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The field of regenerative medicine (RM), encompassing stem cell (SC, therapeutics, and tissue engineering (TE) provides a wide gamut of tools to combat, manage, and, hopefully, cure serious human and animal injuries, dysfunctions, and diseases. Media hype and public expectations combined with divided trends and approaches among scientific, clinical, and business leaders have lead to time- and cost-ineffectiveness and unconsolidated outcomes. Decision making is central to new drug development, which can be very costly, risky, and time-consuming especially for newer therapeutics and technologies such as RM.
The RM field is rapidly evolving with a variety of adult and nonadult tissue resources and growing involvement of diversified players from academia, nonprofit, for-profit, regulatory, and government organizations.
British Pharmacological Society Stem Cells: Pharmacology and Therapeutics Meeting (December 2011) "Engineering Cell Based Solutions for Cardiovascular Diseases" London, UK. Annual Research Day in Transplantation, (December 2011) "Bioartificial Organss: cure for the 21st Century" Toronto, Canada. British Society for Heart and Lung Transplantation (April 2011) "Building Matrix Based Solutions for Disease: An Update" Bristol, UK. Frontiers in Cardiovascular Biology (July 2010) "Estrogen Effects in Stem Cell Function." Berlin, Germany. 4th Congress of the International Society for Gender in Medicine (November 2009) "Sex and Estrogens in Stem Cell Function." Berlin, Germany. Organization for the Study of Sex Differences 2009 Annual Meeting (June 2009) "Sex-based differences in vascular repair with stem cells." Toronto, Canada. The First EACTS meeting on Cardio-Thoracic Regeneration (November 2008) "Are Bioartificial Organs A Piece of the future?" Bern, Switzerland. EACTS-Technology College (September 2008) "Mechanical Circulatory Support" Lisbon, Portugal. Heart Failure Society 12th Annual Scientific Meeting (September 2008) "The Bioartificial Heart" Toronto, Canada.
Stem Cell Therapy for the Failing Heart (December 2006) "Cell Therapy for Heart Failure: Muscle, Bone Marrow, Blood, and Cardiac-Derived Stem Cells"A  "Update Results of Skeletal Myoblast Transplantation", Bangkok, Thailand. The 11th Congress of the International Society for Peritoneal Dialysis (ISPD 2006) (August 2006) "Stem Cell Therapies: A View from the Trenches and Implications for PD Patients", Hong Kong.
Society of Nuclear Medicine 52nd Annual Meeting (June 2005) "Overview of Cardiac Stem Cells." Toronto, Ontario Canada. ISHLT 23rd Annual Meeting and Scientific Sessions (April 2003) "Heart Failure: Who Needs Drugs Anyway?" Vienna, Austria.
International Society for Heart and Lung Transplantation, (March 2001) Plenary Lecture, Vancouver British Columbia, Canada.
New York Cardiovascular Symposium (December 2011) "Stem Cell based Heart Replacement Status of the Taylor Heart" New York, NY. Gordon Research Conference on Assisted Circulation (August 2007) Mechanical Circulatory Support Big Sky, MT. ACC American College of Cardiology Foundation 54th Annual Scientific Session (March 2005) "Cells Lines and Genes: What Is Most Promising? Sarnoff Endowment (May 2003) "Cell Therapy for Vascular Injury: Will it Work?" Washington, DC.
NHLBI Cell Transplantation Workshop: Future Therapeutics for Cardiovascular Disease, (August 1998).
Center for Emerging Cardiovascular Technologies, (1996-1998) Annual Industry MeetingA  New Technologies Panel, "The Challenge for Industry in Cellular Cardiomyoplasty." Duke University. Talent Discovery Forum, (October 1996) Medtronic, Inc., Cellular Cardiomyoplasty and Cardiac Gene Therapy.
My current research topics include viscoelastic behavior of cortical bone using nanoindentation at the nano level and dynamic mechanical analysis (DMA) at the macro-level, bone mineralization analysis using micro-CT and clinical cone beam CT (CBCT). This revolutionary natural male enhancement is the most effective and safest natural alternative to prescription drugs or surgery. All consultations are 100% confidential.  Call today for your consultation at 866-750-5057. This website and the information featured, showcased or otherwise appearing on it is not to be used as a substitute for medical advice, diagnosis or treatment of any health condition or problem. The same regeneration occurs in the connective tissue of the dermal or skin layers, but generally much more rapidly.
