241 results found
Klontzas ME, Reakasame S, Silva R, et al., 2019, Oxidized alginate hydrogels with the GHK peptide enhance cord blood mesenchymal stem cell osteogenesis: A paradigm for metabolomics-based evaluation of biomaterial design, Acta Biomaterialia, Vol: 88, Pages: 224-240, ISSN: 1742-7061
Oxidized alginate hydrogels are appealing alternatives to natural alginate due to their favourable biodegradability profiles and capacity to self-crosslink with amine containing molecules facilitating functionalization with extracellular matrix cues, which enable modulation of stem cell fate, achieve highly viable 3-D cultures, and promote cell growth. Stem cell metabolism is at the core of cellular fate (proliferation, differentiation, death) and metabolomics provides global metabolic signatures representative of cellular status, being able to accurately identify the quality of stem cell differentiation. Herein, umbilical cord blood mesenchymal stem cells (UCB MSCs) were encapsulated in novel oxidized alginate hydrogels functionalized with the glycine-histidine-lysine (GHK) peptide and differentiated towards the osteoblastic lineage. The ADA-GHK hydrogels significantly improved osteogenic differentiation compared to gelatin-containing control hydrogels, as demonstrated by gene expression, alkaline phosphatase activity and bone extracellular matrix deposition. Metabolomics revealed the high degree of metabolic heterogeneity in the gelatin-containing control hydrogels, captured the enhanced osteogenic differentiation in the ADA-GHK hydrogels, confirmed the similar metabolism between differentiated cells and primary osteoblasts, and elucidated the metabolic mechanism responsible for the function of GHK. Our results suggest a novel paradigm for metabolomics-guided biomaterial design and robust stem cell bioprocessing. STATEMENT OF SIGNIFICANCE: Producing high quality engineered bone grafts is important for the treatment of critical sized bone defects. Robust and sensitive techniques are required for quality assessment of tissue-engineered constructs, which result to the selection of optimal biomaterials for bone graft development. Herein, we present a new use of metabolomics signatures in guiding the development of novel oxidised alginate-based hydrogels with umbilical
Devito L, Klontzas ME, Cvoro A, et al., 2019, Comparison of human isogeneic Wharton's jelly MSCs and iPSC-derived MSCs reveals differentiation-dependent metabolic responses to IFNG stimulation, CELL DEATH & DISEASE, Vol: 10, ISSN: 2041-4889
Martins De Jesus Lima Grilo A, Mantalaris A, 2019, The increasingly human and profitable monoclonal antibody market, Trends in Biotechnology, Vol: 37, Pages: 9-16, ISSN: 0167-7799
The monoclonal antibody (mAb) market has changed rapidly in the past 5 years: it has doubled in size, becoming dominated by fully human molecules, launched bispecific molecules, and faced competition from biosimilars. We summarize the market in terms of therapeutic applications, type and structure of mAbs, dominant companies, manufacturing locations, and emerging markets.
Allenby MC, Panoskaltsis N, Tahlawi A, et al., 2019, Dynamic human erythropoiesis in a three-dimensional perfusion bone marrow biomimicry, BIOMATERIALS, Vol: 188, Pages: 24-37, ISSN: 0142-9612
Tsipa A, Koutinas M, Usaku C, et al., 2018, Optimal bioprocess design through a gene regulatory network - Growth kinetic hybrid model: Towards replacing Monod kinetics, METABOLIC ENGINEERING, Vol: 48, Pages: 129-137, ISSN: 1096-7176
Quiroga-Campano AL, Panoskaltsis N, Mantalaris A, 2018, Energy-based culture medium design for biomanufacturing optimization: A case study in monoclonal antibody production by GS-NS0 cells, METABOLIC ENGINEERING, Vol: 47, Pages: 21-30, ISSN: 1096-7176
Buldum G, Bismarck A, Mantalaris A, 2018, Recombinant biosynthesis of bacterial cellulose in genetically modified Escherichia coli, BIOPROCESS AND BIOSYSTEMS ENGINEERING, Vol: 41, Pages: 265-279, ISSN: 1615-7591
Bacterial cellulose (BC) exhibits unique properties such as high purity compared to plant-based cellulose; however, commercial production of BC has remained a challenge, primarily due to the strain properties of cellulose-producing bacteria. Herein, we developed a functional and stable BC production system in genetically modified (GM) Escherichia coli by recombinant expression of both the BC synthase operon (bcsABCD) and the upstream operon (cmcax, ccp Ax). BC production was achieved in GM HMS174 (DE3) and in GM C41 (DE3) by optimization of the culture temperature (22 °C, 30 °C, and 37 °C) and IPTG concentration. BC biosynthesis was detected much earlier in GM C41 (DE3) cultures (3 h after IPTG induction) than those of Gluconacetobacter hansenii. GM HMS174 (DE3) produced dense fibres having a length of approximately 1000–3000 μm and a diameter of 10–20 μm, which were remarkably larger than the fibres of BC typically produced by G. hansenii.
