Table of Contents Author Guidelines Submit a Manuscript
BioMed Research International
Volume 2015, Article ID 842975, 20 pages
http://dx.doi.org/10.1155/2015/842975
Review Article

Comprehensive Review of Adipose Stem Cells and Their Implication in Distraction Osteogenesis and Bone Regeneration

1Division of Paediatric Orthopaedic Surgery, Shriners Hospital for Children, Montreal Children Hospital, McGill University, 1529 Cedar Avenue, Montreal, QC, Canada H3G 1A6
2Department of Experimental Surgery, McGill University, 1650 Cedar Avenue, Montreal, QC, Canada H3G 1A4
3Orthopaedics Department, Shriners Hospital for Children, 1529 Cedar Avenue, Montreal, QC, Canada H3G 1A6
4McGill University Health Centre, Shriners Hospital for Children, Montreal Children Hospital, 1529 Cedar Avenue, Montreal, QC, Canada H3G 1A6

Received 13 March 2015; Accepted 2 August 2015

Academic Editor: Aijun Wang

Copyright © 2015 Mina W. Morcos et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Bone is one of the most dynamic tissues in the human body that can heal following injury without leaving a scar. However, in instances of extensive bone loss, this intrinsic capacity of bone to heal may not be sufficient and external intervention becomes necessary. Several techniques are available to address this problem, including autogenous bone grafts and allografts. However, all these techniques have their own limitations. An alternative method is the technique of distraction osteogenesis, where gradual and controlled distraction of two bony segments after osteotomy leads to induction of new bone formation. Although distraction osteogenesis usually gives satisfactory results, its major limitation is the prolonged duration of time required before the external fixator is removed, which may lead to numerous complications. Numerous methods to accelerate bone formation in the context of distraction osteogenesis have been reported. A viable alternative to autogenous bone grafts for a source of osteogenic cells is mesenchymal stem cells from bone marrow. However, there are certain problems with bone marrow aspirate. Hence, scientists have investigated other sources for mesenchymal stem cells, specifically adipose tissue, which has been shown to be an excellent source of mesenchymal stem cells. In this paper, the potential use of adipose stem cells to stimulate bone formation is discussed.

1. Introduction

Orthopaedic surgeons are always confronted with cases of extensive bone loss—known as critical size defects (CSDs)—where outside intervention is necessary for healing to occur. These large defects may be secondary to trauma, postresection of tumors, or postdebridement of infections. The goal in such cases is to align the bone segments together, facilitate union, obtain equal limb length, and restore the function of the traumatized site [14]. Various surgical techniques have been used to address these CSDs, including the gold standard autogenous bone grafts, allografts, various bone grafts substitutes, and vascularized and nonvascularized bone grafts [1, 3, 59]. However, all these techniques do have multiple limitations [7, 8]. In 1905, an Italian orthopaedic surgeon called Codivilla performed the first lengthening procedure, where he applied skeletal traction through a calcaneal pin followed with an osteotomy of the femur. This proved that limb lengthening could be achieved without jeopardizing the regeneration of muscles and soft tissues [10]. However, the idea of using traction to promote bone regeneration to treat bone defect only gained popularity when a Russian surgeon, Gavriil Ilizarov, developed a revolutionary surgical technique for distraction osteogenesis (DO). He implemented the law of tension stress and pioneered the biological principles of bone and soft tissue regeneration under slow and gradual distraction [1113].

2. Distraction Osteogenesis

DO is a controlled surgical technique in which the intrinsic capacity of bone to heal and regenerate spontaneously is being used to lengthen short bones (Figure 1(a)) or to replace large segments of bone. DO consists of applying an external fixator to the affected bone in order to immobilize the proximal and distal ends of the bone providing stability (Figure 1(b)), followed by low energy osteotomy to divide the bone into two segments (Figure 1(c)). Latency phase that varies between 5 and 10 days, according to the age, is required following the osteotomy to allow the formation and organization of a hematoma and the recruitment of inflammatory cells and mesenchymal stem cells (MSCs) [1416]. Following this phase, distraction is started and the two bone segments are gradually distracted at a rate of 1.0 mm/day and a rhythm of 0.25 mm every 6 hours until the required lengthening is attained (Figure 1(d)). Distracting more than 2 mm/day may lead to poor or delayed regenerated bone formation while distracting at a lower rate such as 0.5 mm/day leads to premature consolidation [12, 16]. The final phase is referred to as the consolidation phase in which the distraction is ceased and the newly formed bone is allowed to mature and consolidate before the removal of the device (Figure 1(e)). This is the longest phase in DO, requiring about one month for each centimeter lengthened [16]. Finally, the external fixator is removed once the newly formed bone is well consolidated and deemed strong enough to withstand external forces [11, 17, 18]. Figure 2 represents the different phases of DO.

Figure 1: Schematic representation of distraction osteogenesis technique. (a) The tibial bone that needs lengthening. (b) Application of circular external fixator. (c) Tibial and fibular osteotomy. (d) Distraction phase and new bone formation. (e) Consolidation phase.
Figure 2: Lengthening of short tibia showing various phases of the distraction process. (a) Application of the fixator and osteotomy of the tibia. (b) Start of distraction. (c) End of distraction. (d and e) Consolidation phase, without any distraction until bone in the distracted gap consolidates. (f) Removal of the fixator (bar scale = 5 cm).

3. Types of Bone Formation Involved in Distraction Osteogenesis

The exact mechanism and type of bone formation in DO are still being debated; however many factors have been identified to play a major role in determining which type of bone formation will predominate including stability of the fixator, rate and rhythm of distractions, and the vascularity of the surrounding tissues [14].

Three types of ossification have been described to take place during new bone formation in DO. Endochondral bone formation usually occurs at early stages of DO and it occurs external to the periosteum immediately adjacent to the fracture site where there is mechanical instability, whereas intramembranous ossification occurs at a later stage [5, 1922]. In our lab, we were able to demonstrate the presence of both types of ossification in several animal models of DO [23, 24]. Last type is called transchondroid bone formation where chondroid bone is formed directly by chondrocyte-like cells that change gradually from fibrous tissue to bone [5, 22].

4. The Molecular and Cellular Events in DO

During the latency phase there is an inflammatory response that leads to the recruitment of MSCs and the secretion of proinflammatory cytokines (interleukin-1, interleukin-6), different growth factors such as transforming growth factor-beta (TGF-β), bone morphogenetic proteins (BMPs), and angiogenic factors [5, 21, 25]. These factors are responsible for recruiting MSCs and promoting them to differentiation and proliferation into chondrocytes and osteocytes. Differentiation of these cells is associated with increase expression of type 1 collagen and alkaline phosphatase [5, 8, 26]. During the distraction phase there is gradual differentiation into fibrous and fibrocartilaginous tissue that will be organized in a parallel pattern to the distraction forces [23]. This new bone starts forming from the osteotomy cuts towards the center forming a fibrous radiolucent interzone between the edges of the bone segments (Figure 3) [20, 23, 27, 28]. The fibroblast cells and collagen fibers are arranged longitudinally along the axis of distraction. In addition, during this phase all the surrounding soft tissues are lengthened at the same time with the formation of the new bone and the formation of new blood vessels with intense angiogenesis, neoangiogenesis, and recruitment of osteoblasts [21, 29]. DO was shown to be a vascular dependent process where multiple neoangiogenesis and angiogenesis factors are found within the distracted zone, including vascular endothelial growth factor (VEGF) and angiopoietin factors [21, 3032]. These vascular processes occur mainly during the latency and distraction phase and then decrease gradually over time. Furthermore, as distraction progresses there is a progressive increase into the deposition of osteoblast along the periosteum and in the distracted gap that is regulated with the mechanical strain applied to the callus. New bone formation during DO is a perfect example of mechanotransduction, where the mechanical forces are converted into molecular and biochemical signals that will activate and regulate multiple cellular events such as neovascular proliferation [21], differentiation, proliferation, and secretory function of various cells including various cytokines, BMPs, extracellular matrix protein, growth factors, and even MSCs [30, 3336]. This will help maintain the delicate balance between bone formation and bone resorption [14, 37]. We and others have shown that the expression of various cytokines and growth factors is upregulated when exposed to the distraction forces while the same factors are downregulated when distraction is ceased. The expression of these various factors, including BMPs, Wnt signaling, insulin growth factor (IGF), fibroblast growth factor (FGF), TGF-β, platelet-derived growth factor (PDGF), and VEGF, is directly related to osteogenesis and chondrogenesis [35, 3850].

Figure 3: Histological changes using trichrome staining, in a rabbit DO model during distraction osteogenesis of the tibia. (a) to (c) represent the cellular change that happen during the distraction phase while (d) to (f) represent the cellular change that happen during the consolidation phase. Co: cortex; LZ: lengthened zone; Ca: callus; FIZ: fibrous interzone (bar scale = 2 mm).

5. Advantages and Clinical Significant of DO

Ilizarov method of DO has gained much popularity throughout the years because of its ability to produce new bone between two vascularized surfaces created by osteotomy and followed by gradual distraction [51]. It is considered to be a unique tissue engineering technique since it can spontaneously regenerate vascularized bone of the same micro- and macrostructure of the native bone in vivo without the need for bone grafts. Moreover, there are simultaneous regeneration and lengthening of the surrounding soft tissues [10]. Donor site morbidity as seen in autologous grafting is absent. DO is considered the best in vivo bone tissue engineering technique [18, 5153].

6. Disadvantages and Complications of DO

The main disadvantage of DO is the long time the external fixator has to stay in place [54]. For every centimeter lengthened, the fixator has to be kept in place for about a month. For example, a child undergoing a 5.0 cm lengthening will require the fixator to be kept in place for about 5 months. This prolonged period of time can lead to multiple complications such as pin-tract infections, broken wires, and joint impairment. Moreover, applying the fixator for a long time can be cumbersome for patients and their families psychologically, socially, and financially [5456]. Since distraction phase cannot be accelerated as this will lead to poor bone regeneration, then the question arises; how can we accelerate the consolidation phase in order to be able to remove the external fixator at an earlier time?

7. Modalities Used in an Attempt to Accelerate DO

Multiple modalities to accelerate bone formation in the context of DO have been described including the application of external biophysical stimuli (i.e., mechanical loading [57, 58], vibration [59], electrical stimulation [60, 61], extracorporeal shock wave [62, 63], and low-energy pulsed ultrasound [6466]), administration of systemic agents (i.e., sclerostin [67], calcitonin [68], bisphosphonates [69, 70], and prostaglandin E2 [71]), and local agents (i.e., growth factors [72, 73], BMPs [42, 44, 50, 74], scaffolds [39, 75], nanoparticles [76, 77], and osteogenic cells including autologous bone graft and MSCs [78, 79]). In the following sections osteogenic cells, scaffolds, and growth factors will be briefly discussed and then a comprehensive review of MSCs with an emphasis on adipose tissue derived mesenchymal stem cells (ASCs) and their application in bone regeneration and DO will be done.

8. Osteogenic Cells

The first important element for bone regeneration is to have a source that will provide viable cells that can differentiate and proliferate into osteogenic cells. For the longest time autologous bone graft has been used and considered as the gold standard material for bone regeneration in orthopedic surgery [8, 80]. Autologous bone is usually harvested from the anterior and posterior iliac crests of the pelvis. It can also be harvested as vascularized bone graft containing an internal vascular network in order to restore a significant bone defect [9, 81, 82] or tricortical graft for structural support [83]. Autologous bone graft possesses many advantages including significant decrease in union time, high union rates, and the ability to restore critical size defects. Moreover, since it uses patient’s own tissue, there is a reduction in the risk of immunoreactions and transmission of infections. Finally it possesses osteogenic, osteoconductive, and osteoinductive capacities through the bone growing cells, different proteins, and growth factors that it contains while providing a scaffold for the new bone to grow within, respectively [83]. Although autologous bone graft is a safe and effective way to provide bone cells still it has multiple limitations including donor site morbidity, limited cells quantity, requirement of a second surgical procedure with frequent consequences of pain, and complications [8486].

An alternative method to harvest autologous bone graft is reamer irrigation aspiration (RIA) system [87]. RIA is an intramedullary reaming system that provides continuous irrigation and aspiration during intramedullary reaming. It was originally designed to decrease the adverse effects of reaming long bone fractures by collecting the reaming material which contains a significant number of osteogenic cells [88]. This provides a large volume of corticocancellous bone material that can be used as autologous bone graft. This is usually harvested from the femur [89]. This technique provides a large volume of autologous bone graft that corresponds to the bone graft obtained from both the anterior and posterior iliac crest [90]; however it still has similar limitations regarding the need for a second operation and the limited quantity of cells that can be provided.

Another methods would be allograft bone that is available in different preparation. However, allograft bone lacks osteogenic capacity as it does not contain living bone cells; therefore it is not considered to be a good source for osteogenic cells. Moreover it carries the risk of disease transmission and immunogenic responses [91]. Therefore it does not fit well with the previously mentioned concepts.

Since both autograft and allograft have restrictions, scientists have investigated the used of MSCs as mentioned above. MSCs are able to differentiate and proliferate into osteogenic cells under the appropriate molecular signals. MSCs have been found in multiple tissues including bone marrow and adipose tissues [9295]. MSCs will be discussed in more detail in the following sections.

