Bernd Denecke - Academia.edu (original) (raw)

Papers by Bernd Denecke

Development, 2011

The generation of astrocytes during the development of the mammalian spinal cord is poorly unders... more The generation of astrocytes during the development of the mammalian spinal cord is poorly understood. Here, we demonstrate for the first time that the extracellular matrix glycoprotein tenascin C regulates the expression of key patterning genes during late embryonic spinal cord development, leading to a timely maturation of gliogenic neural precursor cells. We first show that tenascin C is expressed by gliogenic neural precursor cells during late embryonic development. The loss of tenascin C leads to a sustained generation and delayed migration of Fgfr3-expressing immature astrocytes in vivo. Consistent with an increased generation of astroglial cells, we documented an increased number of GFAP-positive astrocytes at later stages. Mechanistically, we could demonstrate an upregulation and domain shift of the patterning genes Nkx6.1 and Nkx2.2 in vivo. In addition, sulfatase 1, a known downstream target of Nkx2.2 in the ventral spinal cord, was also upregulated. Sulfatase 1 regulates growth factor signalling by cleaving sulphate residues from heparan sulphate proteoglycans. Consistent with this function, we observed changes in both FGF2 and EGF responsiveness of spinal cord neural precursor cells. Taken together, our data implicate Tnc in the regulation of proliferation and lineage progression of astroglial progenitors in specific domains of the developing spinal cord.

The Journal of Biological Chemistry, Apr 10, 2003

Genetic evidence from mutant mice suggests that ␣ 2 -HS glycoprotein/fetuin-A (Ahsg) is a systemi... more Genetic evidence from mutant mice suggests that ␣ 2 -HS glycoprotein/fetuin-A (Ahsg) is a systemic inhibitor of precipitation of basic calcium phosphate preventing unwanted calcification. Using electron microscopy and dynamic light scattering, we demonstrate that precipitation inhibition by Ahsg is caused by the transient formation of soluble, colloidal spheres, containing Ahsg, calcium, and phosphate. These "calciprotein particles" of 30 -150 nm in diameter are initially amorphous and soluble but turn progressively more crystalline and insoluble in a time-and temperature-dependent fashion. Solubilization in Ahsg-containing calciprotein particles provides a novel conceptual framework to explain how insoluble calcium precipitates may be transported and removed in the bodies of mammals. Mutational analysis showed that the basic calcium phosphate precipitation inhibition activity resides in the amino-terminal cystatin-like domain D1 of Ahsg. A structure-function analysis of wild type and mutant forms of cystatin-like domains from Ahsg, full-length fetuin-B, histidine-rich glycoprotein, and kininogen demonstrated that Ahsg domain D1 is most efficient in inhibiting basic calcium phosphate precipitation. The computer-modeled domain structures suggest that a dense array of acidic residues on an extended ␤-sheet of the cystatin-like domain Ahsg-D1 mediates efficient inhibition.

Journal of Neural Transmission, 2009

Aim of the present study was to investigate the neuroprotective effect of dental pulp cells (DPCs... more Aim of the present study was to investigate the neuroprotective effect of dental pulp cells (DPCs) in in vitro models of Alzheimer and Parkinson disease. Primary cultures of hippocampal and ventral mesencephalic neurons were treated for 24 h with amyloid beta (Ab 1-42 ) peptide 1-42 and 6-OHDA, respectively. DPCs isolated from adult rat incisors were previously cultured in tissue culture inserts and added to the neuron cultures 2 days prior to neurotoxin treatment. Cell viability was assessed by the MTT assay. The co-culture with DPCs significantly attenuated 6-OHDA and Ab 1-42 -induced toxicity in primary cultures of mesencephalic and hippocampal neurons, and lead to an increase in neuronal viability in untreated cultures, suggesting a neurotrophic effect in both models. Furthermore, human dental pulp cells expressed a neuronal phenotype and produced the neurotrophic factors NGF, GDNF, BDNF, and BMP2 shown by microarray screening and antibody staining for the representative proteins. DPCs protected primary neurons in in vitro models of Alzheimer's and Parkinson's disease and can be viewed as possible candidates for studies on cell-based therapy.

