prenatal mandibular development

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Prenatal Developmentof the Human Mandible

SUK KEUN LEE,1

YEON SOOK KIM,1

HEE SOO OH,2

KYU HO YANG,2

EUN CHEOL KIM,3 AND JE GEUN CHI4*1Department of Oral Pathology, Kangnung National University College of Dentistry,

Seoul, Korea2Department of Pedodontics, Chonnam National University Dental College,

Seoul, Korea3Department of Oral Pathology, Wonkwang University Dental College, Seoul, Korea

4Department of Pathology, Seoul National University College of Medicine,Chongno-gu, Seoul, Korea

ABSTRACT

In an effort to better understand the interrelationship of the growth and developmentpattern of the mandible and condyle, a sequential growth pattern of human mandibles in 38embryos and 111 fetuses were examined by serial histological sections and soft X-ray views. Thebasic growth pattern of the mandibular body and condyle appeared in week 7 of fertilization.Histologically, the embryonal mandible originated from primary intramembranous ossification inthe fibrous mesenchymal tissue around the Meckel cartilage. From this initial ossification, theramifying trabecular bones developed forward, backward and upward, to form the symphysis,mandibular body, and coronoid process, respectively. We named this initial ossification site ofembryonal mandible as the mandibular primary growth center (MdPGC). During week 8 offertilization, the trabecular bone of the mandibular body grew rapidly to form muscular attach-ments to the masseter, temporalis, and pterygoid muscles. The mandible was then rapidlyseparated from the Meckel cartilage and formed a condyle blastema at the posterior end of linearmandibular trabeculae. The condyle blastema, attached to the upper part of pterygoid muscle,grew backward and upward and concurrent endochondral ossification resulted in the formationof the condyle. From week 14 of fertilization, the growth of conical structure of condyle becameapparent on histological and radiological examinations. The mandibular body showed a conspic-uous radiating trabecular growth pattern centered at the MdPGC, located around the apical areaof deciduous first molar. The condyle growth showed characteristic conical structure and abun-dant hematopoietic tissue in the marrow. The growth of the proximal end of condyle was alsoapproximated to the MdPGC on radiograms. Taken together, we hypothesized that the MdPGChas an important morphogenetic affect for the development of the human mandible, providing agrowth center for the trabecular bone of mandibular body and also indicating the initial growthof endochondral ossification of the condyle. Anat Rec 263:314325, 2001.

2001 Wiley-Liss, Inc.

Key words: mandible growth; condyle growth; mandibular primary growthcenter; human; fetus

The mandible, derived from the first branchial archmesenchyme, remains one of the most debated topics inthe morphogenesis of oro-facial structure. The mandi-ble, comparable to long bone, is movable and antagonis-tic to the maxilla with the control of masticatory, facialexpression, and some suprahyoid muscles (Azeredo etal., 1996; Bareggi et al., 1995; Lee et al., 1992). Ana-tomically, the mandible is connected to the temporalbone through the temporomandibular joint, innervatedby a mandibular branch of the trigeminal nerve andserves important functions such as mastication, deglu-tition, and speech. Through the outcome of phylogenetic

evolution it is likely that the mandible has evolved intomore complex regulatory development via different

Grant sponsor: Ministry of Health and Welfare, Republic ofKorea; Grant number: HMP-98-M-4-0048.

*Correspondence to: Je Geun Chi, MD, Department of Pathol-ogy, Seoul National University College of Medicine, 28 Yongon-dong, Chongno-gu, Seoul 110-799, Korea.E-mail: [email protected]

Received 22 August 2000; Accepted 15 February 2001

Published online 00 Month 2001

THE ANATOMICAL RECORD 263:314325 (2001)

2001 WILEY-LISS, INC.


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pathways, i.e., muscular, alveolar, neural, and articularparts (Goret-Nicaise and Dhem, 1984; Jakobsen et al.,1991; Padwa et al., 1998).

