Growth theories,emphasis on functional matrix theory-regular and revisited.pptx

The document summarizes the different growth theories and emphasizes mainly on functional matrix hypothesis, which proposes that craniofacial bone growth is in response to mechanical stimuli from surrounding soft tissues. It revisits the hypothesis by incorporating recent understandings of mechanotransduction, the connected cellular network of bone cells, and the interplay between genetic and epigenetic factors.

1. Growth theories emphasis on functional matrix theory –regular and revisited Presented by Dr. Phaneendra Reddy

2. Introduction Growth s ite vs growt h centre Theorie s of bone growth Functional matrix hypothesis Limitation of F.M.H Functional matrix hypothesis revisited The concept of mechanotransduction Bone as an osseous connected cellular network Genomic thesis Epigenetic antithesis and resolving synthesis 9.Conclusion CONTENTS

3. Introduction Growth Increase in size or numbers . ( Proffit – 1986) Development All the naturally occurring unidirectional changes in the life of an individual from its existence as a single cell to its elaboration as a multifunctional unit terminating in death (Moyer 1988 ) Development = Growth + Differentiation + Translocation

4. Bone like other tissues , primarily determinant of its own growth Cartilage is the primary determinant of skeletal growth while bone responds secondarily and passively

5. Growth Site vs Growth Centre Growth centre : places of endochondral ossification with tissue separating force, contributing to increase in skeletal mass. Growth site :a region of periosteal or sutural bone formation and modelling resorption adaptive to environmental influences.

6. Theories of bone growth Bone remodelling theory Genetic theory Sutural hypothesis Cartilaginous theory Functional matrix theory Servo system theory Composite hypothesis by von Limborgh Rate limiting ratchet hypothesis Growth relativity hypothesis

7. Bone Remodeling Theory of Craniofacial Growth - Brash (1930) ". This theory concluded that bone grows only by interstitial growth. The three fundamental tenets of this theory are:

8. GENETIC THEORY Allan G. Brodie in 1941 genes determine and control the whole process of craniofacial growth Genes makes our body and mind Homeobox gene and Transcription factor play an important role in craniofacial development.

9. Favorable factors of genetic theory Genetic factors play an 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 vitro. Limitations of genetic theory Does not explain the role of environmental and epigenetic factors on growth Primary genetic control determines only certain features and doesn’t have complete influence on the growth.

10. The Sutural Hypothesis/Sutural Dominance Theory - Sicher and Weinnman-1952 According to Sicher, the sutures are the primary determinants of craniofacial growth. The craniofacial skeleton enlarges due to the expansible forces exerted by the sutures as they separate

11. Favorable factors of sutural theory All bone forming elements cartilage , suture and periosteum are growth centers . ( Growth centres- implies areas that control overall growth of bone) Expansion forces at the sutures lead to expansion of bone and thus growth of craniofacial skeleton.

12. Limitations of sutural theory The theory has been rejected for the reason that suture is tension adapted tissue. The presence of any pressure on suture triggers bone resorption not deposition . In untreated cleft , though the sutures are not present, growth still occurs. No growth occurs in the area where suture is transplanted.

13. Scott Hypothesis/Nasal Septum Theory/ Cartilaginous Theory/Nasocapsular Theory (1950s ) Cartilaginous parts of the craniofacial skeleton played a major role in establishment of the nasal capsule, mandible and cranial base during prenatal development. Primary controlling factors - only in cartilage Periosteum and sutures - secondary

14. According to Scott Spheno occipital synchondrosis cartilage- responsible for growth of cranial base Nasal septum cartilage - growth of maxilla Condylar cartilage - growth of mandible

15. This theory is based on the fact that Cartilage is a pressure adapted tissue and expansion of cartilage provides the force to displace maxilla downward and forwards. According to Scott, bone separation must precede before the adaptive sutural bone growth occurs. The bone separation, he feels, is because of growth of organs like brain, eyeball or cartilage.

