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| Geron and ACT Could Apply in $50 Million Clinical Trial Loan Program
April 7, 2010 at 1:40 PM
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| Two more potential applicants for the California stem cell agency's $50 million clinical trial program were identified today by Nature magazine. In a piece by Christian Torres in its April edition, the magazine indicated that Geron of Menlo Park, Ca., and Advanced Cell Technology of Santa Monica, Ca., may well apply.
Torres wrote:"Trials must take place in the state to qualify, and only | | |
| Implantation of ferumoxides labeled human mesenchymal stem cells in cartilage defects.
April 7, 2010 at 6:43 AM
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| | Implantation of ferumoxides labeled human mesenchymal stem cells in cartilage defects. J Vis Exp. 2010;(38): Authors: Nedopil AJ, Mandrussow LG, Daldrup-Link HE The field of tissue engineering integrates the principles of engineering, cell biology and medicine towards the regeneration of specific cells and functional tissue. Matrix associated stem cell implants (MASI) aim to regenerate cartilage defects due to arthritic or traumatic joint injuries. Adult mesenchymal stem cells (MSCs) have the ability to differentiate into cells of the chondrogenic lineage and have shown promising results for cell-based articular cartilage repair technologies. Autologous MSCs can be isolated from a variety of tissues, can be expanded in cell cultures without losing their differentiation potential, and have demonstrated chondrogenic differentiation in vitro and in vivo(1, 2). In order to provide local retention and viability of transplanted MSCs in cartilage defects, a scaffold is needed, which also supports subsequent differentiation and proliferation. The architecture of the scaffold guides tissue formation and permits the extracellular m! atrix, produced by the stem cells, to expand. Previous investigations have shown that a 2% agarose scaffold may support the development of stable hyaline cartilage and does not induce immune responses(3). Long term retention of transplanted stem cells in MASI is critical for cartilage regeneration. Labeling of MSCs with iron oxide nanoparticles allows for long-term in vivo tracking with non-invasive MR imaging techniques(4). This presentation will demonstrate techniques for labeling MSCs with iron oxide nanoparticles, the generation of cell-agarose constructs and implantation of these constructs into cartilage defects. The labeled constructs can be tracked non-invasively with MR-Imaging. PMID: 20368696 [PubMed - in process] | | |
| Optimization of Fibrinogen Isolation for Manufacturing Autologous Fibrin Glue for Use as Scaffold in Tissue Engineering.
April 7, 2010 at 6:43 AM
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| | Optimization of Fibrinogen Isolation for Manufacturing Autologous Fibrin Glue for Use as Scaffold in Tissue Engineering. Artif Cells Blood Substit Immobil Biotechnol. 2010 Apr 6; Authors: Froelich K, Pueschel RC, Birner M, Kindermann J, Hackenberg S, Kleinsasser NH, Hagen R, Staudenmaier R Abstract: Numerous manufacturing techniques for autogenous fibrin glue used as scaffold material have been described. As there is no consensus regarding the influence of chemical additives on cell biology, it was the aim of this study to establish a method for manufacturing autologous fibrin glue without any additives. The serum part was separated from whole blood. After fibrinogen precipitation, centrifugation was performed to obtain the fibrinogen pellet. Various experimental series were run to examine influences of various temperatures or substituting centrifugation for sedimentation. The method as described here is effective, simple, and performed without any additives, which could potentially influence cell biology. PMID: 20367549 [PubMed - as supplied by publisher] | | |
| Cancellous Bone Osseointegration is Enhanced by In Vivo Loading.