Previous studies on mandibular development were fo-cused mainly on the growth of condyle and symphysis(Bareggi et al., 1995; Ben-Ami et al., 1992; Berraquero etal., 1995; Bjork and Skieller, 1983; Kjaer, 1978b; Mori-moto et al., 1987; Orliaguet et al., 1993b). A study onmandibular growth in an early human fetal development(weeks 814) revealed the mandibular ramus grew fasterthan the body, both in length and height; the greatestgrowth rate was found in the height of ramus; and the

mandibular growth patterns differed significantly fromthose of successive developmental periods (Bareggi et al.,1995). Many authors had emphasized the importance ofgrowth of the Meckel cartilage (Bhaskar et al., 1953),condylar head in mandibular growth (Kjaer 1978a; Mori-moto et al., 1987; Shibata et al., 1996; Xu et al., 1983). Aprecise description of the prenatal human mandibulargrowth and developmental pattern, however, has not beenreported.

The purpose of this study is to investigate a sequentialgrowth pattern of the prenatal human mandible usingradiological and histological methods. This study is in-tended to show how morphogenetic evidence of the prena-tal mandible relates to the developmental mechanism andfunctional structure of the human mandible.

MATERIALS AND METHODS

Thirty-eight normally developed embryos and 111 fe-tuses were obtained from the Department of Pathology,Seoul National University Hospital after thorough grossand microscopic examinations. Gestational age of eachembryo and fetus was deduced from the crown-rumplength or maternal records. The 38 embryos aged from58 weeks of fertilization (six at 5 weeks old; 19 at 6 weeksold; eight at 7 weeks old; and five at 8 weeks old, respec-tively). Embryos were fixed in 10% buffered formalin,embedded in paraffin, serially sectioned in 4 m thicknesson sagittal, transverse, or horizontal planes, and stained

with hematoxylin and eosin. Twenty-three fetal headsdeveloped early, ranging from week 9 to week 15 of fertil-ization (six at 9 weeks old; five at 10 weeks old; one at 12weeks old; four at 13 weeks old; four at 14 weeks old; andthree at 15 weeks old, respectively). Fetal heads werefixed in 10% buffered formalin, decalcified in 10% EDTA,pH 7.0, embedded in paraffin, and serially sectioned onfrontal and horizontal planes in 4 m thickness andstained with hematoxylin and eosin. The later-developedfetal mandibles (from 17 to 40 weeks of gestation) wereremoved and fixed in 10% buffered formalin. Removedmandibles were radiographed on lateral and vertical

views using Faxitron (Hewlett Packard, Corvallis, OR)and soft X-ray film (Fuji, Tokyo, Japan). The specimenswere decalcified in 5% nitric acid, embedded in paraffin, andlongitudinal and cross sections of the mandibles were madein 4 m thickness and stained with hematoxylin and eosin.

A point of concentric radiopacity at the apical area ofdeciduous first molar, from which linear trabecular bonesradiate to all directions of the mandible, was named as themandibular primary growth center (MdPGC). For the sta-tistical analysis, five measurements of the fetal mandiblewere made on the lateral and vertical view: 1) the lengthof condyle growth was measured from MdPGC to condylehead (Co); 2) the length of anterior mandibular growthwas measured from MdPGC to symphysis; 3) the length ofposterior mandibular body growth was measured from

MdPGC to mandibular angle (Go); 4) the length of anteriormandibular height growth was measured from upper borderof alveolar (Al) bone to lower border (Lb) of mandiblethrough the MdPGC; and 5) the length of posterior mandib-ular height growth was measured from Go to Co. The gonialangles formed by lower and posterior borderlines of the man-dible at the mandibular angle were also measured (Fig. 1).

RESULTSGrowth of Mandibular Body

In the middle of week 5 of fertilization (Streeter stage16), a pair of Meckel cartilage appeared in the center ofmandibular arch along with the growth of mandibular

Fig. 1. Measurements of prenatal mandibular growth. a, b: soft X-ray view of 24-week-old fetus, a; lateral

view, b; vertical view, c, d: scheme of (a) and (b). Co, condyle head; Go, Gonion; Al, alveolar bone; Lb, lower

border of mandible; MdPGC, mandibular primary growth center.