9. Scaffolds

Scaffolds are three-dimensional porous structures that need to be biocompatible and biodegradable, producing low immunogenic and antigenic reactions, and have mechanical properties similar to load-bearing bone. They provide support to the attached cells and provide space for it to proliferate (Figure 5) [96]. Scaffolds can be divided into different classes according to the materials used. These include natural polymer (e.g., collagen, fibrin, alginate, and chitosan), synthetic polymers (e.g., polylactic acid (PLA) and polyglycolic acid (PLGA)), and inorganic materials (e.g., calcium phosphates, silicate glasses, hydroxyapatite (HA), ceramics, and calcium sulfate) [3, 75, 97, 98]. These materials have limitations when used on their own including brittleness (e.g., inorganic materials), inflammatory response (e.g., synthetic polymers), and immunogenicity (e.g., natural polymers), which led scientists to investigate nanocomposite scaffolds for their advantages [99]. These advantages include the ability to penetrate deep in tissues without causing damage to the surrounding cells, unique size-scale, large surface to volume ratio, the ability to provide an appropriate vehicle to direct stem cells into specific lineages, the ability to mimic the composition of the natural bone, low immunogenicity, and the ability to enhance the mechanical properties of inorganic materials [100102]. They can be used as two-dimensional (2D) scaffolds where it covers the implants promoting bone regeneration by allowing cell attachment and tissues to grow on the implant surfaces only or three-dimensional (3D) scaffolds that allow cells to grow on the surface and within it too [103, 104]. 3D scaffolds were found to improve proliferation, differentiation, and activity of cells that grow within them [105]. Environment that mimics the conditions found in the bone microenvironments will help the differentiation of MSCs into osteogenic lineage. This will provide the necessary signals to help MSCs to differentiate and proliferate into the osteogenic lineage in order to repair and regenerate bone. Using the nanocomposite scaffolds technology can provide this environment by providing a controlled environment to the implanted cells, help regulate delivery of nutrients and removal of waste, and enhance the direct differentiation of ASCs into the osteogenic lineage. Bone is composite of a very complex extracellular matrix that helps in maintaining the structural integrity of bone and influencing the differentiation and proliferation of stem cells into the osteogenic lineage [106, 107]. Extracellular matrix consists of organic component, composed mainly of mineralized calcium in the form of HA and a mixture of other inorganic salts [106, 108, 109], and inorganic component, primary composed of 95% type I collagen and other noncollagenous proteins [110, 111]. Therefore, it is very important to be able to provide the appropriate nanoparticle composite to induce and enhance the differentiation of ASCs into osteogenic lineage. Few studies have been done looking at different materials and their effect on ASCs. Lu studied the effect of 3D-nanocomposite scaffold composed of biphasic calcium phosphates (BCP) coated with a nanocomposite layer of polycaprolactone (PCL) and HA-nanoparticles and their effect on osteogenic differentiation of ASCs. Lu et al. were able to show that ASCs on BCP/PCL-nHA had earlier osteogenic differentiation compared with control [112]. Ghorbani and his colleague looked at a slightly different nanoparticle composite where they used PCL/Chitosan (Ch)/zinc-doped HA (nZnHA) nanocomposite with ASCs. They were able to demonstrate an increase in ASCs attachment to the nanocomposite and more important significant increase in the proliferation rate of ASCs compared with control [113]. In another study by McCullen et al., they fabricated scaffolds consisting of B-tricalcium phosphate (TCP) crystals and PLA at varying loading levels of TCP (0, 5, 10, and 20 wt%) and assessed the composite scaffolds ability to induce proliferation and osteogenic differentiation of ASCs in vitro. In this study they were able to show that ASCs were able to adhere, proliferate, and osteogenically differentiate on all scaffolds; however there was a significant increase in the amount of cell-mediated mineralization in the highest TCP compared to the lowest TCP which suggest that the biochemical nature of the scaffold can accelerate and induce the overall osteogenic differentiation of ASCs [114]. In another study in vivo, they implanted PLGA/HA nanocomposite compared to PLGA scaffold only in a critical size defects in rat skulls where they found significant new bone formation with PLGA/HA in contrast with PLGA scaffold alone that had nearly no new bone formation. They concluded that the direct contact of cells with HA nanoparticles may stimulate osteogenesis [115]. There have been also some reports about other materials used and their effects on stem cells nonetheless there have not been any consensus on which nanoparticle/polymer composite is superior [97]. However the investigations that have been done till now with nanocomposite scaffolds demonstrate that such technology should be considered for bone tissue engineering application, as it will help and accelerate the differentiation and proliferation of ASCs into the osteogenic lineage leading to bone regeneration.

10. Growth Factors

Growth factors are usually used to enhance cell proliferation and differentiation of MSCs cells into osteogenic lineage. Multiple osteogenic growth factors were able to produce highly purified bioactive cytokines in large quantities, suitable for both cell culture and for in vivo applications. BMPs are considered to be the most promising osteogenic growth factors in stimulating bone formation and the most studied ones. They have been shown to be significantly involved with bone regeneration in fracture healing and DO as they trigger a cascade of events that lead to osteogenesis, chondrogenesis, angiogenesis, and upregulation of numerous growth factors [14]. They belong to the TGF-β superfamily that acts on many different systems including bone. BMPs are considered to be one of the most powerful osteogenic growth factor and the only osteoinductive ones that can act on undifferentiated MSCs early on (Figure 4) [116118].

Figure 4: Schematic representation of BMP’s effect on the differentiation of adipose stem cells into osteoblast.
Figure 5: Schematic representation of stem cell isolation sites. This schematic shows that adult stem cells can be found in both bone marrow and adipose tissue. Both BM-MSC and ASC are capable of differentiating into the same three lineages’ osteoblast, chondrocyte, and adipocyte.

11. Stem Cells

Stem cells are undifferentiated progenitor cells that are capable of both self-renewal and multilineage differentiation [119]. They are classified into two categories, depending on their origin, the embryonic stem cells (ESCs) and the adult stem cells. The ESCs are derived from the inner cell mass of blastocyst-stage embryos [120], while the adult stem cells are derived from differentiated postnatal tissues and these are believed to be intimately involved in tissue/organ regeneration and repair during injury and ageing [121]. Only ESCs are considered to be pluripotent, since they are capable of giving rise to differentiated cell lineages of all three embryonic germ layers: endoderm, mesoderm, and ectoderm [122]. However their use is very limited by ethical, legal, and political concerns. On the other hand, adult stem cells are considered to be multipotent since they have lower degree of plasticity. Previously, it was believed that adult stem cells were only capable of differentiating into lineages that are characteristic of the tissue or organ from which they originated. However, recent evidence suggests that adult stem cells could possess a much higher degree of plasticity than previously thought [123, 124].

12. Mesenchymal Stem Cells

MSCs were initially discovered in bone marrow, after which they were isolated and characterized from several adult and fetal tissues, including adipose tissue, dermis, periosteum, umbilical cord blood, placenta and amniotic fluid, and synovial fluid [93, 125129]. A set of minimal criteria were put in place by the international society for cellular therapy (ISCT) in order to be able to label a cell as MSC: cells must be plastic adherent when they are maintained in standard culture conditions, and they must express CD105, CD73, and CD90, lack the expression of CD45, CD34, CD14, CD11b, CD79α, or CD19 and HLA-DR surface molecules, and be capable of differentiating into osteoblasts, adipocytes, and chondroblasts in vitro [130]. MSCs have significant therapeutic potentials that can be applied to multiple disciplines especially where MSCs show low immunogenicity [131133] and can differentiate into osteoblasts, chondroblasts, and adipocytes [134136].

13. Bone Marrow Derived Mesenchymal Stem Cells (BM-MSCs)

MSCs were originally isolated from bone marrow by Friedenstein et al. [137], which have been considered the main source for MSCs for long time [138]. Bone marrow aspirates are collected from the iliac crest and MSCs are isolated and then cultivated. However, this is a painful and invasive procedure that often results in low yield of MSCs, especially that MSCs are present in relatively small quantities in the bone marrow and constitute about 0.001%–0.01% of the total marrow nucleated cells. Moreover, their ability to proliferate and differentiate declines after extensive passage or with age [93, 125, 138]. These disadvantages urged scientists to search for other sources of MSCs including adipose tissue.

14. Adipose Derived Mesenchymal Stem Cells

ASCs where first isolated from human adipose tissue in 1976 [139], but they were not identified and characterized until 2001 [94]. Zuk et al. studied extensively the isolated ASCs from human lipoaspirates, and they showed that one gram of adipose tissue yields approximately 5 × 103 stem cells, which is 500-fold greater than the number of MSCs in one gram of bone marrow indicating that adipose tissues are rich with MSCs and can be used as a promising alternative source for BM-MSC [140143]. Over the last few years, several reports have shown that ASCs possess several advantages when compared to BM-MSCs. First, ASCs are readily available in large quantities, almost unlimited [141, 144], and can be retrieved in high volumes of cellular population with less invasive methods such as liposuction aspirates or subcutaneous adipose tissue fragments [94]. Moreover, ASCs can easily be expanded in vitro, have an extensive self-renewal capacity [95], and are easily isolated in a laboratory setting by differential sedimentation [94, 145, 146]. ASCs like BM-MSCs can differentiate into various cells, including adipocytes, osteoblasts, and chondrocytes (Figure 5) [134, 147].

15. Isolation of Mesenchymal Stem Cells from Adipose Tissue

Adipose tissue is comprised of adipocytes and a heterogeneous set of cell populations including endothelial cells, endothelial progenitor cells, pericytes, and erythrocytes that surround and support them, which upon isolation are termed the stromal vascular fraction (SVF) [142, 148, 149]. In order to isolate ASCs, adipose cells are harvested and then minced and digested by collagenase type II [145]. Then the SVF is separated by centrifugation as it has a higher density than the adipocytes [141, 145]. Later on, ASCs are isolated from the SVF by plastic adherence in culture, which can easily be cultured and expanded in vitro [145, 149, 150]. Moreover, isolated ASCs can be cryopreserved in a media of serum and dimethyl sulfoxide without losing their ability to differentiate and proliferate [151].

16. Adipose Stem Cells Immunophenotype

In order to be able to characterize ASCs and confirm that they abide with the ISCT guidelines, flow cytometry is used to determine the presence of specific cell surface markers. Since ASCs are not of homogenous population, there have been multiple attempts to find a unique single marker however that is still yet to be identified [95, 135, 152]. ASCs do express the typical MSCs markers such as CD13, CD29, CD44, CD63, CD73, CD90, and CD105, and ASCs show negative expression of for hematopoietic antigens such as CD14, CD31, CD45, CD 34, CD144, and HLA-DR [141, 142, 149, 153]. Some other markers are present at the beginning but do disappear or are lost during the different passaging while other will increase, as passaging will select more homogenous population with more homogenous cell surface markers [153155]. Moreover, ASCs population included four groups with their own cell surface markers. The main two groups are preadipocytes cells, which represent 67.7% of the population and express CD31/CD34+ surface markers, and premature endothelial cells which represent 5.2% and express CD31+/CD34+. The other two groups represent less than 1% and they are pericytes cells, CD146+/CD31/CD34, and the mature endothelial cells, CD31+/CD34 [152, 156, 157]. ASCs have the ability to secrete growth factors such as FGF, VEGF, IGF, and TGF-β1 that stimulate and help tissue regeneration [158, 159]. Also, they are sensitive to different growth factors such FGF, PDGF, and VEGF [160]. This rendered ASCs ideal candidate for tissue engineering and bone regeneration.

17. Techniques for Direct ASCs Differentiation

17.1. Culture Milieu for ASCs Differentiation In Vitro

An important characteristic of ASCs is their ability to differentiation into multiple lineages, in particularly chondrocytes, osteocytes, and adipocytes, when the correct conditions are provided [123, 135, 146, 149]. The induction of ASCs differentiation in vitro is achieved by culturing ASCs in specific media [145]. Table 1 shows the different medias used for the induction of adipocytes, osteocytes, and chondrocytes.

Table 1: Required supplements to induce differentiation of ASC into different lineages.

17.2. The Use of Physical Stimuli to Differentiate MSCs into Osteoblasts

Another less well-explored practice to differentiate stem cells is the application of physical stimuli including mechanical forces, magnetic, and electrical fields (Figure 6). Mechanical load has been identified as an essential factor in the development and maintenance of bone architecture and integrity [166, 167]. Increasing mechanical load leads to increase in bone mass by stimulating bone formation and inhibiting bone resorption through the activation of osteoblast cells and decreasing the activity of osteoclasts cells [168]. The process by which cells convert physical stimuli into biochemical response is called mechanotransduction [37, 169]. Mechanotransduction of stem cells is a very complex process that involves multiple signaling pathways that are not fully understood yet [167]. There have been few studies done to study the effect of mechanical stimuli on MSCs in vitro [170174] and in animal models [175, 176], mainly on BM-MSCs [167]. Kapur et al. demonstrated the existence of multiple signaling pathways for stimulating osteoblast proliferation and differentiation from MSCs in response to mechanical stimuli. Mechanical stimuli can be applied either in the form of cyclic stretch [173, 177, 178] or in the form of fluid shear flow [179182]. Duncan and Turner were able to show that shear stress causes primary and clonal osteoblast-like cells to proliferate and differentiate leading to increase in bone formation [183]. Also, Yoshikawa et al. were able to show that mechanical stimulation promotes the differentiation of osteogenic cells and enhances bone formation in vitro [172]. Moreover Altman et al. were able to show the differentiation of MSCs into osteogenic lineage under mechanical stimulus alone and without any exogenous growth factors [170]. Another source of physical stimuli is the application of electrical field that was shown to stimulate osteogenic differentiation from stem cells [184, 185]. The effect of pulsating electrical fields on osteogenesis has been studied in both animal models and in vitro studies and showed that it enhances stem cell signaling pathways and differentiation by modulating intracellular calcium signaling and augmenting tissue-specific markers [186, 187]. Recently, Hammerick was able to demonstrate an enhancement in early osteogenic markers in mouse ASCs using electrical field via ionic salt bridges; however there was no change in terminal differentiation [188]. Also, McCullen et al. studied the effect of sinusoidal alternating current electric fields on ASCs and demonstrated significant increase in intracellular calcium [189]. Other modalities are currently being investigated including magnetic fields [190, 191], ultrasound [192, 193], and laser irradiation [194, 195]. All these mechanical stimuli provide practical and promising methods to accelerate and facilitate the differentiation and proliferation of MSCs into osteogenic lineage cells that would be extremely significant in bone regeneration and tissue engineering.

