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Brief synopsis of cranial sutures: Optimization by adaptation
Brief Synopsis of Cranial Sutures: Optimization by Adaptation Jack C. Yu,*,† James L. Borke,*,† and Guigen Zhang*,† This article reviews the form and function of cranial sutures across the temporal and spatial scales. The temporal scale spans 530 million years, from ostracoderms to contemporary humans. The spatial scale spans eight orders of magnitude, from the macroarchitectural level (the entire cranium), through the mesoarchitectural (the local/regional bone–suture– bone complex) and microarchitectural levels (tissues and cells), to the nanoarchitectural level (molecules within and outside the cells). A mechanomorphologic loop, or cycle, exists. The mechanical strain experienced by the sutures eventually alters the morphology of the sutures. In turn, these morphological changes affect the strain distribution within and around the sutures. At the microarchitectural level, the responses of bone and sutural cells to environmental perturbations depend on the content (what that perturbation is), the context (the other coexisting extrinsic and intrinsic factors), and the history of the perturbation (how often and for how long). Semin Pediatr Neurol 11:249-255 © 2004 Elsevier Inc. All rights reserved.
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here are three kinds of joints, or arthroses, in the human body: diarthrodial, amphiarthrodial, and synarthrodial. Cranial sutures are synarthrodial joints and are collectively known as suturae cranii. According to the Nomina Anatomica, there are 33 officially recognized and systematically named suturae cranii.1 Sutures allow rapid brain growth and expansion, provide union between the otherwise separate cranial bones, and permit critical cranial kinesis during birth through the inferior pelvic aperture, which is of great importance in the evolution of Homo sapiens.2 To effectively treat infant skull deformities, physicians must understand how these deformities form, their functional demands, and what the different components are capable of under both nominal and perturbed conditions. The frequently quoted phrase “form follows function” is a biological statement. It has an implicit stipulation: There must be sufficient time. It is also only half of the truth. The other half, which necessarily accompanies the first, is that function is constrained by form.3 Given sufficient time, and if the demand is within tolerable limits of the tissue, living tissues can remodel and thus adapt to functional demands. The mor-
*From the Craniofacial Center and the Department of Oral Biology & Maxillofacial Pathology, Medical College of Georgia, Athens, GA. †Biomedical & Health Sciences Institute, Drifter Engineering Center, University of Georgia, Athens, GA. Address reprint requests to Jack C. Yu, DMD, MD, MS, Craniofacial Center, Medical College of Georgia, 1467 Harper Street, HB 5040, Augusta, GA 30912-4080.
1071-9091/05/$-see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.spen.2004.10.002
phology and the current material properties of the tissues are what the organism must contend with, even though these change over time under genetic control to meet new environmental demands. Analysis of the material properties and form, how they get to their present status, and how they change is therefore an integral aspect to understanding sutural function. The first section of this article introduces fundamental terms and concepts of mechanics, emphasizing cranial sutures and bone. The second section briefly reviews the evolution of the cranium and outlines the roles and effects of neural protection and trophic mechanism. The third section examines the cranium at microarchitectural and nanoarchitectural levels and considers osteoblast formation, function, and osteoclastogenesis. The fourth section compares and contrasts cranial growth and distraction osteogenesis, both of which are driven by tensile strain. The final section reflects on an important question facing physicians caring for infants with single-suture synostosis and argues for further research into the natural course of the abnormality, especially the trend of intracranial pressure (ICP).
Biomechanics of Bone and Cranial Sutures Bone is the only living tissue that can efficiently resist significant compressive stress. It does so because it is rigid. What exactly is rigidity? Rigidity is a solid state in which the individual particles that compose the material maintain their position relative to one another over time, even under stress.4 In 249
250 contrast, sutures are nonrigid solids. They can resist being pulled (tensile stress), but they cannot tolerate compressive stress nearly as well; they deform with the slightest pushing together (compression).5 Quantitatively, several important parameters define the materials properties of a solid at the macroarchitectural level. Stress is the amount of force on the material per unit cross-sectional area and is typically reported in Pascals (Pa). Each Pa is equivalent to 1 Newton of force per square meter (N/m2). A Newton is the amount of force capable of accelerating 1 kg of mass at 1 m/sec/sec, or 1 kgm/sec.2 Pa is a small unit relative to many other units commonly used to measure stress; for example, 1 mm Hg equals 133 Pa, and 1 psi equals 6900 Pa. Normal ICP is therefore 1330 Pa, or 1.33 KPa. Stress causes a material to deform, to change its shape. Tensile stress elongates a material along the direction of the stress. When reported as a ratio to the original length, this change in length is known as strain. Strain is therefore unitless. In addition, tensile stress reduces the dimension of the material perpendicular to the stress. The ratio of this transverse contraction to the longitudinal elongation is known as Poisson’s ratio. In bone, Poisson’s ratio is 0.28. Another important ratio is the ratio of stress to strain, the elastic modulus. It has the same unit as stress, because strain is without unit. The elastic modulus of a cranial suture is reported to range from 2 million Pa (2 Mpa) to 610 MPa.6,7 Two reasons underlie this wide range: intrinsic sutural differences (at the mesoarchitectural and microarchitectural levels) and the rate of loading during testing. In general, the slower the load rate, the lower the modulus, and the faster the load rate, the higher the modulus. Sagittal sutures loaded at 0.001 mm/sec have an elastic modulus of 13 to 15 MPa. At 0.04 mm/sec, the elastic modulus increases to 190 MPa. At 42 mm/sec, it can reach 610 MPa on average, sometimes exceeding 730 MPa.8 This time dependence is universal to all viscoelastic materials. Cranial bones have a modulus in the range of 620 to 1400 MPa.9 When a material is under stress, the deformation may be temporary; that is, when the stress is removed, the material regains its original shape. This type of deformation is called elastic deformation. At the point when permanent deformation occurs, the material has reached the yield point, also known as the elastic limit. The stress at the yield point is the yield stress. Above the yield stress, materials undergo plastic deformation and will no longer return to their original shape even after the load is removed. Should the stress continue to increase, the material will break. This point along the stress-strain curve is known as the failure point. The stress that can produce failure is the ultimate stress (sometimes called the ultimate strength), and the strain at failure is the ultimate strain (Fig 1). Cranial bones yield at 0.7% and fail at 3%; cranial sutures yield at 4% and fail at 6%. All of these parameters are manifestations of their mesoarchitecture, microarchitecture, and nanoarchitecture, with failure initiating at minute faults and propagating along the weakest interphases.10 The subcomponents themselves are usually much stronger. Calcium hydroxyapatite crystals, for example, have an elastic modulus of 114,000 MPa, or 114 GPa. Even type I collagen has a modulus of 1 to 3 Gpa when purified. The weakest
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Figure 1 An example of the stress–strain curve of a viscoelastic material illustrating the key points, including yield point and failure point. As stress increases, the material undergoes three types of deformations, starting with viscous deformation, extending through elastic deformation, and ending with plastic deformation. (Color version of figure is available online.)