April 7, 2010 at 6:43 AM
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| | Cancellous Bone Osseointegration is Enhanced by In Vivo Loading. Tissue Eng Part C Methods. 2010 Apr 2; Authors: Willie BM, Yang X, Kelly NH, Han J, Nair T, Wright TM, van der Meulen M, Bostrom M Biophysical stimuli may be an effective therapy to counteract age-related changes in bone structure that affect the primary stability of implants used in joint replacement or fracture fixation. The influence of controlled mechanical loading on osseointegration was investigated using an in vivo device implanted in the distal lateral femur of twelve male rabbits. Compressive loads (1 MPa, 1 Hz, 50 cycles/day, 4 weeks) were applied to a porous titanium foam implant and the underlying cancellous bone. The contralateral limbs served as nonloaded controls. Backscattered electron imaging indicated that the amount of bone ingrowth was significantly greater in the loaded limb compared to the nonloaded control limb, while the amount of underlying cancellous periprosthetic bone was similar. No significant difference in the mineral apposition rate of the bone ingrowth or periprosthetic bone was measured in the loaded compared to the control limb. Histological analysis demonst! rated newly formed woven bone in direct apposition to the implant coating, with a lack of fibrous tissue at the implant-periprosthetic bone interface in both loaded and nonloaded implants. The lack of fibrous tissue demonstrates that mechanical stimulation using this model significantly enhanced cancellous bone ingrowth without the detrimental effects of micromotion. These results suggest that biophysical therapy should be further investigated to augment current treatments to enhance long-term fixation of orthopaedic devices. Additionally, this novel in vivo loading model can be used to further investigate the influence of biophysical stimulation on other tissue engineering approaches requiring bone ingrowth into both metallic and nonmetallic cell seeded scaffolds. PMID: 20367497 [PubMed - as supplied by publisher] | | |
| Electric field stimulation integrated into perfusion bioreactor for cardiac tissue engineering.
April 7, 2010 at 6:43 AM
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| | Electric field stimulation integrated into perfusion bioreactor for cardiac tissue engineering. Tissue Eng Part C Methods. 2010 Apr 2; Authors: Barash Y, Dvir T, Tandeitnik P, Ruvinov E, Guterman H, Cohen S We describe herein the features of a novel cultivation system, combining electrical stimulation with medium perfusion for producing thick, functional cardiac patches. A custom-made electrical stimulator was integrated via inserting two carbon rod electrodes into a perfusion bioreactor, housing multiple neonatal SD rat cardiac cell constructs between two 96% open-pore-area fixing nets. The stimulator produced adjustable stimulation waveform (i.e. duty cycle, number of stimulating channels, maximum stimulation amplitude, etc.), specially-designed for cardiac cell stimulation. The cell constructs were subjected to a homogenous fluid flow regime and electrical stimulation under conditions optimal for cell excitation. The stimulation threshold in the bioreactor was set by first determining its value in a Petri dish under a microscope, and then matching the current density in the two cultivation systems by constructing electric field models. The models were built by Com! sol Multiphysics software using the exact three-dimensional geometry of the two cultivation systems. These models illustrate, for the first time, the local electric conditions required for cardiomyocyte field excitation and they confirmed the uniformity of the electrical field around the cell constructs. Bioreactor cultivation for only 4 d under perfusion and continuous electrical stimulus (74.4 mA/cm;2 , 2 ms, bipolar, 1 Hz) promoted cell elongation and striation in the cell constructs and enhanced the expression level of connexin-43, the gap junction protein responsible for cell-cell coupling. These results thus confirm the validity of the electrical field model in predicting the optimal electrical stimulation in a rather complex cultivation system, a perfusion bioreactor. PMID: 20367291 [PubMed - as supplied by publisher] | | |
| New Dimensions in Vascular Engineering: Opportunities for Cancer Biology.
April 7, 2010 at 6:43 AM
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| | New Dimensions in Vascular Engineering: Opportunities for Cancer Biology. Tissue Eng Part A. 2010 Apr 1; Authors: Rabbany SY, James D, Rafii S Abstract. Angiogenesis is a fundamental pre-requisite for tissue growth, and thus an attractive target for cancer therapeutics. However, current efforts to halt tumor growth using anti-angiogenic agents have been met with limited success. A reason for this may be that studies aimed at understanding tissue and organ formation have to this point utilized two-dimensional cell culture techniques, which fail to faithfully mimic the pathological architecture of disease in an in vivo context. In this issue of Tissue Engineering, the work of Fischbach-Teschl's group manipulate such variables as oxygen concentration, culture three-dimensionality, and cell-extracellular matrix interactions to more closely approximate the biophysical and biochemical microenvironment of tumor angiogenesis. In this manuscript, we discuss how novel tissue engineering platforms provide a framework for the study of tumorigenesis under pathophysiologically relevant in-vitro culture conditions. PMID: 20367255 [PubMed - as supplied by publisher] | | |
| EVALUATION OF THE COMPLEX TRANSCRIPTIONAL TOPOGRAPHY OF MESENCHYMAL STEM CELL CHONDROGENESIS FOR CARTILAGE TISSUE ENGINEERING.