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nerves and vessels to form the hyaline cartilaginoustissue and thick perichondral fibrous mesenchyme.From the middle of week 6 of fertilization (Streeterstage 19), the mandibular ossification appeared as in-tramembranous bony apposition in close approximationto the Meckel cartilage. The initial intramembranousossification of the mandible began at the facial fibrousmesenchyme around the Meckel cartilage, with a directcontact (Fig. 5a), or an encirclement with the Meckelcartilage in contrast to the other long bones. In week 7of fertilization (Streeter stage 21), the linear trabeculaeof mandible developed anteroposteriorly from the initialossification of the mandible. Serial sections revealedthat these linear trabeculae branched toward the futuremandibular symphysis, alveolar bone, mandibularbody, and coronoid process. At this time, the genioglos-sus muscle (Fig. 5b,c) was tightly attached to the lowerside of the anterior portion of Meckel cartilage, whereasthe primordium of masticatory muscle was locatedaround the middle portion of Meckel cartilage, i.e., mas-

seter as well as temporalis muscles on the facial sideand pterygoid muscle on the lingual side of Meckelcartilage respectively. As the ossification of mandibleprogressed into the week 78 of fertilization (Streeterstage 2223), the muscular attachment of the genioglos-sus muscle gradually changed from Meckel cartilageinto the anterior portion of linear trabeculae of mandib-ular symphysis (Fig. 5b). The primordia of masticatorymuscles (Fig. 6a), i.e., masseter, temporalis, and ptery-goid muscles, departed from the Meckel cartilage andrepositioned around the linear trabeculae of mandible.Late in week 9 of fertilization, the serial sections ofmasseter and temporalis muscles showed muscular at-tachment to the buccal side of mandibular body and

coronoid process, respectively. The pterygoid muscle(Fig. 6c), which had been primarily located on the lin-gual side of Meckel cartilage, was far from the lingualside of mandibular body, because the mandibular bodywas gradually shifted toward the facial direction. Si-multaneously, the pterygoid muscle gradually movedtoward the posterior portion of mandibular body andwas divided mesially and laterally respectively; theformer attached to the lingual side of posterior mandib-ular body and the latter attached to the posterior end oflinear trabeculae of mandible, but not to Meckel carti-lage. Serial sections of the embryonic jaw also revealedthat the thinned fibrous mesenchyme around Meckelcartilage was traced to the thickened periosteal mesen-chyme of mandible. Subsequently, the condyle blastemaappeared with the condensation of cellular mesenchymeat the posterior end of linear trabeculae of the mandiblewith an attachment to the lateral pterygoid muscle. Inweek 10 of fertilization, the mandibular ossification ad-vanced to form an anatomical structure of the lower jaw

including the mandibular angle (Fig. 7a), coronoid pro-cess (Fig. 7a), and symphysis (Fig. 5e). By this time, thelower part of genioglossus muscle was attached to thelower portion of mandibular symphysis, while the upperpart of genioglossus muscle was still attached to theanterior portion of Meckel cartilage. In week 11 of fer-tilization, as the anteroposterior growth of the mandibleincreased with multilayered bony trabeculae, then theupper part of genioglossus muscle was almost detachedfrom Meckel cartilage. The site of initial intramembra-nous ossification of the mandible (Fig. 5d), however,remained approximate to the Meckel cartilage (Fig.5d,f,g). In week 12 of fertilization, most of the genioglos-sus muscle was attached to the lower portion of anterior

TABLE 1. Incremental growth of mandibular measurements of human fetus on radiogram

Fertilizationage (week)

Cases(n 111)

Co-MdPGC(mm)

Co-Go(mm)

MdPGC-Go(mm)

MdPGC-Sym(mm)

Al-Lb(mm)

Gonialangle

14 1 14.1 4.5 8.0 4.0 15015 2 15.10.5 6.50.0 9.50.7 5.90.4 4.30.4 148416 2 16.90.1 6.90.1 9.50.7 5.30.5 4.80.4 1484

17 1 17.2 7.0 10.0 6.4 5.0 18 4 18.32.0 7.50.6 10.50.4 7.0.1.1 5.00.7 148319 5 17.90.9 8.40.4 11.00.3 8.01.1 5.8 142320 7 20.90.6 9.90.5 12.41.3 8.21.0 7.40.6 147421 4 23.01.7 11.10.4 12.91.0 8.50.4 7.50.4 144822 3 23.32.3 11.00.5 12.80.3 9.10.0 7.30.6 140023 2 24.91.2 11.60.0 14.50.7 9.50.9 8.0 145024 3 25.74.5 11.80.7 15.20.8 9.31.6 9.01.0 144525 6 24.81.7 12.00.3 14.60.5 9.21.6 7.90.4 146526 3 26.01.8 11.90.2 16.20.8 10.40.3 8.80.3 146427 4 27.81.7 12.30.2 17.81.0 12.11.6 9.30.3 146728 4 27.02.6 13.10.6 16.60.8 12.72.0 9.90.6 146629 6 28.61.9 13.10.8 17.70.8 11.51.3 9.60.5 141630 10 29.62.6 14.30.6 18.21.0 13.22.4 10.70.8 140331 5 30.80.6 14.20.3 18.30.3 13.01.2 11.10.2 141432 5 31.22.0 14.80.8 17.40.5 11.92.1 10.70.4 139733 4 32.32.0 15.80.6 18.10.3 10.51.5 11.60.4 1447