16. Posterior suture system - behind the maxilla and separates it from palatine, lateral mass of ethmoid, lacrimal, zygomatic and vomer bones Anterior suture system - separates premaxilla, nasal and vomer bone. The second suture system disappears in the human face during later part of fetal period or after birth. Scott is of the opinion that there are two suture systems :

17. Extirpation of septal cartilage in growing rats resulted in deficient growth of the nose. Injuries in nasal septum in children during CLP repair resulted in deficient growth of mid face. Sarnat and Long - They found increased proliferative activity of the cells in the posterior regions of nasal septum which reflects endochondral ossification in this region Favorable factors of cartilagenous theory

18. It is seen in 75 to 80 % of human children who suffers from condylar fracture does not impede the mandibular growth Burstone and Latham - case with missing nasal septum. The child had normal resorption and deposition of palate, height of upper face Limitations of cartilagenous theory

19. Enlows ‘v’ principle Most of the facial bones have a V shaped pattern of growth Bone deposition -inner side of V Bone resorption - outer surface Simultaneously deposition takes place at the ends of the two arms of “v” resulting in its widening pattern Base of mandible Mandibular body Palate Coronoid process Condylar process

20. It states that growth in any one region of craniofacial region necessarily influence the growth of its geometrical counterpart ENLOWS COUNTERPART PRINCIPLE Balanced growth - regional part and the counter part enlarge to the same extent Imbalanced growth - Any difference in respective amount or direction of growth between parts and counterparts

21. Different parts and their counter parts Nasomaxillary complex --------- anterior cranial fossa Pharyngeal space --------- middle cranial fossa Maxillary arch --------- mandibular arch Maxillary tuberosity --------- lingual tuberosity Bony maxilla --------- corpus of mandible Imbalance is produced due to variation in Amount of growth between counterpart Timing of growth between counterparts Direction of growth between counterparts

22. 5 FACTORS INTRINSIC GENETIC FACTORS genetic control of skeletal unit themselves LOCAL EPIGENETIC FACTORS Bone growth determined by genetic control originating from adjacent structures LOCAL ENVIRONMENTAL FACTORS Non genetic factors from local external environment Eg- habits muscle forces GENERAL EPIGENETIC FACTORS Genetic factors determining growth from distant structures Eg- hormones GENERAL ENVIRONMENTAL FACTORS General non genetic factors Eg- nutrition oxygen VAN-LIMBORGH’S THEORY multifactorial theory

23. FUNCTIONAL MATRIX HYPOTHESIS Melvin. L. Moss - 1962. He stated that , “ bones do not grow; bones are grown .” According to this theory soft tissues grow and both bone and cartilage react.

24. ‘ Functional matrix hypothesis claims that the origin, growth and maintenance of all skeletal tissues and organs are always secondary compensatory and obligatory responses to temporally and operationally prior events or processes that occur in specifically related non skeletal tissues, organs or functioning spaces, Statement of hypothesis

25. What is functional cranial component :

26. Functional cranial component Skeletal unit Functional matrix Macro skeletal Micro skeletal Periosteal matrix Eg-nerves, teeth muscles Capsular matrix Eg-orofacial, neurocranial

27. Skeletal unit Micro skeletal unit : made of several small contiguous units Macro skeletal unit : when adjacent micro skeletal units work to carry out a single cranial component .

28. Functional matrices “soft tissue” i.e. muscles, gland, nerves, vesicle , fat It is divided into the Periosteal matrices Capsular matrices

29. Periosteal matrices :

30. Capsular matrix Capsular matrix Indirectly & Passively Expansion of Oro-facial capsule With in which facial bones arise and grows.(translation) No deposition and resorption occurs

31. Neuro – cranial capsule Capsular matrices brain, leptomeninges, CSF. skin, connective tissue layer, aponeurotic , loose connective tissue, periosteum, base of skull & 2 layers of dura matter. oropharynx, nasopharynx , which arises within the facial bones , grow and are maintained. Skin and mucosa form the covering Oro – facial capsule. Neuro – cranial capsule Oro – facial capsule.