April 7, 2010 at 6:43 AM
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| | EVALUATION OF THE COMPLEX TRANSCRIPTIONAL TOPOGRAPHY OF MESENCHYMAL STEM CELL CHONDROGENESIS FOR CARTILAGE TISSUE ENGINEERING. Tissue Eng Part A. 2010 Apr 1; Authors: Huang AH, Stein A, Mauck RL Mesenchymal stem cells (MSCs) are a promising cell source for cartilage tissue engineering given their chondrogenic potential. This potential has yet to be fully realized, as the mechanical properties of MSC-based constructs are lower than those of chondrocyte-based constructs cultured identically. Therefore the aim of the current study was to better understand the transcriptional underpinnings of this functional limitation. Matched chondrocytes and MSCs from three donors were cultured in agarose in a defined media containing TGF-beta3. We evaluated the compressive mechanical properties and matrix deposition of maturing constructs over 56 days. Transcriptional differences between the two cell types were assessed on day 0 and day 28 constructs via microarray analysis and real-time PCR; differential deposition of matrix molecules was assessed by immunohistochemistry. Although the mechanical and biochemical properties of cell-seeded constructs improved with culture d! uration, MSC values plateaued at day 28, and remained lower than chondrocyte values. Using microarray analysis, 324 genes were identified as mis-expressed during chondrogenesis. Differential expression of 18 genes was validated, and differential deposition of proteoglycan 4 (PRG4) and transforming-growth-factor-beta induced 68kDa protein (TGFBI) was confirmed. Temporal expression profiles of these 18 genes showed that some genes were never expressed (chondromodulin), some were expressed at lower levels (PRG4), and some were expressed only at later time points (TGFBI) in MSCs compared to chondrocytes. These findings further define the complex transcriptional topography and mechanobiology of MSC chondrogenesis, and provide new benchmarks for optimizing the growth of MSC-based engineered cartilage. PMID: 20367254 [PubMed - as supplied by publisher] | | |
| Sonic Hedgehog influences the balance of osteogenesis and adipogenesis in mouse adipose-derived stromal cells.
April 7, 2010 at 6:43 AM
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| | Sonic Hedgehog influences the balance of osteogenesis and adipogenesis in mouse adipose-derived stromal cells. Tissue Eng Part A. 2010 Mar 30; Authors: James AW, Leucht P, Levi B, Carre AL, Xu Y, Helms J, Longaker M Adipose-derived stromal cells (ASCs) present a great potential for tissue engineering, as they are capable of differentiating into osteogenic and adipogenic cell types, among others. In this study, we examined the role of Hedgehog signaling in the balance of osteogenic and adipogenic differentiation in mouse ASCs. Results showed Hedgehog signaling increased during early osteogenic differentiation (Shh, Ptc1, Gli1), but decreased during adipogenic differentiation. N-terminal Sonic Hedgehog (Shh-N) significantly increased in vitro osteogenic differentiation in mASCs, by all markers examined (*P < 0.01). Concomitantly, Shh-N abrogated adipogenic differentiation, by all markers examined (*P < 0.01). Conversely, blockade of endogenous Hedgehog signaling, with the Hedgehog antagonist cyclopamine, enhanced adipogenesis at the expense of osteogenesis. We next translated these results to a mouse model of appendicular skeletal regeneration. Using qRT-PCR and in situ h! ybridization, we found that skeletal injury (a monocortical 1mm defect in the tibia) results in a localized increase in Hedgehog signaling. Moreover, grafting of ASCs treated with Shh-N resulted in significantly increased bone regeneration within the defect site. In conclusion, Hedgehog signaling enhances the osteogenic differentiation of mASCs, at the expense of adipogenesis. These data suggest that Hedgehog signaling directs the lineage differentiation of mesodermal stem cells and represents a promising strategy for skeletal tissue regeneration. PMID: 20367246 [PubMed - as supplied by publisher] | | |
| Osteoblastic Cell Proliferation with Uniform Distribution in a Large Scaffold using Radial-Flow Bioreactor.