34 3 32.91.4 17.00.5 18.71.2 15.52.2 11.30.6 142335 6 35.53.3 17.30.6 20.01.1 14.22.5 12.00.7 143836 4 35.12.9 17.00.8 20.31.3 13.30.9 12.50.6 141837 4 35.92.2 17.80.6 19.91.2 15.40.5 12.40.5 140438 10 35.12.9 18.21.2 21.21.4 13.90.9 13.40.8 136739 3 39.32.6 19.80.3 22.30.6 15.51.6 12.80.8 1395

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Fig. 2. Growth pattern of prenatal mandible by soft X-ray view, lateral view of mandible. a: 16-week-old

fetus; b: 17-week-old fetus; c: 18-week-old fetus; d: 20-week-old fetus; e: 25-week-old fetus; f: 30-week-old

fetus; g: 34-week-old fetus; h: 38-week-old fetus.



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Fig. 3. Incremental growth of representa-

tive measurements of prenatal human mandi-

ble. Co-MdPGC, length from condyle head to

mandibular primary growth center; MdPGC-

Go, length from mandibular primary growth

center to Gonion; Co-Go, length from condyle

head to Gonion; MdPGC-Sym, length from

mandibular primary growth center to mandib-

ular symphysis; Al-Lb, length from alveolar

bone to lower mandibular border.

Fig. 4. Changes of gonial angle during fetal period.

Fig. 5. Relationship between Meckel cartilage and mandible during morphogenetic stage of human embryos. a: Six weeks old, mandible (Md)appears at facial side of Meckel cartilage (Mc) (HE, 40). Tg, tongue; DL, dental lamina. b: Eight weeks old, lingual side of Meckel cartilage is not

covered with intramembranous ossification of mandible, note the genioglossus muscle (Gg) attached tightly both on the lower side of anterior portion

of Meckel cartilage and on the portion of mandibular symphysis (HE, 20). Mx, maxilla; UL, upper lip; LL, lower lip. c: High magnification of (b),

intramembranous ossification of mandible is closely associated with the fibrous mesenchyme of Meckel cartilage (HE, 70). d: Eleven weeks old,

mandibular ossification continuously grows outwardly from Meckel cartilage with a direct contact (HE, 70), square; site of initial intramembranous

ossification. e: Ten weeks old, frontal section, newly formed mandibular arch is larger than Meckel cartilage arch (HE, 60). Sym, symphysis. f:

Eleven weeks old, horizontal section of mandible shows the initial ossification site of mandible that was named as mandibular primary growth center

(MdPGC) (HE, 10). SM, submandibular gland; Hy, hyoid cartilage. g: High magnification of (f), the MdPGC showed ramifying trabecular structure,

the portion of Meckel cartilage approximated by MdPGC was rapidly resolved (arrows) (HE, 60). h: Twelve weeks old, sagittal section showing

longitudinal alignment of Meckel cartilage and linear trabecular bone of mandible (5). TG, trigeminal ganglion; SM, submandibular gland; IE, inner

ear organ; Ey, Eye. i: High magnification of (h), the linear trabeculae of mandible was approximated to the anterior portion of Meckel cartilage (70).

To, tooth germ. j: Ten weeks old, hyalin cartilage with intact cellular morphology (inlet, 1,000) (HE, 200). k: Twelve weeks old, the chondrocytes

were swollen and some of them disappeared (arrows) (HE, 400). l: Twenty weeks old, the Meckel cartilage was shrunken and separated from

mandible (HE, 200). m: high magnification of (l), peripheral chondrocytes were gradually resolved (arrows) (HE, 1,000).

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Figure 5.



