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Gleadall A.,University of Leicester | Pan J.,University of Leicester | Kruft M.-A.,Purac Biomaterials | Kellomaki M.,BioMediTech
Acta Biomaterialia | Year: 2014

This paper presents an understanding of how initial molecular weight and initial monomer fraction affect the degradation of bioresorbable polymers in terms of the underlying hydrolysis mechanisms. A mathematical model was used to analyse the effects of initial molecular weight for various hydrolysis mechanisms including noncatalytic random scission, autocatalytic random scission, noncatalytic end scission or autocatalytic end scission. Different behaviours were identified to relate initial molecular weight to the molecular weight half-life and to the time until the onset of mass loss. The behaviours were validated by fitting the model to experimental data for molecular weight reduction and mass loss of samples with different initial molecular weights. Several publications that consider initial molecular weight were reviewed. The effect of residual monomer on degradation was also analysed, and shown to accelerate the reduction of molecular weight and mass loss. An inverse square root law relationship was found between molecular weight half-life and initial monomer fraction for autocatalytic hydrolysis. The relationship was tested by fitting the model to experimental data with various residual monomer contents. © 2013 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

The strength retention characteristics of oriented semicrystalline polylactides were monitored during hydrolytic degradation in vitro. The effects of the polymer type, the material's initial inherent viscosity (iv), the sample diameter and the residual monomer content on strength retention were analyzed. The analyzed polylactides had similar, but not identical, strength retention characteristics. It was concluded that a higher degree of initial crystallinity was a major variable determining the earlier and more profound strength loss of PLLA than 96L/4D PLA and 80L/20 D,L PLA. Samples with a higher initial iv were found to have a longer strength retention time than lower iv samples. Size-dependency was observed, as the strength retention time was shorter for the smaller diameter samples. This size-dependency was caused by faster iv decay. The amount of residual monomer content had a remarkable impact on strength retention. Neither the sample diameter, initial iv or residual monomer content were found to have an effect on the iv range in which there was a rapid decline in strength properties. Therefore, it was concluded that the inherent viscosity and/or molecular weight of oriented PLLA, 96L/4D PLA and 80L/20 D,L PLA is a major variable determining the strength retention of these materials.

Huttunen M.,BioMediTech | Huttunen M.,Tampere University of Technology
Journal of Materials Science: Materials in Medicine | Year: 2013

This study focuses on analyzing the effects of several factors on the rate of decay of inherent viscosity (iv) during hydrolytic degradation. The analysis was made for oriented PLLA, 96L/4D PLA and 80L/20D,L PLA. The analyzed polymers were found to have identical rate of iv loss (P<0.05), given that the materials have otherwise similar initial material properties. The effect of the postprocessing residual monomer was dose dependent, i.e. the higher the monomer content the faster the degradation (P<0.05). Samples with a smaller diameter (1.1 mm) were found to have a faster rate of iv loss than the samples with a larger diameter (4 mm) (P<0.05). A multiple linear regression analysis was used to create a five-component linear model to predict changes in the materials' inherent viscosity. This model yielded accurate predictions during the initial stages of the hydrolytic degradation process where the iv loss was virtually linear. © Springer Science+Business Media New York 2013.

Subrizi A.,University of Helsinki | Hiidenmaa H.,University of Tampere | Ilmarinen T.,University of Tampere | Nymark S.,BioMediTech | And 6 more authors.
Biomaterials | Year: 2012

The in vitro generation of a functional retinal pigment epithelium (RPE) for therapeutic applications requires a limitless source of RPE cells and a supporting scaffold, which improves cell survival and promotes the acquisition of the RPE phenotype. We successfully differentiated human embryonic stem cells (hESCs) toward RPE on a transplantable, biopolymer coated polyimide (PI) membrane. We studied various membrane coatings of which several lead to the generation of a tight and highly polarized epithelium having typical characteristics and functions of human RPE. The cells established a distinctive hexagonal, cobblestone morphology with strong pigmentation, expressed RPE specific genes and proteins, and phagocytosed photoreceptor outer segments (POS) after co-culture with rat retinal explants. The barrier function of hESC-derived RPE (hESC-RPE) monolayers was confirmed by transepithelial electrical resistance and permeability measurements. In conclusion, we show that the PI biomembrane is a suitable scaffold for hESC-RPE tissue engineering. © 2012 Elsevier Ltd.