Growth factors from your platelets enhance proliferation of fibroblasts and keratinocytes which produce collagen and keratin respectively . By providing the dermal layers with platelet derived growth factors, new blood vessels are created and improved circulation results. Areas of treatment include cheeks and mid-face, wrinkling around the eyes, smile lines, nasolabial fold, neck and jawline, acne scarring and more. Transmision electron micrograph of osteoblasts (numbered) on a bone surface in which the collagenous matrix has been deposited in two layers (A and B) at right angles to each other. The signal cascade inside the cell after the receptor binding of GFs involves in bone repair.
Schematic representation of the genetically engineered fusion construct, containing a histidine purification tag, a protease site, an auxiliary von Willebrand Factor collagen binding domain.
Bone fracture repair and regeneration is a question of balance among cells, growth factors and biomaterials.7. A Andrades, 2008The effect of type I collagen on osteochondrogenic differentiation in adipose-derived stromal cells in vivo.
My research includes the elastic, viscoelastic, and fracture mechanical testing, the utilization of imaging technique, micro-CT, CBCT, DMA and nanoindentation of bone at bone-implant interface, bone-scaffold constructs, and disease. Our natural male enhancement supports sexual performance and stronger erections.  Discover the natural method for male enhancement. Those who visit this web site should not rely on information provided on it for their own health problems. The Golgi apparatus (G) and rough endoplasmic reticulum (r) are prominent cytoplasmic organelles in osteoblasts. Stem cells are either isolated from the patient (autologous transplantation) or from other donors (allogenous transplantation). Derivation of embryonic stem cells (ESCs), embryonic germ cells (EGCs) and adult stem cells (SCs). They directly differentiate into tissue-specific cells and thus substitute damaged or lost cells (A).
Among the classes of bioactive factors, such as matrix ligand, mechanical stimulation, and cell shape, GFs exert strong effects on the regulation of the lineage differentiation of MSCs. Recombinant hTGF-?1-F2 applied to a bovine collagen matrix as vehicle and delivery system could be of advantage in promoting the survival, proliferation, differentiation, and colony mineralization of the osteogenic precursor cell population. Any questions regarding your own health should be addressed to your physician or other duly licensed healthcare provider.
The cells are expanden in vitro and either applied directly to the patient to substitute lost cells (Cell Therapy), or seeded into 3 dimensional scaffolds (Tissue Engineering) and differentiated into the demanded cell type. E Nimni, 1999aA recombinant human TGF-?1 fusion protein with collagen-binding domain promotes migration, growth, and differentiation of bone marrow mesenchymal cells. E Nimni, J Becerra, 1999b Selection, amplification, induction and differentiation of osteoprogenitor cells: an alternative for bone repair.
This website makes no guarantees, warranties or express or implied representations whatsoever with regard to the accuracy, completeness, timeliness, comparative or controversial nature, or usefulness of any information contained or referenced on this Web site. The composed artificial tissue construct is subsequently implanted into patients’ tissue defect.
Here they promote vascularization, cell proliferation, differentiation within the tissue (B) and modulate inflammatory processes (C). Moreno-Moreno3[1] Laboratory of Bioengineering and Tissue Regeneration (LABRET?UMA), Department of Cell Biology, Genetics and Physiology.
This website and its owners and operators do not assume any risk whatsoever for your use of this website or the information posted herein. Pictures represent two histological sections, stained with Sirius red and observed under light (left, femur segmental resection) and polarized (right, profile of a hydroxyapatite implant) microscopes. Faculty of Sciences, University of Malaga, Spain[2] Networking Biomedical Research Center in Bioengineering, Biomaterials and Nanomedicine (CIBER?BBN), Spain[3] Faculty of Sciences, University of Malaga, Spain1.