Biochimica et biophysica acta, Jan 4, 2016

Surface expressed proteoglycans mediate the binding of cytokines and chemokines to the cell surfa... more Surface expressed proteoglycans mediate the binding of cytokines and chemokines to the cell surface and promote migration of various tumor cell types including epithelial tumor cells. We here demonstrate that binding of the chemokine-like inflammatory cytokine macrophage migration inhibitory factor (MIF) to epithelial lung and breast tumor cell lines A549 and MDA-MB231 is sensitive to enzymatic digestion of heparan sulphate chains and competitive inhibition with heparin. Moreover, MIF interaction with heparin was confirmed by chromatography and a structural comparison indicated a possible heparin binding site. These results suggested that proteoglycans carrying heparan sulphate chains are involved in MIF binding. Using shRNA-mediated gene silencing, we identified syndecan-1 as the predominant proteoglycan required for the interaction with MIF. MIF binding was decreased by induction of proteolytic shedding of syndecan-1, which could be prevented by inhibition of the metalloproteinase...

Discoveries, 2014

Cell transplantation therapy is considered a novel and promising strategy in regenerative medicin... more Cell transplantation therapy is considered a novel and promising strategy in regenerative medicine. Recent studies point out that paracrine effects and inflammation induced by transplanted cells are key factors for the improvement of myocardial function. The present study aims at differentiating paracrine effects from inflammatory reactions after cell transplantation. Therefore, in vitro induced apoptotic bodies were transplanted after myocardial infarction in a rat model. Eight weeks after transplantation, the functional results showed no improvement in left ventricular function. Histological analysis revealed no significant differences in the amount of infiltrated cells and collagen content did not differ among the four groups, which sustains the functional data. Surprisingly, angiogenesis increased in groups with apoptotic bodies derived from HUVEC and endothelial progenitor cells, but not from fibroblasts. A complex genetic analysis of apoptotic bodies indicated that miRNAs could be responsible for these changes. Our study demonstrates that inflammatory reaction is critical for scar remodelling and improvement of the heart function after late cell therapy, while neoangiogenesis alone is not sufficient to improve heart function.

Введение. В последнее время наблюдается значительный прогресс в разработке новых культуральных си... more Введение. В последнее время наблюдается значительный прогресс в разработке новых культуральных систем, основанных на использовании компонентов внеклеточного матрикса для индукции направленной дифференцировки стволовых клеток в необходимый клеточный тип [1]. Помимо воссоздания структурной целостности органов и тканей внеклеточный матрикс выполняет в организме еще и множество физиологических функций. Он обеспечивает доставку питательных веществ к клеткам и служит в качестве резервуара, в котором концентрируются ростовые факторы и другие физиологические медиаторы. Кроме того, некоторые специфические функции специализированных клеток невозможны без взаимодействия клеточных рецепторов с компонентами внеклеточного матрикса. Поэтому биоматериалы, структурно и молекулярно воссоздающие микроокружение терапевтической ткани-мишени, активно используют при разработке протоколов направленной дифференцировки стволовых клеток. При этом, в зависимости от поставленных задач, важна биологическая совместимость биополимера с конкретным видом клеток, поскольку биоматериалы могут как стимулировать, так и угнетать пролиферацию и дифференцировку последних. Идеальный биополимерный матрикс для культивирования клеток в целях тканевой инженерии должен обладать рядом свойств, включая такие, как биодеградабельность или химическая стабильность; сходство по физическим характеристикам (эластичность, твердость или мягкость, упругость) с замещаемой тканью; способность обеспечивать адгезию, пролиферацию и стабильность клеточных культур.

Oncotarget, Jan 3, 2015

Syndecan-1 is a surface expressed heparan sulphate proteoglycan, which is upregulated by several ... more Syndecan-1 is a surface expressed heparan sulphate proteoglycan, which is upregulated by several tumor types and involved in tumor cell migration and metastasis. Syndecan-1 is shed from the cell surface and the remaining transmembrane fragment undergoes intramembrane proteolysis by γ-secretase. We here show that this generates a cytoplasmic C-terminal fragment (cCTF). In epithelial lung tumor A549 cells the endogenously produced cCTF accumulated when its proteasomal degradation was blocked with bortezomib and this accumulation was prevented by γ-secretase inhibition. Overexpression of the cCTF suppressed migration and invasion of A549 cells. This inhibitory effect was only seen when endogenous syndecan-1 was present, but not in syndecan-1 deficient cells. Further, overexpression of syndecan-1 cCTF increased the basal activation of Src kinase, focal adhesion kinase (FAK) and Rho GTPase. This was associated with increased adhesion to fibronectin and collagen G and an increased recruit...

