Mechanobiology of Skeletal Regeneration

Carter, Dennis R.; Beaupré, Gary S.; Giori, Nicholas J.; Helms, Jill A.

doi:10.1097/00003086-199810001-00006

Cited by 654 publications

(546 citation statements)

References 30 publications

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“…A similar concept has been adopted by other authors to explain a number of mechanobiological processes (Carter et al, 1998;Loboa et al, 2001;Henderson and Carter 2002). Fluid flow and shear strain have also been hypothesized as the stimuli that direct MSC differentiation during skeletal regeneration (Prendergast et al, 1997).…”

Section: Repairmentioning

confidence: 84%

The role of mechanical signals in regulating chondrogenesis and osteogenesis of mesenchymal stem cells

Kelly

Jacobs

2010

Birth Defects Research Pt C

216

152

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It is becoming increasingly clear that Mesenchymal Stem Cell (MSC) differentiation is regulated by mechanical signals. Mechanical forces generated intrinsically within the cell in response to its extracellular environment, and extrinsic mechanical signals imposed upon the cell by the extracellular environment, play a central role in determining MSC fate. This paper reviews chondrogenesis and osteogenesis during skeletogenesis, and then considers the role of mechanics in regulating limb development and regenerative events such as fracture repair. However, observing skeletal changes under altered loading conditions can only partially explain the role of mechanics in controlling MSC differentiation. Increasingly, understanding how epigenetic factors such as the mechanical environment regulate stem cell fate is undertaken using tightly controlled in vitro models. Factors such as bio-engineered surfaces, substrates and bioreactor systems are used to control the mechanical forces imposed upon, and generated within, MSCs. From these studies, a clearer picture of how osteogenesis and chondrogenesis of MSCs is regulated by mechanical signals is beginning to emerge. Understanding the response of MSCs to such regulatory factors is a key step towards understanding their role in disease and regeneration.3

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Section: Repairmentioning

confidence: 84%

The role of mechanical signals in regulating chondrogenesis and osteogenesis of mesenchymal stem cells

Kelly

Jacobs

2010

Birth Defects Research Pt C

216

152

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“…Although the precise mechanical and biological events which lead to this condition are not known, theoretical modeling of tissue development within a fracture site predict that such an outcome is possible [2,4,6,9,18,27]. Experimental models of pseudoarthroses have even been established using manually applied mechanical stimulation [ 11, but precisely controlled mechanical treatments and their effects on tissue differentiation have not been established.…”

Section: Discussionmentioning

confidence: 99%

“…Studies of tlie influence of the mechanical environment on fracture healing suggest that less rigid fixation leads to preferred endochondral osteogenesis while more rigid fixation leads to preferred intramembranous ossification [2][3][4]9,11,18,27]. Our stimulation protocol provided motion, but in precisely controlled directions, followed by 23 h of rigid fixation.…”

Section: Discussionmentioning

confidence: 99%

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Induction of a neoarthrosis by precisely controlled motion in an experimental mid‐femoral defect

Cullinane

Fredrick

Eisenberg

et al. 2002

Journal Orthopaedic Research

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Bone regeneration during fracture healing has been demonstrated repeatedly, yet the regeneratioil of articular cartilage and joints has not yet been achieved. It has been recognized however that the mechanical environment during fracture healing can be correlated to the contributions of either the endochondral or intramembranous processes of bone formation, and to resultant tissue architecture. Using this information, the goal of this study was to test tlie hypothesis that induced motion can directly regulate osteogenic and chondrogenic tissue forination in a rat mid-femoral bone defect and thereby influence the anatomical result. Sixteen male Sprague Dawley rats (400 + 20 g) underwent productioii of a mid-diaphyseal, lion-critical sized 3.0 inn1 segmental femoi-a1 defect with rigid external fixation using a custom designed four pin fixator. One group of eight animals represented tlie controls and underwent surgery and constant rigid fixation. In tlie treatment group the custom external fixator was used to introduce daily interfragmentary bending strain in the eight treatment animals ( 12" angular excursion), with a hypothetical symmetrical bending load centered within tlie gap. The eight animals in tlie treatment group received motion at 1.0 Hz, for 10 inin a day, with a 3 days on, one day off loading protocol for tlie first two weeks, and 2 days on, one day off for the remaining three weeks. Data collection included histological and iniiiiiiiioliistological identification of tissue types, and mean collagen fiber angles and angular conformity between individual fibers in superficial, intermediate, and deep zones within the cartilage. These parameters were compared between tlie treatment group, rat knee articular cartilage, and tlie control group as a structural outcome assessment. After 35 days tlie control aniiiials demonstrated varying degrees of osseous union of the defect with soiiie animals showing partial union. In every individual within the niechanical treatment group the defect coinpletely failed to unite. Bony arcades developed in the experimental group, capping tlie termini of the bone seginents on both sides of the defect in four out of six animals completing tlie study. These new structures were typically covered with cartilage, as identified by specific histological staining for Type I1 collagen and proteoglycans. The distribution of collagen within analogous superficial, intermediate, and deep zones of tlie newly formed cartilage tissue demonstrated preferred fiber angles consistent with those seen in articular cartilage. Although not resulting in complete joint development, these iwuurthroses show that the induced motion selectively controlled the formation of cartilage and bone during fracture repair, and that it can be specifically directed. They further demonstrate that the spatial organization of molecular components within the newly formed tissue. at both microanatomical and gross levels, are influenced by their local mechanical environment, confirming previous theoretical models. 0...