materials within a cranial suture are the proteoglycans filling in between the collagen fibers, with a modulus of only 1 MPa.11 The orientation of these components at the microarchitectural level contributes to the material’s behavior at the macroarchitectural level. No structure is perfect, and bone is no exception. There exist points of irregularities, or faults. These faults are potential points of stress concentration or the stress risers within bone and cranial sutures that can produce microcracks on repeated loading before macro-level fractures occur. Because biological systems are under cyclic loads, fractures can occur even if the stress is below the ultimate stress. The accumulation of microcracks reduces the modulus of the material. Quantitatively, the ratio of the decrease in modulus to the original modulus is known as the fatigue damage. Fatigue fractures occur when the microcracks exceed critical accumulation and convert to failure at the macroarchitectural level. Bone and sutures are both anisotropic; that is, their mechanical behavior varies depending on the orientation of the bone or suture. There is an orderly arrangement to the collagen fibers, the Haversian units, and the trabecular architectures rendering higher strength when bone is loaded either perpendicular or parallel to these structures. Almost a century ago, D’Arcy Thompson, in On Growth and Form, observed that bone “attempts” to maximally reduce shear stress.12 Shear is one of the three fundamental types of stress; the other two are the principal stresses, tensile and compressive (Fig 2). The direction of maximum shear stress is at 45 degrees to principal stresses. Unlike tensile stress, which increases the volume of the material (albeit slightly), and compressive stress, which decreases it, shear stress causes isovolumetric deformations and is poorly tolerated by bone. Recent results from finite-element analysis have revealed that sutural forms alter the stress pattern when sutures change from straight to wavy types (Fig 3). The convex bone–
Cranial sutures: optimization by adaptation
Deformation (Strain) Neutral State, Tensile Strain Compressive Strain Shear Strain Figure 2 The three fundamental strains. Tensile strain and compressive strains are known as principal strains and are associated with small but real changes in volume; that is, they are not isovolumetric. In contrast, shear strain is isovolumetric. (Color version of figure is available online.)
suture interphase experiences higher tensile stress, and the concave fronts have higher shear stress when simple uniaxial tensile stress is applied. The locations of high shear stress appear to be where the osteoclasts and matrix metalloproteinase (MMP)-9 are found (Fig 4). Another important finding is that bone stress induces fluid flow in the interconnected small channels of the lacunocanalicular system. This system serves as mass transport conduits for nutrients, and tensile stress induces the maximum material “mixing” and “pooling” effects.13 The biological implica-
251 tions of these data from applying methods of structural mechanics may be significant, in that they explain why sutures tend to be wavy and how this wavy morphology is attained. Importantly, such coupling of mechanics with morphology has the potential for noninvasive assessment of the trend of past ICP.14
Evolutionary Origin In biology, understanding how and why is often difficult. Such questions can be addressed only from a historical perspective, because the present status of biological processes or forms is determined largely by their past status.15 As succinctly stated by the renowned evolutionary biologist Theodosius Dobzhansky, nothing makes sense in biology except in light of evolution. Bony cranium first appeared in the earliest jawless fishes (Agnatha) known as ostracoderms some 530 million years ago during the Cambrian period of the Paleozoic era.16 The story of neurocranial evolution is the story of the progressive refinement of complex sense organs and the brain and a reinforced apparatus to house and protect them; this apparatus is the cranium. The three paired distant sense organs are critical for the survival of the vertebrate by providing the ability to detect environmental perturbations such as chemical changes (olfactory), photonic changes (visual), and sound pressure changes (stato-acoustic). These sense organs are extremely sensitive instruments. For example, the basic unit of the stato-acoustic organs, the hair cells, can detect displacement as fine as 0.1 nm, the size of a hydrogen atom. Like all instru-
Figure 3 Finite-element simulation of a cranial suture with increasing frequency and amplitude of spatial oscillation. The stress contour becomes more complex, and the complexity of the sutural waveform increases. The advancing bone–suture junction has higher tensile stress, and the receding junction has more shear. (Color version of figure is available online.)
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Figure 4 The biological correlates of the finite-element simulation results. This is an immunohistological photograph of a 2-week-old rat sagittal suture in transverse section after a short period of tensile stress staining for an isoform of matrix degradation protein. MMP-9 was converted to finite element mesh and used for stress analysis. MMP-9 activities are seen where stress is high. (Color version of figure is available online.)
ments with extreme sensitivity, these organs must be housed in a stable platform. In addition, the triangulation that allows determination of distance (vision) or direction (stato-acoustic) requires that the separation between the left and right sense organs be highly fixed. These characteristics and protection of the delicate brain demand rigidity. However, maintaining rigidity at a time when brain enlargement is occurring rapidly, ontogenetically, and phylogenetically poses problems: how to be rigid while not impeding brain enlargement, and how to modify a complex structure with many connected elements. The alteration in one part must necessarily have coordinated and corresponding alterations in other parts.17 To complicate matters, this rigid construct must be able to withstand prolonged cyclic loading. The combination of suture, bone, and remodeling capability is the design solution to meet the competing requirements of providing sufficient rigidity without impeding growth and overcoming fatigue damage without producing excessive bone mass.18 In contrast, the evolution of the visceral cranium is intimately related to trophic mechanisms. The very early members of Gnathostomata (animals with jaws and tetrapod body design) were probably filter feeders. This suspension-feeding mechanism is low cost from an energy standpoint and has independently evolved several times during vertebrate evolution, pointing to its high adaptive advantage. Together with the rim-reinforced anterior opening, the branchial clefts allow the unidirectional egress of water. These animals, known as ram-feeders, were followed by suction feeders. A series of coordinated contractions starts with the suprahyoid and infrahyoid muscles (eg, the recti cervicis), which
cause posterior-ventral translation of the hyoid and mandible. The contractions end with the abduction of the operculum by the branciohyoideus muscles and the adduction of the gill bars. The latter cause pressure inside the mouth to drop, causing water to enter the mouth. This sequence is reversed during the second phase of the cycle; the mouth closes and pressure builds up, forcing water out through the branchial clefts. This basic muscle contraction pattern and the neural circuitry that controls these muscles are conserved throughout the vertebrates. The jaw structures and the articulation changed further to allow faster closure and increase the intrinsic strength for prey capture. The muscles closing the jaws became progressively more massive. Many features of the temporoparietal region, such as the fenestrations first seen in reptiles, reflect changes to accommodate more muscles. As in many scenarios in life, here there are conflicting demands. Each beneficial alteration in the existing system regarding primary effects is associated with certain inevitable, often undesirable, secondary effects. The need to accommodate large muscles for a rapid, powerful bite reduces the amount of space previously allocated for bone, potentially weakening the skull. Jaw and cranial structural strength also must increase to withstand the stress produced during fierce struggles between prey and predator. This problem is compounded by weight. Terrestrial existence without the buoyancy of the aquatic environment means that for each 100 mL of body volume, 1 N of “free lift” is lost. Bone is mineralized connective tissue (mostly calcium) that imparts compressive strength. Consequently, it weighs twice as much as soft tissues. Muscles also create complex strain patterns, including bending, shearing, twisting, and turning
Cranial sutures: optimization by adaptation movements, further complicating the issue. This is particularly important in mammals, because intraoral food processing is more elaborate in this group than in any other vertebrates. That muscles are intimately linked to the evolution of the human cranium is recently supported by the discovery of a mutation in the human myosin gene (MYH 16) occurring when humans branched off from other primates. This mutation represents the first such proteomic difference between humans and chimpanzees.19 Two important trends are present in the progression from fishes through amphibians and reptiles to mammals. The crania of early vertebrates contained many ossification centers with a relatively high degree of mobility between the cranial bones. This condition is known as cranial kinesis. The first trend is a reduction in the number of ossification centers; the other is a reduction in cranial kinesis. The number of ossification centers has been a favored target in vertebrate evolution, which suggests that it is a means for efficient and rapid morphological diversification without the need for a “complete overhaul.” As it exists today, craniosynostosis may well represent a continuation of this reduction in ossification centers. The number of different vertebrate species exploded within a very short time on the evolutionary scale. This increase in biodiversity contributes greatly to the stability of the biomass.20 The most likely underlying reason is related to a new type of tissue, the neural crest. The cells within the neural crest are capable of migrating from their original position to populate distant targets, including the future cranium, depending on local cues. Neural crest cells differentiate into different tissue types, including bone and cartilage.21 Bone, an internal mineralized organic matrix, is a uniquely vertebrate feature. Although the different taxa continue to diversify at the macroarchitectural level, bone and cartilage have changed little in the last 400 million years ago. It is as if these tissues were “good enough” and the potential detrimental effects of altering this winning design outweighed the possible gain, thus essentially imposing constraints against further alterations.