Many adult tissues harbour populations of stem cells that have the capacity to self-renew and to ... more Many adult tissues harbour populations of stem cells that have the capacity to self-renew and to regenerate tissue and organ systems after trauma, disease, or ageing. For example, the bone marrow is the major source of adult hematopoietic stem cells (HSC) that renew cells in circulating blood. Bone marrow contains a second population of multipotent stroma cells also called mesenchymal stem cells (MSC). MSC can form, in vitro and in vivo, a variety of mesenchymal tissues including bone, cartilage, tendon, and fat. These cells seem a preferred source for tissue engineering purposes. Important practical considerations in tissue engineering are i) how to deliver and keep the cells to their target tissue ii) the influence on differentiation of growing stems cells in an three-dimensional environment, and iii) the ability of commonly used biomaterials to affect differentiation. To this end we designed scaffolds from different biomaterials and evaluated their influence on the differentiatio...

Pathology - Research and Practice

Stem Cell Engineering, 2010

Microarrays, 2013

Mature microRNA is a crucial component in the gene expression regulation network. At the same tim... more Mature microRNA is a crucial component in the gene expression regulation network. At the same time, microRNA gene expression and procession is regulated in a precise and collaborated way. Pre-microRNAs mediate products during the microRNA transcription process, they can provide hints of microRNA gene expression regulation or can serve as alternative biomarkers. To date, little effort has been devoted to pre-microRNA expression profiling. In this study, three human and three mouse microRNA profile data sets, based on the Affymetrix miRNA 2.0 array, have been re-analyzed for both mature and pre-microRNA signals as a primary test of parallel mature/pre-microRNA expression profiling on a single platform. The results not only demonstrated a glimpse of pre-microRNA expression in human and mouse, but also the relationship of microRNA expressions between pre-and mature forms. The study also showed a possible application of currently available microRNA microarrays in profiling pre-microRNA expression in a time and cost effective manner.

Microarrays, 2013

It came to our attention that a paper has recently been published concerning one of the GEO datas... more It came to our attention that a paper has recently been published concerning one of the GEO datasets (GSE34413) we cited in our published paper [1]. The original reference (reference 27) cited for this dataset leads to a paper about a similar study from the same research group . In order to provide readers with exact citation information, we would like to update reference 27 in our previous paper to the new published paper concerning GSE34413 . The authors apologize for this inconvenience.

Journal of Hematology & Oncology, 2015

Background: Upon inflammation, myeloid cell generation in the bone marrow (BM) is broadly enhance... more Background: Upon inflammation, myeloid cell generation in the bone marrow (BM) is broadly enhanced by the action of induced cytokines which are produced locally and at multiple sites throughout the body.

Biomaterials, 2015

Surface topography impacts on cell growth and differentiation, but it is not trivial to generate ... more Surface topography impacts on cell growth and differentiation, but it is not trivial to generate defined surface structures and to assess the relevance of specific topographic parameters. In this study, we have systematically compared in vitro differentiation of mesenchymal stem cells (MSCs) on a variety of groove/ ridge structures. Micro-and nano-patterns were generated in polyimide using reactive ion etching or multi beam laser interference, respectively. These structures affected cell spreading and orientation of human MSCs, which was also reflected in focal adhesions morphology and size. Time-lapse demonstrated directed migration parallel to the nano-patterns. Overall, surface patterns clearly enhanced differentiation of MSCs towards specific lineages: 15 mm ridges increased adipogenic differentiation whereas 2 mm ridges enhanced osteogenic differentiation. Notably, nano-patterns with a periodicity of 650 nm increased differentiation towards both osteogenic and adipogenic lineages. However, in absence of differentiation media surface structures did neither induce differentiation, nor lineage-specific gene expression changes. Furthermore, nanostructures did not affect the YAP/TAZ complex, which is activated by substrate stiffness. Our results provide further insight into how structuring of tailored biomaterials and implant interfaces e e.g. by multi beam laser interference in sub-micrometer scale e do not induce differentiation of MSCs per se, but support their directed differentiation. Biomaterials j o u r n a l h o m e p a g e : w w w .e l se v i e r. co m/ lo ca t e / b i o m a t e ri a l s http://dx.