Health-related information and opinions change frequently and therefore information contained on this Website may be outdated, incomplete or incorrect. All statements made about products, drugs and such on this website have not been evaluated by the Food and Drug Administration (FDA). A connective tissueBone is a highly specialized form of connective tissue that is nature’s provision for an internal support system in all higher vertebrates. In addition, any testimonials appearing on this website are based on the experiences of a few people and you are not likely to have similar results.
It is a complex living tissue in which the extracellular matrix (ECM) is mineralized, conferring marked rigidity and strength to the skeleton while still maintaining some degree of elasticity. In addition to its supportive and protective organic ions, it actively participates in maintaining calcium homeostasis in the body.Bone is composed of an organic matrix that is strengthened by deposits of calcium salts. Type I collagen constitutes approximately 95% of the organic matrix; the remaining 5% is composed of proteoglycans and numerous noncollagenous proteins.


In cortical bone, densely packed collagen fibrils form concentric lamellae, and the fibrils in adjacent lamellae run in perpendicular planes as in plywood.
Osteoblasts, osteoclasts, and bone lining cells are present on bone surfaces, whereas osteocytes permeate the mineralized interior. Taken from Academic Press Inc., with permissionOsteoblasts are the fully differentiated cells responsible for the production of the bone matrix.
An osteoblast is a typical protein-producing cell with a prominent Golgi apparatus and well-developed rough endoplasmic reticulum. Taken from Academic Press Inc., with permissionThe staggered overlap of the individual collagen molecules provides the characteristic periodicity of type I collagen in bone matrix.
Numerous noncollagenous proteins have been isolated from bone matrix (Sandberg, 1991) but to date there is no consensus for a definitive function of any of them.
Osteoblasts regulate the mineralization of bone matrix, although the mechanism(s) is not completely understood. In woven bone, mineralization is initiated away from the cell surface in matrix vesicles that bud from the plasma membrane of osteoblasts. This is similar to the well-documented role of matrix vesicles in cartilage mineralization (Hohling et al., 1978).
Mineralization begins in the hole region between overlapped collagen molecules where there are few, in any, matrix vesicles (Landis et al., 1993) and appears to be initiated by components of the collagen molecule itself or noncollagenous proteins at this site. Whatever the mechanisms of mineralization, collagen is at least a template for its initiation and propagation and there is always a layer of unmineralized bone matrix (osteoid) of the surface under osteoblasts. Matrix deposition is usually polarized toward the bone surface, but periodically becomes generalized, surrounding the osteoblast and producing the next layer of osteocytes. These cells have the capacity not only to synthesize, but also to resorb matrix to a limited extent. Each osteocyte occupies a space, or lacunae, within the matrix and extends filopodial processes through canaliculi in the matrix to contact processes of adjacent cells by means of gap junctions. Because diffusion of nutrients and metabolites through the mineralized matrix is limited, filopodial connections permit communication between neighbouring osteocytes, internal and external surfaces of bone and with the blood vessels traversing the matrix.
The functional capacities of osteocytes can be easily ascertained from their structure.Bone lining cells are flat, elongated, inactive cells that cover bone surfaces that are undergoing neither bone formation nor resorption. When active, osteoclasts rest directly on the bone surface and have two plasma membrane specializations: a ruffled border and a clear zone.
The ruffled border is the central, highly infolded area of the plasma membrane where bone resorption takes place.
The clear zone is a microfilament-rich, organelle-free area of the plasma membrane that surrounds the ruffled border and serves as the point of attachment of the osteoclast to the underlying bone matrix.
Nuclei are typically located in the part of the cell most removed from the bone surface and are interconnected by cytoskeletal proteins (Watanabe et al., 1995). Osteoclasts contain multiple circumnuclear Golgi stacks, a high density of mitochondria, and abundant lysosomal vesicles that arise from the Golgi and cluster near the ruffled border.When a fracture occurs, a set of signals is triggered.
These signals can be divided into two interactive and interchangeable categories: inflammatory signals and bone building signals. These factors mitigate the migration of phagocytotic cells to the area of the fracture, removing the necrotic tissue and propagating the in-growth of new blood vessels to the site of the fracture, thus providing nutrients and cells to the fracture site and starting the healing cascade.
