cell in any layer may
simultaneously receive several
"weighted" inputs (stimuli).

77. An intracellular signal is generated,
i.e., successful mechanotransduction
occurs. This signal is then transmitted
identically to all the "hidden" layer
cells (adjacent osteocytes) to which
each initial layer cell is connected by
gap junctions (and there are many
styles of connectivity).

78. Next, similar processes of weighted
signal summation, comparison, and
transmission occur in these
intermediate layers until the final
layer cells (osteoblasts) are reached.

79. The outputs of these anatomically
superficial cells determines the site,
rate, direction, magnitude, and
duration of the specific adaptive
response, i.e., deposition, resorption,
and/or maintenance, of each cohort of
osteoblasts.

80. The CCNs show oscillation, i.e.,
iterative reciprocal signaling
(feedback) between layers.
Gap junctions, permitting
bidirectional flow of information, are
the cytological basis for the oscillatory
behavior of a CCN.

81. A skeletal CCN displays the
following attributes: (1)
Developmentally, it is an untrained
self-organized, self-adapting and
epigenetically regulated system.

82. (2) Operationally, it is a stable,
dynamic system that exhibits
oscillatory behavior permitting
feedback. It operates in a noisy,
nonstationary environment, and
probably uses useful and necessary
inhibitory inputs.

83. (3) Structurally, an osseous CCN is
nonmodular, i.e., the variations in
its organization permit discrete
processing of differential signals. It
is this attribute that permits the
triad of histologic responses to a
unitary loading event.

84. The morphogenetic primacy of
periosteal functional matrices on
their skeletal units is consensually
accepted.

85. As a muscular demand alters, e.g.,
myectomy, myotomy, neurectomy,
exercise, hypertrophy, hyperplasia,
atrophy, augmentation, or
repositioning, the triad of active bone
growth processes correspondingly
adapts the form of its specifically
related skeletal unit

86. Although no one mechanical
parameter reliably predicts all bone
adaptational or remodeling
responses, strain probably plays the
primary role and is a competent
stimulus.

87. Although it is reasonably presumed
that mechanosensory processes, of
both the ionic and mechanical type,
involve the plasma membrane of the
osteocytic soma or canalicular
processes, the receptive, and
subsequent transductive, processes are
neither well understood nor
consensually agreed on.

88. In a phrase, bone appears to be
closely "tuned" to skeletal
muscle.

89. Where the original FMH version
offered only verbal descriptions of
periosteal matrix function and
skeletal unit response, the addition
to the FMH of the concepts of
mechanotransduction and of
computational bone biology

90. offers an explanatory chain
extending from the epigenetic event
of skeletal muscle contraction,
hierarchically downward, through
the cellular and molecular levels to
the bone cell genome, and then
upward again, through histologic
levels to the event of gross bone
form adaptational changes.

91. THE GENOMIC
HYPOTHESIS OR THE
GENETIC THEORY.

92. The third part of this article
reviews this genomic theory and
offers a critique that removes
some of the concepts that have
come to surround it recently.

93. "The whole plan of growth, the
whole series of operations to be
carried out, the order and site of
synthesis and their co-ordination
are all written down in the nucleic
acid message."

94. The genomic thesis holds that the
genome, from the moment of
fertilization, contains all the
information necessary to regulate
(cause, control, direct) (1) the
intranuclear formation and
transcription of RNA and

95. (2) Without any external factor
regulate intracellular and
intercellular activities of cell
tissues and organs and all
phenotypic features are expressed
by DNA.

96. In this thesis, morphogenesis is but
the predetermined reading-out of
an intrinsic and inherited genomic
blueprint.

97. The genomic thesis originated with
classical (chromosomal)
Mendelian genetics. And later
created the neo Darwinian
synthesis by the blending of
classical chromosomal and
vertebrate palentological
disciplines.

98. EPIGENETIC HYPOTHESIS

99. It is a fallacy that the genome, the
totality of DNA molecules, is the
main repository for developmental
information; I.e. that there exists a
genetic program, or blueprint,
theoretically capable of creating an
entire organism."

100. "Broadly speaking, epigenetics
refers to the entire series of
interactions among cells and cell
products which leads to
morphogenesis and differentiation.
Thus all cranial development is
epigenetic, by definition."

101. This view is supported here, despite
continued expressions of genomic
regulation of craniofacial
morphogenesis.

102. As previously noted, epigenetic
factors include (1) all of the
extrinsic, extraorganismal,
macroenvironmental factors
impinging on vital structures (for
example, food, light, temperature),
including mechanical loadings and
electromagnetic fields, and

103. (2) all of the intrinsic,
intraorganismal, biophysical,
biomechanical, biochemical, and
bioelectric microenvironmental
events occurring on, in, and
between individual cells,
extracellular materials, and cells
and extracellular substances.

