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  • 1.
    Ali, Zaheer
    et al.
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Islam, Anik
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Sherrell, Peter
    Imperial Coll London, England.
    Le-Moine, Mark
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    Lolas, Georgios
    Univ Athens, Greece.
    Syrigos, Konstantinos
    Univ Athens, Greece.
    Rafat, Mehrdad
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    Jensen, Lasse
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pharmacology.
    Adjustable delivery of pro-angiogenic FGF-2 by alginate: collagen microspheres2018In: BIOLOGY OPEN, ISSN 2046-6390, Vol. 7, no 3, article id UNSP bio027060Article in journal (Refereed)
    Abstract [en]

    Therapeutic induction of blood vessel growth (angiogenesis) in ischemic tissues holds great potential for treatment of myocardial infarction and stroke. Achieving sustained angiogenesis and vascular maturation has, however, been highly challenging. Here, we demonstrate that alginate: collagen hydrogels containing therapeutic, pro-angiogenic FGF-2, and formulated as microspheres, is a promising and clinically relevant vehicle for therapeutic angiogenesis. By titrating the amount of readily dissolvable and degradable collagen with more slowly degradable alginate in the hydrogel mixture, the degradation rates of the biomaterial controlling the release kinetics of embedded proangiogenic FGF-2 can be adjusted. Furthermore, we elaborate a microsphere synthesis protocol allowing accurate control over sphere size, also a critical determinant of degradation/release rate. As expected, alginate: collagen microspheres were completely biocompatible and did not cause any adverse reactions when injected in mice. Importantly, the amount of pro-angiogenic FGF-2 released from such microspheres led to robust induction of angiogenesis in zebrafish embryos similar to that achieved by injecting FGF-2-releasing cells. These findings highlight the use of microspheres constructed from alginate: collagen hydrogels as a promising and clinically relevant delivery system for pro-angiogenic therapy.

  • 2.
    Chaabane, Wiem
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Tunis University, Tunisia.
    Cieślar-Pobuda, Artur
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Silesian University of Technology, Gliwice, Poland.
    El-Gazzah, Mohamed
    Tunis University, Tunisia.
    Jain, Mayur V.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Rzeszowska-Wolny, Joanna
    Silesian University of Technology, Gliwice, Poland.
    Rafat, Mehrdad
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, Faculty of Health Sciences.
    Stetefeld, Joerg
    University of Manitoba, Winnipeg, Canada.
    Ghavami, Saeid
    University of Manitoba, Winnipeg, Canada.
    Los, Marek
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Pomeranian Medical University, Szczecin, Poland.
    Human-Gyrovirus-Apoptin Triggers Mitochondrial Death Pathway—Nur77 is Required for Apoptosis Triggering: 2014In: Neoplasia, ISSN 1522-8002, E-ISSN 1476-5586, Vol. 16, no 9, p. 679-693Article in journal (Refereed)
    Abstract [en]

    The human gyrovirus derived protein Apoptin (HGV-Apoptin) a homologue of the chicken anemia virus Apoptin (CAV-Apoptin), a protein with high cancer cells selective toxicity, trigger apoptosis selectively in cancer cells. In this paper, we show that HGV-Apoptin acts independently from the death receptor pathway as it induces apoptosis in similar rates in Jurkat cells deficient in either FADD-function or caspase-8 (key players of the extrinsic pathway) and their parental clones. HGV-Apoptin induces apoptosis via the activation of the mitochondrial intrinsic pathway. It induces both mitochondrial inner and outer membrane permebilization, characterized by the loss of the mitochondrial potential and the release into cytoplasm of the pro-apoptotic molecules including apoptosis inducing factor (AIF) and cytochrome c. HGV-Apoptin acts via the apoptosome, as lack of expression of APAF1 in murine embryonic fibroblast strongly protected the cells from HGV-Apoptin-induced apoptosis. Moreover, QVD-oph a broad-spectrum caspase inhibitor delayed HGV-Apoptin-induced death. On the other hand, overexpression of the anti-apoptotic BCL-XL confers resistance to HGV-Apoptin induced cell death. In contrast, cells that lack the expression of the pro-apoptotic BAX and BAK are protected from HGV-Apoptin induced apoptosis. Furthermore, HGV-Apoptin acts independently from p53 signal but triggers the cytoplasmic translocation of Nur77. Taking together this data indicate that HGV-Apoptin acts through the mitochondrial pathway, in a caspase-dependent manner but independently from the death receptor pathway.

  • 3.
    Cieslar-Pobuda, Artur
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Bäck, Marcus
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Magnusson, Karin
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Vilas Jain, Mayur
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Rafat, Mehrdad
    Linköping University, Department of Biomedical Engineering. Linköping University, Faculty of Health Sciences.
    Ghavami, Saeid
    Manitoba Institute Child Heatlh, Canada; University of Manitoba, Canada .
    Nilsson, Peter R.
    Linköping University, Department of Physics, Chemistry and Biology, Chemistry. Linköping University, The Institute of Technology.
    Los, Marek Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Cell Type Related Differences in Staining with Pentameric Thiophene Derivatives2014In: Cytometry Part A, ISSN 1552-4922, E-ISSN 1552-4930, Vol. 85A, no 7, p. 628-635Article in journal (Refereed)
    Abstract [en]

    Fluorescent compounds capable of staining cells selectively without affecting their viability are gaining importance in biology and medicine. Recently, a new family of optical dyes, denoted luminescent conjugated oligothiophenes (LCOs), has emerged as an interesting class of highly emissive molecules for studying various biological phenomena. Properly functionalized LCOs have been utilized for selective identification of disease-associated protein aggregates and for selective detection of distinct cells. Herein, we present data on differential staining of various cell types, including cancer cells. The differential staining observed with newly developed pentameric LCOs is attributed to distinct side chain functionalities along the thiophene backbone. Employing flow cytometry and fluorescence microscopy we examined a library of LCOs for stainability of a variety of cell lines. Among tested dyes we found promising candidates that showed strong or moderate capability to stain cells to different extent, depending on target cells. Hence, LCOs with diverse imidazole motifs along the thiophene backbone were identified as an interesting class of agents for staining of cancer cells, whereas LCOs with other amino acid side chains along the backbone showed a complete lack of staining for the cells included in the study. Furthermore, for p-HTMI,a LCO functionalized with methylated imidazole moieties, the staining was dependent on the p53 status of the cells, indicating that the molecular target for the dye is a cellular component regulated by p53. We foresee that functionalized LCOs will serve as a new class of optical ligands for fluorescent classification of cells and expand the toolbox of reagents for fluorescent live imaging of different cells.

  • 4.
    Dilip Deb, Kaushik
    et al.
    DiponEd BioIntelligence LLP, Bangalore, India.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences.
    De Muinck, Ebo
    Linköping University, Department of Medical and Health Sciences, Cardiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Heart and Medicine Center, Department of Cardiology in Linköping.
    Rafat, Mehrdad
    Linköping University, Department of Clinical and Experimental Medicine, Regenerative Medicine. Linköping University, Faculty of Health Sciences. Department of Regenerative Medicine (IGEN) .
    Nanotechnology in stem cells research: advances and applications2012In: Frontiers in Bioscience, ISSN 1093-9946, E-ISSN 1093-4715, Vol. 17, p. 1747-1760Article in journal (Refereed)
    Abstract [en]

    Human beings suffer from a myriad of disorders caused by biochemical or biophysical alteration of physiological systems leading to organ failure. For a number of these conditions, stem cells and their enormous reparative potential may be the last hope for restoring function to these failing organ or tissue systems. To harness the potential of stem cells for biotherapeutic applications, we need to work at the size scale of molecules and processes that govern stem cells fate. Nanotechnology provides us with such capacity. Therefore, effective amalgamation of nanotechnology and stem cells - medical nanoscience or nanomedicine - offers immense benefits to the human race. The aim of this paper is to discuss the role and importance of nanotechnology in stem cell research by focusing on several important areas such as stem cell visualization and imaging, genetic modifications and reprogramming by gene delivery systems, creating stem cell niche, and similar therapeutic applications.