Laboratory Medicine, 2010

Development, 2011

The generation of astrocytes during the development of the mammalian spinal cord is poorly unders... more The generation of astrocytes during the development of the mammalian spinal cord is poorly understood. Here, we demonstrate for the first time that the extracellular matrix glycoprotein tenascin C regulates the expression of key patterning genes during late embryonic spinal cord development, leading to a timely maturation of gliogenic neural precursor cells. We first show that tenascin C is expressed by gliogenic neural precursor cells during late embryonic development. The loss of tenascin C leads to a sustained generation and delayed migration of Fgfr3-expressing immature astrocytes in vivo. Consistent with an increased generation of astroglial cells, we documented an increased number of GFAP-positive astrocytes at later stages. Mechanistically, we could demonstrate an upregulation and domain shift of the patterning genes Nkx6.1 and Nkx2.2 in vivo. In addition, sulfatase 1, a known downstream target of Nkx2.2 in the ventral spinal cord, was also upregulated. Sulfatase 1 regulates growth factor signalling by cleaving sulphate residues from heparan sulphate proteoglycans. Consistent with this function, we observed changes in both FGF2 and EGF responsiveness of spinal cord neural precursor cells. Taken together, our data implicate Tnc in the regulation of proliferation and lineage progression of astroglial progenitors in specific domains of the developing spinal cord.

The Journal of Biological Chemistry, Apr 10, 2003

Genetic evidence from mutant mice suggests that ␣ 2 -HS glycoprotein/fetuin-A (Ahsg) is a systemi... more Genetic evidence from mutant mice suggests that ␣ 2 -HS glycoprotein/fetuin-A (Ahsg) is a systemic inhibitor of precipitation of basic calcium phosphate preventing unwanted calcification. Using electron microscopy and dynamic light scattering, we demonstrate that precipitation inhibition by Ahsg is caused by the transient formation of soluble, colloidal spheres, containing Ahsg, calcium, and phosphate. These "calciprotein particles" of 30 -150 nm in diameter are initially amorphous and soluble but turn progressively more crystalline and insoluble in a time-and temperature-dependent fashion. Solubilization in Ahsg-containing calciprotein particles provides a novel conceptual framework to explain how insoluble calcium precipitates may be transported and removed in the bodies of mammals. Mutational analysis showed that the basic calcium phosphate precipitation inhibition activity resides in the amino-terminal cystatin-like domain D1 of Ahsg. A structure-function analysis of wild type and mutant forms of cystatin-like domains from Ahsg, full-length fetuin-B, histidine-rich glycoprotein, and kininogen demonstrated that Ahsg domain D1 is most efficient in inhibiting basic calcium phosphate precipitation. The computer-modeled domain structures suggest that a dense array of acidic residues on an extended ␤-sheet of the cystatin-like domain Ahsg-D1 mediates efficient inhibition.

Journal of Neural Transmission, 2009

Aim of the present study was to investigate the neuroprotective effect of dental pulp cells (DPCs... more Aim of the present study was to investigate the neuroprotective effect of dental pulp cells (DPCs) in in vitro models of Alzheimer and Parkinson disease. Primary cultures of hippocampal and ventral mesencephalic neurons were treated for 24 h with amyloid beta (Ab 1-42 ) peptide 1-42 and 6-OHDA, respectively. DPCs isolated from adult rat incisors were previously cultured in tissue culture inserts and added to the neuron cultures 2 days prior to neurotoxin treatment. Cell viability was assessed by the MTT assay. The co-culture with DPCs significantly attenuated 6-OHDA and Ab 1-42 -induced toxicity in primary cultures of mesencephalic and hippocampal neurons, and lead to an increase in neuronal viability in untreated cultures, suggesting a neurotrophic effect in both models. Furthermore, human dental pulp cells expressed a neuronal phenotype and produced the neurotrophic factors NGF, GDNF, BDNF, and BMP2 shown by microarray screening and antibody staining for the representative proteins. DPCs protected primary neurons in in vitro models of Alzheimer's and Parkinson's disease and can be viewed as possible candidates for studies on cell-based therapy.