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“…While these observations are relevant to cartilage repair, their relevance to fracture healing may not be so obvious. Periosteum is involved in fracture healing, and goes through the same initial chondrogenic response as in cartilage repair before endochondral ossification takes place [4]. Thus, mechanical factors regulating periosteal callus formation are likely similar to those regulating cartilage repair, at least by periosteum.…”

Section: Discussionmentioning

confidence: 99%

The enhancement of periosteal chondrogenesis in organ culture by dynamic fluid pressure

Mukherjee

Saris

Schultz

et al. 2001

Journal Orthopaedic Research

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Cartilage repair by autologous periosteal arthroplasty is enhanced by continuous passive motion (CPM) of the joint after transplantation of the periosteal graft. However, the mechanisms by which CPM stimulate chondrogenesis are unknown. Based on the observation that an oscillating intra-synovial pressure fluctuation has been reported to occur during CPM (0.&10 kPa), it was hypothesized that the oscillating pressure experienced by the periosteal graft as a result of CPM has a beneficial effect on the chondrogenic response of the graft. We have developed an in vitro model with which dynamic fluid pressures (DFP) that mimic those during CPM can be applied to periosteal explants while they are cultured in agarose gel suspension. In this study periosteal explants were treated with or without DFP during suspension culture in agarose, which is conducive to chondrogenesis. Different DFP application times (30 min, 4 h, 24 Wday) and pressure magnitudes (13, 103 kPa or stepwise 13 to 54 to 103 kPa) were compared for their effects on periosteal chondrogenesis. Low levels of DFP (13 kPa at 0.3 Hz) significantly enhanced chondrogenesis over controls (34 f 7% vs 14 f 5%; P < 0.05), while higher pressures (103 kPa at 0.3 Hz) completely inhibited chondrogenesis, as determined from the percentage of tissue that was determined to be cartilage by histomorphometry. Application of low levels of DFP to periosteal explants also resulted in significantly increased concentrations of Collagen Type I1 protein (43 f 8% vs 10 f 5%; P < 0.05). New proteoglycan synthesis, as measured by 35S-sulphate uptake was increased by 30% in periosteal explants stimulated with DFP (350 f 50 DPM vs 250 f 75 DPM of 35S-sulphate uptakdpg total protein), when compared to controls though this difference was not statistically significant. The DFP effect at low levels was dose-dependant for time of application as well, with 4 hlday stimulation causing significantly higher chondrogenesis than just 30 midday (34 f 7 vs 12 f 4% cartilage; P < 0.05) and not significantly less than that obtained with 24 hlday of DFP (48 f 9% cartilage, P > 0.05). These observations may partially explain the beneficial effect on cartilage repair by CPM. They also validate an in vitro model permitting studies aimed at elucidating the mechanisms of action of mechanical factors regulating chondrogenesis. The fact that these tissues were successfully cultured in a mechanical environment for six weeks makes it possible to study the actions of mechanical factors on the entire chondrogenic pathway, from induction to maturation. Finally, these data support the theoretical predictions regarding the role of hydrostatic compression in fracture healing.

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Mechanobiology of Skeletal Regeneration

Cited by 654 publications

References 30 publications

The role of mechanical signals in regulating chondrogenesis and osteogenesis of mesenchymal stem cells

The role of mechanical signals in regulating chondrogenesis and osteogenesis of mesenchymal stem cells

Induction of a neoarthrosis by precisely controlled motion in an experimental mid‐femoral defect

The enhancement of periosteal chondrogenesis in organ culture by dynamic fluid pressure

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