  • 5.
    Gelmi, Amy
    et al.
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, Faculty of Science & Engineering. Imperial Coll London, England.
    Cieslar-Pobuda, Artur
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Silesian Technical University, Poland.
    de Muinck, Ebo
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping. Linköping University, Center for Medical Image Science and Visualization (CMIV).
    Los, Marek Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Pomeranian Medical University, Poland.
    Rafat, Mehrdad
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, Faculty of Science & Engineering.
    Jager, Edwin
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, Faculty of Science & Engineering.
    Direct Mechanical Stimulation of Stem Cells: A Beating Electromechanically Active Scaffold for Cardiac Tissue Engineering2016In: Advanced Healthcare Materials, ISSN 2192-2640, E-ISSN 2192-2659, Vol. 5, no 12, p. 1471-1480Article in journal (Refereed)
    Abstract [en]

    The combination of stem cell therapy with a supportive scaffold is a promising approach to improving cardiac tissue engineering. Stem cell therapy can be used to repair nonfunctioning heart tissue and achieve myocardial regeneration, and scaffold materials can be utilized in order to successfully deliver and support stem cells in vivo. Current research describes passive scaffold materials; here an electroactive scaffold that provides electrical, mechanical, and topographical cues to induced human pluripotent stem cells (iPS) is presented. The poly(lactic-co-glycolic acid) fiber scaffold coated with conductive polymer polypyrrole (PPy) is capable of delivering direct electrical and mechanical stimulation to the iPS. The electroactive scaffolds demonstrate no cytotoxic effects on the iPS as well as an increased expression of cardiac markers for both stimulated and unstimulated protocols. This study demonstrates the first application of PPy as a supportive electroactive material for iPS and the first development of a fiber scaffold capable of dynamic mechanical actuation.

  • 6.
    Gelmi, Amy
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, The Institute of Technology.
    Higgins, Michael
    University of Wollongong, New South Wales, Australia.
    Wallace, Gordon
    University of Wollongong, New South Wales, Australia.
    Rafat, Mehrdad
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Jager, Edwin
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, The Institute of Technology.
    Electroactive Biomaterial Solutions for Tissue Engineering2013Conference paper (Other academic)
  • 7.
    Gelmi, Amy
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, Faculty of Science & Engineering.
    Kozak Ljunggren, Monika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Rafat, Mehrdad
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, Faculty of Medicine and Health Sciences.
    Jager, Edwin
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, Faculty of Science & Engineering.
    Bioelectronic nanofibre scaffolds for tissue engineering and whole-cell biosensors2014Conference paper (Refereed)
  • 8.
    Gelmi, Amy
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, The Institute of Technology.
    Kozak Ljunggren, Monika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Rafat, Mehrdad
    Linköping University, Department of Biomedical Engineering. Linköping University, Faculty of Health Sciences.
    Jager, Edwin
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, The Institute of Technology.
    Influence of conductive polymer doping on the viability of cardiac progenitor cells2014In: Journal of materials chemistry. B, ISSN 2050-750X, E-ISSN 2050-7518, Vol. 2, no 24, p. 3860-3867Article in journal (Refereed)
    Abstract [en]

    Cardiac tissue engineering via the use of stem cells is the future for repairing impaired heart function that results from a myocardial infarction. Developing an optimised platform to support the stem cells is vital to realising this, and through utilising new smart materials such as conductive polymers we can provide a multi-pronged approach to supporting and stimulating the stem cells via engineered surface properties, electrical, and electromechanical stimulation. Here we present a fundamental study on the viability of cardiac progenitor cells on conductive polymer surfaces, focusing on the impact of surface properties such as roughness, surface energy, and surface chemistry with variation of the polymer dopant molecules. The conductive polymer materials were shown to provide a viable support for both endothelial and cardiac progenitor cells, while the surface energy and roughness were observed to influence viability for both progenitor cell types. Characterising the interaction between the cardiac progenitor cells and the conductive polymer surface is a critical step towards optimising these materials for cardiac tissue regeneration, and this study will advance the limited knowledge on biomaterial surface interactions with cardiac cells.

  • 9.
    Gelmi, Amy
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, Faculty of Science & Engineering.
    Kozak Ljunggren, Monika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Rafat, Mehrdad
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, Faculty of Medicine and Health Sciences.
    Jager, Edwin
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, Faculty of Science & Engineering.
    Smart Electroactive Scaffolds for Cardiac Tissue Regeneration2014Conference paper (Refereed)
  • 10.
    Gelmi, Amy
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, The Institute of Technology.
    Ljunggren, Monika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Rafat, Mehrdad
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Jager, Edwin
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, The Institute of Technology.
    Electroactive scaffolds for cardiac tissue regeneration2013Conference paper (Other academic)
    Abstract [en]

    Myocardial Infarction (MI), commonly known as a heart attack, is the interruption of blood supply to a part of the heart, causing heart cells to die. In order to restore function by-pass surgery or ultimately heart transplantation is needed. However, due to the shortage of organ donors and complications associated with immune suppressive treatments, development of new strategies to help regenerate the injured heart is necessary. Stem cell therapy can be used to repair necrotic heart tissue and achieve myocardial regeneration. This research is focused on developing implantable electroactive fiber scaffolds that will increase the differentiation ratio of mesenchymal stem cells into cardiomyocytes and thus increase the formation of novel cardiac tissue to repair or replace the damaged cardiac tissue after MI. Composite nanofibrous scaffold of poly(dl-lactide-co-glycolide) (PLGA) have been coated with biodoped polypyrrole to create an electroactive fiber scaffold, with controllable fiber dimensions and alignment. The electrical properties of the polymers are an integral factor in creating these 'intelligent' 3-D materials; not only does the inherent conductivity provide a platform for electrical stimulation, but the ionic actuation of the polymer can also provide mechanical stimulation to the seeded cells. The biocompatibility of the polymer, PLGA scaffolds, and coated PLGA scaffolds has been investigated using primary cardiovascular progenitor cells.

  • 11.
    Gelmi, Amy
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, Faculty of Science & Engineering.
    Rafat, Mehrdad
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, Faculty of Medicine and Health Sciences.
    Jager, Edwin
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, Faculty of Science & Engineering.
    Actuating electroactive scaffolds for cardiac tissue regeneration2014Conference paper (Refereed)
  • 12.
    Gelmi, Amy
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, Faculty of Science & Engineering.
    Zhang, Jiabin
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, Faculty of Science & Engineering.
    Cieslar-Pobuda, Artur
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Ljunggren, Monika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Los, Marek
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Rafat, Mehrdad
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, Faculty of Medicine and Health Sciences.
    Jager, Edwin
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, Faculty of Science & Engineering.
    Electroactive polymer scaffolds for cardiac tissue engineering2015In: Proc. SPIE 9430, Electroactive Polymer Actuators and Devices (EAPAD) 2015 / [ed] Bar-Cohen, SPIE - International Society for Optical Engineering, 2015, Vol. 9430, p. 94301T-1-94301T-7Conference paper (Refereed)
    Abstract [en]

    By-pass surgery and heart transplantation are traditionally used to restore the heart’s functionality after a myocardial Infarction (MI or heart attack) that results in scar tissue formation and impaired cardiac function. However, both procedures are associated with serious post-surgical complications. Therefore, new strategies to help re-establish heart functionality are necessary. Tissue engineering and stem cell therapy are the promising approaches that are being explored for the treatment of MI. The stem cell niche is extremely important for the proliferation and differentiation of stem cells and tissue regeneration. For the introduction of stem cells into the host tissue an artificial carrier such as a scaffold is preferred as direct injection of stem cells has resulted in fast stem cell death. Such scaffold will provide the proper microenvironment that can be altered electronically to provide temporal stimulation to the cells. We have developed an electroactive polymer (EAP) scaffold for cardiac tissue engineering. The EAP scaffold mimics the extracellular matrix and provides a 3D microenvironment that can be easily tuned during fabrication, such as controllable fibre dimensions, alignment, and coating. In addition, the scaffold can provide electrical and electromechanical stimulation to the stem cells which are important external stimuli to stem cell differentiation. We tested the initial biocompatibility of these scaffolds using cardiac progenitor cells (CPCs), and continued onto more sensitive induced pluripotent stem cells (iPS). We present the fabrication and characterisation of these electroactive fibres as well as the response of increasingly sensitive cell types to the scaffolds.