Biochimica et biophysica acta, Jan 4, 2016

Surface expressed proteoglycans mediate the binding of cytokines and chemokines to the cell surfa... more Surface expressed proteoglycans mediate the binding of cytokines and chemokines to the cell surface and promote migration of various tumor cell types including epithelial tumor cells. We here demonstrate that binding of the chemokine-like inflammatory cytokine macrophage migration inhibitory factor (MIF) to epithelial lung and breast tumor cell lines A549 and MDA-MB231 is sensitive to enzymatic digestion of heparan sulphate chains and competitive inhibition with heparin. Moreover, MIF interaction with heparin was confirmed by chromatography and a structural comparison indicated a possible heparin binding site. These results suggested that proteoglycans carrying heparan sulphate chains are involved in MIF binding. Using shRNA-mediated gene silencing, we identified syndecan-1 as the predominant proteoglycan required for the interaction with MIF. MIF binding was decreased by induction of proteolytic shedding of syndecan-1, which could be prevented by inhibition of the metalloproteinase...

Discoveries, 2014

Cell transplantation therapy is considered a novel and promising strategy in regenerative medicin... more Cell transplantation therapy is considered a novel and promising strategy in regenerative medicine. Recent studies point out that paracrine effects and inflammation induced by transplanted cells are key factors for the improvement of myocardial function. The present study aims at differentiating paracrine effects from inflammatory reactions after cell transplantation. Therefore, in vitro induced apoptotic bodies were transplanted after myocardial infarction in a rat model. Eight weeks after transplantation, the functional results showed no improvement in left ventricular function. Histological analysis revealed no significant differences in the amount of infiltrated cells and collagen content did not differ among the four groups, which sustains the functional data. Surprisingly, angiogenesis increased in groups with apoptotic bodies derived from HUVEC and endothelial progenitor cells, but not from fibroblasts. A complex genetic analysis of apoptotic bodies indicated that miRNAs could be responsible for these changes. Our study demonstrates that inflammatory reaction is critical for scar remodelling and improvement of the heart function after late cell therapy, while neoangiogenesis alone is not sufficient to improve heart function.

Введение. В последнее время наблюдается значительный прогресс в разработке новых культуральных си... more Введение. В последнее время наблюдается значительный прогресс в разработке новых культуральных систем, основанных на использовании компонентов внеклеточного матрикса для индукции направленной дифференцировки стволовых клеток в необходимый клеточный тип [1]. Помимо воссоздания структурной целостности органов и тканей внеклеточный матрикс выполняет в организме еще и множество физиологических функций. Он обеспечивает доставку питательных веществ к клеткам и служит в качестве резервуара, в котором концентрируются ростовые факторы и другие физиологические медиаторы. Кроме того, некоторые специфические функции специализированных клеток невозможны без взаимодействия клеточных рецепторов с компонентами внеклеточного матрикса. Поэтому биоматериалы, структурно и молекулярно воссоздающие микроокружение терапевтической ткани-мишени, активно используют при разработке протоколов направленной дифференцировки стволовых клеток. При этом, в зависимости от поставленных задач, важна биологическая совместимость биополимера с конкретным видом клеток, поскольку биоматериалы могут как стимулировать, так и угнетать пролиферацию и дифференцировку последних. Идеальный биополимерный матрикс для культивирования клеток в целях тканевой инженерии должен обладать рядом свойств, включая такие, как биодеградабельность или химическая стабильность; сходство по физическим характеристикам (эластичность, твердость или мягкость, упругость) с замещаемой тканью; способность обеспечивать адгезию, пролиферацию и стабильность клеточных культур.

Oncotarget, Jan 3, 2015

Syndecan-1 is a surface expressed heparan sulphate proteoglycan, which is upregulated by several ... more Syndecan-1 is a surface expressed heparan sulphate proteoglycan, which is upregulated by several tumor types and involved in tumor cell migration and metastasis. Syndecan-1 is shed from the cell surface and the remaining transmembrane fragment undergoes intramembrane proteolysis by γ-secretase. We here show that this generates a cytoplasmic C-terminal fragment (cCTF). In epithelial lung tumor A549 cells the endogenously produced cCTF accumulated when its proteasomal degradation was blocked with bortezomib and this accumulation was prevented by γ-secretase inhibition. Overexpression of the cCTF suppressed migration and invasion of A549 cells. This inhibitory effect was only seen when endogenous syndecan-1 was present, but not in syndecan-1 deficient cells. Further, overexpression of syndecan-1 cCTF increased the basal activation of Src kinase, focal adhesion kinase (FAK) and Rho GTPase. This was associated with increased adhesion to fibronectin and collagen G and an increased recruit...