Sutures and Bone at the Cellular and Molecular Levels What biological characteristics about bone, cartilage, and sutures are so advantageous as to render them resistant to diversification? Bone is a fiber-reinforced porous polymer composite. In addition to the cellular elements, it has three major components: bone minerals, organic matrix, and water. Osteoblasts, osteocytes, and osteoclasts are the bone-specific, terminally differentiated cell types present in bone. The reserve mesenchymal stem cells can differentiate into osteoblasts in about 7 days when exposed to “pro-osteogenic media,” which typically contain dexamethasone, vitamin C, and -glycerophosphate. This induced osteoblast differentiation requires 41 transcription factors, including Cbf ␣1 (core-binding factor ␣1) and Bmp-2. They appear at various times, making biomolecules needed for 12 major cellular functions, including apoptosis, cell-cycle control, DNA repair, RNA splicing, protein
253 synthesis/degradation, and nuclear protein synthesis.22 The roles of these proteins can be structural, enzymatic, or signaling. Osteoblasts are basophilic and cuboidal, with an eccentric nucleus when they are actively secreting extracellular matrix (ECM). They are richly interconnected into a syncytium via about 150 intercellular cytoplastic connections known as gap junctions. Only about 1 in 500 (range, 10 to 1000) osteoblasts becomes entombed in the ECM. Once entombed, an osteoblast is called an osteocyte and measures about 25 ⫻ 10 ⫻ 10 3. The density of osteocytes in bone is fairly constant, at 20,000 osteocytes/ mm3. The typical life span of an osteoblast is measured in weeks, whereas an average osteocyte lives for about 25 years. Once bone is formed, only osteoclasts can remove it; osteoclasts are therefore essential for bone remodeling. They are formed by “multinucleation” of hematopoietic monocyte/ macrophage-like cells. These osteoclast precursors start their life journey in the marrow, through the action of a transcription factor called PU-1. They express CD14 on their cell surfaces and enter the circulation. Only 2% to 5% of these circulating mononuclear cells eventually differentiate into osteoclasts after attaching to a bone surface and forming a multinucleated giant cell. Interestingly, osteoblasts are needed for terminal differentiation and the activation of osteoclasts; they do so by releasing macrophage colony-stimulating factor (M-CSF) and expressing osteoclast differentiating factor on their cell surface. Inflammation with an associated increase in tumor necrosis factor-␣ and interleukins (ILs), particularly IL-1 and IL-6, promote this process. Systemic factors (eg, estrogen and parathyroid hormone) are coupled to local-regional factors, such as M-CSF and strain condition, to determine where, how much, and how fast bone resorption occurs. Precisely how the local strain condition (eg, shear strain) is converted to biological signals that result in osteoclast formation and activation is a key question under investigation. Cellular elements in cranial bone and sutures respond to mechanical stimuli by changes in membrane permeability and intracellular calcium concentration, release of growth factors such as fibroblast growth factor (FGF)-2, and changes in gene expression, such as Cx43, Tbx-2, Ets-1, Ets-2, and c-src, to name a few.23,24 Once activated, a single osteoclast can remove bone formed by 1000 osteoblasts in the same amount of time. Without osteoclasts, there would be no Haversian systems and no bone remodeling. Without bone remodeling, fatigue from repeated cyclic loading could not be overcome. Vertebrates would then need very short life spans to stay within the endurance limit or else would need to alter their body design drastically.25 The matrix needed in bone is synthesized in osteoblasts. After exiting the osteoblasts, this eosinophilic, unmineralized bone matrix is 90% water, of which 88% is replaced by minerals (known as the “labile water” of bone). The organic matrix proper is largely type I collagen (95%) and mucopolysaccharides (4%). The remaining 1% is composed of important signaling peptides, including bone morphogenic proteins, transforming growth factors, FGFs, and so on. The two major components of bone mucopolysaccharides are chondroitin sulfates and hyaluronates. Bone minerals compose 73% of
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254 the dry bone mass. Calcium is the predominant element (38%), followed by phosphorus (18%) and nitrogen (8%). The largest subcomponent of the cranium, in both bone and sutures, is type I collagen. These rope-like triple helices have repeating bandings of 64 nm that reflect the orderly overlapping of the individual fibrils. They span the entire cranium in multiple “sheets” with a 90-degree out-of-phase orientation between the sheets, much like plywood. Where sutures are, these type I collagen fibers without minerals can be seen with an electron microscope or directly with an atomic force microscope. Bone begins where sutures end. This bone–suture boundary is marked by minerals and is critical. Normally, the opposing mineralization fronts stop when the distance remaining between them is 200 to 450 m. The loss of this sliver of unmineralized desmocranium is the essence of craniosynostosis. Maintaining this relative constant separation is a form of spatial homeostasis. Like many homeostatic systems, it represents the product of antagonistic balancing, which is at the core of all closed-loop control systems. The center of the suture is highly antiosteogenic through the actions of transcription factors such as Twist, Noggin, and Tbx-2. The peripheral part of the suture is high in pro-osteogenic factors, such as Bmp-2, Cx43, and FGF-2.26 These antagonistic subsystems set up an autoregulatory loop driven by the stress applied; as brain growth expands the cranium, sutures undergo tensile strain, and sutural width increases. The leading edges are then under less antiossification control, and pro-osteogenic factors dominate. The resulting bone formation accommodates brain growth and returns the suture to its original width. Further ossification toward the center of the suture is suppressed by the high antiossification factors present in the center. Increasing experimental evidence supports this theoretical conjecture. For at least some of these antiossification transcription factors, such as Tbx-2 and Twist, this effect is achieved by binding to the promoter regions of the genes necessary to bone formation and decreasing their expression.27