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mandible to form the median symphyseal structure. Asa result, Meckel cartilage became completely detachedfrom the linguo-mandibular architecture (Fig. 5f,g) andrapidly decreased in size (Fig. 5h,i). At this stage, theMeckel cartilage became atrophic and its perichondralfibrous mesenchyme remained thin, and its hyaline car-tilage tissue also showed degenerative changes of chon-

drocytes, i.e., enlarged empty lacunae without nuclei orpyknotic/karyorrhectic nuclei (Fig. 5j,k). The cartilagematrix and chondrocytes of the Meckel cartilage weregradually shrunken and finally resolved with infiltra-tion of tissue macrophages into the perichondral fibroustissue. The Meckel cartilage, however, showed no endo-chondral ossification until later in fetal life (Fig. 5l,m).

From week 12 of fertilization, the intramembranousbony ossification was active at the periphery of ramifyingtrabeculae of the mandibular body, coronoid process andsymphysis. The central trabecular bone became thick andsclerotic (Fig. 5h,i). During weeks 1315 of fertilization,the mandible grew as multilayered trabeculae radiatingfrom the primary ossification site of the embryonic man-dible, namely the mandibular primary growth center (Md-

PGC). From week 16 of fertilization, the radiating trabec-ulae of mandible could easily be demonstrated by a soft X-ray view. Thereafter, the radiating trabecular bonesfrom the MdPGC corroborate the mandibular body growthduring later in fetal life (Fig. 2). The radiological dimen-sions of MdPGC-Sym and MdPGC-Go, which representthe growth of anterior and posterior body of mandiblerespectively, showed similar incremental growth ratesduring the fetal period. The incremental growth rate ofGo-Co, representing the posterior mandibular height, washigher than that of Al-Lb, representing the anterior man-dibular height. The incremental growth rate of Al-Lb wassimilar to those of MdPGC-Sym and MdPGC-Go duringthe fetal period (Fig. 3). The gonial angle was measuredabout 146148 in an early fetal period, and decreased to141143 until late in fetal period (Fig. 4).

Growth of Condyle

In the early week 7 of fertilization (Streeter stage 21), agroup of cellular mesenchymal tissue was formed aroundthe posterior end of linear trabeculae of the mandible (Fig.6a,b). In serial sections, this cellular mesenchymal tissuewas traced to the fibrous mesenchyme around the Meckelcartilage (Fig. 6c). A branch of pterygoid muscle wasclearly associated with the condensed mesenchyme late inweek 7 of fertilization. Early in week 8 of fertilization(Streeter stage 23), the posterior end of linear trabeculaeof the mandible showed an increased osteoblastic hyper-plasia and was well surrounded by the condensed mesen-

chyme that produced a condyle blastema, to which thelateral pterygoid muscle was attached. From early in week9 of fertilization, however, the blastema of the condyleproduced a cartilaginous tissue forming a condylar headat the posterior end of linear trabeculae of the mandible.The condyle grew rapidly with the bony deposition ofendochondral ossification. As the condyle was elongatedupward and laterally, a part of pterygoid muscle movedalong with the condyle head. Simultaneously, the ptery-goid muscle was divided into mesial (internal) and lateral(external) groups (Fig. 6d,e). The mesial pterygoid muscleremained at the mesial side (lingual or internal side) ofthe mandibular body, while the lateral pterygoid musclemoved continuously upward and laterally (externally) in

concert with the rapid condyle head growth. Expansivegrowth of the cartilaginous condyle head produced a con-ical bony structure, which was in contrast to the adjacentmandibular body growth on radiograms and histologicalsections. In week 12 of fertilization, the conical shapedcondyle was elongated toward the temporal squama toform the temporomandibular joint. Thereafter, the con-

dyle grew in a characteristic conical shape. The condyle,composed of a distally thickened cartilaginous cap andproximally thinned apex, converged toward the MdPGC(Fig. 7af), where bundles of vessels and nerves werelocated (Fig. 7g). The conical condyle contained abundanthematopoietic cells in its marrow space, and formed acurve along the angulation from the ramus to the man-dibular body as its growth advanced (Fig. 7h,i). Theamount of incremental growth of the conical condyle (Co-MdPGC), however, was highest in the representative an-atomical dimensions of the human mandible during thefetal period (Fig. 3).