Cervinka T.,BioMediTech | Cervinka T.,Tampere University of Technology | Hyttinen J.,BioMediTech | Hyttinen J.,Tampere University of Technology | And 2 more authors.
IFMBE Proceedings | Year: 2014

An accurate assessment of the whole bone strength is an essential goal in clinical bone research. This is, however, possible only with accurate and precise description of actual bone geometry. In this paper, we introduce a refined automated approach of OBS method for accurate segmentation of cortical bone cross-sectional area. The approach employs morphological operations and utilization of two fixed thresholds. For comparison, the standard OBS and method based on level set evolution (DRLSE) were evaluated. The performance of used methods was tested on in vivo peripheral quantitative computed tomography (pQCT) images of distal tibia. As to the detection of cortical bone geometry in pQCT images, the new refined OBS method performed reasonably well and was indicating somewhat more consistent results in comparison to standard OBS and DRLSE based method. © Springer International Publishing Switzerland 2014.

Juuti-Uusitalo K.,University of Tampere | Delporte C.,Free University of Colombia | Gregoire F.,Free University of Colombia | Perret J.,Free University of Colombia | And 10 more authors.
Investigative Ophthalmology and Visual Science | Year: 2013

PURPOSE. Aquaporins (AQPs), a family of transmembrane water channel proteins, are essential for allowing passive water transport through retinal pigmented epithelial (RPE) cells. Even though human native RPE cells and immortalized human RPEs have been shown to express AQPs, the expression of AQPs during the differentiation in stem cell-derived RPE remains to be elucidated. METHODS. In human embryonic (hESCs) and induced pluripotent stem cells (hiPSCs)-derived RPE cells, the expression of several AQPs was determined by quantitative real-time PCR and the localization of AQP1 was assessed with confocal microscopy. The functionality of AQP water channels was determined by cell volume assay in hESC-derived RPE cells. RESULTS. AQP1, AQP3, AQP4, AQP5, AQP6, AQP7, AQP10, AQP11, and AQP12 were expressed in hESC- and hiPSC-derived RPE cells. Furthermore, the expression of AQP1 and AQP11 genes were significantly upregulated during the maturation of both hESC and iPSC into RPE. Confocal microscopy shows the expression of AQP1 at the apical plasma membrane of polarized cobblestone hESC- and hiPSC-derived RPE cells. Lastly, aquaporin inhibitors significantly reduced AQP functionality in hESC-RPE cells. CONCLUSIONS. hESC-RPE and hiPSC-RPE cells express several AQP genes, which are functional in mature hESC-derived RPE cells. The localization of AQP1 on the apical plasma membrane in mature RPE cells derived from both hESC and hiPSC suggests its functionality. These data propose that hESC- and hiPSC-derived RPE cells, grown and differentiated under serum-free conditions, resemble their native counterpart in the human eye. © 2013 The Association for Research in Vision and Ophthalmology, Inc.

Abu Khamidakh A.E.,Tampere University of Technology | Juuti-Uusitalo K.,BioMediTech | Juuti-Uusitalo K.,University of Tampere | Larsson K.,BioMediTech | And 4 more authors.
Experimental Eye Research | Year: 2013

Ca2+ signaling is vitally important in cellular physiological processes and various drugs also affect Ca2+ signaling. Thus, knowledge of Ca2+ dynamics is important toward understanding cell biology, as well as the development of drug-testing assays. ARPE-19 cells are widely used for modeling human retinal pigment epithelium functions and drug-testing, but intercellular communication has not been assessed in these cells. In this study, we investigated intercellular Ca2+ communication induced by mechanical stimulation in ARPE-19 cells. An intercellular Ca2+ wave was induced in ARPE-19 monolayer by point mechanical stimulation of a single cell. Dynamic changes of intracellular Ca2+ concentration ([Ca2+]i) in the monolayer were tracked with fluorescence microscopy imaging using Ca2+-sensitive fluorescent dye fura-2 in presence and absence of extracellular Ca2+, after depletion of intracellular Ca2+ stores with thapsigargin, and after application of gap junction blocker α-glycyrrhetinic acid and P2-receptor blocker suramin. Normalized fluorescence values, reflecting amplitude of [Ca2+]i increase, and percentage of responsive cells were calculated to quantitatively characterize Ca2+ wave propagation. Mechanical stimulation of a single cell within a confluent monolayer of ARPE-19 cells initiated an increase in [Ca2+]i, which propagated to neighboring cells in a wave-like manner. Ca2+ wave propagated to up to 14 cell tiers in control conditions. The absence of extracellular Ca2+ reduced [Ca2+]i increase in the cells close to the site of mechanical stimulation, whereas the depletion of intracellular Ca2+ stores with thapsigargin blocked the wave spreading to distant cells. The gap junction blocker α-glycyrrhetinic acid reduced [Ca2+]i increase in the cell tiers close to the site of mechanical stimulation, indicating involvement of gap junctions in Ca2+ wave propagation. The P2-receptor blocker suramin reduced the percentage of responsive cells participating in Ca2+ wave spreading beyond the fourth cell tier, showing the necessity of P2-receptors for Ca2+ wave propagation. In disconnected, i.e., subconfluent, ARPE-19 cell clusters Ca2+ wave spreading was considerably less efficient compared to that in confluent ARPE-19 monolayer at the same distances. ARPE-19 cells showed repeatable and robust Ca2+ dynamics after mechanical stimulus. The ARPE-19 cells exhibited two different mechanisms of Ca2+ wave propagation dependent on the cell location: in the cells close to the site of mechanical stimulation the Ca2+ wave propagated mainly through gap junctions and required Ca2+ from both intracellular Ca2+ stores and extracellular media, while farther away the propagation was more dependent on the purinergic receptors and did not require extracellular Ca2+. The proposed method could provide a tool to assess the drug-induced changes in intercellular communication in in vitro assays in human retinal pigment epithelial cells. © 2013 Elsevier Ltd.