Kang Y, Georgiou AI, MacFarlane RJ, et al., 2017, Fibronectin stimulates the osteogenic differentiation of murine embryonic stem cells, JOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE, Vol: 11, Pages: 1929-1940, ISSN: 1932-6254
Tsipa A, Koutinas M, Vernardis SI, et al., 2017, The impact of succinate trace on pWW0 and ortho-cleavage pathway transcription in Pseudomonas putida mt-2 during toluene biodegradation, BIORESOURCE TECHNOLOGY, Vol: 234, Pages: 397-405, ISSN: 0960-8524
Severn CE, Macedo H, Eagle MJ, et al., 2016, Polyurethane scaffolds seeded with CD34(+) cells maintain early stem cells whilst also facilitating prolonged egress of haematopoietic progenitors, Scientific Reports, Vol: 6, ISSN: 2045-2322
We describe a 3D erythroid culture system that utilises a porous polyurethane (PU) scaffold to mimic the compartmentalisation found in the bone marrow. PU scaffolds seeded with peripheral blood CD34+ cells exhibit a remarkable reproducibility of egress, with an increased output when directly compared to human bone scaffolds over 28 days. Immunofluorescence demonstrated the persistence of CD34+ cells within the scaffolds for the entirety of the culture. To characterise scaffold outputs, we designed a flow cytometry panel that utilises surface marker expression observed in standard 2D erythroid and megakaryocyte cultures. This showed that the egress population is comprised of haematopoietic progenitor cells (CD36+GPA−/low). Control cultures conducted in parallel but in the absence of a scaffold were also generally maintained for the longevity of the culture albeit with a higher level of cell death. The harvested scaffold egress can also be expanded and differentiated to the reticulocyte stage. In summary, PU scaffolds can behave as a subtractive compartmentalised culture system retaining and allowing maintenance of the seeded “CD34+ cell” population despite this population decreasing in amount as the culture progresses, whilst also facilitating egress of increasingly differentiated cells.
Kostoglou M, Fuentes-Gari M, Garcia-Munzer D, et al., 2016, A comprehensive mathematical analysis of a novel multistage population balance model for cell proliferation, Computers & Chemical Engineering, Vol: 91, Pages: 157-166, ISSN: 0098-1354
Multistage population balances provide a more detailed mathematical description of cellular growth than lumped growth models, and can therefore describe better the physics of cell evolution through cycles. These balances can be formulated in terms of cell age, mass, size or cell protein content and they can be univariate or multivariate. A specific three stage population balance model based on cell protein content has been derived and used recently to simulate evolution of cell cultures for several applications. The behavior of the particular mathematical model is studied in detail here. A one equation analog of the multistage model is formulated and it is solved analytically in the self-similarity domain. The effect of the initial condition on the approach to self-similarity is studied numerically. The three equations model is examined then by using asymptotic and numerical techniques. It is shown that in the case of sharp interstage transition the discontinuities of the initial condition are preserved during cell growth leading to oscillating solutions whereas for distributed transition, the cell distribution converges to a self-similar (long time asymptote) shape. The closer is the initial condition to the self similar distribution the faster is the convergence to the self-similarity and the smaller the amplitude of oscillations of the total cell number. The findings of the present work lead to a better understanding of the multistage population balance model and to its more efficient use for description of experimental data by employing the expected solution behavior.
Tsipa A, Koutinas M, Pistikopoulos EN, et al., 2016, Transcriptional kinetics of the cross-talk between the ortho-cleavage and TOL pathways of toluene biodegradation in Pseudomonas putida mt-2, JOURNAL OF BIOTECHNOLOGY, Vol: 228, Pages: 112-123, ISSN: 0168-1656
Klontzas M, Kenanidis EI, MacFarlane RJ, et al., 2016, Investigational drugs for fracture healing: preclinical & clinical data, Expert Opinion on Investigational Drugs, ISSN: 1354-3784
Papathanasiou MM, Avraamidou S, Oberdieck R, et al., 2016, Advanced control strategies for the multicolumn countercurrent solvent gradient purification process, AIChE Journal, ISSN: 0001-1541
The multicolumn countercurrent solvent gradient purification process (MCSGP) is a semicontinuous, chromatographic separation process used in the production of monoclonal antibodies) . The process is characterized by high model complexity and periodicity that challenge the development of control strategies, necessary for feasible and efficient operation and essential toward continuous production. A novel approach for the development of control policies for the MCSGP process, which enables efficient continuous process control is presented. Based on a high fidelity model, the recently presented PAROC framework and software platform that allows seamless design and in-silico validation of advanced controllers for complex systems are followed. The controller presented in this work is successfully tested against disturbances and is shown to efficiently capture the process periodic nature.