The basic conceptsToday great hope is set on Regenerative Medicine in all medical fields and, of course, it has developed to be of interest in orthopedics, being bone defects one of the main focus. In the last two decades, Regenerative Medicine approaches have been extensively studied to improve bone healing, or even generate functional bone tissue to substitute lost bone in orthopedics, neurosurgery, and dentistry.
These types of studies include two different strategies of cell-based therapy: in the first approach, called Cell Therapy, cells are applied to substitute damaged cells within a tissue to reconstitute its integrity and function. 2012, with permissionStem cells (SCs) are of particular interest in Regenerative Medicine, since they inhere several unique characteristics that distinguish them from other cell types. SCs represent unspecialized cells, which have the ability to differentiate into cells of all three germ layers, different adult cell types, and represent the only cell type which has the ability to renew itself indefinitely. It is important to distinguish embryonic stem cells (ESCs), which are truly pluripotent from multipotent adult stem cells and only found in early developmental stages of the organism.
The successful dedifferentiation of somatic cells into a pluripotent ESC-like status by transfection with four embryonic transcription factors, the so-called induced pluripotent stem cells (iPS cells), provide the possibility of autologous therapy with pluripotent and easily accessible cells in the future.
Beside the great potential this technique undoubtedly represents, it bears some essential safety problems which are currently far from being solved.
In contrast, a variety of multipotent adult SCs exists in assumedly all tissues of the organism. Usually, these adult SCs show limited differentiation potential to tissues of one germ layer.Bone regeneration is a physiological process which can be observed in healing fracture and continuous remodeling along by adult life. Bone holds the most regenerative ability of human tissues contained on the mayor source of osteogenic cells capable for forming bones, the bone marrow (BM).
However, a loss considerable amount of bone due to any anomalies such as severe trauma, skeletal deformations, bone tumor resection or periprosthetic osteolysis can obstruct this capacity. Nevertheless, the capacity of proliferation and differentiation of BMSCs, as well as cells concentration, are reduced with the increase of the age of the patient. Many in vitro studies were performed to investigate applicability of different SC types for bone regeneration. Here, promising capacity for differentiating towards bone cells, enhancing bone healing and vascularization could be proven for ESCs and different adult mesenchymal stem cells (MSCs). However, due to the ethical and safety concerns, which currently forbid applications of ESCs or iPS cells in patients, we will focus on adult stem cells for therapeutic applications. Therefore, MSCs presently seem to be the most promising candidates for bone regeneration, due to their excellent osteogenic differentiation capacity. They can be isolated from a number of adult mesenchymal tissues, among others, umbilical cord blood, peripheral blood, placenta, synovial fluid, adipose tissue, skeletal muscle or BM, as mentioned, where they contribute to normal tissue turnover and repair. Recently, the multitude of cell surface markers used in various studies has been limited to a marker panel representing, in addition to plastic adherence and differentiation capacity, the minimal criteria for the identification of MSCs.
The molecular mechanisms of human MSCs regulation and the importance of specific GFs during the different stages of osteogenic differentiation, as well as the secreted signaling proteins known as Wnts, implicated in various differentiation programs including osteogenesis, are subjects of intensive research right now.
Several studies have demonstrated improved results of MSCs therapy with genetically modified cells which produce osteogenic and angiogenic GFs in a local delivery of therapy strategy for bone healing. Also, there is recent information about the use of endothelial progenitor cells (EPCs) that improves the treatment of fracture and bone regeneration.Besides their unique ability to differentiate into different cell types, MSCs secrete a variety of cytokines, showing anti-inflammatory activity and create an anabolic microenvironment. On one hand, they indirectly influence tissue regeneration by secretion of soluble factors. The differentiation potential of MSCs in bone engineering has been extensively studied in vitro and in vivo. By first time, Urist (1965), and Reddi and Huggins (1972) showed the capacity of a molecule, called bone morphogenetic protein (BMP), with potent osteoinductive properties in healing fractures and bone regeneration.