DISCUSSION

We observed that mandibular ossification started fromthe mandibular primary growth center (MdPGC), andthat the mandibular growth pattern was characterized byintramembranous ossification of the mandibular body andendochondral ossification of the condyle. In our previousstudy, we explored the growth pattern of human prenatalmaxillae and confirmed a pair of maxillary primarygrowth centers (MxPGC). The MxPGC showed the char-acteristic radiating, trabecular patterns by both the his-tological and radiological observations (Lee et al., 1992). Itwas suggested that the MxPGC is an initial ossificationsite of the maxilla. The MxPGC was an important ana-tomical landmark to analyze the stress-bearing maxillarystructure, and remained as a sclerotic trabecular bonecontaining channels of nerve bundles and vessels later in

fetal life, while major growth sites of the maxilla were atthe distal ends of trabecular bones that radiated from theMxPGC. In this study we found a similar growth patternin the mandibular development of human fetuses. Duringthe developmental stages of the mandible, its primarygrowth center (MdPGC) was detected as a primary site ofintramembranous ossification around the middle portionof the embryonal jaw. The MdPGC became the centralpart of the mandibular body, which appeared as a scleroticfocus of radiating trabeculae of the mandibular body

Fig. 6. ad: Condyle growth. eg: Cross section of mandibular body. a:

Seven weeks old, condyle blastema (CB) developed from the posterior

end of linear trabeculae of mandible (HE, 40). Tp, temporalis muscle;MN, mandibular nerve; LPt, lateral pterygoid muscle; MPt, mesial ptery-

goid muscle; Ms, masseter muscle. b: High magnification of (a), the

condyle blastema consists of active osteoblastic deposition (arrow) and

abundant mesenchymal condensation (HE, 400). c: Eleven weeks old.

d: Twelve weeks old. e: High magnification of (d), condyle blastema (CB)

attached by lateral pterygoid muscle (LPt) grew toward temporal bone

(Te), note upper lateral pterygoid muscle (ULPt) and lower lateral ptery-

goid muscle (LLPt) (HE, 40). f: Sixteen weeks old, cross section of

mandible at first deciduous molar area (To), retrogressive Meckel carti-

lage (Mc) is remained at the lingual side of mandible (Md) (HE, 40). g:

High magnification of (f), the Meckel cartilage (Mc) has no direct con-

nection to mandibular ossification (HE, 200). h: Twenty weeks old,

cross section of mandible, the Meckel cartilage (Mc) is rudimentary and

almost isolated from the mandible (Md) (HE, 40).

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Figure 6.



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shown on radiograms taken later in fetal life, whereasmajor growth sites of the mandible were at the distal endsof trabecular bones radiated from MdPGC.

The sequential development of the human mandiblestarted from the middle of week 5 of fertilization, with theformation of core cartilage in mandibular swelling i.e.,Meckel cartilage, and the mandible grew actively to

form a mandibular arch protuberance. Three stages ofStreeters development appeared particularly importantduring the mandibular development: stage 16 (appear-ance of Meckel cartilage), stage 20 (beginning of membra-nous ossification), and stage 23 (end of the human embry-onic period, week 8) (Orliaguet et al., 1993a). Manyauthors presumed that the Meckel cartilage, the firstbranchial arch cartilage, had no relationship to the pro-cesses of mandibular ossification (Merida-Velasco et al.,1993; Orliaguet et al., 1993b, 1994; Rodriguez-Vazquez etal., 1997a,b; Tomo et al., 1997). Unlike the long bones,Meckel cartilage entirely regressed during the later fetalperiod (Ellis and Carlson, 1986). In this study, however,we observed the primary intramembranous ossification ofembryonal mandible developed in Streeter stage 19, ear-