  • 13.
    Griffith, May
    et al.
    University of Ottawa, Canada.
    Carlsson, David J.
    University of Ottawa, Canada.
    Li, Fengfu
    University of Ottawa, Canada.
    Liu, Yuwen
    University of Ottawa, Canada.
    Marmo, Christopher
    University of Ottawa, Canada.
    Asmanrafat, Mehrdad
    University of Ottawa, Canada.
    Vision Enhancing Ophthalmic Devices and Related Methods and Compositions2005Patent (Other (popular science, discussion, etc.))
    Abstract [en]

    Devices, methods, and compositions for improving vision or treating diseases, disorders or injury of the eye are described. Ophthalmic devices, such as corneal onlays, corneal inlays, and full-thickness corneal implants, are made of a material that is effective in facilitating nerve growth through or over the device. The material may include an amount of collagen greater than 1% (w/w), such as between about 10% (w/w) and about 30% (w/w). The material may include collagen polymers and/or a second biopolymer or water-soluble synthetic polymer cross-linked using EDC/NHS chemistry. The material may additionally comprise a synthetic polymer. The devices are placed into an eye to correct or improve the vision of an individual or to treat a disease, disorder or injury of an eye of an individual.

  • 14.
    Griffith, May
    et al.
    University of Ottawa, Canada.
    Carlsson, David, J
    University of Ottawa, Canada.
    Li, Fengfu
    University of Ottawa, Canada.
    Liu, Yuwen
    University of Ottawa, Canada.
    Rafat, Mehrdad
    University of Ottawa, Canada.
    Ophthalmic Devices and Related Methods and Compositions2005Patent (Other (popular science, discussion, etc.))
    Abstract [en]

    Devices, methods, and compositions for improving vision or treating diseases, disorders or injury of the eye are described. Ophthalmic devices, such as corneal onlays, corneal inlays, and full-thickness corneal implants, are made of a material that is effective in facilitating nerve growth through or over the device. The material may include an amount of collagen greater than 1% (w/w), such as between about 10% (w/w) and about 30% (w/w). The material may include collagen polymers and/or a second biopolymer or water-soluble synthetic polymer cross-linked using EDC/NHS chemistry. The material may additionally comprise a synthetic polymer. The devices are placed into an eye to correct or improve the vision of an individual or to treat a disease, disorder or injury of an eye of an individual.

  • 15.
    Griffith, May
    et al.
    Ottawa Health Research Institute University of Ottawa, Canada.
    Fengfu, Li
    Ottawa Health Research Institute University of Ottawa, Canada.
    Wenguang, Liu
    Ottawa Health Research Institute University of Ottawa, Canada.
    Rafat, Mehrdad
    Ottawa Health Research Institute University of Ottawa, Canada.
    Interpenetrating Networks, and Related Methods and Compositions2007Patent (Other (popular science, discussion, etc.))
    Abstract [en]

    The present invention provides interpenetrating polymeric networks (IPNs), and related methods and compositions. The hydrogel material of this invention comprises an interpenetrating network of two or more polymer networks, wherein at least one of the polymer networks is based on a biopolymer. Also provided is a method of producing the hydrogel material comprising, combining a first polymeric network with a second polymeric network, wherein the first polymeric network or the second polymeric network is based on a biopolymer. The present application also discloses devices manufactured from the IPN hydrogel material and uses thereof.

  • 16.
    Griffith, May
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Rafat, Mehrdad
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Corneal stromal mesenchymal stem cells for corneal stroma reconstruction2011In: Acta Ophthalmologica; Special Issue: Abstracts from the 2011 European Association for Vision and Eye Research ConferenceVolume 89, Issue Supplement s248, page 0, September 2011, 2011Conference paper (Refereed)
    Abstract [en]

    Purpose

    To date, corneal epithelial reconstruction has been very successful. However, in a number of cases of injury or disease, the stromal layer is affected. Our goal is to develop biomaterials that will enable the regeneration of the corneal stroma. In this study, we compare endogenous vs exogenous stem cell courses for corneal stromal regeneration.

    Methods

    We have previously developed collagen-based corneal stromal extracellular matrix substitutes based on EDC crosslinked collagen, and have shown that they promote ingrowth of stromal cells from the host cornea (Merrett et al. 2009; Fagerholm et al. 2010). For cases where stromal progenitors are depleted, we developed a non-toxic collagen-based hydrogel system where a macromolecular photoinitiator (Dex-BBA)was used to form the hydrogel around cells. The feasibility of Dex-BBA as a photoinitiator to initiate the gelation of aminoethylmethacylate-modified collagen (Coll-AEMA) was examined with or without the presence of stroma cells.

    Results

    The Dex-BBA crosslinked hydrogels were weaker than the EDC crosslinked constructs. However, they were fairly robust and no apparent toxicity of the hydrogel system to mesenchymal stroma (or stem) cells (MSCs)were observed during the culture of 7 days, which indicated that Dex-BBA based macrophotoinitiator and our collagen-based hydrogel system may have potential in corneal stromal regeneration applications.

    Conclusions

    We show that corneal stromal regeneration can be achieved by endogenous stimulation of existing corneal progenitor cells. Where the host cells may be depleted, our results show that hydrogel encapsulated stem cells may be used in the future.

  • 17.
    Hackett, Joanne M.
    et al.
    University of Ottawa Eye Institute, Canada.
    Sethi, Benu
    University of Ottawa, Canada.
    Cao, Xudong
    University of Ottawa, Canada.
    Rafat, Mehrdad
    University of Ottawa Eye Institute, Ontario, Canada.
    Friffith, May
    University of Ottawa Eye Institute, Canada.
    Biomaterials for Enhancing Corneas and Spinal Cord Regeneration2009In: Stem Cells: Basics and Applications / [ed] K.D. Deb, S.M. Totey and Tata McGraw Hill, McGraw-Hill, 2009Chapter in book (Other academic)
    Abstract [en]

    Repairing damaged or diseased tissues or organs to prevent failure using natural or bioengineered materials, is the essence of regenerative medicine. Technologies can involve the use of stem cells, gene therapy, tissue engineering, and the use of artificial organs. To date, researchers have been recreating a range of tissues and organs in vitro, with varying degrees of success. The tools to create scaffolds and structures are limited, and fine control over mechanical and environmental variables is complex. Also, there is a limited means of diagnosing at the molecular, cellular, and tissue levels what is actually happening within the constructs. In this review, we focus on efforts employed to build in vitro models of the nervous system, in particular, the peripheral nervous system and the related visual system. We examine the development of novel  biomaterials that serve as the building blocks for the fabrication of scaffolds in engineered tissues.

    Scaffolds must be fabricated from biologically compatible materials to be used as cellular supports for an engineered tissue or organ. Cells must be able to proliferate and differentiate into the appropriate target tissue or organ, when a chosen 3D scaffold is used. Engineered tissues need to mimic morphological, physiological and biochemical properties of the natural tissue as closely as possible. Thus, construction requirements are rigorous and demanding. The cornea and peripheral nervous system (PNS) are currently experiencing advances in tissue engineering efforts, for both transplantation and in vitro testing.