32. 1.Orthodontic tooth movement (periosteal matrix) – alveolar bone transformation (micro skeletal unit) 2.Orofacial orthopedics (capsular matrix) – jaw bones (macro skeletal unit) 3.Widening of midpalatal sutures (RPE) 4.Repositioning of maxillary segments in cleft cases 5.Functional appliance therapy 6.Bilateral condylectomy 7.Distraction osteogenesis Clinical applications of functional matrix hypothesis

33. Separated mid palatal suture is filled with bone as a compensatory activity of the sutures Slow expansion – better adaptation of muscles Rapid palatal expansion

34. Pads and shields – stretching of periosteum resulting in bone remodeling . Functional appliances

35. 36 Relapse after surgery--causes Alterations in state of equilibrium of matrix Failure of matrix adaptation Altered muscle fiber length and position Treatment concept Reattach muscles to specific regions rather than permitting spontaneous reattachment Orthognathic surgeries

36. Against the theory Craniostenosis – premature stenosis of sutures inhibits growth – sutures have some capacity to regulate the activity of functional matrix in 75 to 80% of the children who suffer a condylar fracture, the resulting loss of condyle does not impede mandibular growth

37. CONSTRAINTS OF FUNCTIONAL MATRIX HYPOTHESIS 1.METHODOLOGIC: Macroscopic measurements permitted only method-specific description that cannot be structure-ally detailed. 2. HIERARCHICAL: does not explain how the extrinsic, epigenetic functional matrix stimuli are transduced into regulatory signals at the cellular, multicellular or molecular levels.

38. JULY 1997 AUGUST 1997 OCTOBER 1997 SEPTEMBER 1997

39. FUNCTIONAL MATRIX REVISITED-1 (MOSS :july,1997) 

40. Mechanosensing processes : enables a cell to sense and to respond to extrinsic loadings, by using the processes of mechanoreception and mechanotransduction . Mechanoreception : transmits an extracellular physical stimulus into a receptor cell. Mechanotransduction : transduces or transforms the stimulus's energetic or informational content into an intracellular signal

41. Static and dynamic loadings - tending to deform both extracellular matrix and bone cells. Stimulus - exceeds threshold values, the loaded tissue responds by the triad of bone cell adaptation processes. Both osteocytes and osteoblast s are competent for intracellular stimulus reception and transduction and for subsequent intercellular signal transmission

42. Uniqueness of osseous mechanotransduction: Bone cells are not cytologically specialized One bone-loading stimulus can evoke three adaptational responses , whereas non osseous processes generally evoke one Osseous signal transmission is a neural The evoked bone adaptational responses are confined within each "bone organ" independently.

43. There are two possibly mechanotransductive processes 1.IONIC 2. MECHANICAL

44. Stretch-activated channels When activated in strained osteocytes, they permit passage of a certain sized ion or set of ions, including K+, Ca2+,& Na+. Such ionic flow - initiate intracellular electrical events , for example, bone cell S-A channels may modulate membrane potential as well as Ca2+ ion flux.  

45. Electrical events 1. Electromechanical 2. Electrokinetic 3. Electric field strength

46. Electromechanical Osteocytic plasma membrane contains voltage-activated ion channels, and transmembrane ion flow may be a significant osseous mechano-transductive process. It is also possible that ionic flow through ion channels generate osteocytic action potential capable of transmission to other bone cells through gap junctions  

47. 2. Electrokinetic Bound and unbound electric charges exist in bone tissue. Electrical effects in fluid-filled bone are not piezoelectric electrokinetic, that is, streaming potential (SP) origin . The SP is a measure of the strain-generated potential (SGP) of connected electric charges in the fluid flow of deformed bone. SGP of ±2 mV can initiate both osteogenesis and osteocytic action potentials.  

48. Bone responds to exogenous electrical fields A significant parallel exists between the parameters of these exogenous electrical fields and the endogenous fields produced by muscle activity. 3 .Electric field strength

49. The mechanical properties of the extracellular matrix influence cell behavior. Loaded mineralized bone matrix tissue is deformed or strained. Series of extracellular macromolecular mechanical levers exist, capable of transmitting information from the strained matrix to the bone cell nuclear membrane. Mechanical processes

50. Basis of this mechanism - physical continuity of the transmembrane molecule integrin

51. Conclusion Cytoskeletal lever chain, connecting to the nuclear membrane, can provide a physical stimulus able to activate the osteocytic genome, possibly by first stimulating the activity of such components. 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, including their phenotypic expression.