Figure 6: Schematic representation of different stimulating factors that can affect the differentiation of adipose stem cells into osteoblast.

18. BM-MSCs versus ASCs

Few studies were conducted to compare the characteristic differences between BM-MSCs and ASCs. Rebelatto et al. [134] have shown that both BM-MSCs and ASCs are morphologically and immunophenotypically similar expressing CD44, CD105, CD90, and CD73 and not expressing CD34, CD45, and HLA-DR. Moreover, both can differentiate into tissues of mesodermal and nonmesodermal origins. Strioga et al. compared the ontology and biology and preclinical and clinical application of ASCs and BM-MSCs [92]. They showed that both BM-MSCs and ASCs share many biological characteristics. However, some differences in their immunophenotype, differentiation potential, transcriptome, proteome, and immunomodulatory activity do exist and these differences may represent specific features of BM-MSCs and ASCs and inherent heterogeneity, simply due to the different isolation and culture protocols [92]. Nevertheless, ASCs are as effective as BM-MSCs in clinical applications. In fact ASCs are gaining the upper hand in clinical translational setting and stem cell-based tissue engineering. Table 2 summarizes the major differences between BM-MSCs and ASCs.

Table 2: Difference between BM-MSC and ASC.

19. Clinical Applications of ASCs in Bone Regeneration and DO

Bone regeneration represents a complex physiological and biological process that involves multiple cells recruitment and various signaling molecules and pathways that repair and regenerate bone in response to injury. In order for this complex mechanism to maximize its efficiency there are some requirements that have been identified including osteogenic cells, osteoconductive systems, and osteoinductive growth factors. This triangle concept represents an emerging state-of-the-art science and bone tissue engineering. This evolutionary science aims to repair a failing bone organ [3, 196].

However Giannoudis et al. have took this concept and modified into the diamond concept, which acknowledges the importance of implanting osteogenic cells in osteoconductive scaffolds and adding the essential growth factor in order to promote bone regeneration [197]. However, they emphasized the importance of two other factors that need to be addressed prior to any implantation or intervention. These factors are the optimization of the nonunion bed of the host in terms of adequate vascularization and the presence of adequate mechanical stability that will provide an appropriate environment for the cells to interact with the scaffold and growth factors in order to promote successful osteogenesis [198, 199]. For the purpose of this paper we have briefly discussed osteogenic cells including ASCs, scaffolds, and growth factors. The implication of ASCs in bone regeneration and DO will be summarized in the following paragraph.

Table 3 represents a summary of all the recent studies performed on ASCs in cases of DO and bone CSDs with the exception of maxillary/mandibular studies.

Table 3: Overview of the studies performed on bone regeneration and distraction osteogenesis using ASC.

Liu et al. were the first to show that allogeneic ASCs combined with coral scaffolds are able to regenerate bone in critical-size defect model [204]. Cowan et al. introduced ASCs with PGLA scaffolds into CSD of mouse calvarial and had a significant increase in intramembranous bone formation by the end of two weeks and a complete bridging by 12 weeks without using any growth factors [205]. One study combined the benefits of using growth factors like BMP-2 with ASCs, where bone regeneration in calvarial CSD was enhanced [214]. Di Bella et al. reported that isolated autologous ASCs from rabbits implanted with osteoinduction fibronectin-coated porous cylindrical scaffolds improved bone regeneration in a critical-sized skull defect of rabbits [206]. On the clinical side, Lendeckel and colleagues described in a case report the use of autologous ASCs, bone graft, and fibrin glue all isolated from the patients tissue which were combined to treat cranial CSD in a young girl [207]. Three-month follow-up CT scan showed almost complete calvarial healing. All the previously mentioned studies concluded that ASCs can differentiate into osteoblasts with the capacity to regenerate bone and heal CSDs, this indicates that ASCs can be used as an alternative to bone graft in treating bone defects.

Studies describing the use of BM-MSCs or ASCs during DO are scarce in the literature. BM-MSCs were shown to accelerate new bone formation in DO models with shortened consolidation period [215]. Nomura et al. introduced ASCs mixed with collagen gels in rats after performing DO [208]. The research group observed an increase in bone formation in the ASC-Collagen injected rats compared to the control, and analysis of the formed callus showed both osteogenic differentiation and secretion of growth factors, which proves that ASCs promoted the formation of new bone. The therapeutic potentials of ASCs in tibial defects managed by DO were investigated in rabbits [209]. Radiologic analyses showed an increase in callus density, with increased ossification rate, in rabbits treated with osteoblast differentiated-ASCs compared to the control group treated with undifferentiated-ASC; they concluded that osteoblasts-differentiated ASCs shorten the consolidation period of DO [209]. In conclusion using ASCs instead of BM-MSCs ensure the availability of stem cells in abundance through a minimal invasive method without imposing any morbidity to the donor. Moreover, ASCs ability to regenerate bone in DO will accelerate the process and decrease the consolidation phase leading to an early removal of the fixator, which in return will decrease complications associated with DO such as infection, nonunion, psychological, and financial burden.

20. Perspectives and Challenges

Large bone defects continue to pose a formidable challenge to healing physicians. DO has been a very successful technique that is being used worldwide to treat multiple orthopedic and craniofacial complex conditions. However, as mentioned before, one major limitation is the long time the fixator needs to be kept in place until consolidation is done. Multiple methods and modalities have been used to accelerate the consolidation phase including the application of ASCs. As discussed above, ASCs fulfill most of the requirements needed for tissue engineering as they are available in an abundant quantities, can supply large number of cells, are easily accessible, have low immunogenicity, and are able to differentiate into multiple lineages and easy to isolate and expand in vitro [144]. ASCs have the potential to be used in the treatment of acute and chronic musculoskeletal disorders and other conditions. The Food and Drug Administration needs to approve the use of ASCs in bone regeneration and DO before it can be considered as a standard treatment. This will require significant preclinical research and development, some of which is outlined below.

ASCs are usually expanded and induced into osteogenic lineage using fetal bovine serum (FBS) medium. FBS medium is an animal derived product that can, theoretically, cause transmission of prions and bacterial or viral infections, even though it is very small [216] and increases the risk of immune reactions in the host to the xenogeneic materials used [217]. In order to overcome this problem, FBS free defined medium needs to be developed, optimized, and standardized. Few studies have already compared the use of human autologous serum to FBS on both ASCs and BM-MSCs and showed that human autologous serum produces comparable morphology, immunophenotype, and proliferation and differentiation capacity to FBS [148, 217220]. Another alternative is allogeneic human serum that also showed promising results [221]. Therefore establishing and optimizing a safe and rapid expansion protocol for ASCs based on xeno-free culture are essential for cell-based therapies such as tissue engineering and regenerative medicine.

Also well-defined protocols for osteogenic differentiation from ASCs are needed for cell-based therapy. As discussed before there are multiple studies that have been done on this topic; however there has not been any consensus yet. Osteogenic differentiation may be enhanced if various techniques were combined together instead of being used alone. Therefore, combining the usually used culture media and supplementing it with growth factors such as BMPs and then allowing it to undergo some kind of physical stimuli might provide the optimal conditions required for osteogenic differentiation. This has not been studied enough yet but hopefully will be in the near future.

Another important area that needs to be clarified before taking any clinical testing is the potential tumorigenic feature of ASCs. There is a significant controversy in the current literature about the effect of ASCs on tumor growth as some studies showed that ASCs may favor the growth of tumor cells while other studies contradicted these results [222225]. Yu et al. have shown that coinjection of human ASCs (hASCs) with tumor cells into BALB/c nude mice had increased the tumor cell viability in vivo and reduced the apoptotic cell death therefore favoring tumor growth in vivo [225]. Muehlberg et al. have also shown that mouse ASCs cause a significant rapid growth in cancer when added to murine breast cancer cell line. Moreover they showed that ASCs play an important role in tumor metastasis [223]. On the other hand, Cousin and his colleagues have shown that ASCs strongly inhibit pancreatic ductal adenocarcinoma proliferation both in vitro and in vivo. Moreover, ASCs induce tumor cell death [224]. Also Grisendi and colleagues have shown that ASCs can be used to support tumor necrosis factor related apoptosis-inducing ligand (TRAIL), which is a proapoptotic ligand that induces apoptosis in a variety of human cancers but not normal cells [226]. Hence, the literature is contradictory on the implication of ASCs in tumor growth and that can be partially explained by the different protocols used both in vivo and in vitro, which makes it hard to compare them. As in some studies, they combined ASCs injection with tumor cells while others did not. Moreover, different sources of ASCs were used including human and mouse ASCs and different types of cancers cells were investigated. To our knowledge, there are no studies which have been done to investigate the effect of ASCs on bone cancer. Thus, it is necessary to conduct more studies with consensual protocols to study the tumorigenic feature of ASCs and the long-term safety of using this technique before ASCs can be used as therapeutic tools in regenerative medicine and DO.

Another area of interest is the use of ASCs in DO. To date the scarce executed studies discussing the use of ASCs in DO did not provide a guideline with precise stepwise protocol of application of ASCs in DO model. From a therapeutic point of view, the use of ASCs should be carefully described according to the type of bone defect and callus shape. Donnan et al. classified callus depending on the shape, polarity, and consistency of callus regeneration [227]. Then Halvorsen et al. [162] described another classification based on callus shape and radiographic features which also was not used clinically due to its complexity. Finally Hamdy and McCarthy [228] developed a simplified version of Li classification that included seven callus shapes. Figure 7 shows in detail the classified callus shapes, and Figures 7(a) through 7(c) show satisfactory regenerated bone that should heal without squeal; therefore no addition procedures are needed. Figure 7(d) suggests that the rate of distraction is too fast, which can be easily corrected. However, Figures 7(e) through 7(g) are examples of poorly formed regeneration that may require enhancement before fixator removal to minimize complications. In order to improve the treatment outcome in these situations, the potential use of ASCs in bone engineering should be explored. Theoretically, in cases of partial/complete absence of bone formation in DO, the local administration of nanofibrous scaffolds with ASCs should be able to enhance and stimulate bone regeneration (Figures 7(e) and 7(f)). On the other hand nanocomposite scaffolds should be used in combination with ASCs to provide mechanical and biological support when there is suboptimal callus formation in DO (Figure 7(g)). To the best of our knowledge there have not been any previous studies investigating this promising strategies in the context of ASCs and DO.

Figure 7: Representation of callus classification. Illustration and radiographs demonstrate the modified Li classification of callus shape in distraction osteogenesis. (a) New bone formation in the distraction gap extends beyond the outer borders of the cortical bone. (b) New bone formation toward one side of the distraction gap with extension beyond the outer borders of the adjacent cortical bone. (c) New bone formation within the distraction gap with margins parallel to the adjacent cortical bone. (d) Biconcave-shaped new bone formation within the distraction gap. (e) New bone formation limited to one side of the bone without extension beyond the outer borders of the cortical bone. (f) New bone formation in the center with limited new bone regeneration in the lateral portion of the distraction gap. (g) Only speckled bone formation is present (bar scale = 5 cm).

Optimizing the concentrations of ASCs, mode of delivery and the time of application need to be extensively investigated in order to use this technology in DO and CSDs. It is important to validate if ASCs should be injected at the beginning, midway, or the end of distraction as this can have different impact on callus formation, the efficiency of ASCs proliferation, and differentiation. Moreover, the optimal concentration was never investigated before and such studies will be important to standardize a reproducible controlled guideline, to be used in clinical translational approaches.

Tissue engineering on bone regeneration as mentioned above requires scaffolds, growth factors and osteogenic cells. In DO the application of exogenic biological agents including growth factors has been a very-well documented approach to accelerate bone regeneration; however there are still some limitations such as short-half life, rapid clearance, and safety concerns [72]. Therefore developing an effective delivery system and combining them with stem cells are required. Nanobiomaterials have been used to convey growth factors in DO before [229], since they can achieve more effective and controlled release of the growth factors. Moreover, they can add strength to the mechanical properties of scaffolds and provide an environment that resembles the extracellular matrix of bone hence, promoting ASCs proliferation and differentiation into osteoblasts. Therefore, choosing the right nanocomposite scaffold is essential for the successful differentiation and proliferation of ASCs in DO. Further research is then needed to answer all these questions including when to inject stem cells in DO and when to inject nanocomposite scaffolds and which material is optimal in inducing osteogenic differentiation in DO? Which growth factor and delivery system are the optimal one to be used with stem cells for osteogenic induction? All these questions should be addressed in order to optimize the use of ASCs in bone regeneration and DO. Well-designed preclinical and translational studies to establish the safe and efficacious use of cell-therapies to enhance bone regeneration are needed.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