Kyllonen L.,University of Tampere | Haimi S.,University of Tampere | Haimi S.,University of Twente | Mannerstrom B.,University of Tampere | And 8 more authors.
Stem Cell Research and Therapy | Year: 2013

Introduction. Currently, human adipose stem cells (hASCs) are differentiated towards osteogenic lineages using culture medium supplemented with L-ascorbic acid 2-phosphate (AsA2-P), dexamethasone (Dex) and beta-glycerophosphate (β-GP). Because this osteogenic medium (OM1) was initially generated for the differentiation of bone marrow-derived mesenchymal stem cells, the component concentrations may not be optimal for the differentiation of hASCs. After preliminary screening, two efficient osteogenic media (OM2 and OM3) were chosen to be compared with the commonly used osteogenic medium (OM1). To further develop the culture conditions towards clinical usage, the osteo-inductive efficiencies of OM1, OM2 and OM3 were compared using human serum (HS)-based medium and a defined, xeno-free medium (RegES), with fetal bovine serum (FBS)-based medium serving as a control. Methods. To compare the osteo-inductive efficiency of OM1, OM2 and OM3 in FBS-, HS- and RegES-based medium, the osteogenic differentiation was assessed by alkaline phosphatase (ALP) activity, mineralization, and expression of osteogenic marker genes (runx2A, DLX5, collagen type I, osteocalcin, and ALP). Results: In HS-based medium, the ALP activity increased significantly by OM3, and mineralization was enhanced by both OM2 and OM3, which have high AsA2-P and low Dex concentrations. ALP activity and mineralization of hASCs was the weakest in FBS-based medium, with no significant differences between the OM compositions due to donor variation. However, the qRT-PCR data demonstrated significant upregulation of runx2A mRNA under osteogenic differentiation in FBS- and HS-based medium, particularly by OM3 under FBS conditions. Further, the expression of DLX5 was greatly stimulated by OM1 to 3 on day 7 when compared to control. The regulation of collagen type I, ALP, and osteocalcin mRNA was modest under induction by OM1 to 3. The RegES medium was found to support the proliferation and osteogenic differentiation of hASCs, but the composition of the RegES medium hindered the comparison of OM1, OM2 and OM3. Conclusions: Serum conditions affect hASC proliferation and differentiation significantly. The ALP activity and mineralization was the weakest in FBS-based medium, although osteogenic markers were upregulated on mRNA level. When comparing the OM composition, the commonly used OM1 was least effective. Accordingly, higher concentration of AsA2-P and lower concentration of Dex, as in OM2 and OM3, should be used for the osteogenic differentiation of hASCs in vitro. © 2013 Kyllönen et al.; licensee BioMed Central Ltd.

Turpeinen H.,University of Tampere | Kukkurainen S.,BioMediTech | Kukkurainen S.,University of Tampere | Pulkkinen K.,University of Tampere | And 5 more authors.
BMC Genomics | Year: 2011