April 7, 2010 at 6:43 AM
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| | Osteoblastic Cell Proliferation with Uniform Distribution in a Large Scaffold using Radial-Flow Bioreactor. Tissue Eng Part C Methods. 2010 Mar 30; Authors: Arano T, Sato T, Matsuzaka K, Ikada Y, Yoshinari MY Bioreactors employing different types of in vitro physiological cell stimulation have been developed to obtain three-dimensional cultivation for tissue engineering. The purpose of this study was to determine whether osteoblastic cells proliferated uniformly over a large scaffold with a diameter of 18 mm and height of 10 mm under dynamic cultivation with the radial-flow bioreactor (RFB), and thereby ascertain the potential of this system in the regeneration of jaw bone. Mouse osteoblastic cells (MC3T3-E1) were seeded onto type-1 collagen sheets. Cells were then incubated outside the reactor for 6 hours to produce pre-cultured sheets. The 6 pre-cultured sheets were then placed in the RFB to fabricate the scaffolds. Cells were dynamically cultured for one week at 37 C, pH 7.4, DO 6.86 ppm, and with the culture medium circulating at 3 mL/min. As a control, static cultivation cultured in the same manner without circulating culture medium and single cultivation in a cul! ture dish were performed. The resulting cell proliferation and cell distribution were analyzed. After one week of dynamic cultivation, cells showed a 5-fold and 4-fold increase with uniform distribution throughout the three-dimensional scaffolds than those under the static and single cultivation as a control, respectively. These results indicate that the RFB is a promising system for three-dimensional cultivation of osteoblastic cells for treating large bone defects by tissue engineering. PMID: 20367244 [PubMed - as supplied by publisher] | | |
| Mesenchymal stem cell-encapsulated collagen microspheres for bone tissue engineering.
April 7, 2010 at 6:43 AM
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| | Mesenchymal stem cell-encapsulated collagen microspheres for bone tissue engineering. Tissue Eng Part C Methods. 2010 Apr;16(2):225-35 Authors: Chan BP, Hui TY, Wong MY, Yip KH, Chan GC There is a demonstrated clinical need for alternatives of autologous fresh bone graft with excellent biological performance in osteoconductivity, osteoinductivity, and osteogenicity. We previously developed a collagen microencapsulation technology entrapping bone marrow-derived mesenchymal stem cells (MSCs) in a biomimetic collagen fiber meshwork and produced injectable collagen-MSC microspheres. In this study, we hypothesize that injectable microspheres with osteoconductivity, osteogenicity, and osteoinductivity can be fabricated by differentiating the encapsulated MSCs, from either human or mouse sources, toward osteogenic lineages in these three-dimensional microspheres. The osteogenicity, osteoconductivity, and osteoinductivity of the microspheres were evaluated in vitro. Osteogenic markers of the differentiating MSCs including alkaline phosphatase and calcium deposition showed positive staining. Osteoconductivity of the collagen meshwork in the microsphere wa! s demonstrated by the presence of calcium phosphate deposits among the collagen fibers and by the significantly increased calcium content extracted from the microspheres. Moreover, osteoinductivity of the MSC-encapsulated microspheres was demonstrated by the ability to induce osteogenic differentiation of undifferentiated MSCs in both contact and noncontact coculture. This study contributes toward the future development of injectable alternatives for fresh bone grafts using autologous MSCs. PMID: 20367213 [PubMed - in process] | | |
| Stem cells for tendon tissue engineering and regeneration.