References

  1. P. S. Pipitone and S. Rehman, “Management of traumatic bone loss in the lower extremity,” Orthopedic Clinics of North America, vol. 45, no. 4, pp. 469–482, 2014. View at Publisher · View at Google Scholar · View at Scopus
  2. F. Rauch and F. H. Glorieux, “Osteogenesis imperfecta,” The Lancet, vol. 363, no. 9418, pp. 1377–1385, 2004. View at Publisher · View at Google Scholar · View at Scopus
  3. O. Ashman and A. M. Phillips, “Treatment of non-unions with bone defects: which option and why?” Injury, vol. 44, supplement 1, pp. S43–S45, 2013. View at Publisher · View at Google Scholar · View at Scopus
  4. H. Tsuchiya, “Treatment of segmental bone loss due to tumors,” in Management of Limb-Length Discrepancies, R. H. A. J. J. McCarthy, Ed., pp. 173–178, American Academy of Orthopaedic Surgeons, Rosemont, Ill, USA, 2011. View at Google Scholar
  5. Z. S. Al-Aql, A. S. Alagl, D. T. Graves, L. C. Gerstenfeld, and T. A. Einhorn, “Molecular mechanisms controlling bone formation during fracture healing and distraction osteogenesis,” Journal of Dental Research, vol. 87, no. 2, pp. 107–118, 2008. View at Publisher · View at Google Scholar · View at Scopus
  6. C. Papakostidis, M. Bhandari, and P. V. Giannoudis, “Distraction osteogenesis in the treatment of long bone defects of the lower limbs: effectiveness, complications and clinical results; a systematic review and meta-analysis,” Bone and Joint Journal, vol. 95, no. 12, pp. 1673–1680, 2013. View at Publisher · View at Google Scholar · View at Scopus
  7. A. Nauth, M. D. McKee, T. A. Einhorn, J. T. Watson, R. Li, and E. H. Schemitsch, “Managing bone defects,” Journal of Orthopaedic Trauma, vol. 25, no. 8, pp. 462–466, 2011. View at Publisher · View at Google Scholar · View at Scopus
  8. R. Dimitriou, E. Jones, D. McGonagle, and P. V. Giannoudis, “Bone regeneration: current concepts and future directions,” BMC Medicine, vol. 9, article 66, 2011. View at Publisher · View at Google Scholar · View at Scopus
  9. K. N. Malizos, C. G. Zalavras, P. N. Soucacos, A. E. Beris, and J. R. Urbaniak, “Free vascularized fibular grafts for reconstruction of skeletal defects,” The Journal of the American Academy of Orthopaedic Surgeons, vol. 12, no. 5, pp. 360–369, 2004. View at Google Scholar · View at Scopus
  10. A. Codivilla, “On the means of lengthening, in the lower limbs, the muscles and tissues which are shortened through deformity,” The Journal of Bone & Joint Surgery, vol. 2, no. 4, pp. 353–369, 1905. View at Google Scholar
  11. G. A. Ilizarov, “The tension-stress effect on the genesis and growth of tissues. Part I. The influence of stability of fixation and soft-tissue preservation,” Clinical Orthopaedics and Related Research, no. 238, pp. 249–281, 1989. View at Google Scholar · View at Scopus
  12. A. A. Green, “The Ilizarov method of distraction osteogenesis,” in Management of Limb Length Discrepancies, R. C. Hamdy and J. J. McCarthy, Eds., pp. 39–44, American Academy of Orthopaedic Surgeons, Rosemont, Ill, USA, 2011. View at Google Scholar
  13. G. A. Ilizarov, “Clinical application of the tension-stress effect for limb lengthening,” Clinical Orthopaedics and Related Research, no. 250, pp. 8–26, 1990. View at Google Scholar · View at Scopus
  14. R. C. Hamdy, J. S. Rendon, and M. Tabrizian, “Distraction osteogenesis and its challenges in bone regeneration,” in Bone Regeneration, chapter 8, InTech, Rijeka, Croatia, 2012. View at Publisher · View at Google Scholar
  15. J. G. Birch and M. L. Samchukov, “Use of the Ilizarov method to correct lower limb deformities in children and adolescents,” Journal of the American Academy of Orthopaedic Surgeons, vol. 12, no. 3, pp. 144–154, 2004. View at Google Scholar · View at Scopus
  16. G. A. Ilizarov, “The tension-stress effect on the genesis and growth of tissues: part II. The influence of the rate and frequency of distraction,” Clinical Orthopaedics and Related Research, no. 239, pp. 263–285, 1989. View at Google Scholar · View at Scopus
  17. R. Y. Goldstein, C. J. Jordan, T. M. Mclaurin, and A. Grant, “The evolution of the ilizarov technique: part 2: the principles of distraction osteosynthesis,” Bulletin of the Hospital for Joint Disease, vol. 71, no. 1, pp. 96–103, 2013. View at Google Scholar · View at Scopus
  18. J. H. Murray and R. D. Fitch, “Distraction histiogenesis: principles and indications,” Journal of the American Academy of Orthopaedic Surgeons, vol. 4, no. 6, pp. 317–327, 1996. View at Google Scholar
  19. B. Fink, C. Pollnau, M. Vogel, R. Skripitz, and A. Enderle, “Histomorphometry of distraction osteogenesis during experimental tibial lengthening,” Journal of Orthopaedic Trauma, vol. 17, no. 2, pp. 113–118, 2003. View at Publisher · View at Google Scholar · View at Scopus
  20. J. Aronson, B. Good, C. Stewart, B. Harrison, and J. Harp, “Preliminary studies of mineralization during distraction osteogenesis,” Clinical Orthopaedics and Related Research, no. 250, pp. 43–49, 1990. View at Google Scholar · View at Scopus
  21. I. H. Choi, C. Y. Chung, T.-J. Cho, and W. J. Yoo, “Angiogenesis and mineralization during distraction osteogenesis,” Journal of Korean Medical Science, vol. 17, no. 4, pp. 435–447, 2002. View at Publisher · View at Google Scholar · View at Scopus
  22. N. Yasui, M. Sato, T. Ochi et al., “Three modes of ossification during distraction osteogenesis in the rat,” Journal of Bone and Joint Surgery B, vol. 79, no. 5, pp. 824–830, 1997. View at Publisher · View at Google Scholar · View at Scopus
  23. R. C. Hamdy, A. Silvestri, C. H. Rivard, and M. Ehrlich, “Histologic evaluation of bone regeneration in cases of limb lengthening by Ilizarov's technique. An experimental study in the dog,” Annales de Chirurgie, vol. 51, no. 8, pp. 875–883, 1997. View at Google Scholar · View at Scopus
  24. R. C. Hamdy, M. Amako, L. Beckman et al., “Effects of osteogenic protein-1 on distraction osteogenesis in rabbits,” Bone, vol. 33, no. 2, pp. 248–255, 2003. View at Publisher · View at Google Scholar · View at Scopus
  25. M. Sato, N. Yasui, T. Nakase et al., “Expression of bone matrix proteins mRNA during distraction osteogenesis,” Journal of Bone and Mineral Research, vol. 13, no. 8, pp. 1221–1231, 1998. View at Publisher · View at Google Scholar · View at Scopus
  26. L. C. Gerstenfeld, D. M. Cullinane, G. L. Barnes, D. T. Graves, and T. A. Einhorn, “Fracture healing as a post-natal developmental process: molecular, spatial, and temporal aspects of its regulation,” Journal of Cellular Biochemistry, vol. 88, no. 5, pp. 873–884, 2003. View at Publisher · View at Google Scholar · View at Scopus
  27. J. Aronson, B. H. Harrison, C. L. Stewart, and J. H. Harp Jr., “The histology of distraction osteogenesis using different external fixators,” Clinical Orthopaedics and Related Research, no. 241, pp. 106–116, 1989. View at Google Scholar · View at Scopus
  28. J. Aronson, X. C. Shen, R. A. Skinner, W. R. Hogue, T. M. Badger, and J. Lumpkin C.K., “Rat model of distraction osteogenesis,” Journal of Orthopaedic Research, vol. 15, no. 2, pp. 221–226, 1997. View at Publisher · View at Google Scholar · View at Scopus
  29. M. Makarov, J. Birch, and M. Samchukov, “The role of variable muscle adaptation to limb lengthening in the development of joint contractures: an experimental study in the goat,” Journal of Pediatric Orthopaedics, vol. 29, no. 2, pp. 175–181, 2009. View at Publisher · View at Google Scholar · View at Scopus
  30. D. Y. Lee, T.-J. Cho, J. A. Kim et al., “Mobilization of endothelial progenitor cells in fracture healing and distraction osteogenesis,” Bone, vol. 42, no. 5, pp. 932–941, 2008. View at Publisher · View at Google Scholar · View at Scopus
  31. I. H. Choi, J. H. Ahn, C. Y. Chung, and T.-J. Cho, “Vascular proliferation and blood supply during distraction osteogenesis: a scanning electron microscopic observation,” Journal of Orthopaedic Research, vol. 18, no. 5, pp. 698–705, 2000. View at Publisher · View at Google Scholar · View at Scopus
  32. D. M. Pacicca, N. Patel, C. Lee et al., “Expression of angiogenic factors during distraction osteogenesis,” Bone, vol. 33, no. 6, pp. 889–898, 2003. View at Publisher · View at Google Scholar · View at Scopus
  33. F. Rauch, D. Lauzier, S. Croteau, R. Travers, F. H. Glorieux, and R. Hamdy, “Temporal and spatial expression of bone morphogenetic protein- 2, -4, and -7 during distraction osteogenesis in rabbits,” Bone, vol. 27, no. 3, pp. 453–459, 2000. View at Publisher · View at Google Scholar · View at Scopus
  34. T. Haque, M. Amako, S. Nakada, D. Lauzier, and R. C. Hamdy, “An immunohistochemical analysis of the temporal and spatial expression of growth factors FGF 1, 2 and 18, IGF 1 and 2, and TGFbeta1 during distraction osteogenesis,” Histology and Histopathology, vol. 22, no. 2, pp. 119–128, 2007. View at Google Scholar · View at Scopus
  35. T. Haque, F. Hamade, N. Alam et al., “Characterizing the BMP pathway in a wild type mouse model of distraction osteogenesis,” Bone, vol. 42, no. 6, pp. 1144–1153, 2008. View at Publisher · View at Google Scholar · View at Scopus
  36. T. Haque, M. Mandu-Hrit, F. Rauch, D. Lauzier, M. Tabrizian, and R. C. Hamdy, “Immunohistochemical localization of bone morphogenetic protein-signaling Smads during long-bone distraction osteogenesis,” Journal of Histochemistry and Cytochemistry, vol. 54, no. 4, pp. 407–415, 2006. View at Publisher · View at Google Scholar · View at Scopus
  37. C. Huang and R. Ogawa, “Mechanotransduction in bone repair and regeneration,” The FASEB Journal, vol. 24, no. 10, pp. 3625–3632, 2010. View at Publisher · View at Google Scholar · View at Scopus
  38. S. Weiss, R. Baumgart, M. Jochum, C. J. Strasburger, and M. Bidlingmaier, “Systemic regulation of distraction osteogenesis: a cascade of biochemical factors,” Journal of Bone and Mineral Research, vol. 17, no. 7, pp. 1280–1289, 2002. View at Publisher · View at Google Scholar · View at Scopus
  39. Z. S. Haidar, M. Tabrizian, and R. C. Hamdy, “A hybrid rhOP-1 delivery system enhances new bone regeneration and consolidation in a rabbit model of distraction osteogenesis,” Growth Factors, vol. 28, no. 1, pp. 44–55, 2010. View at Publisher · View at Google Scholar · View at Scopus
  40. Z. S. Haidar, R. C. Hamdy, and M. Tabrizian, “Delivery of recombinant bone morphogenetic proteins for bone regeneration and repair. Part A: current challenges in BMP delivery,” Biotechnology Letters, vol. 31, no. 12, pp. 1817–1824, 2009. View at Publisher · View at Google Scholar · View at Scopus
  41. Z. S. Haidar, F. Azari, R. C. Hamdy, and M. Tabrizian, “Modulated release of OP-1 and enhanced preosteoblast differentiation using a core-shell nanoparticulate system,” Journal of Biomedical Materials Research Part A, vol. 91, no. 3, pp. 919–928, 2009. View at Publisher · View at Google Scholar
  42. B. Dohin, N. Dahan-Oliel, F. Fassier, and R. Hamdy, “Enhancement of difficult nonunion in children with osteogenic protein-1 (OP-1): early experience,” Clinical Orthopaedics and Related Research, vol. 467, no. 12, pp. 3230–3238, 2009. View at Publisher · View at Google Scholar · View at Scopus
  43. M. Mandu-Hrit, E. Seifert, M. Kotsiopriftis et al., “OP-1 injection increases VEGF expression but not angiogenesis in a rabbit model of distraction osteogenesis,” Growth Factors, vol. 26, no. 3, pp. 143–151, 2008. View at Publisher · View at Google Scholar · View at Scopus
  44. K. Zakhary, D. Motakis, R. H. Hamdy, P. Campisi, Y. Amar, and M.-L. Lessard, “Effect of recombinant human bone morphogenetic protein 7 on bone density during distraction osteogenesis of the rabbit mandible,” Journal of Otolaryngology, vol. 34, no. 6, pp. 407–414, 2005. View at Publisher · View at Google Scholar · View at Scopus
  45. P. Campisi, R. C. Hamdy, D. Lauzier, M. Amako, F. Rauch, and M. L. Lessard, “Expression of bone morphogenetic proteins during mandibular distraction osteogenesis,” Plastic and Reconstructive Surgery, vol. 111, no. 1, pp. 201–210, 2003. View at Publisher · View at Google Scholar · View at Scopus
  46. B. Kasaai, P. Moffatt, L. Al-Salmi, D. Lauzier, L. Lessard, and R. C. Hamdy, “Spatial and temporal localization of WNT signaling proteins in a mouse model of distraction osteogenesis,” Journal of Histochemistry and Cytochemistry, vol. 60, no. 3, pp. 219–228, 2012. View at Publisher · View at Google Scholar · View at Scopus
  47. O. Holbein, C. Neidlinger-Wilke, G. Suger, L. Kinzl, and L. Claes, “Ilizarov callus distraction produces systemic bone cell mitogens,” Journal of Orthopaedic Research, vol. 13, no. 4, pp. 629–638, 1995. View at Publisher · View at Google Scholar · View at Scopus