Savvopoulos S, Misener R, Panoskaltsis N, et al., 2016, A Personalized Framework for Dynamic Modeling of Disease Trajectories in Chronic Lymphocytic Leukemia, IEEE Transactions on Biomedical Engineering, Vol: 63, Pages: 2396-2404, ISSN: 1558-2531
Chronic Lymphocytic Leukemia (CLL) is themost common peripheral blood and bone marrow cancerin the developed world. This manuscript proposesmathematical model equations representing the diseasedynamics of B-cell CLL. We interconnect delay differentialcell cycle models in each of the tumor-involved diseasecenters using physiologically-relevant cell migration. Wefurther introduce 5 hypothetical case studies representingCLL heterogeneity commonly seen in clinical practiceand demonstrate how the proposed CLL model frameworkmay capture disease pathophysiology across patienttypes. We conclude by exploring the capacity of theproposed temporally- and spatially-distributed model tocapture the heterogeneity of CLL disease progression. Byusing Global Sensitivity Analysis, the critical parametersinfluencing disease trajectory over space and time are:(i) the initial number of CLL cells in peripheral blood,the number of involved lymph nodes, the presence anddegree of splenomegaly; (ii) the migratory fraction of nonproliferatingas well as proliferating CLL cells from bonemarrow into blood and of proliferating CLL cells fromblood into lymph nodes; (iii) the parameters inducing nonproliferativecells to proliferate. The proposed model offersa practical platform which may be explored in futurepersonalized patient protocols once validated.
Reissis D, Quen OT, Cooper NC, et al., 2016, Current clinical evidence for the use of mesenchymal stem cells in articular cartilage repair, Expert Opinion on Biological Therapy, Vol: 16, Pages: 535-557, ISSN: 1744-7682
Zubairi SI, Mantalaris A, Bismarck A, et al., 2016, Polyhydroxyalkanoates (PHAs) for tissue engineering applications: biotransformation of palm oil mill effluent (POME) to value-added polymers, Jurnal Teknologi, Vol: 78, Pages: 13-29, ISSN: 0127-9696
The study of cancer cell has been hindered by the lack of appropriate ex vivo models, which can mimic this microenvironment. It is hypothesized that the fabrication of porous 3-D scaffolds for the biomimetics growth of cancer cells ex vivo could facilitate the study of the disease in its native 3-D niche. For that reason, biomaterials are used for fabrication of 3-D scaffold, in general, may be natural polymers such as proteins, collagens and gelatin, or synthetic biopolymers. Among the various available biodegradable polymers, polyhydroxyalkanoates (PHAs) have gained significant interest as one of the value-added materials which can be synthesized from abundantly available source of palm oil mill effluent (POME). Down the group of the PHA, poly-3-hydroxybutyrate (PHB) and copolymerizing this PHB that produced PHBVs; these two polymers have the most prevalent polymer used for scaffolds fabrication. A physico-chemical and biological modification has developed to improve wetting, adhesion, and printing of polymer surfaces, generally by introducing a variety of polar groups. These techniques must be tailored to introduce a specific functional group when the surface modification is a precursor to attach a bioactive compound. There are a few methods in order to fabricate porous 3-D scaffolds such as solvent casting, particulate leaching, thermally induced phase separation, gas forming, fiber bonding, electrospinning and also solid free form method. A review of the polyhydroxyalkanoates (PHAs) for tissue engineering applications is presented, beginning with the basic naturally derived polymerization of PHAs, biotransformation of palm oil mill effluent (POME) to the value-added polymers, novel methods of scaffold fabrication capabilities and its physico- chemical and biological surface modifications to increase cell-biomaterial affinity.