lier than the ossification of long bones usually found atStreeter stage 20 (Orliaguet et al., 1993a). We found thatthe intramembranous ossification as well as the con-densed cellular mesenchyme of the condylar blastema wasclosely associated with a portion of perichondral fibroustissue of the Meckel cartilage. Because the primary in-tramembranous ossification of the mandible greatly af-fects the following histomorphogenetic processes of thewhole mandible (Bareggi et al., 1995; Berraquero et al.,1995; Orliaguet et al., 1993b, 1994; Rodriguez-Vazquez etal., 1997b; Tomo et al., 1997), we accentuate the primaryintramembranous ossification and named it as the man-dibular primary growth center (MdPGC). The MdPGCwas approximated to the middle portion but lateral inposition of the Meckel cartilage in the early embryonalperiod. Then, the trabecular bones originating from theMdPGC grew out rapidly toward the facial side, losing therelationship to the Meckel cartilage. These findings implyan important role of Meckel cartilage for the initial ossi-fication of the mandible. We have also observed that theprimary intramembranous ossification of the embryonicmandible did not encircle the Meckel cartilage the same aslong bones but rather dislocated gradually to the facialside apart from the Meckel cartilage. It was also notedthat the human Meckel cartilage did not undergo endo-chondral ossification unlike the core cartilages of longbones, although some animals showed calcification of theMeckel cartilage during the fetal period (Ishizeki et al.,1999; Tomo et al., 1997; Yamazaki et al., 1997). In the

serial sections of human embryonic mandibles, however,we observed that the ossifying mandible and its attachedmuscles were detached from Meckel cartilage and dislo-cated outwardly as the lingual growth was advanced to fillthe stomodeal cavity and to influence the mandibularmovement. Thus, we hypothesize that early mandibularmovement by the masseter and suprahyoid muscles mayinfluence the premature dislocation of the primary man-dible from Meckel cartilage in the early embryonic period.

From the serial sections of human embryos we alsoobserved that the genioglossus muscle was attached to theperichondral fibrous tissue of Meckel cartilage in the earlyweek 6 of fertilization. The genioglossus muscle was suc-cessively reattached to the inferior portion of mandibular

symphysis at 12 week of fertilization. Other muscles, suchas masticatory, mylohyoid, etc., were not attached butwere positioned around the perichondral fibrous tissue ofMeckel cartilage during weeks 67 of fertilization. Whenthe intramembranous ossification of the mandible ad-vanced to form multilayered linear trabeculae, the masti-catory and mylohyoid muscles were attached tightly to the

outgrowing mandible rather than Meckel cartilage duringweeks 8 9 of fertilization. Although the direct histoge-netic effect of Meckel cartilage on the embryonal inductionof mandible remains unclear, we presume that the Meckelcartilage plays an important role to integrate the forma-tion of human mandible, which was evolutionarilyadapted to provide increased arch size and mobility. Thequestion of What influences the transition of the mandib-ular core skeleton from Meckel cartilage into mandible?remained unanswered. It was suggested that it may de-pend on the early mouth opening movement, primarilyinduced by tongue musculature which matured quiteearly in orofacial structures (Bresin et al., 1999; Kang etal., 1992; Kiliaridis and Katsaros, 1998; Lee et al., 1990;Lightfoot and German 1998; Ogutcen-Toller and Juniper,

1993; Radlanski et al., 1999; Robertson and Bankier 1999;Sato et al., 1994). It was also reported that it may beinfluenced by mandibular movement in the human em-bryo beginning around week 8 of fertilization, when thetemporomandibular joint is yet to be formed (Hall1982a,b; Kjaer, 1997; Ouchi et al., 1998). Although themechanism of an early mouth movement is unclear, it isapparent that the masticatory muscles do not induce theearly embryonic mandibular movement at this stage be-cause of their immaturity. We presume that the tonguemovements directly induce the early mandibular move-ment, because Meckel cartilage, a primary skeleton of themandible during weeks 57 of fertilization, was tightlyattached to the genioglossus muscle. We also observed,however, that the primordia of the masseter, temporalis,and pterygoid muscles became attached to the newlyformed mandible in the late week 8 of fertilization. Thisfinding may imply that the early mouth opening move-ment causes the primordia of the masseter, temporalis,and pterygoid muscles relocate from the Meckel cartilageto the newly formed mandible moving along with tonguemovement. Thus, we believe that the mandible supportedby masticatory and tongue muscles would be able to con-trol the development of the lower jaw as a new articulationwithout the influence of Meckel cartilage from approxi-mately week 8 of fertilization.