  • 18.
    Islam, Mohammad M.
    et al.
    Swedish Medical Nanoscience Center, Karolinska Institutet, Stockholm, Sweden.
    Cėpla, Vytautas
    Center for Physical Sciences and Technology, Vilnius, Lithuania.
    He, Chaoliang
    Ottawa Hospital Research Institute, Ontario, Canada.
    Edin, Joel
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Rakickas, Tomas
    Center for Physical Sciences and Technology, Vilnius, Lithuania.
    Kobuch, Karin
    Technische Universität München, Germany.
    Ruželė, Živilė
    Center for Physical Sciences and Technology, Vilnius, Lithuania.
    Jackson, Bruce W.
    Ottawa Hospital Research Institute, Ontario, Canada.
    Rafat, Mehrdad
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Department of Biomedical Engineering. Linköping University, Faculty of Health Sciences. Ottawa Hospital Research Institute, Ontario, Canada.
    Lohmann, Chris P.
    Technische Universität München, Germany.
    Valiokas, Ramūnas
    Center for Physical Sciences and Technology, Vilnius, Lithuania.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Swedish Medical Nanoscience Center, Karolinska Institutet, Stockholm, Sweden; Ottawa Hospital Research Institute, Ontario, Canada.
    Functional fabrication of recombinant human collagen–phosphorylcholine hydrogels for regenerative medicine applications2015In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 12, p. 70-80Article in journal (Refereed)
    Abstract [en]

    The implant-host interface is a critical element in guiding tissue or organ regeneration. We previously developed hydrogels comprising interpenetrating networks of recombinant human collagen type III and 2-methacryloyloxyethyl phosphorylcholine (RHCIII-MPC) as substitutes of the corneal extracellular matrix that promote endogenous regeneration of corneal tissue. To render them functional for clinical application, we have now optimized their composition and thereby enhanced their mechanical properties. We have demonstrated that such optimized RHCIII-MPC hydrogels are suitable for precision femtosecond laser cutting to produce complementing implants and host surgical beds for subsequent tissue welding. This avoids the tissue damage and inflammation associated with manual surgical techniques, thereby leading to more efficient healing. Although we previously demonstrated in clinical testing that RHCIII-based implants stimulated cornea regeneration in patients, the rate of epithelial cell coverage of the implants needs improvement, e.g. modification of the implant surface. We now show that our 500 μm thick RHCIII-MPC constructs comprising over 85% water, are suitable for microcontact printing with fibronectin. The resulting fibronectin micropatterns promote cell adhesion, as compared to the bare RHCIII-MPC hydrogel. Interestingly, a pattern of 30 μm wide fibronectin stripes enhanced cell attachment and showed highest mitotic rates, an effect that potentially can be utilized for faster integration of the implant. We have therefore shown that laboratory-produced mimics of naturally occurring collagen and phospholipids can be fabricated into robust hydrogels that can be laser profiled and patterned to enhance their potential function as artificial substitutes of donor human corneas.

  • 19.
    Khulbe, K. C.
    et al.
    Department of Chemical Engineering, IMRI, University of Ottawa, Ottawa, Ontario, Canada.
    Feng, C. Y.
    Department of Chemical Engineering, IMRI, University of Ottawa, Ottawa, Ontario, Canada.
    Matsuura, T.
    Department of Chemical Engineering, IMRI, University of Ottawa, Ottawa, Ontario, Canada.
    Mosqueada-Jimenaez, D. C.
    Department of Civil Engineering, University of Ottawa, Ottawa, Ontario, Canada.
    Rafat, Mehrdad
    Department of Chemical Engineering, IMRI, University of Ottawa, Ottawa, Ontario, Canada.
    Kingston, D.
    Nanostructure Material Research Group, National Research Council of Canada, Ottawa, Ontario, Canada.
    Narbaitz, R. M,
    Department of Civil Engineering, University of Ottawa, Ottawa, Ontario, Canada.
    Khayet, M.
    Department of Applied Physics, University Complutense of Madrid, Madrid, Spain.
    Characterization of Surface Modified Hollow Fiber Polyethersulfone Membranes Prepared at Different Air Gaps2006In: Journal of Applied Polymer Science, ISSN 0021-8995, E-ISSN 1097-4628, Vol. 104, no 2, p. 710-721Article in journal (Refereed)
    Abstract [en]

    Hollow fibers were spun from a solution of surface-modifying macromolecule blended polyethersulfone in dimethyl acetamide by using dry-wet spinning method at different air gaps and at room temperature. The air gap was varied from 10 to 90 cm. The ultrafiltration performance of hollow fibers was studied by using aqueous solutions of polyethylene glycols and polyethylene oxides of different molecular weights. Significant difference in surface morphology between the inner and outer surface of the hollow fibers was observed by atomic force microscopy (AFM). Similar results were obtained by contact angle measurement and XPS. Mean pore sizes of the inner surface and outer surface were calculated from AFM images and compared with the pore sizes obtained from mass transport data. Pore size distribution curves were drawn from both data, i.e., from AFM images and mass-transport data, both methods gave similar results.Roughness parameters of the inner and outer surfaces and the sizes of nodular aggregates on both surfaces were measured. An attempt was made to correlate the above parameters with the performance of the membranes. Unexpected values of contact angles of both inner surface and outer surface were obtained. It was observed that the studied membranes could be put into two groups: (i) the membranesfabricated between 10 and 50 cm air gap and (ii) fabricated at higher than 50 cm air gap. A plausible mechanism for the unexpected results was discussed.

  • 20.
    Koulikovska, Marina
    et al.
    Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping. Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Rafat, Mehrdad
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, Faculty of Science & Engineering. Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. LinkoCare Life Sciences AB, Linköping, Sweden.
    Petrovski, Goran
    University of Debrecen, Debrecen, Hungary; University of Szeged, Szeged, Hungary.
    Veréb, Zoltán
    University of Debrecen, Debrecen, Hungary; University of Szeged, Szeged, Hungary.
    Akhtar, Saeed
    Department of Optometry, College of Applied Medicine, King Saud University, Riyadh, Saudi Arabia.
    Fagerholm, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Lagali, Neil
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Enhanced Regeneration of Corneal Tissue Via a Bioengineered Collagen Construct Implanted by a Nondisruptive Surgical Technique2015In: Tissue Engineering. Part A, ISSN 1937-3341, E-ISSN 1937-335X, Vol. 21, no 5-6, p. 1116-1130Article in journal (Refereed)
    Abstract [en]

    Severe shortage of donor corneas for transplantation, particularly in developing countries, has prompted the advancement of bioengineered tissue alternatives. Bioengineered corneas that can withstand transplantation while maintaining transparency and compatibility with host cells, and that are additionally amenable to standardized low-cost mass production are sought. In this study, a bioengineered porcine construct (BPC) was developed to function as a biodegradable scaffold to promote corneal stromal regeneration by host cells. Using high-purity medical-grade type I collagen, high 18% collagen content and optimized EDC-NHS cross-linker ratio, BPCs were fabricated into hydrogel corneal implants with over 90% transparency and four-fold increase in strength and stiffness compared with previous versions. Remarkably, optical transparency was achieved despite the absence of collagen fibril organization at the nanoscale. In vitro testing indicated that BPC supported confluent human epithelial and stromal-derived mesenchymal stem cell populations. With a novel femtosecond laser-assisted corneal surgical model in rabbits, cell-free BPCs were implanted in vivo in the corneal stroma of 10 rabbits over an 8-week period. In vivo, transparency of implanted corneas was maintained throughout the postoperative period, while healing occurred rapidly without inflammation and without the use of postoperative steroids. BPC implants had a 100% retention rate at 8 weeks, when host stromal cells began to migrate into implants. Direct histochemical evidence of stromal tissue regeneration was observed by means of migrated host cells producing new collagen from within the implants. This study indicates that a cost-effective BPC extracellular matrix equivalent can incorporate cells passively to initiate regenerative healing of the corneal stroma, and is compatible with human stem or organ-specific cells for future therapeutic applications as a stromal replacement for treating blinding disorders of the cornea.

  • 21.
    Matsuura, Takeshi
    et al.
    Department of Chemical Engineering, University of Ottawa, Ottawa, Ontario, Canada.
    Rafat, Mehrdad
    Department of Chemical Engineering, University of Ottawa, Ottawa, Ontario, Canada.
    Polymeric Membranes2005In: Encyclopaedia of Chemical Processing / [ed] Sunggyu Lee, New York: Marcel Dekker, 2005, p. 2323-Chapter in book (Refereed)
    Abstract [en]

    In this entry, properties of polymers, such as crystallinity, hydrophilicity/hydrophobicity, molecular weight, chemical property, thermal property, mechanical property, and electrochemical property are first discussed in relation to suitability of polymers for membrane materials. Various methods of membrane preparation from polymeric materials are described. These methods include the phase inversion technique, methods to coat a thin layer on a porous substrate, methods to modify membrane surfaces, and methods to prepare dry membranes. Examples of polymers used to prepare the membranes for different membrane processes such as reverse osmosis, nanofiltration, ultrafiltration, microfiltration, membrane gas and vapor separation, pervaporation, electrodialysis, and fuel cell are also given.