Their experiments demonstrated the presence of osteoinductive cytokines in bone matrix that have abilities to induce MSCs differentiation into osteoblasts. The GFs, also including transforming growth factor-beta (TGF-?), fibroblast growth factor (FGF), platelet derived growth factor (PDGF), vascular endothelial growth factor (VEGF) or insulin-like growth factor (IGF), among others, are delivered of paracrine or autocrine manner, generating a chemotaxis process toward MSCs by recruitment, which induce their differentiation.Extracellular matrix (ECM) is the native scaffold in most tissues. Besides the direct injection in the surrounding tissue, biomaterials are frequently used as carriers for cells, bioactive molecules and drugs. These materials have to be immune-compatible and nontoxic, whereas the bio-degradation process must neither release toxic substances nor tissue-toxic concentrations of degradation products.
Scaffolds must be of three-dimensional structures, with great influence on cell growth and differentiation, and must be highly porous with interconnected pores of a diameter of at least 100 µm to allow ingrowth of cells and vessels. Despite the tissue engineering of bone, for which various inorganic materials, such as HA, calcium phosphate, calcium carbonate (due to their similarity to bone mineral, as well as their inherent biocompatibility and osteoconductivity), or glasses was tested, mainly organic biomaterials have been investigated for scaffold production.
These are either naturally derived, for example, collagen, fibrin, agarose, alginate, gelatin, silk or hyaluronic acid; or produced synthetically, such as polyhydroxyacids. Different methods have been employed in the fabrication of nanomaterials for bone engineering, such as the principle of electrospinning, that produce a variety of synthetic biomaterials, or the novel thermally induced phase separation (TIPS) technique to fabricate nanofibers to mimic natural collagen fibers. Rapid developments in this field of nanotechnology will be a key for many clinical benefits in the field of bone tissue engineering. The main advantage is that several novel biomaterials can be fabricated into nanostructures that closely mimic the bone in structure and composition.
The optimization in the surface features of scaffolds has strongly improved cell behavior in terms of adhesion, proliferation, differentiation and tissue formation in three dimensions.3.
Stem cells as sourceThe popularity of SCs in the clinical arena has significantly increases, given the rapid improvement in our understanding of their biology. Classically, SCs are defined by their capacity to retain an undifferentiated state for a prolonged period while retaining the potential to differentiate along one lineage (unipotent), multiple lineages (multipotent), or into all three germ layers (pluripotent) (Young, 2003). Recently discovered, another source of pluripotent SCs are induced pluripotent stem (iPS) cells, derived from somatic cells treated with few defined factors (Hamilton et al., 2009).
Mesenchymal stem cells as candidatesFurthermore, naturally occurring adult SCs have also been identified and categorized into their hematopoietic stem cells (HSCs), a source of various hematopoietic cell lineages, and nonhematopietic SCs, which can give rise to cells of mesenchymal origin (de Barros et al., 2010). Many reports have suggested that these nonhematopoietic SCs, also known as mesenchymal stem cells (MSCs), can be isolated from a wide variety of adult tissues such as blood, adipose, skin, mandibule, trabecular bone, fetal blood, liver, lung and even the umbilical cord and placenta (Steinhardt et al., 2008). While these multipotent progenitor cells share many similar characteristics, they can be differentiated based on their expression profile and differentiation propensity along various lineages (Wagner et al., 2005).
Unlike ESCs, MSCs provide the flexibility of autologous transplantation, circumventing ethical concerns or immunological rejection (Igura et al., 2004). These cells also play a sentinel role in proliferation and differentiation of hematopoietic cells (Briquet et al., 2010). Additionally, MSCs are considered to be immune privileged and have the capacity for allogenic transplantation a property has been used in the clinical setting for the treatment of various autoimmune diseases (Le Blanc et al., 2008). While many studies have suggested that MSCs are immunoprivileged and do not undergo rejection, others have cast doubt on this notion, showing that in certain scenarios, MSCs induce immune rejection (Nauta et al., 2006) (Fig. 2012, with permissionConsiderable effort has been put forth to identify specific surface markers that characterize MSCs, yet disagreement within the literature has prevented the creation of definitive standards.
Additional studies have also suggested that CD146 is considered an important marker of BM progenitor cells (Sorrentino et al., 2008).
These guidelines were set in place to enable a unified approach for comparison amongst different studies.BM is generally considered milieu plentiful for various cell types, collectively referred to as stromal cells.