Many adult tissues harbour populations of stem cells that have the capacity to self-renew and to ... more Many adult tissues harbour populations of stem cells that have the capacity to self-renew and to regenerate tissue and organ systems after trauma, disease, or ageing. For example, the bone marrow is the major source of adult hematopoietic stem cells (HSC) that renew cells in circulating blood. Bone marrow contains a second population of multipotent stroma cells also called mesenchymal stem cells (MSC). MSC can form, in vitro and in vivo, a variety of mesenchymal tissues including bone, cartilage, tendon, and fat. These cells seem a preferred source for tissue engineering purposes. Important practical considerations in tissue engineering are i) how to deliver and keep the cells to their target tissue ii) the influence on differentiation of growing stems cells in an three-dimensional environment, and iii) the ability of commonly used biomaterials to affect differentiation. To this end we designed scaffolds from different biomaterials and evaluated their influence on the differentiatio...

Pathology - Research and Practice

Stem Cell Engineering, 2010

Microarrays, 2013

Mature microRNA is a crucial component in the gene expression regulation network. At the same tim... more Mature microRNA is a crucial component in the gene expression regulation network. At the same time, microRNA gene expression and procession is regulated in a precise and collaborated way. Pre-microRNAs mediate products during the microRNA transcription process, they can provide hints of microRNA gene expression regulation or can serve as alternative biomarkers. To date, little effort has been devoted to pre-microRNA expression profiling. In this study, three human and three mouse microRNA profile data sets, based on the Affymetrix miRNA 2.0 array, have been re-analyzed for both mature and pre-microRNA signals as a primary test of parallel mature/pre-microRNA expression profiling on a single platform. The results not only demonstrated a glimpse of pre-microRNA expression in human and mouse, but also the relationship of microRNA expressions between pre-and mature forms. The study also showed a possible application of currently available microRNA microarrays in profiling pre-microRNA expression in a time and cost effective manner.

Microarrays, 2013

It came to our attention that a paper has recently been published concerning one of the GEO datas... more It came to our attention that a paper has recently been published concerning one of the GEO datasets (GSE34413) we cited in our published paper [1]. The original reference (reference 27) cited for this dataset leads to a paper about a similar study from the same research group . In order to provide readers with exact citation information, we would like to update reference 27 in our previous paper to the new published paper concerning GSE34413 . The authors apologize for this inconvenience.

Journal of Hematology & Oncology, 2015

Background: Upon inflammation, myeloid cell generation in the bone marrow (BM) is broadly enhance... more Background: Upon inflammation, myeloid cell generation in the bone marrow (BM) is broadly enhanced by the action of induced cytokines which are produced locally and at multiple sites throughout the body.

Biomaterials, 2015

Surface topography impacts on cell growth and differentiation, but it is not trivial to generate ... more Surface topography impacts on cell growth and differentiation, but it is not trivial to generate defined surface structures and to assess the relevance of specific topographic parameters. In this study, we have systematically compared in vitro differentiation of mesenchymal stem cells (MSCs) on a variety of groove/ ridge structures. Micro-and nano-patterns were generated in polyimide using reactive ion etching or multi beam laser interference, respectively. These structures affected cell spreading and orientation of human MSCs, which was also reflected in focal adhesions morphology and size. Time-lapse demonstrated directed migration parallel to the nano-patterns. Overall, surface patterns clearly enhanced differentiation of MSCs towards specific lineages: 15 mm ridges increased adipogenic differentiation whereas 2 mm ridges enhanced osteogenic differentiation. Notably, nano-patterns with a periodicity of 650 nm increased differentiation towards both osteogenic and adipogenic lineages. However, in absence of differentiation media surface structures did neither induce differentiation, nor lineage-specific gene expression changes. Furthermore, nanostructures did not affect the YAP/TAZ complex, which is activated by substrate stiffness. Our results provide further insight into how structuring of tailored biomaterials and implant interfaces e e.g. by multi beam laser interference in sub-micrometer scale e do not induce differentiation of MSCs per se, but support their directed differentiation. Biomaterials j o u r n a l h o m e p a g e : w w w .e l se v i e r. co m/ lo ca t e / b i o m a t e ri a l s http://dx.

Laboratory Medicine, 2010