104. In terms of clinical orthodontics,
and of the FMH, all therapy is
applied epigenetics, and all
appliances (and most other
therapies) act as prosthetic
functional matrices.

105. Clinical therapeutics includes a
number of epigenetic processes,
whose prior operations evoke a
number of corresponding
epigenetic mechanisms.

106. BASIS FOR THE
MECHANISM OF ACTION
OF FUNCTIONAL
APPLIANCES

107. When we use functional appliances
we cause loading.
Now what exactly is loading?

108. Many different epigenetic processes
can evoke mechanisms capable of
modifying DNA. At clinically
significant structural levels, physical
loading is unquestionably of the
greatest importance. "Among the
numerous epigenetic factors
influencing the vertebrate face is
mechanical loading.“

109. Loading per se. Loads may be
imposed at many structural levels.
While clinical observations usually
are macroscopic, the loadings act
microscopically, at molecular
and/or cellular levels. Loadings are
able to regulate several alternative
molecular (cellular) synthetic
pathways (mechanisms) of many
tissues, including bone.

110. It should be noted that loading may
be dynamic (for example, muscle
contraction) or static (that is,
gravity); and to be effective, loads
may increase, decrease, or remain
constant.
Mechanical loading is known to
influence gene expression.

111. Extrinsic musculoskeletal loading
can rapidly change (1) both
articular cartilage intercellular
molecular syntheses and
mineralization and (2) osteoblastic
(skeletal unit) gene expression.

112. Extracellular matrix deformation.
Musculoskeletal tissue loading
inevitably deforms an extracellular
matrix (ECM) .

113. ECM regulates the formation,
development, and maintenance of
its included cells that synthesize the
ECM. Further, ECM can regulate
multicellular tissue morphogenesis
and contribute to genomic
regulation of its enclosed cells.

114. Cell-shape changes. Tissue loading
can also alter cell shape. This
deforms intracellular constitutents,
including the cytoskeleton.

115. The epigenetic process of
changing cell shape invokes the
epigenetic mechanisms of
mechanotransduction of
biophysical forces into genomic
and morphogenetically regulatory
signals.

116. Cell-shape change processes can
also activate several other
epigenetic mechanisms, for
example, stretch-activated ion
channels.

117. Cell-shape change may lead to
nuclear shape deformation. This,
in turn, is a mechanism that can
directly cause (regulate) a
consequent alteration of the
mechanisms of genomic activity.

118. This genomic activity is expressed
phenotypically and we see the
changes brought about.
This is the basis for how the
functional appliance works
according to the functional matrix
theory.

119. A RESOLVING SYNTHESIS
BETWEEN GENETIC AND
EPIGENETIC THEORIES
.
The prevailing tension between the
genomic thesis and epigenetic
antithesis will continue unabated.

120. But one has to know that
Individually both are necessary
causes, but neither are sufficient
causes alone. Together they
provide both the necessary and
sufficient causes for the control
(regulation) of morphogenesis.

121. Nevertheless, epigenetic processes
and events are the immediately
proximate causes of development,
and as such they are the primary
agencies.

122. THE ARGUMENT STILL
CONTINUES

123. “We can conclude this session by
looking at this simple saying taken
from “The Ways Of Life”
Real Words Are Not Vain
Vain Words Not Real
And Since Those Who Argue Prove
Nothing
A Sensible Man Does Not Argue

124. CONCLUSION

125. 1.There has been an explosion of
experimental documentation for
mechanisms of growth
2.There have been many clinical
advances in orthodontics, although
they are mainly technical and
mechanistic .

126. 3. The trend to rehash old questions is
good, but only to the extent that all of
the facts that bear upon a given
problem are considered. Old ideas do
not become bad or obsolete ideas only
because they are old. If a new idea is
better, it has to be based on facts to
substantiate the idea.

127. 4. Superficial conflicts of concepts
exist, but, overall, the central
tendency represented by
publications is toward a
conservative perspective of
functional treatment possibilities
using growth modalities

128. 5.There is an apparent time delay
of about 10 years before a theory is
applied clinically based on the
interval between theoretical and
clinical articles that appear on a
particular topic.

129. 6. The time delay between theory
and practice seems to have
increased over the years, May be
this is due to having to weigh and
consider more facts rather than
simply compensating for the
authors’ biases.