Researchers have pioneered the creation of stable animal models aimed at mimicking human conditions to study the therapeutic capacity of these BM-derived cells (Kadiyala et al., 1997). Hence, the idea of using SCs, which are self-renewing and differentiate into various tissues, surfaced.4. Direction by growth factorsGrowth factors (GFs) serve a critical role in Regenerative Medicine, facilitating tissue growth in vitro and repair in vivo.
In the case of skeletal tissues, they are being using to regulate chemotaxis, proliferation, and differentiation of MSCs.


Also, selected hormones, cytokines, and nutrients are potentially useful in controlling MSCs growth.A GF is a signaling biomolecule, commonly polypeptide, that is not a nutrient.
Typically they act as signaling molecules via binding to specific receptors on the same cells that secrete the factors (autocrine signaling) or on neighboring cells (paracrine signaling).
The binding of the receptor initiates a cascade of cellular reactions, often involving the activation of specific gene transcription.
These cellular activities lead to alterations in cell proliferation, differentiation, maturation, and production of other GFs and ECM, all of which result in the formation of specific tissues. Unlike hormones, which act on cells distant from the source (endocrine signaling), GFs have a local (nonsystemic) effect and are often secreted at low concentrations (Fig.
Transforming growth factor-beta (TGF-?)The term transforming growth factor beta is applied to the superfamily of length well-known growth factors involved generally with connective tissue repair and bone regeneration present in many types of tissue (Lieberman et al., 2002). TGF-? exists as five isoforms, three of them have received the most attention regarding fracture repair and proliferation of MSCs (TGF-?1, TGF-?2, TGF-?3), although TGF-?3 has the most pronounced effect on increases proliferation of MSCs and chondrogenesis (Weiss et al., 2010). All TGF-? members superfamily are synthesized as large precursors which are proteolytically cleaved to yield mature protein dimers (Massague et al., 1994). Receptor I phosphorylates the primary intracellular superfamily signal effector molecules, SMADs, causing their translocation into the nucleus and specific gene transcription (Valcourt et al., 2002). TGF-?s inhibit osteoclast formation and bone resorption, thus favoring bone formation over resorption by two different mechanisms (Mohan & Baylink, 1991). The TGF-? activates fibroblasts and preosteoblasts to increase their numbers, as well as promoting their differentiation toward mature functioning osteoblasts. It influences the osteoblasts to lay down bone matrix and the fibroblast to lay down collagen matrix to support capillary growth (Marx et al., 1996).
They also play a role in osteogenesis, its actions are diverse and it is thought to influence the activity of BMPs (Salgado et al., 2004).
8), and further, that these selected cells exhibit unique properties in the chodroosteogenic lineage that can ultimately be utilized to therapeutic advantageFigure 8.Schematic representation of the genetically engineered fusion construct, containing a histidine purification tag, a protease site, an auxiliary von Willebrand Factor collagen binding domain. He observed the ability from demineralized bone matrix (DBM), to induce ectopic bone formation when implanted under the skin of rodents, and showed that there was a recapitulation of all the events that taking place during skeletal development.
More lately, others searchers, as Reddi and Huggins (1972) demonstrated that these molecules are important during development. Even present, at least many than 30 BMPs have been identified and BMP?s functions have been studied by means of analysis of mutant genes and knockout experiments in mice.
These proteins induce a cascade of cellular pathways that promote cell growth, migration and differentiation of MSCs to repair the injury, stimulates angiogenesis, as well as synthesis of ECM and play a regulatory role in tissue homeostasis (Reddi, 2001).
In studies of fracture healing, BMP-2 mRNA expression showed maximal levels within 24 hrs of injury, suggesting that this BMP plays a role in initiating the repair cascade. BMP-5 and BMP-6 and other members of the TGF-?s superfamily are constitutively expressed from days 3-21 during fracture in mice, suggesting that they have a regulatory effect on both intramembranous and endochondral ossification. In preclinical models, BMP-2 has the ability to induce bone formation and heal bone defects and promote the maturation and consolidation of regenerated bone. Recombinant human BMP-7 and BMP-2 are among the first growth factor based products available for clinical use to treat patients afflicted with bone diseases. The expression of the BMP antagonists, as noggin, which blocks BMP-2, BMP-4, and BMP-7 interaction with its receptor, also is modulated during bone repair (Balemans et al. Wnt proteinsThe Wnt pathway was initially identified as a proto-oncogene in mammary tumors that was activated by integration of the mouse mammary virus (Nusse & Varmus, 1982). It knows Wnt proteins are secreted cysteine-rich glycosylated family proteins to share a highly conserved pattern of 23–24 cysteine residues and several asparagines-linked glycosylation sites (Li et al., 2006).