In other words, cranial growth is a natural form of prolonged multifocal (about 30) distraction osteogenesis. The key feature that makes this natural distraction differ from clinical distraction is highly antiosteogenic factors that delay the complete ossification of the regenerates for many decades. Distraction osteogenesis was initially described by Codivilla in the early 1900s. Later, it was independently developed and systematically refined by Gavriel Ilizrov. Through the work of Joseph McCarthy, distraction osteogenesis has become one of the most commonly performed operations in the craniofacial skeleton to correct congenital, posttraumatic, and postoncological deformities.27 Both natural and clinical distraction osteogenesis harness the body’s inherent ability to grow when stretched. Clinical distraction has three phases: latency, activation, and consolidation. Immediately after osteotomy (periosteal and marrow-preserving corticotomy in the original Ilizarov protocol) and application of a mechanical lengthener (distractor), a latency of 24 to 48 hours is followed by activation, which typically includes lengthening of 1.0 mm/day, at 0.25 mm four times per day. This is an extremely large amount of strain, in the range of 1 million microstrains, compared with physiologic bone strain in the range of several thousand microstrains. Consolidation follows activation. In most centers, this time is reduced to 1 month, decreased from twice the time required for activation stipulated in the classic Ilizarov protocol applied to appendicular skeletons. Because the amount of lengthening is a constant of 1 mm/day, with an increasing gap length, the strain decreases as distraction progresses. Distraction is endogenous tissue engineering. Not only does it induce osteogenesis, but other tissue types, including nerve, muscle, skin, and blood vessels, also form in response to the increased strain. The bone formed is woven bone that is laid down at an amazing rate, as high as 250 /day. Later remodeling processes replace this woven bone with lamellar bone, orienting the Haversian systems to maximally reduce shear strain during function. The result is an optimized mesoarchitecture best suited to respond to those functional loads.28,29
Cranial Morphogenesis and Distraction Osteogenesis
Clinical Implications
Based on observations, the cranium has three essential properties: (1) It is of sufficient size to house and protect the brain and distant sense organs; (2) it does not impede the growth of the brain and the sense organs; and (3) an extremely well-conserved basic plan (the baüplan) dictates the number of ossification centers and their location. However, the final form of the cranium is not intrinsically invariant. The earliest form of the cranium, both phylogenetically and ontogenetically, was a fibrous capsule surrounding the anterior end of the central nervous system. This fibrous capsule is the thelia parameningealis in lower vertebrates and the desmocranium in embryonic mammals. With selected mineralization in key areas and restriction in others, the adult mammalian cranium enjoys the first two properties. This antagonistic coupling of osteogenesis and antiosteogenesis means that cranial growth is an “enslaved” process, driven by another extrinsic determinant, the growth of the brain. This coupling is the essential foundation underpinning the fulfillment of all three properties.
An important question that has remained incompletely answered since the advent of craniofacial surgery is whether the brain in single-suture craniosynostosis requires releasing.30,31 Based on the current understanding of how the cranium forms and on the behaviors and capabilities of the bone, suture, and cells involved, this question must be reexamined. Because the operations to correct single-suture closure can be associated with complications or even death, the potential benefit can be fully evaluated only if the natural course without surgical intervention is well known.32,33 A review of the first several large case series reported after the advent of fronto-orbital advancements for synostotic plagiocephaly produced an interesting observation: a conspicuous lack of adult patients. This finding is contrary to expectations after the introduction of a new treatment for an existing disease condition.34,35 In any given stable population, it is reasonable to assume that the development of a new surgical technique has no effect on the incidence of single-
Cranial sutures: optimization by adaptation suture craniosynostosis. Thus the incidence of single-suture craniosynostosis would have remained constant before and after the development of fronto-orbital advancement. Applying simple principles of epidemiology, one can derive the total number of new cases per year by multiplying the incidence and total birth rates. Based on this calculation and the mortality rate, the sum of cases in all age groups in a population for a given time can be calculated if a steady state exists. The result is known as prevalence. A large discrepancy appears to have existed in the 1970s and 1980s; the prevalence was either unknown or too low compared with the incidence. Two theoretical explanations can account for a large discrepancy between incidence and prevalence. One explanation is that the process is extremely lethal. Even though the incidence is high, the affected individuals soon die of the process, resulting in a low prevalence. Ebola infection is one such example. The second explanation is that the disease process is self-limiting; that is, the “burn-out” rate is high, and individuals with the disease eventually outgrow the problem. There are other complicating variables, such as thresholds for making the diagnosis and an individual’s desire to seek medical attention. Nonetheless, it is imperative that efforts be directed to address this question. Given that cranial sutures respond to cranial wall stress and that cranial wall stress is necessarily a function of ICP, the past trend of ICP can be inferred by quantitatively measuring sutural complexity. Detailed fractal dimension analysis of the suture may provide the answer, which is long overdue.
Summary This brief review of cranial sutures has attempted to provide a basic understanding of the biomechanics of cranial bones and sutures. Both descriptive data at various levels and theoretical work from different disciplines have been presented to provide an overall appreciation of the cranium as a complex adaptive system. On initial examination, some features may seem utterly inexplicable. When studied in detail and considering that these systems evolved over hundreds of millions of years and contain within them memories of their distant past, the system’s beauty, constraints, and complexity become more understandable.