  48. P. Campisi, R. C. Hamdy, D. Lauzier, M. Amako, M. D. Schloss, and M. L. Lessard, “Overview of the radiology, histology, and bone morphogenetic protein expression during distraction osteogenesis of the mandible,” Journal of Otolaryngology, vol. 31, no. 5, pp. 281–286, 2002. View at Publisher · View at Google Scholar · View at Scopus
  49. M. Mandu-Hrit, T. Haque, D. Lauzier et al., “Early injection of OP-1 during distraction osteogenesis accelerates new bone formation in rabbits,” Growth Factors, vol. 24, no. 3, pp. 172–183, 2006. View at Publisher · View at Google Scholar · View at Scopus
  50. N. Alam, R. St-Arnaud, D. Lauzier, V. Rosen, and R. C. Hamdy, “Are endogenous BMPs necessary for bone healing during distraction osteogenesis?” Clinical Orthopaedics and Related Research, vol. 467, no. 12, pp. 3190–3198, 2009. View at Publisher · View at Google Scholar · View at Scopus
  51. V. D. Polyzois, I. P. Stathopoulos, K. Lampropoulou-Adamidou, E. S. Vasiliadis, J. Vlamis, and S. G. Pneumaticos, “Strategies for managing bone defects of the lower extremity,” Clinics in Podiatric Medicine and Surgery, vol. 31, no. 4, pp. 577–584, 2014. View at Publisher · View at Google Scholar · View at Scopus
  52. J. J. Keeling, J. R. Hsu, S. B. Shawen, and R. C. Andersen, “Strategies for managing massive defects of the foot in high-energy combat injuries of the lower extremity,” Foot and Ankle Clinics, vol. 15, no. 1, pp. 139–149, 2010. View at Publisher · View at Google Scholar · View at Scopus
  53. D. S. Feldman and S. Chaudhry, “Distraction osteogenesis: lengthening with external fixators,” in Management of Limb-Length Discrepancies, American Academy of Orthopaedic Surgeons, Rosemont, Ill, USA, 2011. View at Google Scholar
  54. R. J. Velazquez, D. F. Bell, P. F. Armstrong, P. Babyn, and R. Tibshirani, “Complications of use of the Ilizarov technique in the correction of limb deformities in children,” The Journal of Bone & Joint Surgery—American Volume, vol. 75, no. 8, pp. 1148–1156, 1993. View at Google Scholar · View at Scopus
  55. D. Paley, “Problems, obstacles, and complications of limb lengthening by the Ilizarov technique,” Clinical Orthopaedics and Related Research, no. 250, pp. 81–104, 1990. View at Google Scholar · View at Scopus
  56. E. García-Cimbrelo, B. Olsen, M. Ruiz-Yagüe, N. Fernandez-Baíllo, and L. Munuera-Martínez, “Ilizarov technique. Results and difficulties,” Clinical Orthopaedics and Related Research, no. 283, pp. 116–123, 1992. View at Google Scholar
  57. L. Claes, P. Augat, S. Schorlemmer, C. Konrads, A. Ignatius, and C. Ehrnthaller, “Temporary distraction and compression of a diaphyseal osteotomy accelerates bone healing,” Journal of Orthopaedic Research, vol. 26, no. 6, pp. 772–777, 2008. View at Publisher · View at Google Scholar · View at Scopus
  58. S. Mori, M. Akagi, A. Kikuyama, Y. Yasuda, and C. Hamanishi, “Axial shortening during distraction osteogenesis leads to enhanced bone formation in a rabbit model through the HIF-1α/vascular endothelial growth factor system,” Journal of Orthopaedic Research, vol. 24, no. 4, pp. 653–663, 2006. View at Publisher · View at Google Scholar · View at Scopus
  59. W. W. Hou, Z. L. Zhu, Y. Zhou, C. X. Zhang, and H. Y. Yu, “Involvement of Wnt activation in the micromechanical vibration-enhanced osteogenic response of osteoblasts,” Journal of Orthopaedic Science, vol. 16, no. 5, pp. 598–605, 2011. View at Publisher · View at Google Scholar · View at Scopus
  60. T. Hagiwara and W. H. Bell, “Effect of electrical stimulation on mandibular distraction osteogenesis,” Journal of Cranio-Maxillofacial Surgery, vol. 28, no. 1, pp. 12–19, 2000. View at Publisher · View at Google Scholar · View at Scopus
  61. K. Kawamoto, W.-C. Kim, Y. Tsuchida et al., “Effects of alternating current electrical stimulation on lengthening callus,” Journal of Pediatric Orthopaedics Part B, vol. 14, no. 4, pp. 299–302, 2005. View at Publisher · View at Google Scholar · View at Scopus
  62. K. Narasaki, H. Shimizu, M. Beppu, H. Aoki, M. Takagi, and M. Takashi, “Effect of extracorporeal shock waves on callus formation during bone lengthening,” Journal of Orthopaedic Science, vol. 8, no. 4, pp. 474–481, 2003. View at Publisher · View at Google Scholar · View at Scopus
  63. J.-P. Lai, F.-S. Wang, C.-M. Hung, C.-J. Wang, C.-J. Huang, and Y.-R. Kuo, “Extracorporeal shock wave accelerates consolidation in distraction osteogenesis of the rat mandible,” Journal of Trauma—Injury, Infection and Critical Care, vol. 69, no. 5, pp. 1252–1258, 2010. View at Publisher · View at Google Scholar · View at Scopus
  64. A. Shimazaki, K. Inui, Y. Azuma, N. Nishimura, and Y. Yamano, “Low-intensity pulsed ultrasound accelerates bone maturation in distraction osteogenesis in rabbits,” Journal of Bone and Joint Surgery: Series B, vol. 82, no. 7, pp. 1077–1082, 2000. View at Publisher · View at Google Scholar · View at Scopus
  65. L. Claes and B. Willie, “The enhancement of bone regeneration by ultrasound,” Progress in Biophysics and Molecular Biology, vol. 93, no. 1–3, pp. 384–398, 2007. View at Publisher · View at Google Scholar · View at Scopus
  66. J. W. Busse, J. Kaur, B. Mollon et al., “Low intensity pulsed ultrasonography for fractures: systematic review of randomised controlled trials,” British Medical Journal, vol. 338, article b351, 2009. View at Publisher · View at Google Scholar · View at Scopus
  67. A. M. Makhdom, F. Rauch, D. Lauzier, and R. C. Hamdy, “The effect of systemic administration of sclerostin antibody in a mouse model of distraction osteogenesis,” Journal of Musculoskeletal Neuronal Interactions, vol. 14, no. 1, pp. 124–130, 2014. View at Google Scholar · View at Scopus
  68. C. Sen, T. Gunes, M. Erdem, R. D. Koseoglu, and N. O. Filiz, “Effects of calcitonin and alendronate on distraction osteogenesis,” International Orthopaedics, vol. 30, no. 4, pp. 272–277, 2006. View at Publisher · View at Google Scholar · View at Scopus
  69. A. Abbaspour, M. Takahashi, K. Sairyo et al., “Optimal increase in bone mass by continuous local infusion of alendronate during distraction osteogenesis in rabbits,” Bone, vol. 44, no. 5, pp. 917–923, 2009. View at Publisher · View at Google Scholar · View at Scopus
  70. P. Kiely, K. Ward, C. M. Bellemore, J. Briody, C. T. Cowell, and D. G. Little, “Bisphosphonate rescue in distraction osteogenesis: a case series,” Journal of Pediatric Orthopaedics, vol. 27, no. 4, pp. 467–471, 2007. View at Publisher · View at Google Scholar · View at Scopus
  71. K. Yamane, T. Okano, H. Kishimoto, and H. Hagino, “Effect of ED-71 on modeling of bone in distraction osteogenesis,” Bone, vol. 24, no. 3, pp. 187–193, 1999. View at Publisher · View at Google Scholar · View at Scopus
  72. A. M. Makhdom and R. C. Hamdy, “The role of growth factors on acceleration of bone regeneration during distraction osteogenesis,” Tissue Engineering—Part B: Reviews, vol. 19, no. 5, pp. 442–453, 2013. View at Publisher · View at Google Scholar · View at Scopus
  73. B. C. Cho, J. H. Moon, H. Y. Chung, J. W. Park, I. C. Kweon, and I. S. Kim, “The bone regenerative effect of growth hormone on consolidation in mandibular distraction osteogenesis of a dog model,” The Journal of Craniofacial Surgery, vol. 14, no. 3, pp. 417–425, 2003. View at Publisher · View at Google Scholar · View at Scopus
  74. S. N. Lissenberg-Thunnissen, D. J. J. de Gorter, C. F. M. Sier, and I. B. Schipper, “Use and efficacy of bone morphogenetic proteins in fracture healing,” International Orthopaedics, vol. 35, no. 9, pp. 1271–1280, 2011. View at Publisher · View at Google Scholar · View at Scopus
  75. Z. S. Haidar, R. C. Hamdy, and M. Tabrizian, “Delivery of recombinant bone morphogenetic proteins for bone regeneration and repair. Part B. Delivery systems for BMPs in orthopaedic and craniofacial tissue engineering,” Biotechnology Letters, vol. 31, no. 12, pp. 1825–1835, 2009. View at Publisher · View at Google Scholar · View at Scopus
  76. Z. S. Haidar, R. C. Hamdy, and M. Tabrizian, “Biocompatibility and safety of a hybrid core-shell nanoparticulate OP-1 delivery system intramuscularly administered in rats,” Biomaterials, vol. 31, no. 10, pp. 2746–2754, 2010. View at Publisher · View at Google Scholar · View at Scopus
  77. Z. S. Haidar, R. C. Hamdy, and M. Tabrizian, “Protein release kinetics for core-shell hybrid nanoparticles based on the layer-by-layer assembly of alginate and chitosan on liposomes,” Biomaterials, vol. 29, no. 9, pp. 1207–1215, 2008. View at Publisher · View at Google Scholar · View at Scopus
  78. H. I. Canter, I. Vargel, and M. E. Mavili, “Reconstruction of mandibular defects using autografts combined with demineralized bone matrix and cancellous allograft,” Journal of Craniofacial Surgery, vol. 18, no. 1, pp. 95–103, 2007. View at Publisher · View at Google Scholar · View at Scopus
  79. I. Hatzokos, S. I. Stavridis, E. Iosifidou, D. Karataglis, and A. Christodoulou, “Autologous bone marrow grafting combined with demineralized bone matrix improves consolidation of docking site after distraction osteogenesis,” The Journal of Bone & Joint Surgery—American Volume, vol. 93, no. 7, pp. 671–678, 2011. View at Publisher · View at Google Scholar · View at Scopus
  80. M. K. Sen and T. Miclau, “Autologous iliac crest bone graft: should it still be the gold standard for treating nonunions?” Injury, vol. 38, no. 1, pp. S75–S80, 2007. View at Publisher · View at Google Scholar · View at Scopus
  81. A. J. Weiland, “Current concepts review. Vascularized free bone transplants,” Journal of Bone and Joint Surgery A, vol. 63, no. 1, pp. 166–169, 1981. View at Google Scholar · View at Scopus
  82. M. B. Wood, “Free vascularized fibular grafting-25 years' experience: tips, techniques, and pearls,” Orthopedic Clinics of North America, vol. 38, no. 1, pp. 1–12, 2007. View at Publisher · View at Google Scholar · View at Scopus
  83. T. W. Bauer and G. F. Muschler, “Bone graft materials: an overview of the basic science,” Clinical Orthopaedics and Related Research, no. 371, pp. 10–27, 2000. View at Google Scholar · View at Scopus
  84. E. Ahlmann, M. Patzakis, N. Roidis, L. Shepherd, and P. Holtom, “Comparison of anterior and posterior iliac crest bone grafts in terms of harvest-site morbidity and functional outcomes,” The Journal of Bone & Joint Surgery—American Volume, vol. 84, no. 5, pp. 716–720, 2002. View at Publisher · View at Google Scholar · View at Scopus
  85. E. M. Younger and M. W. Chapman, “Morbidity at bone graft donor sites,” Journal of Orthopaedic Trauma, vol. 3, no. 3, pp. 192–195, 1989. View at Publisher · View at Google Scholar · View at Scopus
  86. J. A. Goulet, L. E. Senunas, G. L. DeSilva, and M. L. V. H. Greenfield, “Autogenous iliac crest bone graft: complications and functional assessment,” Clinical Orthopaedics and Related Research, no. 339, pp. 76–81, 1997. View at Google Scholar · View at Scopus
  87. J. T. Newman, P. F. Stahel, W. R. Smith, G. V. Resende, D. J. Hak, and S. J. Morgan, “A new minimally invasive technique for large volume bone graft harvest for treatment of fracture nonunions,” Orthopedics, vol. 31, no. 3, pp. 257–261, 2008. View at Publisher · View at Google Scholar · View at Scopus
  88. F. M. Kovar and G. E. Wozasek, “Bone graft harvesting using the RIA (reaming irrigation aspirator) system—a quantitative assessment,” Wiener Klinische Wochenschrift, vol. 123, no. 9-10, pp. 285–290, 2011. View at Publisher · View at Google Scholar · View at Scopus
  89. N. K. Kanakaris, D. Morell, S. Gudipati, S. Britten, and P. V. Giannoudis, “Reaming irrigator aspirator system: early experience of its multipurpose use,” Injury, vol. 42, supplement 4, pp. S28–S34, 2011. View at Publisher · View at Google Scholar · View at Scopus
  90. H. C. Sagi, M. L. Young, L. Gerstenfeld, T. A. Einhorn, and P. Tornetta, “Qualitative and quantitative differences between bone graft obtained from the medullary canal (with a reamer/irrigator/aspirator) and the iliac crest of the same patient,” Journal of Bone and Joint Surgery: Series A, vol. 94, no. 23, pp. 2128–2135, 2012. View at Publisher · View at Google Scholar · View at Scopus
  91. C. G. Finkemeier, “Bone-grafting and bone-graft substitutes,” The Journal of Bone & Joint Surgery—American Volume, vol. 84, no. 3, pp. 454–464, 2002. View at Google Scholar