Several lines of evidence have demonstrated the importance of canonical Wnt signaling in promoting osteogenesis in vitro and in vivo (Chung et al., 2009). Wnt signaling is a prime target for bone active drugs and the approaches include inhibition of Wnt antagonist like Dkk1, sclerostin, and Sfrp1 with neutralizing antibodies and inhibition of glycogen synthase kinase 3? (GSK-3?), which promotes phosphorylation and degradation of ?-catenin. Enhancement of Wnt signaling either by Wnt overexpression or deficiency of Wnt antagonists (ten Dijke et al., 2008) is associated with increased bone formation in mice and humans.
Canonical Wnt signaling in osteoblast differentiation is modulated by Runx2 and osterix transcription factors (Hill et al., 2005).
Growth hormone and insulin-like growth factors (GH and IGF)In clinic, the patients that present short stature are treated with the Growth Hormone (GH); for this reason, many researcher study the effects of GH in the treatment for osteoporosis and repair bone fracture.
It is released by pituitary gland and travels through the circulation to the liver, where target cells are stimulated to release IGF. However, IGF-I is 4 to 7 times more potent in synthesis of bone matrix (type I collagen and non-collagen matrix proteins) (Lind, 1996). IGF-II acts on phase of endochondral bone formation and induces type I collagen production, stimulates cartilage matrix synthesis, and cellular proliferation. Both factors have been localized in bone studies of animals and humans with GH-deficient levels. The expression and secretion of IGFBPs, IGF-I and IGF-II (Birnbaum et al., 1995) changes during in vitro MSCs cultures.
IGF production is not only under the control of GH, is also regulated by estrogen, PTH, cortisol (inhibits IGF-I synthesis), local GFs and cytokines (Ohlsson et al., 1998). Fibroblast growth factor (FGF)FGF is a secreted glycoproteins family whose signals are implicated in wound healing and angiogenesis, which influence in cellular proliferation, differentiation, migration, survival and polarity transduced through their receptors (FGFR1, FGFR2, FGFR3 and FGFR4). These receptors are constituted of extracellular immunoglobulin-like (Ig-like) domains and cytoplasmic tyrosine kinase activity domain. As with many of the tyrosine kinase receptors, activation of the intrinsic tyrosine kinase activity occurs through receptor dimerization in response to ligand binding.
An additional complexity may be added to the receptor-ligand association through the binding of FGF ligand by either secreted or membrane-bound proteoglycans, heparin-like proteoglycans in particular because their high affinity (Givol & Yayon, 1992).
Nine members of the FGF family have been identified of which, the most abundant in human tissue are FGF-1 (acid character) and FGF-2 (basic character) (Lieberman et al., 2002).