Fuentes-Gari M, Zemenides S, Misener R, et al., 2015, Use of Mathematical Modelling Indicates That Patients Treated for Acute Myeloid Leukaemia (AML) Are Undertreated When Ideal Body Weight Is Used to Dose Chemotherapy, 57th Annual Meeting of the American-Society-of-Hematology, Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Brito dos Santos SUSANA, Allenby M, Mantalaris A, et al., 2015, Effect of Oxygen and 3D Microenvironment on Physiologic Erythropoiesis, 57th Annual Meeting of the American-Society-of-Hematology, Publisher: AMER SOC HEMATOLOGY, ISSN: 0006-4971
Zavitsanou S, Mantalaris A, Georgiadis MC, et al., 2015, In Silico Closed-Loop Control Validation Studies for Optimal Insulin Delivery in Type 1 Diabetes, IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, Vol: 62, Pages: 2369-2378, ISSN: 0018-9294
Fuentes-Gaŕ M, Misener R, Georgiadis MC, et al., 2015, Chemotherapy optimization in Leukemia: Selecting the right mathematical models for the right biological processes, Pages: 534-539, ISSN: 1474-6670
© 2015, IFAC (International Federation of Automatic Control) Hosting by Elsevier Ltd. All rights reserved. Clinical chemotherapy dosage strategies for leukemia rely on weight/height calculations theoretically correlated to patient drug tolerance. However, over-and under-dosage still exist in clinical practice, which could be overcome by quantifying the actual fraction of cancer cells susceptible to be eradicated. In this work, we show how choosing models that are accurate enough in simulating the biological processes ultimately affecting drug efficacy is critical in order to disentangle patient to patient heterogeneity. Incorporating heterogeneity from measurable sources in such a manner brings us a step closer in our path towards the development of personalized rational therapies.
Zubairi SI, Mantalaris A, Bismarck A, 2015, Pore Interconnectivity Analysis of Porous Three Dimensional Scaffolds of Poly (3-Hydroxybutyric Acid) (PHB) and Poly(3-Hydroxybutyric-co-3-Hydroxyvaleric Acid) (PHBV) Through Non-Invasive Color Staining Method, SAINS MALAYSIANA, Vol: 44, Pages: 1351-1356, ISSN: 0126-6039
Brito dos Santos SUSANA, Allenby MC, Panoskaltsis N, et al., 2015, In Vitro Physiologic Erythropoiesis in a 3D Bone Marrow Biomimicry, 4th TERMIS World Congress, Publisher: MARY ANN LIEBERT, INC, Pages: S228-S228, ISSN: 1937-3341
Velliou EG, Brito dos Santos SUSANA, Papathanasiou MM, et al., 2015, Towards unravelling the kinetics of an acute myeloid leukaemia model system under oxidative and starvation stress: a comparison between two- and three-dimensional cultures, BIOPROCESS AND BIOSYSTEMS ENGINEERING, Vol: 38, Pages: 1589-1600, ISSN: 1615-7591
Fuentes Gari M, Misener R, Georgiadis MC, et al., 2015, Selecting a differential equation cell cycle model for simulating leukemia treatment, Industrial & Engineering Chemistry Research, Vol: 54, Pages: 8847-8859, ISSN: 1520-5045
This manuscript studies three differential equation models of the leukemia cell cycle: a population balance model (PBM) using intracellular protein expression levels as state variables representing phase progress; a delay differential equation model (DDE) with temporal phase durations as delays; and an ordinary differential equation model (ODE) of inter-phase progression. In each type of model, global sensitivity analysis determines the most significant parameters while parameter estimation fits experimental data. In order to compare models based purely on the output of their structural properties, an expected behavior was defined, and each model was coupled to a pharmacokinetic/pharmacodynamic model of chemotherapy delivery. Results suggest that the particular cell cycle model chosen highly affects the simulated treatment outcome, given the same steady state kinetic parameters and drug dosage/scheduling. The manuscript shows how cell cycle models should be selected according to the complexity, sensitivity and parameter availability of the application envisioned.
Fauzi I, Panoskaltsis N, Mantalaris A, 2015, In vitro differentiation of embryonic stem cells into hematopoietic lineage: towards erythroid progenitor’s production, Methods in Molecular Biology, Vol: 1341, Pages: 217-234, ISSN: 1940-6029
Embryonic stem cells (ESCs) differentiation via embryoid body (EB) formation is an established method that generates the three germ layers. However, EB differentiation poses several problems including formation of heterogeneous cell populations. Herein, we described a differentiation protocol on enhancing mesoderm derivation from murine ESCs (mESCs) using conditioned medium (CM) from HepG2 cells. We used this technique to direct hematopoiesis by generating “embryoid-like” colonies (ELCs) from murine (m) ESCs without following standard formation of EBs. Our CM-mESCs group yielded an almost fivefold increase in ELC formation (p ≤ 0.05) and higher expression of mesoderm genes;-Brachyury-T, Goosecoid, and Flk-1 compared with control mESCs group. Hematopoietic colony formation from CM-mESCs was also enhanced by twofold at days 7 and 14 with earlier colony commitment compared to control mESCs (p ≤ 0.05). This early clonogenic capacity was confirmed morphologically by the presence of nucleated erythrocytes and macrophages as early as day 7 in culture using standard 14-day colony-forming assay. Early expression of hematopoietic primitive (ζ-globin) and definitive (β-globin) erythroid genes and proteins was also observed by day 7 in the CM-treated culture. These data indicate that hematopoietic cells more quickly differentiate from CM-treated, compared with those using standard EB approaches, and provide an efficient bioprocess platform for erythroid-specific differentiation of ESCs.