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ments and implications for mechanisms of pediatric brain injury. J Biomech Eng 122:364-371, 2000 Russell AP, Thomason JJ: Mechanical analysis of the mammalian head skeleton, in Hanken J, Hall BK (eds): Skull Functional and Evolutionary Mechanisms. Chicago, University of Chicago Press, 1993, pp 345-383 Doblare M, Garcia JM, Gomez MJ: Modeling bone fracture and healing: A review. Engineer Fract Mech 71:1809-1840, 2004 Pashley D, Borke JL, Yu J: Biomechanics and craniofacial morphogenesis, in Lin K, Ogle RC, Jane JA (eds): Craniofacial Surgery: Science and Surgical Technique. Philadelphia, Saunders, 2002, pp 84-100 Thompson DW: On Growth and Form. Cambridge, UK, Cambridge University Press, 1997, pp 319-321 Steck R, Niederer P, Knothe Tate ML: A finite element analysis for the prediction of load-induced fluid flow and mechanochemical transduction in bone. J Theor Biol 220:249-259, 2003 Yu JC, Wright RL, Williamson MA, et al: A fractal analysis of human cranial sutures. Cleft Palate Craniofac J 40:409-415, 2003 Morris SC: Evolution: Bringing molecules into the fold. Cell 100:1-11, 2000 Janvier P: The phylogeny of the craniata, with particular reference to the significant of fossil “agnathans.” J Vertebr Paleontol 1:121-159, 1981 Enlow DH: Handbook of Facial Growth. Philadelphia, Saunders, 1975, pp 18-47 Martin RB: Fatigue damage, remodeling, and the minimization of skeletal weight. J Theor Biol 220:271-276, 2003 Stedman HH, Kozyak BW, Nelson A, et al: Myosin gene mutation correlates with anatomical changes in the human lineage. Nature 428: 415-418, 2004 Ives AR, Gross K, Klug JL: Stability and variability in competitive communities. Science 286:542-544, 1999 Thorogood P: The developmental specification of the vertebrate skull. Development 103(suppl):141-153, 1988 Qi H, Aguiar DJ, Williams SM, et al: Identification of genes responsible for osteoblast differentiation from human mesodermal progenitor cells. Proc Natl Acad Sci U S A 100:3305-3310, 2003 Yu J, Lucas JH, Borke JL: Tension-induced FGF-2 release in neonatal rat cranial sutures: a self-organizing mechanism in cranial development, in Chen Y (ed): Craniofacial Surgery. Bolonga, Monduzzi, 1999, pp 29-32 Yu JC, Lucas JH, Fryberg K, et al: Extrinsic tension results in FGF-2 release, membrane permeability change, and intracellular Ca⫹⫹ increase in immature cranial sutures. J Craniofac Surg 12:391-398, 2001 Frost HM: Bone Remodeling Dynamics. Springfield, IL, Charles C Thomas, 1963 Warren SM, Brunet LJ, Harland RM, et al: The BMP antagonist noggin regulates cranial suture fusion. Nature 422:625-629, 2003 Mofid MM, Manson PN, Robertson BC, et al: Craniofacial distraction osteogenesis: A review of 3278 cases. Plast Reconstr Surg 108:11031114, 2001 Swennen G, Schliephake H, Dempf R, et al: Craniofacial distraction osteogenesis: A review of the literature. Part 1: Clinical studies. Int J Oral Maxillofac Surg 30:89-103, 2001 Mofid MM, Inoue N, Atabey A, et al: Callus stimulation in distraction osteogenesis. Plast Reconstr Surg 109:1621-1629, 2002 Miller RI, Clarren SK: Long-term developmental outcomes in patients with deformational plagiocephaly. Pediatrics 105:E26, 2000 Magge SN, Westerveld M, Pruzinsky T, et al: Long-term neuropsychological effects of sagittal craniosynostosis on child development. J Craniofac Surg 13:99-104, 2002 Fearon JA, Yu J, Bartlett SP, et al: Infections in craniofacial surgery: A combined report of 567 procedures from two centers. Plast Reconstr Surg 100:862-868, 1997 Kececi Y, Ozek C, Gurler T, et al. Complications in craniofacial surgery: The Turkish experience. J Craniofac Surg 11:168-171, 2000 Munro IR, Sabatier RE: An analysis of 12 years of craniomaxillofacial surgery in Toronto. Plast Reconstr Surg 76:29-35, 1985 Whitaker LA, Bartlett SP, Schut L, et al: Craniosynostosis: An analysis of the timing, treatment, and complications in 164 consecutive patients. Plast Reconstr Surg 80:195-212, 1987
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here are three kinds of joints, or arthroses, in the human body: diarthrodial, amphiarthrodial, and synarthrodial. Cranial sutures are synarthrodial joints and are collectively known as suturae cranii. According to the Nomina Anatomica, there are 33 officially recognized and systematically named suturae cranii.1 Sutures allow rapid brain growth and expansion, provide union between the otherwise separate cranial bones, and permit critical cranial kinesis during birth through the inferior pelvic aperture, which is of great importance in the evolution of Homo sapiens.2 To effectively treat infant skull deformities, physicians must understand how these deformities form, their functional demands, and what the different components are capable of under both nominal and perturbed conditions. The frequently quoted phrase “form follows function” is a biological statement. It has an implicit stipulation: There must be sufficient time. It is also only half of the truth. The other half, which necessarily accompanies the first, is that function is constrained by form.3 Given sufficient time, and if the demand is within tolerable limits of the tissue, living tissues can remodel and thus adapt to functional demands. The mor-
*From the Craniofacial Center and the Department of Oral Biology & Maxillofacial Pathology, Medical College of Georgia, Athens, GA. †Biomedical & Health Sciences Institute, Drifter Engineering Center, University of Georgia, Athens, GA. Address reprint requests to Jack C. Yu, DMD, MD, MS, Craniofacial Center, Medical College of Georgia, 1467 Harper Street, HB 5040, Augusta, GA 30912-4080.
1071-9091/05/$-see front matter © 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.spen.2004.10.002
phology and the current material properties of the tissues are what the organism must contend with, even though these change over time under genetic control to meet new environmental demands. Analysis of the material properties and form, how they get to their present status, and how they change is therefore an integral aspect to understanding sutural function. The first section of this article introduces fundamental terms and concepts of mechanics, emphasizing cranial sutures and bone. The second section briefly reviews the evolution of the cranium and outlines the roles and effects of neural protection and trophic mechanism. The third section examines the cranium at microarchitectural and nanoarchitectural levels and considers osteoblast formation, function, and osteoclastogenesis. The fourth section compares and contrasts cranial growth and distraction osteogenesis, both of which are driven by tensile strain. The final section reflects on an important question facing physicians caring for infants with single-suture synostosis and argues for further research into the natural course of the abnormality, especially the trend of intracranial pressure (ICP).
Biomechanics of Bone and Cranial Sutures Bone is the only living tissue that can efficiently resist significant compressive stress. It does so because it is rigid. What exactly is rigidity? Rigidity is a solid state in which the individual particles that compose the material maintain their position relative to one another over time, even under stress.4 In 249
250 contrast, sutures are nonrigid solids. They can resist being pulled (tensile stress), but they cannot tolerate compressive stress nearly as well; they deform with the slightest pushing together (compression).5 Quantitatively, several important parameters define the materials properties of a solid at the macroarchitectural level. Stress is the amount of force on the material per unit cross-sectional area and is typically reported in Pascals (Pa). Each Pa is equivalent to 1 Newton of force per square meter (N/m2). A Newton is the amount of force capable of accelerating 1 kg of mass at 1 m/sec/sec, or 1 kgm/sec.2 Pa is a small unit relative to many other units commonly used to measure stress; for example, 1 mm Hg equals 133 Pa, and 1 psi equals 6900 Pa. Normal ICP is therefore 1330 Pa, or 1.33 KPa. Stress causes a material to deform, to change its shape. Tensile stress elongates a material along the direction of the stress. When reported as a ratio to the original length, this change in length is known as strain. Strain is therefore unitless. In addition, tensile stress reduces the dimension of the material perpendicular to the stress. The ratio of this transverse contraction to the longitudinal elongation is known as Poisson’s ratio. In bone, Poisson’s ratio is 0.28. Another important ratio is the ratio of stress to strain, the elastic modulus. It has the same unit as stress, because strain is without unit. The elastic modulus of a cranial suture is reported to range from 2 million Pa (2 Mpa) to 610 MPa.6,7 Two reasons underlie this wide range: intrinsic sutural differences (at the mesoarchitectural and microarchitectural levels) and the rate of loading during testing. In general, the slower the load rate, the lower the modulus, and the faster the load rate, the higher the modulus. Sagittal sutures loaded at 0.001 mm/sec have an elastic modulus of 13 to 15 MPa. At 0.04 mm/sec, the elastic modulus increases to 190 MPa. At 42 mm/sec, it can reach 610 MPa on average, sometimes exceeding 730 MPa.8 This time dependence is universal to all viscoelastic materials. Cranial bones have a modulus in the range of 620 to 1400 MPa.9 When a material is under stress, the deformation may be temporary; that is, when the stress is removed, the material regains its original shape. This type of deformation is called elastic deformation. At the point when permanent deformation occurs, the material has reached the yield point, also known as the elastic limit. The stress at the yield point is the yield stress. Above the yield stress, materials undergo plastic deformation and will no longer return to their original shape even after the load is removed. Should the stress continue to increase, the material will break. This point along the stress-strain curve is known as the failure point. The stress that can produce failure is the ultimate stress (sometimes called the ultimate strength), and the strain at failure is the ultimate strain (Fig 1). Cranial bones yield at 0.7% and fail at 3%; cranial sutures yield at 4% and fail at 6%. All of these parameters are manifestations of their mesoarchitecture, microarchitecture, and nanoarchitecture, with failure initiating at minute faults and propagating along the weakest interphases.10 The subcomponents themselves are usually much stronger. Calcium hydroxyapatite crystals, for example, have an elastic modulus of 114,000 MPa, or 114 GPa. Even type I collagen has a modulus of 1 to 3 Gpa when purified. The weakest
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Figure 1 An example of the stress–strain curve of a viscoelastic material illustrating the key points, including yield point and failure point. As stress increases, the material undergoes three types of deformations, starting with viscous deformation, extending through elastic deformation, and ending with plastic deformation. (Color version of figure is available online.)