April 7, 2010 at 6:43 AM
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| | Stem cells for tendon tissue engineering and regeneration. Expert Opin Biol Ther. 2010 Apr 2; Authors: Yin Z, Chen X, Chen JL, Ouyang HW Importance of the field: Tendon injuries are common especially in sports activities, but tendon is a unique connective tissue with poor self-repair capability. With advances in stem cell biology, tissue engineering is becoming increasingly powerful for tissue regeneration. Stem cells with capacity of multipotency and self-renewal are an ideal cell source for tissue engineering. Areas covered in this review: This review focus on discussing the potential strategies including inductive growth factors, bio-scaffolds, mechanical stimulation, genetic modification and co-culture techniques to direct tendon-lineage differentiation of stem cells for complete tendon regeneration. Attempting to use embryonic stem cells as seed cells for tendon tissue engineering have achieved encouraging results. The combination of chemical and physical signals in stem cell microenvironment could be regulated to induce differentiation of the embryonic stem cells into tendon. What the reader ! will gain: We summarize fundamental questions, as well as future directions in tendon biology and tissue engineering. Take home message: Multifaceted technologies are increasingly required to control stem cell differentiation, to develop novel stem cell-based therapy, and, ultimately, to achieve more effective repair or regeneration of injured tendons. PMID: 20367125 [PubMed - as supplied by publisher] | | |
| Acellular dermal matrix seeded with autologous gingival fibroblasts for the treatment of gingival recession: a proof-of-concept study.
April 7, 2010 at 6:43 AM
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| | Acellular dermal matrix seeded with autologous gingival fibroblasts for the treatment of gingival recession: a proof-of-concept study. J Periodontol. 2010 Apr;81(4):616-25 Authors: Jhaveri HM, Chavan MS, Tomar GB, Deshmukh VL, Wani MR, Miller PD BACKGROUND: One of the most common esthetic concerns associated with periodontal tissues is gingival recession. There are multiple periodontal plastic surgery approaches documented in the literature for the treatment of such defects. With the tremendous advances being made in periodontal science and technology, tissue engineering could be considered among the latest exciting techniques for recession management. METHODS: In this split-mouth, controlled, double-masked clinical case series, 20 sites from 10 patients with Miller Class I or II recessions affecting canines or premolars in the maxillary arch were selected. One tooth in each patient was randomized to receive either a subepithelial connective tissue graft (SCTG) (control group) or an acellular dermal matrix allograft (ADMA) seeded with autologous gingival fibroblasts (test group) under a coronally positioned flap. Clinical parameters, including recession depth, probing depth, clinical attachment level, wid! th of keratinized tissue, attached gingiva, and plaque scores, were recorded by a calibrated examiner at baseline and 3 and 6 months. The inflammation of grafted sites was scored, and the healing time was calculated. The final esthetic outcome of treated sites was assessed by the root coverage esthetic score at the end of 6 months. RESULTS: There were no significant differences between test and control sites for all measured clinical parameters. However, the test sites demonstrated less inflammation in the early postoperative period. CONCLUSION: Within the limits of this case series, the results indicate that an ADMA seeded with autologous gingival fibroblasts by tissue-engineering technology may be explored as a substitute to an SCTG for the treatment of Miller Class I and II recession defects. PMID: 20367104 [PubMed - in process] | | |
| Introducing the scanning air puff tonometer for biological studies.
April 7, 2010 at 6:43 AM
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| | Introducing the scanning air puff tonometer for biological studies. Phys Rev E Stat Nonlin Soft Matter Phys. 2010 Feb;81(2 Pt 1):021920 Authors: Fleury V, Al-Kilani A, Boryskina OP, Cornelissen AJ, Nguyen TH, Unbekandt M, Leroy L, Baffet G, le Noble F, Sire O, Lahaye E, Burgaud V It is getting increasingly evident that physical properties such as elastoviscoplastic properties of living materials are quite important for the process of tissue development, including regulation of genetic pathways. Measuring such properties in vivo is a complicated and challenging task. In this paper, we present an instrument, a scanning air puff tonometer, which is able to map point by point the viscoelastic properties of flat or gently curved soft materials. This instrument is an improved version of the air puff tonometer used by optometrists, with important modifications. The instrument allows one to obtain a direct insight into gradients of material properties in vivo. The instrument capabilities are demonstrated on substances with known elastoviscoplastic properties and several biological objects. On the basis of the results obtained, the role of the gradients of elastoviscoplastic properties is outlined for the process of angiogenesis, limb development, ! bacterial colonies expansion, etc. which is important for bridging the gaps in the theory of the tissue development and highlighting new possibilities for tissue engineering, based on a clarification of the role of physical features in developing biological material. PMID: 20365608 [PubMed - in process] | | |
| Stochastic model of self-assembly of cell-laden hydrogels.