52. FUNCTIONAL MATRIX REVISITED-2 (MOSS :august,1997) 

53. The role of an osseous connected cellular network

54. Osseous connected cellular network SUPERFICIAL OSTEOBLAST SUPERFICIAL OSTEOBLAST PERIOSTEAL AND ENDOSTEAL OSTEOBLAST PERIOSTEAL AND ENDOSTEAL OSTEOBLAST PRE OSTEOBLASTIC CELLS PREOSTEOBLASTIC CELLS

55. All bone cells except osteoclasts, are extensively inter connected by gap junctions that form an osseous CCN. Gap junctions

56. Mechanotransductively activated bone cells, e.g., osteocytes, can initiate membrane action potentials capable of transmission through interconnecting gap junctions. Gap junctions, permitting bidirectional flow of information , are the cytological basis for the oscillatory behavior of a CCN. Functions of gap junctions In addition to permitting the intercellular transmission of ions and small molecules

57. Open gap junctions- interconnect osteoblasts of similar cohort( engaged in identical adaptational process) Close gap junctions- histologic discontinuities between phenotypically different osteoblasts , so prevent the flow of information 2 types of gap junctions

58. The basis of connectionist theory are sufficiently secure to permit modeling of a biologically realistic osseous CCN Bone cells are organized into 3 layers: Initial input layer 2. Intermediate/Hidden layer.  3. Final output layer

59. Initial layer cells : Receive loadings (weighted inputs/ “stimuli”) within each cell The weighted inputs are summed & compared with a threshold value. If it exceeds threshold value , intracellular “signal” is generated Transmitted to intermediate osteocytes (hidden layer cells) via gap junctions

60. 3 . Final layer: Similar processes repeat Final “output” determines the site, rate, direction, magnitude & duration of the final specific “response” i.e. deposition/ resorption/ maintenance.  2. Hidden layer : Similar processes of weighted signal Summation, comparison & transmission occurs until “ Signal” reaches the final layer of cells

61. A skeletal CCN displays the following attributes Developmentally, It is an untrained self-organized &self-adapting and epigenetically regulated system. Operationally I t is a stable, dynamic system that exhibits oscillatory behavior permitting feedback Structurally An osseous CCN is non modular i.e. permits discrete processing of differential signals . Functions of CCN

62. 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 offers an explanatory chain through the cellular and molecular levels to the bone cell genome. Conclusion

63. FUNCTIONAL MATRIX REVISITED-3 (MOSS :september,1997) 

64. The genomic thesis “ 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”

65. This thesis holds that from the moment of fertilization the genome contains all information necessary to regulate – 1. The intra nuclear formation &transcription of RNA . 2.Without any additional information regulate intracellular &intercellular activities of cell tissues and organs & all phenotypic features are expressed by DNA. 

66. The Biologic Bases for the Genomic Thesis The somatic cells of an individual metazoan inherit two classes of molecular information: (1) an identical diploid DNA and (2) the maternal cytoplasmic constituents of the egg: e.g., mitochondria, cytoskeleton, membranes.

67. The human genome has approximately 100,000 genes . Only approximately 10% of the genome seems related to phenotypic ontogenesis, "well over 90% . . . does not encode precursors to mRNAs or any other RNA.“ The encoding 10% of the DNA exists in two families; 1.“Housekeeping" genes 2. “Structural" genes.

68. 1.Housekeeping genes Genes regulate the normal molecular synthesis of agents involved in (1) The common energetic (metabolic, respiratory) activities of all cells and (2 ) The specific activities of special cell types (e.g., neurons, osteoblasts, ameloblasts etc.).