  • 22.
    McLaughlin, Christopher
    et al.
    University of Ottawa Eye Institute, Ottawa, Ontario, Canada.
    Fagerholm, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Östergötlands Läns Landsting, Reconstruction Centre, Department of Ophthalmology UHL.
    Muzakare, Lea
    University of Ottawa Eye Institute, Ottawa, Ontario, Canada.
    Lagali, Neil
    University of Ottawa Eye Institute, Ottawa, Ontario, Canada.
    Forrester, John
    Department of Ophthalmology University of Aberdeen, Aberdeen, Scotland, United Kingdom.
    Kuffova, Lucia
    Department of Ophthalmology University of Aberdeen, Aberdeen, Scotland, United Kingdom.
    Rafat, Mehrdad
    University of Ottawa Eye Institute, Ottawa, Ontario, Canada.
    Liu, Yuwen
    National Research Council Canada, Ottawa, Ontario, Canada.
    Shinozaki, Naoshi
    Tokyo Dental College-Ichikawa General Hospital Cornea Centre, Ichikawa, Chiba, Japan.
    Vascotto, Sandy
    University of Ottawa Eye Institute, Ottawa, Ontario, Canada.
    Munger, Rejean
    University of Ottawa Eye Institute, Ottawa, Ontario, Canada.
    Griffith, May
    University of Ottawa Eye Institute, Ottawa, Ontario, Canada.
    Regeneration of Corneal Cells and Nerves in an Implanted Collagen Corneal Substitute2008In: Cornea, ISSN 0277-3740, E-ISSN 1536-4798, Vol. 27, no 5, p. 580-589Article in journal (Refereed)
    Abstract [en]

    PURPOSE: Our objective was to evaluate promotion of tissue regeneration by extracellular matrix (ECM) mimics, by using corneal implantation as a model system.

    METHODS: Carbodiimide cross-linked porcine type I collagen was molded into appropriate corneal dimensions to serve as substitutes for natural corneal ECM. These were implanted into corneas of mini-pigs after removal of the host tissue, and tracked over 12 months, by clinical examination, slit-lamp biomicroscopy, in vivo confocal microscopy, topography, and esthesiometry. Histopathology and tensile strength testing were performed at the end of 12 months. Other samples were biotin labeled and implanted into mice to evaluate matrix remodeling.

    RESULTS: The implants promoted regeneration of corneal cells, nerves, and the tear film while retaining optical clarity. Mechanical testing data were consistent with stable, seamless host-graft integration in regenerated corneas, which were as robust as the untreated fellow corneas. Biotin conjugation is an effective method for tracking the implant within the host tissue.

    CONCLUSIONS: We show that a simple ECM mimetic can promote regeneration of corneal cells and nerves. Gradual turnover of matrix material as part of the natural remodeling process allowed for stable integration with host tissue and restoration of mechanical properties of the organ. The simplicity in fabrication and shown functionality shows potential for ECM   

  • 23.
    Merrett, Kimberly
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Kozak Ljunggren, Monika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Mondal, Debasish
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Rafat, Mehrdad
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Collagen Type I: A Promising Scaffold Material for Tissue Engineering and Regenerative Medicine2012In: Type I collagen: biological functions, synthesis & medicinal applications / [ed] Maria Eduarda Henriques and Marcio Pinto, Nova Science Publishers, Inc., 2012, p. 1-43Chapter in book (Other academic)
    Abstract [en]

    It is now recognized that biological macromolecules such as components of the extracellular matrix (ECM) are important as instructive templates in Regenerative Medicine applications. They are now increasingly used in the development of a new generation of bio-mimetic materials that allow for restoration of function when the self-renewal capacity of a tissue or organ cannot overcome degeneration caused by disease, injury or age-related wear. For example, macromolecules derived from connective tissue have been isolated, chemically modified, and used in medical applications ranging from tissue repair and reconstruction to drug and cell delivery systems. Common ECM macromolecules of vertebrates include collagen, proteoglycans, elastin, and other cell-interactive proteins such as fibronectin and laminin. Of these, type I collagen is the most abundant ECM macromolecule and is the primary scaffolding material that maintains the 3-dimensional structure of tissues and organs within the body. It also provides the micro-environmental milieu for cellular attachment, migration, and proliferation.

    Animal-derived collagen is frequently used in tissue engineering applications due to its biocompatibility, but there are significant concerns about the immunogenicity of xenogeneic material as well as the possibility of pathogen transmission. Most recently, synthetic collagens and recombinant human collagens have been produced for medical application. Regardless of the source, however, macromolecules require processing and chemical treatment in order to improve their stability both in vitro and in vivo. This is most commonly achieved by cross-linking using a variety of agents. Cross-linking also allows for the development of “tailor-made” collagen-based biomaterials that possess specific properties for tissue engineering. Chemical cross-linkers such as glutaraldehyde and epoxy compounds are frequently used but their cytotoxicities have limited their clinical application. This has led to the use of zero-length cross-linkers such as carbodiimides and naturally derived agents such as genipin. Enzymatic cross-linking is becoming an attractive method to induce in situ biomaterial formation due to the mildness of the reaction. Naturally occurring enzymes such as transglutaminase are now commonly used. Photosensitizers used in combination with ultra-violet light irradiation can be used as exogenous cross-linkers. For example, riboflavin in combination with ultra-violet light is used clinically to augment the properties of collagen-based tissues such as the sclera and the cornea.

    Collagen type I is a good candidate for tissue engineering and in vivo delivery systems for cells, proteins, and drugs. Important to its versatile and functional nature are its chemotactic properties, which promote cellular proliferation and differentiation, richness in cross-linking sites, and biodegradability. Collagen based delivery matrices have been reported to improve the results of cell delivery by improving cell viability.

  • 24.
    Mikhailova, Alexandra
    et al.
    BioMediTech, University of Tampere, Tampere, Finland.
    Ilmarinen, Tanja
    Faculty of Medicine, University of Szeged, Szeged, Hungary.
    Ratnayake, Anjula
    LinkoCare Life Sciences AB.
    Petrovski, Goran
    Faculty of Medicine, University of Szeged, Szeged, Hungary.
    Uusitalo, Hannu
    University of Tampere and Tays Eye Center, Tampere, Finland.
    Skottman, Heli
    BioMediTech, University of Tampere, Tampere, Finland.
    Rafat, Mehrdad
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, Faculty of Science & Engineering. LinkoCare Life Sciences AB.
    Human pluripotent stem cell-derived limbal epithelial stem cells on bioengineered matrices for corneal reconstruction2016In: Experimental Eye Research, ISSN 0014-4835, Vol. 146, p. 26-34Article in journal (Refereed)
    Abstract [en]

    Corneal epithelium is renewed by limbal epithelial stem cells (LESCs), a type of tissue-specific stem cells located in the limbal palisades of Vogt at the corneo-scleral junction. Acute trauma or inflammatory disorders of the ocular surface can destroy these stem cells, leading to limbal stem cell deficiency (LSCD) – a painful and vision-threatening condition. Treating these disorders is often challenging and complex, especially in bilateral cases with extensive damage. Human pluripotent stem cells (hPSCs) provide new opportunities for corneal reconstruction using cell-based therapy. Here, we investigated the use of hPSC-derived LESC-like cells on bioengineered collagen matrices in serum-free conditions, aiming for clinical applications to reconstruct the corneal epithelium and partially replace the damaged stroma. Differentiation of hPSCs towards LESC-like cells was directed using small-molecule induction followed by maturation in corneal epithelium culture medium. After four to five weeks of culture, differentiated cells were seeded onto bioengineered matrices fabricated as transparent membranes of uniform thickness, using medical-grade porcine collagen type I and a hybrid cross-linking technology. The bioengineered matrices were fully transparent, with high water content and swelling capacity, and parallel lamellar microstructure. Cell proliferation of hPSC-LESCs was significantly higher on bioengineered matrices than on collagen-coated control wells after two weeks of culture, and LESC markers p63 and cytokeratin 15, along with proliferation marker Ki67 were expressed even after 30 days in culture. Overall, hPSC-LESCs retained their capacity to self-renew and proliferate, but were also able to terminally differentiate upon stimulation, as suggested by protein expression of cytokeratins 3 and 12. We propose the use of bioengineered collagen matrices as carriers for the clinically-relevant hPSC-derived LESC-like cells, as a novel tissue engineering approach for corneal reconstruction.