April 7, 2010 at 6:43 AM
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| | Stochastic model of self-assembly of cell-laden hydrogels. Phys Rev E Stat Nonlin Soft Matter Phys. 2009 Dec;80(6 Pt 1):061901 Authors: Shi Z, Chen N, Du Y, Khademhosseini A, Alber M Recent progress in bottom-up tissue engineering has demonstrated that three-dimensional tissue constructs with predefined architectures may be obtained by assembling shape-controlled hydrogels in multiphase reactor systems. Driven by the hydrophobic force between gel unit and liquid media, highly ordered hydrogel clusters can be formed. Many complex factors occurring at microscale (i.e., gel unit collisions, hydrophobic forces, and gel unit movement) are involved in the self-assembly process. In this paper a two-dimensional off-lattice Monte Carlo model with Lennard-Jones-type potential describing unit-unit interactions is introduced for studying this process. Simulations are shown to agree well with the experimental results for hydrogel assembly in mineral oil. The simulation method is demonstrated for rectangular hydrogel units of different aspect ratios as well as extended to the case of more complex hydrogel unit geometries. PMID: 20365184 [PubMed - in process] | | |
| Cell contraction forces in scaffolds with varying pore size and cell density.
April 7, 2010 at 6:43 AM
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| | Cell contraction forces in scaffolds with varying pore size and cell density. Biomaterials. 2010 Mar 31; Authors: Corin KA, Gibson LJ The contractile behavior of cells is relevant in understanding wound healing and scar formation. In tissue engineering, inhibition of the cell contractile response is critical for the regeneration of physiologically normal tissue rather than scar tissue. Previous studies have measured the contractile response of cells in a variety of conditions (e.g. on two-dimensional solid substrates, on free-floating tissue engineering scaffolds and on scaffolds under some constraint in a cell force monitor). Tissue engineering scaffolds behave mechanically like open-cell elastomeric foams: between strains of about 10 and 90%, cells progressively buckle struts in the scaffold. The contractile force required for an individual cell to buckle a strut within a scaffold has been estimated based on the strut dimensions (radius, r, and length, l) and the strut modulus, E(s). Since the buckling force varies, according to Euler's law, with r(4)/l(2), and the relative density of the scaf! fold varies as (r/l)(2), the cell contractile force associated with strut buckling is expected to vary with the square of the pore size for scaffolds of constant relative density. As the cell density increases, the force per cell to achieve a given strain in the scaffold is expected to decrease. Here we model the contractile response of fibroblasts by analyzing the response of a single tetrakaidecahedron to forces applied to individual struts (simulating cell contractile forces) using finite element analysis. We model tetrakaidecahedra of different strut lengths, corresponding to different scaffold pore sizes, and of varying numbers of loaded struts, corresponding to varying cell densities. We compare our numerical model with the results of free-floating contraction experiments of normal human dermal fibroblasts (NHDF) in collagen-GAG scaffolds of varying pore size and with varying cell densities. PMID: 20362329 [PubMed - as supplied by publisher] | | |
| Biocomposites containing Natural Polymers and Hydroxyapatite for Bone Tissue Engineering.