materials within a cranial suture are the proteoglycans filling in between the collagen fibers, with a modulus of only 1 MPa.11 The orientation of these components at the microarchitectural level contributes to the material’s behavior at the macroarchitectural level. No structure is perfect, and bone is no exception. There exist points of irregularities, or faults. These faults are potential points of stress concentration or the stress risers within bone and cranial sutures that can produce microcracks on repeated loading before macro-level fractures occur. Because biological systems are under cyclic loads, fractures can occur even if the stress is below the ultimate stress. The accumulation of microcracks reduces the modulus of the material. Quantitatively, the ratio of the decrease in modulus to the original modulus is known as the fatigue damage. Fatigue fractures occur when the microcracks exceed critical accumulation and convert to failure at the macroarchitectural level. Bone and sutures are both anisotropic; that is, their mechanical behavior varies depending on the orientation of the bone or suture. There is an orderly arrangement to the collagen fibers, the Haversian units, and the trabecular architectures rendering higher strength when bone is loaded either perpendicular or parallel to these structures. Almost a century ago, D’Arcy Thompson, in On Growth and Form, observed that bone “attempts” to maximally reduce shear stress.12 Shear is one of the three fundamental types of stress; the other two are the principal stresses, tensile and compressive (Fig 2). The direction of maximum shear stress is at 45 degrees to principal stresses. Unlike tensile stress, which increases the volume of the material (albeit slightly), and compressive stress, which decreases it, shear stress causes isovolumetric deformations and is poorly tolerated by bone. Recent results from finite-element analysis have revealed that sutural forms alter the stress pattern when sutures change from straight to wavy types (Fig 3). The convex bone–
Cranial sutures: optimization by adaptation
Deformation (Strain) Neutral State, Tensile Strain Compressive Strain Shear Strain Figure 2 The three fundamental strains. Tensile strain and compressive strains are known as principal strains and are associated with small but real changes in volume; that is, they are not isovolumetric. In contrast, shear strain is isovolumetric. (Color version of figure is available online.)
suture interphase experiences higher tensile stress, and the concave fronts have higher shear stress when simple uniaxial tensile stress is applied. The locations of high shear stress appear to be where the osteoclasts and matrix metalloproteinase (MMP)-9 are found (Fig 4). Another important finding is that bone stress induces fluid flow in the interconnected small channels of the lacunocanalicular system. This system serves as mass transport conduits for nutrients, and tensile stress induces the maximum material “mixing” and “pooling” effects.13 The biological implica-
251 tions of these data from applying methods of structural mechanics may be significant, in that they explain why sutures tend to be wavy and how this wavy morphology is attained. Importantly, such coupling of mechanics with morphology has the potential for noninvasive assessment of the trend of past ICP.14
Evolutionary Origin In biology, understanding how and why is often difficult. Such questions can be addressed only from a historical perspective, because the present status of biological processes or forms is determined largely by their past status.15 As succinctly stated by the renowned evolutionary biologist Theodosius Dobzhansky, nothing makes sense in biology except in light of evolution. Bony cranium first appeared in the earliest jawless fishes (Agnatha) known as ostracoderms some 530 million years ago during the Cambrian period of the Paleozoic era.16 The story of neurocranial evolution is the story of the progressive refinement of complex sense organs and the brain and a reinforced apparatus to house and protect them; this apparatus is the cranium. The three paired distant sense organs are critical for the survival of the vertebrate by providing the ability to detect environmental perturbations such as chemical changes (olfactory), photonic changes (visual), and sound pressure changes (stato-acoustic). These sense organs are extremely sensitive instruments. For example, the basic unit of the stato-acoustic organs, the hair cells, can detect displacement as fine as 0.1 nm, the size of a hydrogen atom. Like all instru-
Figure 3 Finite-element simulation of a cranial suture with increasing frequency and amplitude of spatial oscillation. The stress contour becomes more complex, and the complexity of the sutural waveform increases. The advancing bone–suture junction has higher tensile stress, and the receding junction has more shear. (Color version of figure is available online.)
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Figure 4 The biological correlates of the finite-element simulation results. This is an immunohistological photograph of a 2-week-old rat sagittal suture in transverse section after a short period of tensile stress staining for an isoform of matrix degradation protein. MMP-9 was converted to finite element mesh and used for stress analysis. MMP-9 activities are seen where stress is high. (Color version of figure is available online.)