  • 25.
    Puckert, C.
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, Faculty of Science & Engineering.
    Gelmi, A.
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, Faculty of Science & Engineering.
    Kozak Ljunggren, Monika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Rafat, Mehrdad
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, Faculty of Science & Engineering.
    Jager, Edwin
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, Faculty of Science & Engineering.
    Optimisation of conductive polymer biomaterials for cardiac progenitor cells2016In: RSC Advances, ISSN 2046-2069, E-ISSN 2046-2069, Vol. 6, no 67, p. 62270-62277Article in journal (Refereed)
    Abstract [en]

    The characterisation of biomaterials for cardiac tissue engineering applications is vital for the development of effective treatments for the repair of cardiac function. New smart materials developed from conductive polymers can provide dynamic benefits in supporting and stimulating stem cells via controlled surface properties, electrical and electromechanical stimulation. In this study we investigate the control of surface properties of conductive polymers through a systematic approach to variable synthesis parameters, and how the resulting surface properties influence the viability of cardiac progenitor cells. A thorough analysis investigating the effect of electropolymerisation parameters, such as current density and growth, and reagent variation on physical properties provides a fundamental understanding of how to optimise conductive polymer biomaterials for cardiac progenitor cells.

  • 26.
    Rafat, Mehrdad
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Book Review On Integrated Biomaterials For biomedical Technology2013In: Advanced Materials Letters, ISSN 0976-3961, E-ISSN 0976-397X, Vol. 4, no 3, p. 250-250Article, book review (Other academic)
    Abstract [en]

    This book covers a wide range of biomaterials from polymers and ceramics to metals, composites, nanomaterials, and biosensor materials for various biomedical applications. I strongly recommend this book for those who have a basic knowledge in biomaterials who want to expand their knowledge and to know more about biomaterials’ applications.  Having said that, the book is so well-designed that is understandable by those with no prior knowledge in biomaterials such as students and young researchers or experienced researchers in other fields. For instance, at the beginning of each chapter, there is an introduction section with enough background information, which prepares the readers for the next sections. More specifically, I’m quite impressed with the application sections providing the readers with real-world health problems and how a specific biomaterial or a medical device, which is comprised of several biomaterials, can address those problems. This book can definitely help bridging the gap between science and technology in the biomedical field. I would like to congratulate the editors and the authors of this book for the excellent work and look forward to their next contribution to the field.

  • 27.
    Rafat, Mehrdad
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Ottawa Hospital Research Institute, Ottawa Hospital, General Division, Ottawa, Canada.
    Cléroux, Carolyne A.
    Ottawa Hospital Research Institute, Ottawa Hospital, General Division, Ottawa, Canada.
    Fong, Wai Gin
    Ottawa Hospital Research Institute, Ottawa Hospital, General Division, Ottawa, Canada.
    Baker, Adam N.
    Ottawa Hospital Research Institute, Ottawa Hospital, General Division, Ottawa, Canada.
    Leonard, Brian C.
    Ottawa Hospital Research Institute, Ottawa Hospital, General Division, Ottawa, Canada.
    O'Connor, Michael D.
    Ottawa Hospital Research Institute, Ottawa Hospital, General Division, Ottawa, Canada.
    Tsilfidis, Catherine
    Ottawa Hospital Research Institute, Ottawa Hospital, General Division, Ottawa, Canada.
    PEG-PLAmicroparticles for encapsulation and delivery of Tat-EGFP to retinal cells2010In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 31, no 12, p. 3414-3421Article in journal (Refereed)
    Abstract [en]

    The efficient and controlled delivery of genes and proteins to retinal cells remains a challenge. In this study, we evaluated polyethylene glycol-polylactic acid (PEG–PLA) microparticles for encapsulation and delivery of a Transactivator of transcription-enhanced green fluorescent protein fusion (Tat-EGFP) to retinal cells. Our main objective was to develop a microparticle system that delivers Tat-EGFP with an initial rapid release (within 24 h) followed by a sustained release. We prepared four different formulations of Tat-EGFP encapsulated PEG–PLA particles to investigate the effects of protein and polymer concentrations on particle morphology and protein release, using scanning electron microscopy (SEM) and fluorometry techniques. The optimum formulation was selected based on higher protein release, and smaller particle size. The optimum formulation was then tested in vitro for cell biocompatibility and protein internalization, and in vivo for cellular toxicity following sub-retinal injections into rat eyes. The results suggest that PEG–PLA microparticles can deliver proteins in cell culture allowing protein internalization in as little as 1 h. In vivo, protein was shown to localize within the photoreceptor layer of the retina, and persist for at least 9 weeks with no observed toxicity.

  • 28.
    Rafat, Mehrdad
    et al.
    Industrial Membrane Research Institute, Department of Chemical Engineering, University of Ottawa, Ottawa, Canada.
    De, Dibyendu
    Research and Development, Baxter Healthcare Corporation, Miami Lakes, Florida, USA.
    Khulbe, K. C.
    Industrial Membrane Research Institute, Department of Chemical Engineering, University of Ottawa, Ottawa, Canada.
    Nguyen, Thanh
    Research and Development, Baxter Healthcare Corporation, Miami Lakes, Florida, USA.
    Matsuura, Takeshi
    Industrial Membrane Research Institute, Department of Chemical Engineering, University of Ottawa, Ottawa, Canada.
    Surface Characterization of Hollow Fibre Membranes Used in Artificial Kidney2006In: Journal of Applied Polymer Science, ISSN 0021-8995, E-ISSN 1097-4628, Vol. 101, no 6, p. 4386-4400Article in journal (Refereed)
    Abstract [en]

    The internal and external curved surfaces of polysulfone hollow fiber membranes were characterized by atomic force microscopy (AFM), contact angle measurement (CAM), and scanning electron microscopy (SEM) with the aim of improving the membrane surface properties for blood compatibility. Novel approaches were applied to evaluate a number of properties, including the roughness, pore size, nodule size, and wettability of the surfaces of the hollow fibers. CAM studies were carried out by directly observing the liquid meniscus at the surfaces of hollow fibers. Observation of the meniscus and measurement of the contact angle became possible by using an imaging system developed in our laboratory. AFM and SEM studies were also conducted on the surfaces of the hollow fiber membranes by cutting them at an inclined angle. The effect of the molecular weight of poly(ethylene glycol) (PEG) in the polymer blend on the surface properties of the hollow fibers was studied. Increasing the PEG molecular weight increased the average pore size whereas it decreased the contact angle. The contact angle depended on the microscopic surface morphology, including nodule size and roughness parameters. The theoretical prediction along with the experimental data showed that the measured contact angle would be greater than the value intrinsic to the membrane material because of the formation of composite surface structures. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 101: 4386–4400, 2006

  • 29.
    Rafat, Mehrdad
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Fagerholm, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Merret, K,
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Lagali, Neil
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Collagen-based bioengineered corneas: a material development update2011Conference paper (Other academic)
    Abstract [en]

    Purpose

    Our overall objective is to develop novel biomimetic materials that support the regeneration of diseased or damaged corneal tissue. This presentation will provide an update on such materials developed in our group.

    Methods

    We have developed a range of collagen-based materials as mimics of the cell-free corneal stromal extracellular matrix. Promising material formulations were tested pre-clinically for their physical properties (e.g. mechanical, optical, water uptake, etc.) and physiological properties (e.g. interactions with corneal cells, biodegradation, in vivo implantation in animals etc.). One of the early formulations was clinically tested in the corneas of 10 patients, results of which will be discussed.

    Results

    More recently, our team of Canadian and Swedish researchers reported the successful implantation of cell-free, bioengineered corneas into patients with keratoconus and central scarring in a Phase 1 clinical trial. These implants acted as stable scaffolds that promoted functional regeneration of corneal cells and nerves. At 24 months post-operative, six of the ten patients could see four times further than before the operation. With the help of rigid contact lenses – the results in all ten patients were similar to what the traditional corneal transplant with human donor tissue would be, with one patient achieving 20/20 vision and two others with 20/25 vision.