Zubairi SI, Bismarck A, Mantalaris A, 2015, THE EFFECT OF SURFACE HETEROGENEITY ON WETTABILITY OF POROUS THREE DIMENSIONAL (3-D) SCAFFOLDS OF POLY(3-HYDROXYBUTYRIC ACID) (PHB) AND POLY(3-HYDROXYBUTYRIC-CO-3-HYDROXYVALERIC ACID) (PHBV), JURNAL TEKNOLOGI, Vol: 75, Pages: 305-312, ISSN: 0127-9696
Fuentes Gari M, Misener R, Pefani E, et al., 2015, Cell cycle model selection for leukemia and its impact in chemotherapy outcomes, Computer Aided Chemical Engineering, Vol: 37, Pages: 2159-2164, ISSN: 1570-7946
The cell cycle is the biological process used by cells to replicate their genetic material and give birth to new cells that are in turn eligible to proliferate. It is highly regulated by the timed expression of proteins which trigger cell cycle events such as the start of DNA replication or the commencement of mitosis (when the cell physically divides into two daughter cells). Mathematical models of the cell cycle have been widely developed both at the intracellular (protein kinetics) and macroscopic (cell duplication) levels. Due to the cell cycle specificity of most chemotherapeutic drugs, these models are increasingly being used for the study and simulation of cellular kinetics in the area of cancer treatment.In this work, we present a population balance model (PBM) of the cell cycle in leukemia that uses intracellular protein expression as state variable to represent phase progress. Global sensitivity analysis highlighted cell cycle phase durations as the most significant parameters; experiments were performed to extract them and the model was validated. Our model was then tested against other differential cell cycle models (ODEs, delay differential equations (DDEs)) in their ability to fit experimental data and oscillatory behavior. We subsequently coupled each of them with a pharmacokinetic / pharmacodynamic model of chemotherapy delivery that was previously developed by our group. Our results suggest that the particular cell cycle model chosen highly affects the outcome of the simulated treatment, given the same steady-state kinetic parameters and drug dosage/scheduling, with our PBM appearing to be the most sensitive under the same dose.
Allenby MC, Tahlawi A, Brito Dos Santos S, et al., 2015, Development of a Hematopoietic Microenvironment for the Production of Red Blood Cells (RBCs) in a Novel 3D Hollow Fibre Bioreactor, Tissue Engineering Part A, Vol: 21, Pages: S-15-S-16, ISSN: 1937-335X
Fuentes-Garí M, Misener R, García-Munzer D, et al., 2015, A mathematical model of subpopulation kinetics for the deconvolution of leukaemia heterogeneity., Journal of the Royal Society Interface, Vol: 12, ISSN: 1742-5689
Acute myeloid leukaemia is characterized by marked inter- and intra-patient heterogeneity, the identification of which is critical for the design of personalized treatments. Heterogeneity of leukaemic cells is determined by mutations which ultimately affect the cell cycle. We have developed and validated a biologically relevant, mathematical model of the cell cycle based on unique cell-cycle signatures, defined by duration of cell-cycle phases and cyclin profiles as determined by flow cytometry, for three leukaemia cell lines. The model was discretized for the different phases in their respective progress variables (cyclins and DNA), resulting in a set of time-dependent ordinary differential equations. Cell-cycle phase distribution and cyclin concentration profiles were validated against population chase experiments. Heterogeneity was simulated in culture by combining the three cell lines in a blinded experimental set-up. Based on individual kinetics, the model was capable of identifying and quantifying cellular heterogeneity. When supplying the initial conditions only, the model predicted future cell population dynamics and estimated the previous heterogeneous composition of cells. Identification of heterogeneous leukaemia clones at diagnosis and post-treatment using such a mathematical platform has the potential to predict multiple future outcomes in response to induction and consolidation chemotherapy as well as relapse kinetics.
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