  92. M. Strioga, S. Viswanathan, A. Darinskas, O. Slaby, and J. Michalek, “Same or not the same? comparison of adipose tissue-derived versus bone marrow-derived mesenchymal stem and stromal cells,” Stem Cells and Development, vol. 21, no. 14, pp. 2724–2752, 2012. View at Publisher · View at Google Scholar · View at Scopus
  93. A. I. Caplan, “The mesengenic process,” Clinics in Plastic Surgery, vol. 21, no. 3, pp. 429–435, 1994. View at Google Scholar · View at Scopus
  94. P. A. Zuk, M. Zhu, H. Mizuno et al., “Multilineage cells from human adipose tissue: implications for cell-based therapies,” Tissue Engineering, vol. 7, no. 2, pp. 211–228, 2001. View at Publisher · View at Google Scholar · View at Scopus
  95. P. A. Zuk, M. Zhu, P. Ashjian et al., “Human adipose tissue is a source of multipotent stem cells,” Molecular Biology of the Cell, vol. 13, no. 12, pp. 4279–4295, 2002. View at Publisher · View at Google Scholar · View at Scopus
  96. P. Lichte, H. C. Pape, T. Pufe, P. Kobbe, and H. Fischer, “Scaffolds for bone healing: concepts, materials and evidence,” Injury, vol. 42, no. 6, pp. 569–573, 2011. View at Publisher · View at Google Scholar · View at Scopus
  97. F. Matassi, L. Nistri, D. C. Paez, and M. Innocenti, “New biomaterials for bone regeneration,” Clinical Cases in Mineral and Bone Metabolism, vol. 8, no. 1, pp. 21–24, 2011. View at Google Scholar · View at Scopus
  98. S. J. Seo, C. Mahapatra, R. K. Singh, J. Knowles, and H. Kim, “Strategies for osteochondral repair: focus on scaffolds,” Journal of Tissue Engineering, vol. 5, pp. 1–14, 2014. View at Publisher · View at Google Scholar
  99. X. Li, L. Wang, Y. Fan, Q. Feng, F. Z. Cui, and F. Watari, “Nanostructured scaffolds for bone tissue engineering,” Journal of Biomedical Materials Research Part A, vol. 101, no. 8, pp. 2424–2435, 2013. View at Publisher · View at Google Scholar
  100. L. Zhang, F. X. Gu, J. M. Chan, A. Z. Wang, R. S. Langer, and O. C. Farokhzad, “Nanoparticles in medicine: therapeutic applications and developments,” Clinical Pharmacology & Therapeutics, vol. 83, no. 5, pp. 761–769, 2008. View at Google Scholar
  101. W.-J. Li, R. Tuli, X. Huang, P. Laquerriere, and R. S. Tuan, “Multilineage differentiation of human mesenchymal stem cells in a three-dimensional nanofibrous scaffold,” Biomaterials, vol. 26, no. 25, pp. 5158–5166, 2005. View at Publisher · View at Google Scholar · View at Scopus
  102. Y. Khan, M. J. Yaszemski, A. G. Mikos, and C. T. Laurencin, “Tissue engineering of bone: material and matrix considerations,” The Journal of Bone & Joint Surgery—American Volume, vol. 90, supplement 1, pp. 36–42, 2008. View at Publisher · View at Google Scholar · View at Scopus
  103. K. Tuzlakoglu, N. Bolgen, A. J. Salgado, M. E. Gomes, E. Piskin, and R. L. Reis, “Nano- and micro-fiber combined scaffolds: a new architecture for bone tissue engineering,” Journal of Materials Science: Materials in Medicine, vol. 16, no. 12, pp. 1099–1104, 2005. View at Publisher · View at Google Scholar · View at Scopus
  104. A. Tautzenberger, A. Kovtun, and A. Ignatius, “Nanoparticles and their potential for application in bone,” International Journal of Nanomedicine, vol. 7, pp. 4545–4557, 2012. View at Publisher · View at Google Scholar · View at Scopus
  105. K. M. Woo, J.-H. Jun, V. J. Chen et al., “Nano-fibrous scaffolding promotes osteoblast differentiation and biomineralization,” Biomaterials, vol. 28, no. 2, pp. 335–343, 2007. View at Publisher · View at Google Scholar · View at Scopus
  106. A. S. Posner, “The mineral of bone,” Clinical Orthopaedics and Related Research, vol. 200, pp. 87–99, 1985. View at Google Scholar · View at Scopus
  107. S. Weiner, W. Traub, and H. D. Wagner, “Lamellar bone: structure-function relations,” Journal of Structural Biology, vol. 126, no. 3, pp. 241–255, 1999. View at Publisher · View at Google Scholar · View at Scopus
  108. C. Hellmich and F. Ulm, “Average hydroxyapatite concentration is uniform in the extracollagenous ultrastructure of mineralized tissues: evidence at the 1-10-μm scale,” Biomechanics and Modeling in Mechanobiology, vol. 2, no. 1, pp. 21–36, 2003. View at Publisher · View at Google Scholar
  109. C. Rey, H.-M. Kim, L. Gerstenfeld, and M. J. Glimcher, “Structural and chemical characteristics and maturation of the calcium-phosphate crystals formed during the calcification of the organic matrix synthesized by chicken osteoblasts in cell culture,” Journal of Bone and Mineral Research, vol. 10, no. 10, pp. 1577–1588, 1995. View at Google Scholar · View at Scopus
  110. B. R. Olsen, “Morphogenesis: collagen it takes and bone it makes,” Current Biology, vol. 6, no. 6, pp. 645–647, 1996. View at Publisher · View at Google Scholar · View at Scopus
  111. M. F. Young, J. M. Kerr, K. Ibaraki, A.-M. Heegaard, and P. G. Robey, “Structure, expression, and regulation of the major noncollagenous matrix proteins of bone,” Clinical Orthopaedics and Related Research, no. 281, pp. 275–294, 1992. View at Google Scholar · View at Scopus
  112. Z. Lu, S.-I. Roohani-Esfahani, G. Wang, and H. Zreiqat, “Bone biomimetic microenvironment induces osteogenic differentiation of adipose tissue-derived mesenchymal stem cells,” Nanomedicine, vol. 8, no. 4, pp. 507–515, 2012. View at Publisher · View at Google Scholar · View at Scopus
  113. F. M. Ghorbani, B. Kaffashi, P. Shokrollahi, E. Seyedjafari, and A. Ardeshirylajimi, “PCL/chitosan/Zn-doped nHA electrospun nanocomposite scaffold promotes adipose derived stem cells adhesion and proliferation,” Carbohydrate Polymers, vol. 118, pp. 133–142, 2015. View at Publisher · View at Google Scholar · View at Scopus
  114. S. D. McCullen, Y. Zhu, S. H. Bernacki et al., “Electrospun composite poly(L-lactic acid)/tricalcium phosphate scaffolds induce proliferation and osteogenic differentiation of human adipose-derived stem cells,” Biomedical Materials, vol. 4, no. 3, Article ID 035002, 2009. View at Publisher · View at Google Scholar
  115. S. Kim, K. Ahn, M. S. Park, J. Lee, C. Y. Choi, and B. Kim, “A poly(lactide-co-glycolide)/hydroxyapatite composite scaffold with enhanced osteoconductivity,” Journal of Biomedical Materials Research—Part A, vol. 80, no. 1, pp. 206–215, 2007. View at Publisher · View at Google Scholar
  116. E. Gazzerro and E. Canalis, “Bone morphogenetic proteins and their antagonists,” Reviews in Endocrine and Metabolic Disorders, vol. 7, no. 1-2, pp. 51–65, 2006. View at Publisher · View at Google Scholar · View at Scopus
  117. K. Miyazono, Y. Kamiya, and M. Morikawa, “Bone morphogenetic protein receptors and signal transduction,” The Journal of Biochemistry, vol. 147, no. 1, pp. 35–51, 2010. View at Publisher · View at Google Scholar · View at Scopus
  118. S. Ebara and K. Nakayama, “Mechanism for the action of bone morphogenetic proteins and regulation of their activity,” Spine, vol. 27, no. 16, supplement 1, pp. S10–S15, 2002. View at Publisher · View at Google Scholar · View at Scopus
  119. I. L. Weissman, “Translating stem and progenitor cell biology to the clinic: barriers and opportunities,” Science, vol. 287, no. 5457, pp. 1442–1446, 2000. View at Publisher · View at Google Scholar · View at Scopus
  120. M. J. Shamblott, J. Axelman, S. Wang et al., “Derivation of pluripotent stem cells from cultured human primordial germ cells,” Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 23, pp. 13726–13731, 1998. View at Publisher · View at Google Scholar · View at Scopus
  121. A. M. Poulsom R, S. J. Forbes, and N. A. Wright, “Adult stem cell plasticity,” The Journal of Pathology, vol. 197, pp. 441–456, 2002. View at Google Scholar
  122. J. Itskovitz-Eldor, M. Schuldiner, D. Karsenti et al., “Differentiation of human embryonic stem cells into embryoid bodies compromising the three embryonic germ layers,” Molecular Medicine, vol. 6, no. 2, pp. 88–95, 2000. View at Google Scholar · View at Scopus
  123. B. C. Heng, T. Cao, H. K. Haider, D. Z. M. Wang, E. K.-W. Sim, and S. C. Ng, “An overview and synopsis of techniques for directing stem cell differentiation in vitro,” Cell and Tissue Research, vol. 315, no. 3, pp. 291–303, 2004. View at Publisher · View at Google Scholar · View at Scopus
  124. C. M. Verfaillie, “Adult stem cells: assessing the case for pluripotency,” Trends in Cell Biology, vol. 12, no. 11, pp. 502–508, 2002. View at Publisher · View at Google Scholar · View at Scopus
  125. M. F. Pittenger, A. M. Mackay, S. C. Beck et al., “Multilineage potential of adult human mesenchymal stem cells,” Science, vol. 284, no. 5411, pp. 143–147, 1999. View at Publisher · View at Google Scholar · View at Scopus
  126. V. Feisst, A. E. S. Brooks, C.-J. J. Chen, and P. R. Dunbar, “Characterization of mesenchymal progenitor cell populations directly derived from human dermis,” Stem Cells and Development, vol. 23, no. 6, pp. 631–642, 2014. View at Publisher · View at Google Scholar · View at Scopus
  127. J. G. Toma, M. Akhavan, K. J. L. Fernandes et al., “Isolation of multipotent adult stem cells from the dermis of mammalian skin,” Nature Cell Biology, vol. 3, no. 9, pp. 778–784, 2001. View at Publisher · View at Google Scholar · View at Scopus
  128. I. Rogers and R. F. Casper, “Umbilical cord blood stem cells,” Best Practice and Research: Clinical Obstetrics and Gynaecology, vol. 18, no. 6, pp. 893–908, 2004. View at Publisher · View at Google Scholar · View at Scopus
  129. S. Kern, H. Eichler, J. Stoeve, H. Klüter, and K. Bieback, “Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue,” Stem Cells, vol. 24, no. 5, pp. 1294–1301, 2006. View at Publisher · View at Google Scholar · View at Scopus
  130. M. Dominici, K. Le Blanc, I. Mueller et al., “Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement,” Cytotherapy, vol. 8, no. 4, pp. 315–317, 2006. View at Publisher · View at Google Scholar · View at Scopus
  131. K. Le Blanc, L. Tammik, B. Sundberg, S. E. Haynesworth, and O. Ringdén, “Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex,” Scandinavian Journal of Immunology, vol. 57, no. 1, pp. 11–20, 2003. View at Publisher · View at Google Scholar · View at Scopus
  132. G. Siegel, R. Schäfer, and F. Dazzi, “The immunosuppressive properties of mesenchymal stem cells,” Transplantation, vol. 87, no. 9, pp. S45–49, 2009. View at Publisher · View at Google Scholar · View at Scopus
  133. T. Yi and S. U. Song, “Immunomodulatory properties of mesenchymal stem cells and their therapeutic applications,” Archives of Pharmacal Research, vol. 35, no. 2, pp. 213–221, 2012. View at Publisher · View at Google Scholar · View at Scopus
  134. C. K. Rebelatto, A. M. Aguiar, M. P. Moretão et al., “Dissimilar differentiation of mesenchymal stem cells from bone marrow, umbilical cord blood, and adipose tissue,” Experimental Biology and Medicine, vol. 233, no. 7, pp. 901–913, 2008. View at Publisher · View at Google Scholar · View at Scopus
  135. F. P. Barry and J. M. Murphy, “Mesenchymal stem cells: clinical applications and biological characterization,” International Journal of Biochemistry and Cell Biology, vol. 36, no. 4, pp. 568–584, 2004. View at Publisher · View at Google Scholar · View at Scopus
  136. M. B. Murphy, K. Moncivais, and A. I. Caplan, “Mesenchymal stem cells: environmentally responsive therapeutics for regenerative medicine,” Experimental & Molecular Medicine, vol. 45, no. 11, article e54, 2013. View at Publisher · View at Google Scholar · View at Scopus
  137. A. J. Friedenstein, R. K. Chailakhjan, and K. S. Lalykina, “The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells,” Cell and Tissue Kinetics, vol. 3, no. 4, pp. 393–403, 1970. View at Google Scholar · View at Scopus
  138. J. M. Seong, B.-C. Kim, J.-H. Park, I. K. Kwon, A. Mantalaris, and Y.-S. Hwang, “Stem cells in bone tissue engineering,” Biomedical Materials, vol. 5, no. 6, Article ID 062001, 2001. View at Publisher · View at Google Scholar
  139. R. L. R. Van, C. E. Bayliss, and D. A. K. Roncari, “Cytological and enzymological characterization of adult human adipocyte precursors in culture,” The Journal of Clinical Investigation, vol. 58, no. 3, pp. 699–704, 1976. View at Publisher · View at Google Scholar · View at Scopus
  140. H. Mizuno, “Adipose-derived stem cells for tissue repair and regeneration: ten years of research and a literature review,” Journal of Nippon Medical School, vol. 76, no. 2, pp. 56–66, 2009. View at Publisher · View at Google Scholar · View at Scopus
  141. L. Aust, B. Devlin, S. J. Foster et al., “Yield of human adipose-derived adult stem cells from liposuction aspirates,” Cytotherapy, vol. 6, no. 1, pp. 7–14, 2004. View at Publisher · View at Google Scholar · View at Scopus