    Conclusions

    Despite the promising clinical results, more robust and elastic materials are required to withstand the adverse host conditions faced for high risk transplantation in severely damaged or diseased corneas as well as for full-thickness corneal implants. Examples of next generation biomaterials that have been implanted into animal models as partial and full-thickness grafts that allow regeneration of nerve sub-types and show resistance to neovascularization will be shown.

  • 30.
    Rafat, Mehrdad
    et al.
    Department of Chemical Engineering, University of Ottawa and University of Ottawa Eye Institute, Ottawa, Ontario, Canada.
    Griffith, May
    University of Ottawa Eye Institute and Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
    Hakim, Malik
    Department of Chemical Engineering, University of Ottawa and University of Ottawa Eye Institute, Ottawa, Ontario, Canada.
    Muzakare, Lea
    University of Ottawa Eye Institute, Ottawa, Ontario, Canada.
    Li, Frank
    University of Ottawa Eye Institute, Ottawa, Ontario, Canada.
    Khulbe, K.C.
    Department of Chemical Engineering, University of Ottawa, Ottawa, Ontario, Canada.
    Matsuura, Takeshi
    Department of Chemical Engineering, University of Ottawa, Ottawa, Ontario, Canada.
    Plasma surface modification and characterization of collagen-based artificial cornea for enhanced epithelialization2007In: Journal of Applied Polymer Science, ISSN 0021-8995, E-ISSN 1097-4628, Vol. 106, no 3, p. 2056-2064Article in journal (Refereed)
    Abstract [en]

    Argon plasma treatment enhanced the attachment of epithelial cells to a collagen-based artificial cornea crosslinked using glutaraldehyde (GA) and glutaraldehyde-polyethylene oxide dialdehyde (GA-PEODA) systems. The epithelialization of untreated and treated surfaces was evaluated by the seeding and growth of human corneal epithelial cells. Characterization of polymer surface properties such as surface hydrophilicity and roughness was also made by contact angle measurement and atomic force microscopy, respectively. Contact angle analysis revealed that the surface hydrophilicity significantly increased after the treatment. In addition, AFM characterization showed an increase in surface roughness through argon plasma treatment. Based on the biological and surface analysis, argon plasma treatment displays promising potential for biocompatibility enhancement of collagen-based artificial corneas. It was also found that the cell attachment to artificial cornea surfaces was influenced by the combined effects of surface chemistry (i.e., surface energy), polymer surface morphology (i.e., surface roughness), and polar interactions between functional groups at the polymer surface and cell membrane proteins.

  • 31.
    Rafat, Mehrdad
    et al.
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, Faculty of Arts and Sciences.
    Hackett, Joanne
    Linköping University, Department of Clinical and Experimental Medicine, Division of Inflammation Medicine. Linköping University, Faculty of Health Sciences.
    Fagerholm, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Artificial Cornea2011In: Ocular Periphery and Disorders / [ed] Darlene A. Dartt, Peter Bex, Patricia D'Amore, Reza Dana, Linda Mcloon, Jerry Niederkorn, Elsevier, 2011, p. 311-317Chapter in book (Other academic)
    Abstract [en]

    This selection of articles from the Encyclopedia of the Eye is the first single-volume overview presenting articles on the function, biology, physiology, and pathology of the structures of the ocular periphery, as well as the related disorders and their treatment. The peripheral structures are implicated in a number of important diseases, including optic neuritis, thyroid eye disease, and strabismus. The volume offers a basic science background of these topics rather than a strictly clinical focus.

    *The first single volume to integrate comparative studies into a comprehensive resource on the neuroscience of the ocular periphery

    *Chapters are carefully selected from the Encyclopedia of the Eye by the world's leading vision researchers

    *The best researchers in the field provide their conclusions in the context of the latest experimental results

  • 32.
    Rafat, Mehrdad
    et al.
    Device Surveillance Division, Medical Devices Bureau, HPFB, Health Canada, Ottawa, Canada.
    Karov, J.
    Device Surveillance Division, Medical Devices Bureau, HPFB, Health Canada, Ottawa, Canada.
    Griffith, May
    Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada.
    Courtman, D.
    The Ottawa Hospital Research Institute, Ottawa, Canada.
    Arzhangi, Z.
    Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada.
    Daka, J.N.
    Research and Radiation Directorate, Healthy Environment and Consumer Safety, Health Canada, Ottawa, Canada.
    Development and Safety Evaluation of Nanomaterials for Encapsulation andDelivery of Stem Cells to Dysfunctional Heart Tissue2009In: Book of Abstracts 2009, Health CanadaScience Forum, Health Canada Science Plan -Implementing Health Canada’s Science and Technology Strategy, 2009Conference paper (Refereed)
    Abstract [en]

    SUMMARY: Tissue-specific delivery of stem cells holds the potential to regenerate damaged heart tissue and to restore its functions after Myocardial Infarction. In this study we describe a novel cell encapsulation technique for target delivery of stem cells to damaged heart tissue. This research is conducted in collaboration with OHRI and UOttawa.

    BACKGROUND/ISSUE(S)/OBJECTIVES: Heart failure is the number one cause of death in developed countries. Stem cell transplantation has drawn a lot of attention as a promising therapy for heart disease. However, extensive cell attrition, and loss at the site of transplantation present a limit to therapeutic efficacy. We have hypothesized that by encapsulating the cells in naturally-derived materials, e.g., collagen and alginate, cells viability, and target delivery can be enhanced. Our main objective is to develop encapsulation techniques for effective delivery of stem cells. The other objective is to develop characterization techniques for safety evaluation of such systems at nano and micro scales.

    DESIGN/METHOD/DESCRIPTION: Novel collagen-alginate microspheres loaded with GFP-BOEC cells (green florescence expressing -blood outgrowth endothelial cells) were developed. The method involves the gelation of a hybrid collagenalginate- cell solution using a drop-wise technique in a calcium chloride bath. Microspheres were washed and transferred to a Petri dish containing  culture medium and incubated at 37°C. Microspheres formation, and morphology (shape and size) and viability of the cells were monitored using a Nikon inverted light microscope.

    OUTPUTS/RESULTS: Light microscopy images suggest successful formation of hybrid collagen-alginate microspheres in a size range of about 1000-2000 μm. The images also show that cells fluoresce an apple green when excited with near UV light implying that most of the cells are viable.

    IMPACTS/OUTCOMES/CONCLUSIONS/IMPLICATIONS/NEXT STEPS: Preliminary results from these experiments reveal that GFP-BOEC cells can be encapsulated in collagen-alginate microspheres. The results suggest that cells are viable over a period of three days. Also, light microscopy techniques were successfully utilized for physical (i.e., shape and size) and biological (i.e., viability) characterizations of microspheres. The next steps will include the use of Mesenchymal Stem Cells instead of GFP-BOEC, fine-tuning of material formulations, and further characterizations, i.e., scanning electron microscopy (SEM). We anticipate that this work will help us to better understand new emerging technologies such as nanotechnology, stem cells therapeutics, and tissue engineering that will ultimately benefit the regulatory process of medical   products that are based on such technologies.

  • 33.
    Rafat, Mehrdad
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Koh, Li Buay
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics. Linköping University, The Institute of Technology.
    Islam, Mohammad Mirazul
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Liedberg, Bo
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics. Linköping University, The Institute of Technology.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Highly elastic epoxycross‐linked collagen hydrogels for corneal tissueengineering2012In: Acta Ophthalmologica; Special Issue: Abstracts from the 2012 European Association for Vision and Eye Research Conference, Volume 90, Issue Supplement s249, page 0, September 2012, John Wiley & Sons, 2012Conference paper (Refereed)
    Abstract [en]

    Purpose Our objective is to develop novel materials that support the regeneration of diseased or damaged corneas. Despite the promising clinical results that we previously reported on biosynthetic corneas, more robust and elastic materials are required to withstand the adverse host conditions faced for high risk transplantation in severely damaged or diseased corneas. This presentation will provide details on an epoxy cross-linked collagen-based scaffold with enhanced mechanical properties.