The present study also indicates that the characteristicstructure of the mandibular body exhibits a radiatingtrabecular pattern from the MdPGC that is closely relatedto the attachment of surrounding muscles. The pullingforce of associated muscles may induce continuous appo-sitional growth of intramembranous ossification on theperiosteal side, rather than in the MdPGC, which is nolonger proliferative later in fetal life. We suggest that theMdPGC is a primary ossification site of the fetal mandible,forming a rigid center of the mandibular structure. Serialsections of fetal mandibles showed that the linear trabec-ulae of the mandibular body were focused at the center ofthe MdPGC. In week 12 of fertilization, however, thearchitecture of the mandibular body was almost completewith the characteristic shapes of the mandibular body,coronoid process, mandibular angle, and symphysis. Fromweek 15 to 16 of fertilization, the growth of mandibular

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body and condyle was clearly distinguished by radiogra-phy. The MdPGC clearly showed a radiating trabecularpattern originating from the apical area of the deciduousfirst molar tooth germ. This growth pattern of the man-dibular body became most conspicuous during weeks20 25 of gestation. The MdPGC was conspicuously de-tected near the apical area of the first deciduous molar

tooth germ. Numerous linear bony trabeculae originatingfrom the MdPGC grew peripherally, extending to the coro-noid process, mandibular angle, symphyseal area, andeven to the alveolar ridge (Fig. 8). Later in the fetal period,from week 30 of fertilization, the image of the radiatingtrabecular pattern was gradually overlapped with the im-age of tooth germs and peripheral cortical bone consoli-dated by muscular attachments.

A morphological study on the developing lateral ptery-goid muscle and its relationships to the temporomandib-ular joint and Meckel cartilage indicated that all of tem-poromandibular joint structures and lateral pterygoidmuscle assumed their adult shapes by week 14 of fetal life.At this stage, the lateral pterygoid muscle formed a com-plex structure with several aponeuroses dividing the mus-

cle into three main parts: superior, inferomedial, and in-feroanterior (Ogutcen-Toller and Juniper, 1993). Thismeans that the muscular forces arising from mandibularmovement directly influence the growth of the condyle andtemporomandibular joint simultaneously. Thus, in thisstudy we observed that the lateral pterygoid muscle wasprimarily attached to the condyle blastema tissue andbecame elongated through rapid condylar growth duringweeks 810 of fertilization. This may imply that the lat-eral pterygoid muscle guides the conical condyle to formthe temporomandibular joint. These data, however, sug-gest that the mandibular movement primarily controlledby the genioglossus muscle in the early embryonic periodcould affect the growth of the mandibular body and thecondyle. Premature mandibular movement occurred atleast 2 weeks earlier than the temporomandibular jointmovement and stimulated the adaptational growth of themandibular body and condyle. Thereafter, condyle growthwas highly accelerated to form its conical structure andbecame independent of mandibular body growth.

The incremental growth of the mandibular dimensionon the radiogram showed well-harmonized growth curvesbetween the growth rate of mandibular body and condyleduring the fetal period. The incremental growths of Md-PGC-Sym, MdPGC-Go, and Al-Lb represent the pattern ofmandibular body growth and the incremental growths ofMdPGC-Co and Co-Go represent the pattern of condylegrowth. The former group, however, showed a slightlyreduced growth curve compared with that of the latter

group. This may imply that condylar growth is much ac-celerated compared with those of the mandibular body.The slight reduction in gonial angle during the fetal periodmay also indicate increased growth of the condyle more ina vertical than a horizontal direction. These findings areconcurrent with previous concepts of the mandibular de-velopment and growth (Baccetti et al., 1997; Bareggi et al.,1995; Buschang et al., 1999; Keith, 1982; Kjaer 1978a,b;Radlanski et al., 1999; Ronning, 1995).

In summary, we studied the sequential growth of thehuman fetal mandible and found that radiating trabecu-lae of the mandibular body focused into a primary growthcenter, MdPGC. From the MdPGC, the mandibular devel-opment was divided into two distinctive growth patterns

of the mandibular body and condyle, as shown in Figure 8.We suggest that the MdPGC is an important anatomicallandmark from which we can measure the growth direc-tions or amounts of the mandible and that the MdPGC hasan important morphogenetic implication for the develop-

ment of human mandible, providing a growth center forthe trabecular bone of the mandibular body and also in-dicating an initial growth of endochondral ossification ofthe condyle.

ACKNOWLEDGMENTS

We would like to express our sincere appreciation to thedevoted donors of human materials, who made it possibleto perform this study through the legally approved proce-dure from the center of Congenital Malformation, Seoul,Korea. We are very thankful to Dr. Soo Il Chung and Dr. Yoo Mie Chung for their kind and critical review of themanuscript.

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