69. These genes regulate the synthesis of the specific molecular gene products . The presence, absence, or abnormal molecular configuration of these genes is associated with the pathologic conditions with a unitary genetic cause (Mendelian disorders )/ single-gene disorders) 2.Structural genes

70. Genomic thesis for orofacial growth: A characteristic article claims that prenatal craniofacial development is controlled by two interrelated, temporally sequential, processes: (1) Initial regulatory (homeobox) gene activity , followed by (2) Two regulatory molecular groups : growth factor families and steroid/thyroid superfamily

71. Homeobox genes: Coordinate the development of complex craniofacial structures. Development of the skeletal and connective tissue of the face is dependent on a cascade of overlapping activity of homeobox genes. Regulatory molecules: Alter the manner in which homeobox genes coordinate cell migration and subsequent cell interactions that regulate growth.

72. Orthodontic implications of genomic thesis Poorly coordinated control of form and size of structures, or groups of structures (e.g., teeth and jaws) by regulator genes explain the mismatches found in malocclusions and other dentofacial deformities. Single Homeobox gene can control the development of complex structures indicating that single genes can determine the morphology of complex structures, as the inheritance of jaw patterns"

73. Limitations of genomic thesis 1.Gene is a unit of heredity(DNA sequences incorporate information needed for the generation of a RNA) 2.Genetic machinery is a kind of information which DNA/RNA molecules are inherently capable of containing- nothing about which proteins will be expressed in which cells at what time and in what quantities .

74. FUNCTIONAL MATRIX REVISITED-4 (MOSS : october ,1997) 

75. 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  Epigenetic antithesis and Resolving synthesis

76. Epigenetic factors include 1. E xtrinsic - extra-organismal, macro-environmental factors impinging on vital structures (for example, food, light, temperature), including mechanical loadings and electromagnetic fields. 2. Intrinsic - intra-organismal, biophysical, biomechanical, biochemical, and bioelectric micro-environmental events occurring on, in, and between individual cells, extracellular materials, cells and extracellular substances. 

77. Epigenetic process and mechanism: 1.Loading 2.Extra cellular matrix deformation 3.Cell-shape changes 4.Epigenetic cell signaling processes. 5.Chains of intracellular molecular levers

78. Resolving synthesis : It argues that morphogenesis is regulated (controlled, caused) by the activity of both genomic and epigenetic processes and mechanisms. Their integrated activities provide the necessary and sufficient causes of growth and development. Genomic factors are intrinsic and prior causes ; Epigenetic factors are extrinsic and proximate causes.

79. Conclusion: There is no reason for conflict between the genomic and epigenetic hypothesis of ontogenetic regulation Interdependent, yet different, categories of necessary causes and that only their unity provides the sufficient condition for growth and development to occur.

80. References: Contemporary orthodontics- William r. Proffit Brodie AG. On the growth pattern of the human head. From the third month to the eighth year of life. Am J anat. 1941;68(2):209–62. Essentials of facial growth- enlow-hans Textbook of Craniofacial Growth – Sridhar Premkumar Scott JH. The cartilage of nasal septum a contribution to the study of facial growth BR dent J 1953 Melvin l. Moss and the functional matrix – Letty moss- salentijn (J dent res 76(12) 1997) the primary role of functional matrices in facial growth (Jun(20-31)1969)

81. Moss ML. A theoretical analysis of the functional matrix. Acta Biotheoretica. 1968 Mar 1;18(1-4):195-202. Moss ML. The functional matrix hypothesis revisited. 1. The role of mechanotransduction. American journal of orthodontics and dentofacial orthopaedics. 1997 Jul 1;112(1):8-11. Moss ML. The functional matrix hypothesis revisited. 2. The role of an osseous connected cellular network. American Journal of Orthodontics and dentofacial orthopaedics. 1997 Aug 1;112(2):221-6. Moss ML. The functional matrix hypothesis revisited. 3. The genomic thesis. American journal of orthodontics and dentofacial orthopaedics. 1997 Sep 1;112(3):338-42. Moss ML. The functional matrix hypothesis revisited. 4. The epigenetic antithesis. 1997