ments with extreme sensitivity, these organs must be housed in a stable platform. In addition, the triangulation that allows determination of distance (vision) or direction (stato-acoustic) requires that the separation between the left and right sense organs be highly fixed. These characteristics and protection of the delicate brain demand rigidity. However, maintaining rigidity at a time when brain enlargement is occurring rapidly, ontogenetically, and phylogenetically poses problems: how to be rigid while not impeding brain enlargement, and how to modify a complex structure with many connected elements. The alteration in one part must necessarily have coordinated and corresponding alterations in other parts.17 To complicate matters, this rigid construct must be able to withstand prolonged cyclic loading. The combination of suture, bone, and remodeling capability is the design solution to meet the competing requirements of providing sufficient rigidity without impeding growth and overcoming fatigue damage without producing excessive bone mass.18 In contrast, the evolution of the visceral cranium is intimately related to trophic mechanisms. The very early members of Gnathostomata (animals with jaws and tetrapod body design) were probably filter feeders. This suspension-feeding mechanism is low cost from an energy standpoint and has independently evolved several times during vertebrate evolution, pointing to its high adaptive advantage. Together with the rim-reinforced anterior opening, the branchial clefts allow the unidirectional egress of water. These animals, known as ram-feeders, were followed by suction feeders. A series of coordinated contractions starts with the suprahyoid and infrahyoid muscles (eg, the recti cervicis), which
cause posterior-ventral translation of the hyoid and mandible. The contractions end with the abduction of the operculum by the branciohyoideus muscles and the adduction of the gill bars. The latter cause pressure inside the mouth to drop, causing water to enter the mouth. This sequence is reversed during the second phase of the cycle; the mouth closes and pressure builds up, forcing water out through the branchial clefts. This basic muscle contraction pattern and the neural circuitry that controls these muscles are conserved throughout the vertebrates. The jaw structures and the articulation changed further to allow faster closure and increase the intrinsic strength for prey capture. The muscles closing the jaws became progressively more massive. Many features of the temporoparietal region, such as the fenestrations first seen in reptiles, reflect changes to accommodate more muscles. As in many scenarios in life, here there are conflicting demands. Each beneficial alteration in the existing system regarding primary effects is associated with certain inevitable, often undesirable, secondary effects. The need to accommodate large muscles for a rapid, powerful bite reduces the amount of space previously allocated for bone, potentially weakening the skull. Jaw and cranial structural strength also must increase to withstand the stress produced during fierce struggles between prey and predator. This problem is compounded by weight. Terrestrial existence without the buoyancy of the aquatic environment means that for each 100 mL of body volume, 1 N of “free lift” is lost. Bone is mineralized connective tissue (mostly calcium) that imparts compressive strength. Consequently, it weighs twice as much as soft tissues. Muscles also create complex strain patterns, including bending, shearing, twisting, and turning
Cranial sutures: optimization by adaptation movements, further complicating the issue. This is particularly important in mammals, because intraoral food processing is more elaborate in this group than in any other vertebrates. That muscles are intimately linked to the evolution of the human cranium is recently supported by the discovery of a mutation in the human myosin gene (MYH 16) occurring when humans branched off from other primates. This mutation represents the first such proteomic difference between humans and chimpanzees.19 Two important trends are present in the progression from fishes through amphibians and reptiles to mammals. The crania of early vertebrates contained many ossification centers with a relatively high degree of mobility between the cranial bones. This condition is known as cranial kinesis. The first trend is a reduction in the number of ossification centers; the other is a reduction in cranial kinesis. The number of ossification centers has been a favored target in vertebrate evolution, which suggests that it is a means for efficient and rapid morphological diversification without the need for a “complete overhaul.” As it exists today, craniosynostosis may well represent a continuation of this reduction in ossification centers. The number of different vertebrate species exploded within a very short time on the evolutionary scale. This increase in biodiversity contributes greatly to the stability of the biomass.20 The most likely underlying reason is related to a new type of tissue, the neural crest. The cells within the neural crest are capable of migrating from their original position to populate distant targets, including the future cranium, depending on local cues. Neural crest cells differentiate into different tissue types, including bone and cartilage.21 Bone, an internal mineralized organic matrix, is a uniquely vertebrate feature. Although the different taxa continue to diversify at the macroarchitectural level, bone and cartilage have changed little in the last 400 million years ago. It is as if these tissues were “good enough” and the potential detrimental effects of altering this winning design outweighed the possible gain, thus essentially imposing constraints against further alterations.
Sutures and Bone at the Cellular and Molecular Levels What biological characteristics about bone, cartilage, and sutures are so advantageous as to render them resistant to diversification? Bone is a fiber-reinforced porous polymer composite. In addition to the cellular elements, it has three major components: bone minerals, organic matrix, and water. Osteoblasts, osteocytes, and osteoclasts are the bone-specific, terminally differentiated cell types present in bone. The reserve mesenchymal stem cells can differentiate into osteoblasts in about 7 days when exposed to “pro-osteogenic media,” which typically contain dexamethasone, vitamin C, and -glycerophosphate. This induced osteoblast differentiation requires 41 transcription factors, including Cbf ␣1 (core-binding factor ␣1) and Bmp-2. They appear at various times, making biomolecules needed for 12 major cellular functions, including apoptosis, cell-cycle control, DNA repair, RNA splicing, protein
253 synthesis/degradation, and nuclear protein synthesis.22 The roles of these proteins can be structural, enzymatic, or signaling. Osteoblasts are basophilic and cuboidal, with an eccentric nucleus when they are actively secreting extracellular matrix (ECM). They are richly interconnected into a syncytium via about 150 intercellular cytoplastic connections known as gap junctions. Only about 1 in 500 (range, 10 to 1000) osteoblasts becomes entombed in the ECM. Once entombed, an osteoblast is called an osteocyte and measures about 25 ⫻ 10 ⫻ 10 3. The density of osteocytes in bone is fairly constant, at 20,000 osteocytes/ mm3. The typical life span of an osteoblast is measured in weeks, whereas an average osteocyte lives for about 25 years. Once bone is formed, only osteoclasts can remove it; osteoclasts are therefore essential for bone remodeling. They are formed by “multinucleation” of hematopoietic monocyte/ macrophage-like cells. These osteoclast precursors start their life journey in the marrow, through the action of a transcription factor called PU-1. They express CD14 on their cell surfaces and enter the circulation. Only 2% to 5% of these circulating mononuclear cells eventually differentiate into osteoclasts after attaching to a bone surface and forming a multinucleated giant cell. Interestingly, osteoblasts are needed for terminal differentiation and the activation of osteoclasts; they do so by releasing macrophage colony-stimulating factor (M-CSF) and expressing osteoclast differentiating factor on their cell surface. Inflammation with an associated increase in tumor necrosis factor-␣ and interleukins (ILs), particularly IL-1 and IL-6, promote this process. Systemic factors (eg, estrogen and parathyroid hormone) are coupled to local-regional factors, such as M-CSF and strain condition, to determine where, how much, and how fast bone resorption occurs. Precisely how the local strain condition (eg, shear strain) is converted to biological signals that result in osteoclast formation and activation is a key question under investigation. Cellular elements in cranial bone and sutures respond to mechanical stimuli by changes in membrane permeability and intracellular calcium concentration, release of growth factors such as fibroblast growth factor (FGF)-2, and changes in gene expression, such as Cx43, Tbx-2, Ets-1, Ets-2, and c-src, to name a few.23,24 Once activated, a single osteoclast can remove bone formed by 1000 osteoblasts in the same amount of time. Without osteoclasts, there would be no Haversian systems and no bone remodeling. Without bone remodeling, fatigue from repeated cyclic loading could not be overcome. Vertebrates would then need very short life spans to stay within the endurance limit or else would need to alter their body design drastically.25 The matrix needed in bone is synthesized in osteoblasts. After exiting the osteoblasts, this eosinophilic, unmineralized bone matrix is 90% water, of which 88% is replaced by minerals (known as the “labile water” of bone). The organic matrix proper is largely type I collagen (95%) and mucopolysaccharides (4%). The remaining 1% is composed of important signaling peptides, including bone morphogenic proteins, transforming growth factors, FGFs, and so on. The two major components of bone mucopolysaccharides are chondroitin sulfates and hyaluronates. Bone minerals compose 73% of