Background: Subtilisin/kexin-like proprotein convertase (PCSK) enzymes have important regulatory function in a wide variety of biological processes. PCSKs proteolytically process at a target sequence that contains basic amino acids arginine and lysine, which results in functional maturation of the target protein. In vitro assays have showed significant biochemical redundancy between the seven family members, but the phenotypes of PCSK deficient mice and patients carrying an inactive PCSK allele argue for a specific biological function. Modeling the structures of individual PCSK enzymes has offered little insights into the specificity determinants. However, previous studies have shown that there can be a coordinated expression between a PCSK and its target molecule. Here, we have surveyed the putative PCSK target proteins using genome-wide expression correlation analysis and cleavage site prediction algorithms.Results: We first performed a gene expression correlation analysis over the whole genome for all PCSK enzymes. PCSKs were found to cluster differently based on the strength of correlations. The screen for putative PCSK target proteins showed a significant enrichment (p-values from 1.2e-4 to < 1.0e-10) of putative targets among the most positively correlating genes for most PCSKs. Interestingly, there was no enrichment in putative targets among the genes that correlated positively with the biologically redundant PCSK7, whereas PCSK5 showed an inverse correlation. PCSKs also showed a highly variable degree of shared target genes that were identified by expression correlation and cleavage site prediction. Multiple alignments were used to evaluate the putative targets to pinpoint the important residues for the substrate recognition. Finally, we validated our approach and identified biochemically PAPPA1 and ADAMTS6 as novel targets for FURIN proteolytic activity.Conclusions: Most PCSK enzymes display strong positive expression correlation with predicted target proteins in our genome-wide analysis. We also show that expression correlation screen combined with a cleavage site-prediction analysis can be used to identify novel bona fide target molecules for PCSKs. Exploring the positively correlating genes can thus offer additional insights into the biology of proprotein convertases. © 2011 Turpeinen et al; licensee BioMed Central Ltd.

News Article | October 13, 2016

The DNA itself has no part in the electrical function, but acts as a scaffold for forming a linear, pearl-necklace-like nanostructure consisting of three gold nanoparticles. Credit: the University of Jyväskylä Nature has inspired generations of people, offering a plethora of different materials for innovations. One such material is the molecule of the heritage, or DNA, thanks to its unique self-assembling properties. Researchers at the Nanoscience Center (NSC) of the University of Jyväskylä and BioMediTech (BMT) of the University of Tampere have now demonstrated a method to fabricate electronic devices by using DNA. The DNA itself has no part in the electrical function, but acts as a scaffold for forming a linear, pearl-necklace-like nanostructure consisting of three gold nanoparticles. The nature of electrical conduction in nanoscale materials can differ vastly from regular, macroscale metallic structures, which have countless free electrons forming the current, thus making any effect by a single electron negligible. However, even the addition of a single electron into a nanoscale piece of metal can increase its energy enough to prevent conduction. This kind of addition of electrons usually happens via a quantum-mechanical effect called tunnelling, where electrons tunnel through an energy barrier. In this study, the electrons tunnelled from the electrode connected to a voltage source, to the first nanoparticle and onwards to the next particle and so on, through the gaps between them. "Such single-electron devices have been fabricated within the scale of tens of nanometres by using conventional micro- and nanofabrication methods for more than two decades," says Senior Lecturer Jussi Toppari from the NSC. Toppari has studied these structures already in his PhD work. "The weakness of these structures has been the cryogenic temperatures needed for them to work. Usually, the operation temperature of these devices scales up as the size of the components decreases. Our ultimate aim is to have the devices working at room temperature, which is hardly possible for conventional nanofabrication methods - so new venues need to be found." Modern nanotechnology provides tools to fabricate metallic nanoparticles with the size of only a few nanometres. Single-electron devices fabricated from these metallic nanoparticles could function all the way up to room temperature. The NSC has long experience of fabricating such nanoparticles. "After fabrication, the nanoparticles float in an aqueous solution and need to be organised into the desired form and connected to the auxiliary circuitry," explains researcher Kosti Tapio. "DNA-based self-assembly together with its ability to be linked with nanoparticles offer a very suitable toolkit for this purpose." Gold nanoparticles are attached directly within the aqueous solution onto a DNA structure designed and previously tested by the involved groups. The whole process is based on DNA self-assembly, and yields countless of structures within a single patch. Ready structures are further trapped for measurements by electric fields. "The superior self-assembly properties of the DNA, together with its mature fabrication and modification techniques, offer a vast variety of possibilities," says Associate Professor Vesa Hytönen. Electrical measurements carried out in this study demonstrated for the first time that these scalable fabrication methods based on DNA self-assembly can be efficiently utilised to fabricate single-electron devices that work at room temperature. The research builds on a long-term multidisciplinary collaboration between the research groups involved. In addition to the above persons, Dr Jenni Leppiniemi (BMT), Boxuan Shen (NSC), and Dr Wolfgang Fritzsche (IPHT, Jena, Germany) contributed to the research. The study was published on 13 October 2016 in Nano Letters. Collaborative travel funding was obtained from DAAD in Germany. Explore further: Chains of nanogold – forged with atomic precision More information: Kosti Tapio et al, Toward Single Electron Nanoelectronics Using Self-Assembled DNA Structure, Nano Letters (2016). DOI: 10.1021/acs.nanolett.6b02378

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