April 7, 2010 at 6:43 AM
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| | Biocomposites containing Natural Polymers and Hydroxyapatite for Bone Tissue Engineering. Int J Biol Macromol. 2010 Mar 30; Authors: Swetha M, Sahithi K, Moorthi A, Srinivasan N, Ramasamy K, Selvamurugan N Bone tissue engineering is an alternative strategy to generate bone utilizing a combination of biomaterials and cells. Biomaterials that mimic the structure and composition of bone tissues at nano scale are important for the development of bone tissue engineering applications. Natural or biopolymer-based composites containing chitin, chitosan, or collagen have advantages such as biocompatibility, biodegradability that are essential for bone tissue engineering. The inclusion of nanoparticles of hydroxyapatite (one of the most widely used bioceramic materials) into the biopolymer matrix improves the mechanical properties and incorporates the nanotopographic features that mimic the nanostructure of bone. This review summarizes the recent work on the development of biocomposites containing natural polymers with hydroxyapatite particles suitable for use in bone defects/bone regeneration. PMID: 20361991 [PubMed - as supplied by publisher] | | |
| Human stem cell delivery for treatment of large segmental bone defects.
April 7, 2010 at 6:43 AM
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| | Human stem cell delivery for treatment of large segmental bone defects. Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3305-10 Authors: Dupont KM, Sharma K, Stevens HY, Boerckel JD, García AJ, Guldberg RE Local or systemic stem cell delivery has the potential to promote repair of a variety of damaged or degenerated tissues. Although various stem cell sources have been investigated for bone repair, few comparative reports exist, and cellular distribution and viability postimplantation remain key issues. In this study, we quantified the ability of tissue-engineered constructs containing either human fetal or adult stem cells to enhance functional repair of nude rat critically sized femoral defects. After 12 weeks, defects treated with cell-seeded polymer scaffolds had significantly higher bone ingrowth and torsional strength compared to those receiving acellular scaffolds, although there were no significant differences between the cell sources. Next, stem cells were labeled with fluorescent quantum dots (QDs) in an attempt to noninvasively track their distribution after delivery on scaffolds. Clear fluorescence was observed at implantation sites throughout the study;! however, beginning 7-10 days after surgery, signals were also observed at contralateral sites treated with acellular QD-free scaffolds. Although immunostaining for human nuclei revealed retention of some cells at the implantation site, no human cells were detected in the control limb defects. Additional histological analysis of implantation and control defect tissues revealed macrophages containing endocytosed QDs. Furthermore, QD-labeling appeared to diminish transplanted cell function resulting in reduced healing responses. In summary, augmentation of polymeric scaffolds with stem cells derived from fetal and adult tissues significantly enhanced healing of large segmental bone defects; however, QD labeling of stem cells eliminated the observed therapeutic effect and failed to conclusively track stem cell location long-term in vivo. PMID: 20133731 [PubMed - indexed for MEDLINE] | | |
| Autologous engineering of cartilage.
April 7, 2010 at 6:43 AM
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| | Autologous engineering of cartilage. Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3418-23 Authors: Emans PJ, van Rhijn LW, Welting TJ, Cremers A, Wijnands N, Spaapen F, Voncken JW, Shastri VP Treatment of full-thickness damage to hyaline cartilage is hampered by the limited availability of autologous healthy cartilage and the lengthy, cost-prohibitive cell isolation and expansion steps associated with autologous cartilage implantation (ACI). Here we report a strategy for de novo engineering of ectopic autologous cartilage (EAC) within the subperiosteal space (in vivo bioreactor), through the mere introduction of a biocompatible gel that might promote hypoxia-mediated chondrogenesis, thereby effectively overcoming the aforementioned limitations. The EAC is obtained within 3 wk post injection of the gel, and can be press-fit into an osteochondral defect where it undergoes remodeling with good lateral and subchondral integration. The implanted EAC showed no calcification even after 9 mo and attained an average O'Driscoll score of 11 (versus 4 for controls). An "on demand" autologous source of autologous cartilage with remodeling capacity is expected to si! gnificantly impact the clinical options in repair of trauma to articular cartilage. PMID: 20133690 [PubMed - indexed for MEDLINE] | | |
| Engineered vascularized bone grafts.