  142. P. C. Baer and H. Geiger, “Adipose-derived mesenchymal stromal/stem cells: tissue localization, characterization, and heterogeneity,” Stem Cells International, vol. 2012, Article ID 812693, 11 pages, 2012. View at Publisher · View at Google Scholar · View at Scopus
  143. C. T. Gomillion and K. J. L. Burg, “Stem cells and adipose tissue engineering,” Biomaterials, vol. 27, no. 36, pp. 6052–6063, 2006. View at Publisher · View at Google Scholar · View at Scopus
  144. J. M. Gimble and F. Guilak, “Adipose-derived adult stem cells: isolation, characterization, and differentiation potential,” Cytotherapy, vol. 5, no. 5, pp. 362–369, 2003. View at Publisher · View at Google Scholar · View at Scopus
  145. F. Mosna, L. Sensebé, and M. Krampera, “Human bone marrow and adipose tissue mesenchymal stem cells: a user's guide,” Stem Cells and Development, vol. 19, no. 10, pp. 1449–1470, 2010. View at Publisher · View at Google Scholar · View at Scopus
  146. C. Brayfield, K. Marra, and J. P. Rubin, “Adipose stem cells for soft tissue regeneration,” Handchirurgie, Mikrochirurgie, Plastische Chirurgie, vol. 42, no. 2, pp. 124–128, 2010. View at Publisher · View at Google Scholar
  147. J. M. Gimble and F. Guilak, “Differentiation potential of adipose derived adult stem (ADAS) cells,” Current Topics in Developmental Biology, vol. 58, pp. 137–160, 2003. View at Publisher · View at Google Scholar · View at Scopus
  148. B. Lindroos, R. Suuronen, and S. Miettinen, “The potential of adipose stem cells in regenerative medicine,” Stem Cell Reviews and Reports, vol. 7, no. 2, pp. 269–291, 2011. View at Publisher · View at Google Scholar · View at Scopus
  149. B. A. Bunnell, M. Flaat, C. Gagliardi, B. Patel, and C. Ripoll, “Adipose-derived stem cells: isolation, expansion and differentiation,” Methods, vol. 45, no. 2, pp. 115–120, 2008. View at Publisher · View at Google Scholar · View at Scopus
  150. A. C. Boquest, A. Shahdadfar, J. E. Brinchmann, and P. Collas, “Isolation of stromal stem cells from human adipose tissue,” Methods in Molecular Biology, vol. 325, pp. 35–46, 2006. View at Google Scholar · View at Scopus
  151. K. Gonda, T. Shigeura, T. Sato et al., “Preserved proliferative capacity and multipotency of human adipose-derived stem cells after long-term cryopreservation,” Plastic and Reconstructive Surgery, vol. 121, no. 2, pp. 401–410, 2008. View at Publisher · View at Google Scholar · View at Scopus
  152. H. Li, L. Zimmerlin, K. G. Marra, V. S. Donnenberg, A. D. Donnenberg, and J. P. Rubin, “Adipogenic potential of adipose stem cell subpopulations,” Plastic and Reconstructive Surgery, vol. 128, no. 3, pp. 663–672, 2011. View at Publisher · View at Google Scholar
  153. J. B. Mitchell, K. McIntosh, S. Zvonic et al., “Immunophenotype of human adipose-derived cells: temporal changes in stromal-associated and stem cell-associated markers,” Stem Cells, vol. 24, no. 2, pp. 376–385, 2006. View at Publisher · View at Google Scholar · View at Scopus
  154. K. McIntosh, S. Zvonic, S. Garrett et al., “The immunogenicity of human adipose-derived cells: temporal changes in vitro,” Stem Cells, vol. 24, no. 5, pp. 1246–1253, 2006. View at Publisher · View at Google Scholar · View at Scopus
  155. B. Puissant, C. Barreau, P. Bourin et al., “Immunomodulatory effect of human adipose tissue-derived adult stem cells: comparison with bone marrow mesenchymal stem cells,” British Journal of Haematology, vol. 129, no. 1, pp. 118–129, 2005. View at Publisher · View at Google Scholar · View at Scopus
  156. S. S. Tholpady, R. Llull, R. C. Ogle, J. P. Rubin, J. W. Futrell, and A. J. Katz, “Adipose tissue: stem cells and beyond,” Clinics in Plastic Surgery, vol. 33, no. 1, pp. 55–62, 2006. View at Publisher · View at Google Scholar · View at Scopus
  157. S. Gronthos, D. M. Franklin, H. A. Leddy, P. G. Robey, R. W. Storms, and J. M. Gimble, “Surface protein characterization of human adipose tissue-derived stromal cells,” Journal of Cellular Physiology, vol. 189, no. 1, pp. 54–63, 2001. View at Publisher · View at Google Scholar · View at Scopus
  158. A. J. B. O. G. Salgado, R. L. G. Reis, N. J. C. Sousa, and J. M. Gimble, “Adipose tissue derived stem cells secretome: soluble factors and their roles in regenerative medicine,” Current Stem Cell Research and Therapy, vol. 5, no. 2, pp. 103–110, 2010. View at Publisher · View at Google Scholar · View at Scopus
  159. J. Rehman, D. Traktuev, J. Li et al., “Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells,” Circulation, vol. 109, no. 10, pp. 1292–1298, 2004. View at Publisher · View at Google Scholar · View at Scopus
  160. H. Hauner, K. Rohrig, and T. Petruschke, “Effects of epidermal growth factor (EGF), platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) on human adipocyte development and function,” European Journal of Clinical Investigation, vol. 25, no. 2, pp. 90–96, 1995. View at Publisher · View at Google Scholar · View at Scopus
  161. Y. Kubo, S. Kaidzu, I. Nakajima, K. Takenouchi, and F. Nakamura, “Organization of extracellular matrix components during differentiation of adipocytes in long-term culture,” In Vitro Cellular and Developmental Biology—Animal, vol. 36, no. 1, pp. 38–44, 2000. View at Publisher · View at Google Scholar · View at Scopus
  162. Y.-D. C. Halvorsen, D. Franklin, A. L. Bond et al., “Extracellular matrix mineralization and osteoblast gene expression by human adipose tissue-derived stromal cells,” Tissue Engineering, vol. 7, no. 6, pp. 729–741, 2001. View at Publisher · View at Google Scholar · View at Scopus
  163. Y. Wei, X. Sun, W. Wang, and Y. Hu, “Adipose-derived stem cells and chondrogenesis,” Cytotherapy, vol. 9, no. 8, pp. 712–716, 2007. View at Publisher · View at Google Scholar · View at Scopus
  164. W. S. Khan, S. R. Tew, A. B. Adesida, and T. E. Hardingham, “Human infrapatellar fat pad-derived stem cells express the pericyte marker 3G5 and show enhanced chondrogenesis after expansion in fibroblast growth factor-2,” Arthritis Research & Therapy, vol. 10, no. 4, article R74, 2008. View at Publisher · View at Google Scholar · View at Scopus
  165. B. T. Estes and F. Guilak, “Three-dimensional culture systems to induce chondrogenesis of adipose-derived stem cells,” in Adipose-Derived Stem Cells, J. M. Gimble and B. A. Bunnell, Eds., vol. 702 of Methods in Molecular Biology, pp. 201–217, Humana Press, 2011. View at Publisher · View at Google Scholar
  166. J. Wolff, The Law of Bone Remodeling, Translation from the Original: Das Gesetz der Transformation der knochen, August Hirsch, Springer, 1986.
  167. Y.-X. Qin and M. Hu, “Mechanotransduction in musculoskeletal tissue regeneration: effects of fluid flow, loading, and cellular-molecular pathways,” BioMed Research International, vol. 2014, Article ID 863421, 12 pages, 2014. View at Publisher · View at Google Scholar · View at Scopus
  168. S. Goodman and P. Aspenberg, “Effects of mechanical stimulation on the differentiation of hard tissues,” Biomaterials, vol. 14, no. 8, pp. 563–569, 1993. View at Publisher · View at Google Scholar · View at Scopus
  169. K. T. Salisbury Palomares, R. E. Gleason, Z. D. Mason et al., “Mechanical stimulation alters tissue differentiation and molecular expression during bone healing,” Journal of Orthopaedic Research, vol. 27, no. 9, pp. 1123–1132, 2009. View at Publisher · View at Google Scholar · View at Scopus
  170. G. H. Altman, R. L. Horan, I. Martin et al., “Cell differentiation by mechanical stress,” The FASEB Journal, vol. 16, no. 2, pp. 270–272, 2002. View at Publisher · View at Google Scholar
  171. S. Kapur, D. J. Baylink, and K.-H. W. Lau, “Fluid flow shear stress stimulates human osteoblast proliferation and differentiation through multiple interacting and competing signal transduction pathways,” Bone, vol. 32, no. 3, pp. 241–251, 2003. View at Publisher · View at Google Scholar · View at Scopus
  172. T. Yoshikawa, S. A. F. Peel, J. R. Gladstone, and J. E. Davies, “Biochemical analysis of the response in rat bone marrow cell cultures to mechanical stimulation,” Bio-Medical Materials and Engineering, vol. 7, no. 6, pp. 369–377, 1997. View at Google Scholar · View at Scopus
  173. C. A. Simmons, S. Matlis, A. J. Thornton, S. Chen, C.-Y. Wang, and D. J. Mooney, “Cyclic strain enhances matrix mineralization by adult human mesenchymal stem cells via the extracellular signal-regulated kinase (ERK1/2) signaling pathway,” Journal of Biomechanics, vol. 36, no. 8, pp. 1087–1096, 2003. View at Publisher · View at Google Scholar · View at Scopus
  174. N. Matsuda, N. Morita, K. Matsuda, and M. Watanabe, “Proliferation and differentiation of human osteoblastic cells associated with differential activation of MAP kinases in response to epidermal growth factor, hypoxia, and mechanical stress in vitro,” Biochemical and Biophysical Research Communications, vol. 249, no. 2, pp. 350–354, 1998. View at Publisher · View at Google Scholar · View at Scopus
  175. J. M. LaMothe and R. F. Zernicke, “Rest insertion combined with high-frequency loading enhances osteogenesis,” Journal of Applied Physiology, vol. 96, no. 5, pp. 1788–1793, 2004. View at Publisher · View at Google Scholar · View at Scopus
  176. M. Morinobu, M. Ishijima, S. R. Rittling et al., “Osteopontin expression in osteoblasts and osteocytes during bone formation under mechanical stress in the calvarial suture in vivo,” Journal of Bone and Mineral Research, vol. 18, no. 9, pp. 1706–1715, 2003. View at Publisher · View at Google Scholar · View at Scopus
  177. R. D. Sumanasinghe, J. A. Osborne, and E. G. Loboa, “Mesenchymal stem cell-seeded collagen matrices for bone repair: effects of cyclic tensile strain, cell density, and media conditions on matrix contraction in vitro,” Journal of Biomedical Materials Research A, vol. 88, no. 3, pp. 778–786, 2009. View at Publisher · View at Google Scholar · View at Scopus
  178. M. Jagodzinski, M. Drescher, J. Zeichen et al., “Effects of cyclic longitudinal mechanical strain and dexamethasone on osteogenic differentiation of human bone marrow stromal cells,” European Cells and Materials, vol. 7, pp. 35–41, 2004. View at Google Scholar · View at Scopus
  179. L. Liu, W. Yuan, and J. Wang, “Mechanisms for osteogenic differentiation of human mesenchymal stem cells induced by fluid shear stress,” Biomechanics and Modeling in Mechanobiology, vol. 9, no. 6, pp. 659–670, 2010. View at Publisher · View at Google Scholar · View at Scopus
  180. M. Knippenberg, M. N. Helder, B. Z. Doulabi, C. M. Semeins, P. I. J. M. Wuisman, and J. Klein-Nulend, “Adipose tissue-derived mesenchymal stem cells acquire bone cell-like responsiveness to fluid shear stress on osteogenic stimulation,” Tissue Engineering, vol. 11, no. 11-12, pp. 1780–1788, 2005. View at Publisher · View at Google Scholar · View at Scopus
  181. L. Liu, B. Yu, J. Chen et al., “Different effects of intermittent and continuous fluid shear stresses on osteogenic differentiation of human mesenchymal stem cells,” Biomechanics and Modeling in Mechanobiology, vol. 11, no. 3-4, pp. 391–401, 2012. View at Publisher · View at Google Scholar · View at Scopus
  182. W. G. Billotte and M.-C. Hofmann, “Establishment of a shear stress protocol to study the mechanosensitivity of human primary osteogenic cells in vitro,” Biomedical Sciences Instrumentation, vol. 35, pp. 327–332, 1999. View at Google Scholar · View at Scopus
  183. R. L. Duncan and C. H. Turner, “Mechanotransduction and the functional response of bone to mechanical strain,” Calcified Tissue International, vol. 57, no. 5, pp. 344–358, 1995. View at Publisher · View at Google Scholar · View at Scopus
  184. M. Hartig, U. Joos, and H.-P. Wiesmann, “Capacitively coupled electric fields accelerate proliferation of osteoblast-like primary cells and increase bone extracellular matrix formation in vitro,” European Biophysics Journal, vol. 29, no. 7, pp. 499–506, 2000. View at Publisher · View at Google Scholar · View at Scopus
  185. C. H. Lohmann, Z. Schwartz, Y. Liu et al., “Pulsed electromagnetic field stimulation of MG63 osteoblast-like cells affects differentiation and local factor production,” Journal of Orthopaedic Research, vol. 18, no. 4, pp. 637–646, 2000. View at Publisher · View at Google Scholar · View at Scopus
  186. S. Sun, Y. Liu, S. Lipsky, and M. Cho, “Physical manipulation of calcium oscillations facilitates osteodifferentiation of human mesenchymal stem cells,” The FASEB Journal, vol. 21, no. 7, pp. 1472–1480, 2007. View at Publisher · View at Google Scholar · View at Scopus