FGFs are important regulators of fracture repair expressed by MSCs, maturing chondrocytes and osteoblasts and have been demonstrated to enhance TGF-? expression in osteoblastic cells (Bolander, 1998). They play a role in maintaining the balance between bone-forming cells and bone-resorbing cells and promote angiogenesis. PDGF is a dimeric molecule can exist either as a homodimeric (PDGF-AA, PDGF-BB, etc) or a heterodimeric form (PDGF-AB) according to the relative levels of each subunit generating a level of ligand complexity in cells in which both polypeptides are expressed. The different PDGF isoforms exert their effect on target cells by binding with different specificity to two structurally related protein tyrosine kinase receptors, denoted as the ?-receptors and ?-receptors, which are autophosphorylate ligand bound (Tokunaga et al., 2008). Several groups have found PDGF-BB to induce both proliferation and migration in MSCs (Fierro et al., 2007). While PDGFR? inhibits osteogenesis, however, PDGFR? has been observed to induce osteogenesis. It also begins an angiogenesis of capillary budding into the graft by inducing endothelial cell mitosis and macrophage activator effect. Biomaterials as supportNatural bone consists of an ECM with nanosized apatitic minerals and collagen fibers that support bone cell functions. The success in regenerating a damaged tissue using the tissue engineering approach depends on the various types of interactions between the cells, scaffolds, and GFs. At the cell level, substrates of this kind must have specific biochemical (molecular) properties, physicochemical characteristics (surface free energy, charge, hydrophobicity, and so on), and a specific geometric conformation (they must be three dimensional and show interconnected porosity) (Jin, 2000). Biological polymers, such as collagen and hyaluronic acid provide guidance to cells that favors cell attachment and promotes chemotactic responses, but, a disadvantage is immunogenicity for the potential risk of disease transmission. On the other hand, other alternative is synthetic polymers such as polyfumarates, polylactic acid (PLA), polyglycolic acid (PGA), copolymers of PLA and PGA (PLGA), and polycaprolactone. Nevertheless, there are a wide range of bioactive inorganic materials similar in composition to the mineral phase of bone, for example, tricalcium phosphate, HA, bioactive glasses, and their combinations; and all of these can be tailored to deliver ions such as Si at levels capable of activating complex gene transduction pathways, leading to enhanced cell differentiation and osteogenesis. Hydrogels, such as polyethylene glycol or alginate-based, are to provide a three-dimensional cellular microenvironment with high water content, this is suitable for cartilage regeneration.
Polyethylene glycol (PEG) hydrogels were investigated as encapsulation matrices for osteoblasts to assess their applicability in promoting bone tissue engineering.
Non-adhesive hydrogels were modified with adhesive Arg-Gly-Asp (RGD) peptide sequences to facilitate the adhesion, spreading, and, consequently, cytoskeletal organization of osteoblasts.
Finally, mineral deposits were seen in all hydrogels after 4 weeks of in vitro culture, but a significant increase in mineralization was observed upon introduction of adhesive peptides throughout the network. In recent years, biomaterials in general and bone-related implant materials in particular have been considerably refined, with the objective of developing functionalized materials, so-called smart materials, containing bioactive molecules to directly influence cell behaviour (Mieszawska and Kaplan, 2010). Rapid developments in nanotechnology have yielded many clinical benefits, in particular in the field of bone tissue engineering. The main advantage in that several novel biomaterials can be fabricated into nanostructures that closely mimic the bone in structure and composition. The optimization in the surface features of biomaterials has strongly improved cell behaviour in terms of adhesion, proliferation, differentiation and tissue formation in three dimensions. In this context, nanoparticles that are in the same size range as integral parts of natural bone, such as HA crystals or cellular compartments, are promising candidates for local applications. In bone, locally applied nanoparticles may be suitable for numerous potential uses with respect to the improvement of tissue regeneration, the enhanced osseointegration of implants, and the prevention of infections.Increasingly refined nanoparticles are being developed for a wide range of applications (Fig. Moreover, drug delivery systems with improved pharmacologic characteristics are being developed. They promote enhanced therapeutic outcome by providing controlled release of bioactive molecules, such as growth factors or anticancer drugs (Allen and Cullis, 2004). However, it becomes clear that parameters such as chemistry, size, and shape in some cases greatly affect the particle uptake behaviour of MSCs as well as their natural differentiation potential.
ConclusionOver the last decades we have advanced in many aspects of bone defects treatment. Osteoprogenitor cells are necessary to replace the inserted scaffold and to create new bone tissue. These cells, MSCS, can come from the periosteum, the BM, or from chemotaxis and blood vessels entering the haematoma at the fracture site. Specific mechanical and biological stimulants cause the cells to differentiate into osteoblasts, which are the bone forming cells (Fig. However, in critical size bone defects the natural migration of osteoprogenitor cells does not suffice for fracture healing. However, when a bone is broken, these cells, using special probing signals, roam in the blood and settle in the fracture site, differentiate into bone cells and start to construct the callus.
There are scant data with respect to this part of the question, and in the next few years this field must undergo a transition, giving clinicians tools to deal with these critical everyday problems.



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