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254 the dry bone mass. Calcium is the predominant element (38%), followed by phosphorus (18%) and nitrogen (8%). The largest subcomponent of the cranium, in both bone and sutures, is type I collagen. These rope-like triple helices have repeating bandings of 64 nm that reflect the orderly overlapping of the individual fibrils. They span the entire cranium in multiple “sheets” with a 90-degree out-of-phase orientation between the sheets, much like plywood. Where sutures are, these type I collagen fibers without minerals can be seen with an electron microscope or directly with an atomic force microscope. Bone begins where sutures end. This bone–suture boundary is marked by minerals and is critical. Normally, the opposing mineralization fronts stop when the distance remaining between them is 200 to 450 m. The loss of this sliver of unmineralized desmocranium is the essence of craniosynostosis. Maintaining this relative constant separation is a form of spatial homeostasis. Like many homeostatic systems, it represents the product of antagonistic balancing, which is at the core of all closed-loop control systems. The center of the suture is highly antiosteogenic through the actions of transcription factors such as Twist, Noggin, and Tbx-2. The peripheral part of the suture is high in pro-osteogenic factors, such as Bmp-2, Cx43, and FGF-2.26 These antagonistic subsystems set up an autoregulatory loop driven by the stress applied; as brain growth expands the cranium, sutures undergo tensile strain, and sutural width increases. The leading edges are then under less antiossification control, and pro-osteogenic factors dominate. The resulting bone formation accommodates brain growth and returns the suture to its original width. Further ossification toward the center of the suture is suppressed by the high antiossification factors present in the center. Increasing experimental evidence supports this theoretical conjecture. For at least some of these antiossification transcription factors, such as Tbx-2 and Twist, this effect is achieved by binding to the promoter regions of the genes necessary to bone formation and decreasing their expression.27
In other words, cranial growth is a natural form of prolonged multifocal (about 30) distraction osteogenesis. The key feature that makes this natural distraction differ from clinical distraction is highly antiosteogenic factors that delay the complete ossification of the regenerates for many decades. Distraction osteogenesis was initially described by Codivilla in the early 1900s. Later, it was independently developed and systematically refined by Gavriel Ilizrov. Through the work of Joseph McCarthy, distraction osteogenesis has become one of the most commonly performed operations in the craniofacial skeleton to correct congenital, posttraumatic, and postoncological deformities.27 Both natural and clinical distraction osteogenesis harness the body’s inherent ability to grow when stretched. Clinical distraction has three phases: latency, activation, and consolidation. Immediately after osteotomy (periosteal and marrow-preserving corticotomy in the original Ilizarov protocol) and application of a mechanical lengthener (distractor), a latency of 24 to 48 hours is followed by activation, which typically includes lengthening of 1.0 mm/day, at 0.25 mm four times per day. This is an extremely large amount of strain, in the range of 1 million microstrains, compared with physiologic bone strain in the range of several thousand microstrains. Consolidation follows activation. In most centers, this time is reduced to 1 month, decreased from twice the time required for activation stipulated in the classic Ilizarov protocol applied to appendicular skeletons. Because the amount of lengthening is a constant of 1 mm/day, with an increasing gap length, the strain decreases as distraction progresses. Distraction is endogenous tissue engineering. Not only does it induce osteogenesis, but other tissue types, including nerve, muscle, skin, and blood vessels, also form in response to the increased strain. The bone formed is woven bone that is laid down at an amazing rate, as high as 250 /day. Later remodeling processes replace this woven bone with lamellar bone, orienting the Haversian systems to maximally reduce shear strain during function. The result is an optimized mesoarchitecture best suited to respond to those functional loads.28,29
Cranial Morphogenesis and Distraction Osteogenesis
Clinical Implications
Based on observations, the cranium has three essential properties: (1) It is of sufficient size to house and protect the brain and distant sense organs; (2) it does not impede the growth of the brain and the sense organs; and (3) an extremely well-conserved basic plan (the baüplan) dictates the number of ossification centers and their location. However, the final form of the cranium is not intrinsically invariant. The earliest form of the cranium, both phylogenetically and ontogenetically, was a fibrous capsule surrounding the anterior end of the central nervous system. This fibrous capsule is the thelia parameningealis in lower vertebrates and the desmocranium in embryonic mammals. With selected mineralization in key areas and restriction in others, the adult mammalian cranium enjoys the first two properties. This antagonistic coupling of osteogenesis and antiosteogenesis means that cranial growth is an “enslaved” process, driven by another extrinsic determinant, the growth of the brain. This coupling is the essential foundation underpinning the fulfillment of all three properties.
An important question that has remained incompletely answered since the advent of craniofacial surgery is whether the brain in single-suture craniosynostosis requires releasing.30,31 Based on the current understanding of how the cranium forms and on the behaviors and capabilities of the bone, suture, and cells involved, this question must be reexamined. Because the operations to correct single-suture closure can be associated with complications or even death, the potential benefit can be fully evaluated only if the natural course without surgical intervention is well known.32,33 A review of the first several large case series reported after the advent of fronto-orbital advancements for synostotic plagiocephaly produced an interesting observation: a conspicuous lack of adult patients. This finding is contrary to expectations after the introduction of a new treatment for an existing disease condition.34,35 In any given stable population, it is reasonable to assume that the development of a new surgical technique has no effect on the incidence of single-
Cranial sutures: optimization by adaptation suture craniosynostosis. Thus the incidence of single-suture craniosynostosis would have remained constant before and after the development of fronto-orbital advancement. Applying simple principles of epidemiology, one can derive the total number of new cases per year by multiplying the incidence and total birth rates. Based on this calculation and the mortality rate, the sum of cases in all age groups in a population for a given time can be calculated if a steady state exists. The result is known as prevalence. A large discrepancy appears to have existed in the 1970s and 1980s; the prevalence was either unknown or too low compared with the incidence. Two theoretical explanations can account for a large discrepancy between incidence and prevalence. One explanation is that the process is extremely lethal. Even though the incidence is high, the affected individuals soon die of the process, resulting in a low prevalence. Ebola infection is one such example. The second explanation is that the disease process is self-limiting; that is, the “burn-out” rate is high, and individuals with the disease eventually outgrow the problem. There are other complicating variables, such as thresholds for making the diagnosis and an individual’s desire to seek medical attention. Nonetheless, it is imperative that efforts be directed to address this question. Given that cranial sutures respond to cranial wall stress and that cranial wall stress is necessarily a function of ICP, the past trend of ICP can be inferred by quantitatively measuring sutural complexity. Detailed fractal dimension analysis of the suture may provide the answer, which is long overdue.
Summary This brief review of cranial sutures has attempted to provide a basic understanding of the biomechanics of cranial bones and sutures. Both descriptive data at various levels and theoretical work from different disciplines have been presented to provide an overall appreciation of the cranium as a complex adaptive system. On initial examination, some features may seem utterly inexplicable. When studied in detail and considering that these systems evolved over hundreds of millions of years and contain within them memories of their distant past, the system’s beauty, constraints, and complexity become more understandable.
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