  187. J. B. Haddad, A. G. Obolensky, and P. Shinnick, “The biologic effects and the therapeutic mechanism of action of electric and electromagnetic field stimulation on bone and cartilage: new findings and a review of earlier work,” Journal of Alternative and Complementary Medicine, vol. 13, no. 5, pp. 485–490, 2007. View at Publisher · View at Google Scholar · View at Scopus
  188. K. E. Hammerick, A. W. James, Z. Huang, F. B. Prinz, and M. T. Longaker, “Pulsed direct current electric fields enhance osteogenesis in adipose-derived stromal cells,” Tissue Engineering Part A, vol. 16, no. 3, pp. 917–931, 2010. View at Publisher · View at Google Scholar · View at Scopus
  189. S. D. McCullen, J. P. McQuilling, R. M. Grossfeld, J. L. Lubischer, L. I. Clarke, and E. G. Loboa, “Application of low-frequency alternating current electric fields via interdigitated electrodes: effects on cellular viability, cytoplasmic calcium, and osteogenic differentiation of human adipose-derived stem cells,” Tissue Engineering—Part C: Methods, vol. 16, no. 6, pp. 1377–1386, 2010. View at Publisher · View at Google Scholar · View at Scopus
  190. H. Kotani, H. Kawaguchi, T. Shimoaka et al., “Strong static magnetic field stimulates bone formation to a definite orientation in vitro and in vivo,” Journal of Bone and Mineral Research, vol. 17, no. 10, pp. 1814–1821, 2002. View at Publisher · View at Google Scholar · View at Scopus
  191. Y. Yamamoto, Y. Ohsaki, T. Goto, A. Nakasima, and T. Iijima, “Effects of static magnetic fields on bone formation in rat osteoblast cultures,” Journal of Dental Research, vol. 82, no. 12, pp. 962–966, 2003. View at Publisher · View at Google Scholar · View at Scopus
  192. M. S. Machen, J. E. Tis, N. Inoue, R. H. Meffert, E. Y. S. Chao, and K. A. McHale, “The effect of low intensity pulsed ultrasound on regenerate bone in a less-than-rigid biomechanical environment,” Bio-Medical Materials and Engineering, vol. 12, no. 3, pp. 239–247, 2002. View at Google Scholar · View at Scopus
  193. K. Lim, J. Kim, H. Seonwoo, S. H. Park, P.-H. Choung, and J. H. Chung, “In vitro effects of low-intensity pulsed ultrasound stimulation on the osteogenic differentiation of human alveolar bone-derived mesenchymal stem cells for tooth tissue engineering,” BioMed Research International, vol. 2013, Article ID 269724, 15 pages, 2013. View at Publisher · View at Google Scholar · View at Scopus
  194. Y. Ozawa, N. Shimizu, G. Kariya, and Y. Abiko, “Low-energy laser irradiation stimulates bone nodule formation at early stages of cell culture in rat calvarial cells,” Bone, vol. 22, no. 4, pp. 347–354, 1998. View at Publisher · View at Google Scholar · View at Scopus
  195. Y. Ueda and N. Shimizu, “Pulse irradiation of low-power laser stimulates bone nodule formation,” Journal of Oral Science, vol. 43, no. 1, pp. 55–60, 2001. View at Publisher · View at Google Scholar · View at Scopus
  196. M. Mravic, B. Péault, and A. W. James, “Current trends in bone tissue engineering,” BioMed Research International, vol. 2014, Article ID 865270, 5 pages, 2014. View at Publisher · View at Google Scholar · View at Scopus
  197. P. V. Giannoudis, T. A. Einhorn, and D. Marsh, “Fracture healing: the diamond concept,” Injury, vol. 38, supplement 4, pp. S3–S6, 2007. View at Publisher · View at Google Scholar · View at Scopus
  198. G. M. Calori and P. V. Giannoudis, “Enhancement of fracture healing with the diamond concept: the role of the biological chamber,” Injury, vol. 42, no. 11, pp. 1191–1193, 2011. View at Publisher · View at Google Scholar · View at Scopus
  199. P. V. Giannoudis, T. A. Einhorn, G. Schmidmaier, and D. Marsh, “The diamond concept—open questions,” Injury, vol. 39, supplement 2, pp. S5–S8, 2008. View at Publisher · View at Google Scholar · View at Scopus
  200. E. Yoon, S. Dhar, D. E. Chun, N. A. Gharibjanian, and G. R. D. Evans, “In vivo osteogenic potential of human adipose-derived stem cells/poly lactide-co-glycolic acid constructs for bone regeneration in a rat critical-sized calvarial defect model,” Tissue Engineering, vol. 13, no. 3, pp. 619–627, 2007. View at Publisher · View at Google Scholar · View at Scopus
  201. L. Cui, B. Liu, G. Liu et al., “Repair of cranial bone defects with adipose derived stem cells and coral scaffold in a canine model,” Biomaterials, vol. 28, no. 36, pp. 5477–5486, 2007. View at Publisher · View at Google Scholar · View at Scopus
  202. P. P. Carvalho, I. B. Leonor, B. J. Smith et al., “Undifferentiated human adipose-derived stromal/stem cells loaded onto wet-spun starch-polycaprolactone scaffolds enhance bone regeneration: nude mice calvarial defect in vivo study,” Journal of Biomedical Materials Research: Part A, vol. 102, no. 9, pp. 3102–3111, 2014. View at Publisher · View at Google Scholar · View at Scopus
  203. T. Schubert, S. Lafont, G. Beaurin et al., “Critical size bone defect reconstruction by an autologous 3D osteogenic-like tissue derived from differentiated adipose MSCs,” Biomaterials, vol. 34, no. 18, pp. 4428–4438, 2013. View at Publisher · View at Google Scholar · View at Scopus
  204. G. Liu, Y. Zhang, B. Liu, J. Sun, W. Li, and L. Cui, “Bone regeneration in a canine cranial model using allogeneic adipose derived stem cells and coral scaffold,” Biomaterials, vol. 34, no. 11, pp. 2655–2664, 2013. View at Publisher · View at Google Scholar · View at Scopus
  205. C. M. Cowan, Y.-Y. Shi, O. O. Aalami et al., “Adipose-derived adult stromal cells heal critical-size mouse calvarial defects,” Nature Biotechnology, vol. 22, no. 5, pp. 560–567, 2004. View at Publisher · View at Google Scholar · View at Scopus
  206. C. Di Bella, P. Farlie, and A. J. Penington, “Bone regeneration in a rabbit critical-sized skull defect using autologous adipose-derived cells,” Tissue Engineering Part: A, vol. 14, no. 4, pp. 483–490, 2008. View at Publisher · View at Google Scholar · View at Scopus
  207. S. Lendeckel, A. Jödicke, P. Christophis et al., “Autologous stem cells (adipose) and fibrin glue used to treat widespread traumatic calvarial defects: case report,” Journal of Cranio-Maxillofacial Surgery, vol. 32, no. 6, pp. 370–373, 2004. View at Publisher · View at Google Scholar · View at Scopus
  208. I. Nomura, K. Watanabe, H. Matsubara, K. Hayashi, N. Sugimoto, and H. Tsuchiya, “Uncultured autogenous adipose-derived regenerative cells promote bone formation during distraction osteogenesis in rats,” Clinical Orthopaedics and Related Research, vol. 472, no. 12, pp. 3798–3806, 2014. View at Publisher · View at Google Scholar · View at Scopus
  209. O. Sunay, G. Can, Z. Cakir et al., “Autologous rabbit adipose tissue-derived mesenchymal stromal cells for the treatment of bone injuries with distraction osteogenesis,” Cytotherapy, vol. 15, no. 6, pp. 690–702, 2013. View at Publisher · View at Google Scholar · View at Scopus
  210. E. Arrigoni, L. De Girolamo, A. Di Giancamillo et al., “Adipose-derived stem cells and rabbit bone regeneration: histomorphometric, immunohistochemical and mechanical characterization,” Journal of Orthopaedic Science, vol. 18, no. 2, pp. 331–339, 2013. View at Publisher · View at Google Scholar · View at Scopus
  211. S. W. Cheng, Z. Q. Lin, W. Wang et al., “Osteogenic capability of autologous rabbit adipose-derived stromal cells in repairing calvarial defects,” Chinese Journal of Traumatology, vol. 14, no. 5, pp. 288–292, 2011. View at Google Scholar
  212. C.-Y. Lin, Y.-H. Chang, K.-C. Li et al., “The use of ASCs engineered to express BMP2 or TGF-β3 within scaffold constructs to promote calvarial bone repair,” Biomaterials, vol. 34, no. 37, pp. 9401–9412, 2013. View at Publisher · View at Google Scholar · View at Scopus
  213. B. Peterson, J. Zhang, R. Iglesias et al., “Healing of critically sized femoral defects, using genetically modified mesenchymal stem cells from human adipose tissue,” Tissue Engineering, vol. 11, no. 1-2, pp. 120–129, 2005. View at Publisher · View at Google Scholar · View at Scopus
  214. B. Levi, A. W. James, E. R. Nelson et al., “Human adipose derived stromal cells heal critical size mouse calvarial defects,” PLoS ONE, vol. 5, no. 6, Article ID e11177, 2010. View at Publisher · View at Google Scholar · View at Scopus
  215. H. Kitoh, T. Kitakoji, H. Tsuchiya, M. Katoh, and N. Ishiguro, “Distraction osteogenesis of the lower extremity in patients with achondroplasia/hypochondroplasia treated with transplantation of culture-expanded bone marrow cells and platelet-rich plasma,” Journal of Pediatric Orthopaedics, vol. 27, no. 6, pp. 629–634, 2007. View at Publisher · View at Google Scholar · View at Scopus
  216. H. W. Doerr, J. Cínatl, M. Stürmer, and H. F. Rabenau, “Prions and orthopedic surgery,” Infection, vol. 31, no. 3, pp. 163–171, 2003. View at Google Scholar · View at Scopus
  217. A. Shahdadfar, K. Frønsdal, T. Haug, F. P. Reinholt, and J. E. Brinchmann, “In vitro expansion of human mesenchymal stem cells: choice of serum is a determinant of cell proliferation, differentiation, gene expression, and transcriptome stability,” Stem Cells, vol. 23, no. 9, pp. 1357–1366, 2005. View at Publisher · View at Google Scholar · View at Scopus
  218. B. Lindroos, S. Boucher, L. Chase et al., “Serum-free, xeno-free culture media maintain the proliferation rate and multipotentiality of adipose stem cells in vitro,” Cytotherapy, vol. 11, no. 7, pp. 958–972, 2009. View at Publisher · View at Google Scholar · View at Scopus
  219. K. Rajala, B. Lindroos, S. M. Hussein et al., “A defined and xeno-free culture method enabling the establishment of clinical-grade human embryonic, induced pluripotent and adipose stem cells,” PLoS ONE, vol. 5, no. 4, Article ID e10246, 2010. View at Publisher · View at Google Scholar · View at Scopus
  220. W. Im, J.-Y. Chung, S.-H. Kim, and M. Kim, “Efficacy of autologous serum in human adipose-derived stem cells; cell markers, growth factors and differentiation,” Cellular and Molecular Biology, vol. 57, pp. 1470–1475, 2011. View at Publisher · View at Google Scholar · View at Scopus
  221. B. Lindroos, K.-L. Aho, H. Kuokkanen et al., “Differential gene expression in adipose stem cells cultured in allogeneic human serum versus fetal bovine serum,” Tissue Engineering. Part A, vol. 16, no. 7, pp. 2281–2294, 2010. View at Publisher · View at Google Scholar · View at Scopus
  222. L. Kucerova, V. Altanerova, M. Matuskova, S. Tyciakova, and C. Altaner, “Adipose tissue-derived human mesenchymal stem cells mediated prodrug cancer gene therapy,” Cancer Research, vol. 67, no. 13, pp. 6304–6313, 2007. View at Publisher · View at Google Scholar · View at Scopus
  223. F. L. Muehlberg, Y.-H. Song, A. Krohn et al., “Tissue-resident stem cells promote breast cancer growth and metastasis,” Carcinogenesis, vol. 30, no. 4, pp. 589–597, 2009. View at Publisher · View at Google Scholar · View at Scopus
  224. B. Cousin, E. Ravet, S. Poglio et al., “Adult stromal cells derived from human adipose tissue provoke pancreatic cancer cell death both in vitro and in vivo,” PLoS ONE, vol. 4, no. 7, Article ID e6278, 2009. View at Publisher · View at Google Scholar · View at Scopus
  225. J. M. Yu, E. S. Jun, Y. C. Bae, and J. S. Jung, “Mesenchymal stem cells derived from human adipose tissues favor tumor cell growth in vivo,” Stem Cells and Development, vol. 17, no. 3, pp. 463–473, 2008. View at Publisher · View at Google Scholar · View at Scopus
  226. G. Grisendi, R. Bussolari, L. Cafarelli et al., “Adipose-derived mesenchymal stem cells as stable source of tumor necrosis factor-related apoptosis-inducing ligand delivery for cancer therapy,” Cancer Research, vol. 70, no. 9, pp. 3718–3729, 2010. View at Publisher · View at Google Scholar · View at Scopus
  227. L. T. Donnan, M. Saleh, A. S. Rigby, and A. McAndrew, “Radiographic assessment of bone formation in tibia during distraction osteogenesis,” Journal of Pediatric Orthopaedics, vol. 22, no. 5, pp. 645–651, 2002. View at Publisher · View at Google Scholar · View at Scopus
  228. M. R. Hamdy and J. McCarthy, “Monitoring of regenerate bone,” in Management of Limb-Length Discrepancies, pp. 191–196, American Academy of Orthopaedic Surgeons, Rosemont, Ill, USA, 2011. View at Google Scholar
  229. A. M. Makhdom, L. Nayef, M. Tabrizian, and R. C. Hamdy, “The potential roles of nanobiomaterials in distraction osteogenesis,” Nanomedicine: Nanotechnology, Biology, and Medicine, vol. 11, no. 1, pp. 1–18, 2015. View at Publisher · View at Google Scholar · View at Scopus