April 7, 2010 at 6:43 AM
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| | Engineered vascularized bone grafts. Proc Natl Acad Sci U S A. 2010 Feb 23;107(8):3311-6 Authors: Tsigkou O, Pomerantseva I, Spencer JA, Redondo PA, Hart AR, O'Doherty E, Lin Y, Friedrich CC, Daheron L, Lin CP, Sundback CA, Vacanti JP, Neville C Clinical protocols utilize bone marrow to seed synthetic and decellularized allogeneic bone grafts for enhancement of scaffold remodeling and fusion. Marrow-derived cytokines induce host neovascularization at the graft surface, but hypoxic conditions cause cell death at the core. Addition of cellular components that generate an extensive primitive plexus-like vascular network that would perfuse the entire scaffold upon anastomosis could potentially yield significantly higher-quality grafts. We used a mouse model to develop a two-stage protocol for generating vascularized bone grafts using mesenchymal stem cells (hMSCs) from human bone marrow and umbilical cord-derived endothelial cells. The endothelial cells formed tube-like structures and subsequently networks throughout the bone scaffold 4-7 days after implantation. hMSCs were essential for stable vasculature both in vitro and in vivo; however, contrary to expectations, vasculature derived from hMSCs briefly cul! tured in medium designed to maintain a proliferative, nondifferentiated state was more extensive and stable than that with hMSCs with a TGF-beta-induced smooth muscle cell phenotype. Anastomosis occurred by day 11, with most hMSCs associating closely with the network. Although initially immature and highly permeable, at 4 weeks the network was mature. Initiation of scaffold mineralization had also occurred by this period. Some human-derived vessels were still present at 5 months, but the majority of the graft vasculature had been functionally remodeled with host cells. In conclusion, clinically relevant progenitor sources for pericytes and endothelial cells can serve to generate highly functional microvascular networks for tissue engineered bone grafts. PMID: 20133604 [PubMed - indexed for MEDLINE] | | |
| Tissue regeneration of the vocal fold using bone marrow mesenchymal stem cells and synthetic extracellular matrix injections in rats.
April 7, 2010 at 6:43 AM
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| | Tissue regeneration of the vocal fold using bone marrow mesenchymal stem cells and synthetic extracellular matrix injections in rats. Laryngoscope. 2010 Mar;120(3):537-45 Authors: Johnson BQ, Fox R, Chen X, Thibeault S OBJECTIVES/HYPOTHESIS: To determine the effectiveness of bone marrow mesenchymal stem cell (BM-MSC) transplantation in isolation or within a synthetic extracellular matrix (sECM) for tissue regeneration of the scarred vocal fold lamina propria. METHODS: In vitro stability and compatibility of mouse BM-MSC embedded in sECM was assessed by flow cytometry detection of BM-MSC marker expression and proliferation. Eighteen rats were subjected to vocal fold injury bilaterally, followed by 1 month post-treatment with unilateral injections of saline or sECM hydrogel (Extracel; Glycosan BioSystems, Inc., Salt Lake City, UT), green fluorescence protein (GFP)-mouse BM-MSC, or BM-MSC suspended in sECM. Outcomes measured 1 month after treatment included procollagen-III, fibronectin, hyaluronan synthase-III (HAS3), hyaluronidase (HYAL3), smooth muscle actin (SMA), and transforming growth factor-beta 1(TGF-beta1) mRNA expression. The persistence of GFP BM-MSC, proliferation, apop! tosis, and myofibroblast differentiation was assessed by immunofluorescence. RESULTS: BM-MSC grown in vitro within sECM express Sca-1, are positive for hyaluronan receptor CD44, and continue to proliferate. In the in vivo study, groups injected with BM-MSC had detectable GFP-labeled BM-MSC remaining and showed proliferation and low apoptotic or myofibroblast markers compared to the contralateral side. Embedded BM-MSC in the sECM group exhibited increased levels of procollagen III, fibronectin, and TGF-beta1. BM-MSC within sECM downregulated the expression of SMA compared to BM-MSC alone and exhibited upregulation of HYAL3 and no change in HAS3 compared to saline. CONCLUSIONS: Treatment of vocal fold scarring with BM-MSC injected in a sECM displayed the most favorable outcomes in ECM production, hyaluronan metabolism, myofibroblast differentiation, and production of TGF-beta1. Furthermore, the combined treatment had no detectable cytotoxicity and preserved local cell prolife! ration. PMID: 20131370 [PubMed - indexed for MEDLINE] | | | | 
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