    Methods We have developed a range of collagen-based materials as mimics of the cell-free corneal stromal extracellular matrix. In this study, cross-linked polymer networks of collagen hydrogels were prepared using a hybrid of 1,4-butanediol diglycidyl ether (BDDGE) and carbodiimides (e.g. EDC-NHS) as cross-linkers. Briefly, 10w/w% porcine collagen type I was mixed in a T-piece system at various compositions and pH, e.g. pH 5, pH 11, and incorporated with laminin adhesive peptides (YIGSR, and IKVAV). Promising material formulations were tested for their physiochemical properties (e.g. mechanical, optical, water uptake, FTIR, and thermal degradation) and physiological properties (e.g. interactions with corneal cells, and biodegradation).

    Results The hybrid BDDGE hydrogels demonstrated improved mechanical properties and degree of cross-linking while maintaining their optical clarity and biocompatibility compared to controls (e.g. EDC/NHS-crosslinked hydrogels). Incorporation of laminin-derived cell-adhesive peptide (IKVAV) demonstrated significant increase in corneal cells (HCECs) proliferation compared to controls.

    Conclusion The hybrid BDDGE-crosslinked collagen-based hydrogels have the potential for use as tissue-engineered corneal substitutes.

  • 34.
    Rafat, Mehrdad
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Lagali, Neil
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Koulikovska, Marina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Fagerholm, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Development of a Highly Elastic Bioengineered Cornea: From Research to Commercialization2013Conference paper (Other academic)
    Abstract [en]

    Background: Despite the promising clinical results that we previously reported on biosynthetic corneas, more elastic materials are required for surgical manipulation and withstanding the adverse host conditions faced by high risk corneal transplants.

    Purpose: The overall objective was to develop novel bioengineered materials that can replace the damaged corneal tissue. Another objective was to evaluate the in vivo integration of the materials in rabbit models using a femtosecond laser intrastromal surgical technique.

    Methods: Bioengineered corneas were prepared using porcine collagen cross-linked by carbodiimides at various compositions and pH. Promising formulations were tested for their mechanical, optical, and enzymatic and thermal degradation properties as well as for interactions with corneal cells, and in vivo implantation in rabbit’s eyes. A femtosecond laser was used to cut 100 mircon thick discs of mid-stromal tissue from corneas of 15 rabbits and replaced with the bioengineered materials.

    Results: The new material demonstrated improved mechanical properties while maintaining its clarity and biocompatibility. The bioengineered implant retained its shape, thickness, and clarity 8 weeks post-surgery in rabbits.  

    Conclusions: The bioengineered cornea developed in this work has the potential to be used and commercialized as corneal implants to replace the damaged tissue or for corrective surgery applications.

  • 35.
    Rafat, Mehrdad
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Lagali, Neil
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Koulikovska, Marina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Fagerholm, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuroscience. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    In vivo integrity of intra‐corneal bioengineered discs in rabbit models2013In: Acta Ophthalmologica; Special Issue: Abstracts from the 2013 European Association for Vision and Eye Research Conference, August 2013 Volume 91, Issue Supplement s252, John Wiley & Sons, 2013Conference paper (Other academic)
    Abstract [en]

    Background: We have previously reported the successful integration and safety of bioengineered materials as corneal substitutes in human models. Despite the promising results as corneal implants, more elastic and robust materials are required for use as thin intra-corneal lenses to withstand surgical manipulation for corrective surgery and improved vision. Most of the existing corneal inlays are made of synthetic materials. Here we describe the potential of bioengineerd materials for vision correction. Objectives: to develop bioengineered materials as inlays within the corneal tissue as well as evaluating the in vivo integrity and integration of the materials in rabbit models. Methods: Bioengineered inlays were prepared from collagen and tested for their physical and biological propertis. A femtosecond laser was used to cut 100 mircon thick discs of mid-stromal tissue from corneas of 20 rabbits and replaced with bioengineered inlays. Results: The new materials demonstrated improved mechanical properties while maintaining their clarity and biocompatibility. The bioengineered inlays retained their shapes, thickness, and clarity 8 weeks post-surgery in rabbits.

  • 36.
    Rafat, Mehrdad
    et al.
    Department of Chemical Engineering University of Ottawa, Ottawa, Ontario K1N 6N5, Canada.
    Li, Fengfu
    University of Ottawa Eye Institute, Ottawa, Ontario K1H 8L6, Canada.
    Fagerholm, Per
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Östergötlands Läns Landsting, Reconstruction Centre, Department of Ophthalmology UHL.
    Lagali, Neil S.
    University of Ottawa Eye Institute, Ottawa, Ontario K1H 8L6, Canada.
    Watsky, Mitchell A.
    University of Tennessee Health Center, Memphis, TN, USA.
    Munger, Rejean
    University of Ottawa Eye Institute, Ottawa, Ontario K1H 8L6, Canada.
    Matsuura, Takeshi
    Department of Chemical Engineering University of Ottawa, Ottawa, Ontario K1N 6N5, Canada.
    Griffith, May
    University of Ottawa Eye Institute, Ottawa, Ontario K1H 8L6, Canada.
    PEG-stabilized carbodiimide crosslinked collagen-chitosan hydrogels for corneal tissue engineering2008In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 29, no 29, p. 3960-3972Article in journal (Refereed)
    Abstract [en]

    Implantable biomaterials that mimic the extracellular matrix (ECM) in key physical and physiological functions require components and microarchitectures that are carefully designed to maintain the correct balance between biofunctional and physical properties. Our goal was to develop hybrid polymer networks (HPN) that combine the bioactive features of natural materials and physical characteristics of synthetic ones to achieve synergy between the desirable mechanical properties of some components with the biological compatibility and physiological relevance of others. In this study, we developed collagen-chitosan composite hydrogels as corneal implants stabilized by either a simple carbodiimide cross-linker or a hybrid cross-linking system comprised of a long-range bi-functional cross-linker (e.g. poly(ethylene glycol) dibutyraldehyde (PEG-DBA)), and short-range amide-type cross-linkers (e.g. 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC), and N-hydroxysuccinimide (NHS)). Optimum hybrid hydrogel demonstrated significantly enhanced mechanical strength and elasticity by 100 and 20%, respectively, compared to its non-hybrid counterpart. It demonstrated excellent optical properties, optimum mechanical properties and suturability, and good permeability to glucose and albumin. It had excellent biocompatibility and when implanted into pig corneas for 12 months, allowed seamless host-graft integration with successful regeneration of host corneal epithelium, stroma, and nerves. © 2008 Elsevier Ltd. All rights reserved.

  • 37.
    Rafat, Mehrdad
    et al.
    Department of Chemical Engineering, University of Ottawa, Ottawa, Canada.
    Matsuura, T.
    Department of Chemical Engineering, University of Ottawa, Ottawa, Canada.
    Griffith, May
    Department of Chemical Engineering, University of Ottawa, Ottawa, Canada.
    Surface Modification and Characterization of Artificial Cornea for Reduced Endothelialization2006Conference paper (Other academic)
  • 38.
    Rafat, Mehrdad
    et al.
    Department of Chemical Engineering, University of Ottawa and University of Ottawa Eye Institute, Ottawa, Ontario, Canada.
    Matsuura, Takeshi
    Department of Chemical Engineering, University of Ottawa, Ottawa, Ontario, Canada.
    Li, Fengfu
    University of Ottawa Eye Institute, Ottawa, Ontario, Canada.
    Griffith, May
    University of Ottawa Eye Institute and Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
    Surface modification of collagen-based artificial cornea for reduced endothelialization2009In: Journal of Biomedical Materials Research. Part A, ISSN 1549-3296, E-ISSN 1552-4965, Vol. 88A, no 3, p. 755-768Article in journal (Refereed)
    Abstract [en]

    Our objective was to develop collagen-based hydrogels as tissue substitutes for corneal transplantation The design of the full-thickness corneal grafts includes prevention of cell migration onto the posterior surface of the implants, using a plasma-assisted surface modification technique. Briefly, the hydrogel materials were Subjected to ammonia plasma functionalization followed by grafting of alginate macromolecules to the target surface. The treated materials Surfaces showed observable decreases in endothelial cell attachment. The decrease in cell attachment and adhesion was dependant upon the concentration of alginate and plasma radio frequency (RF) power. High concentrations of alginate 5%, (w/v) and high I F power of 100 W produced surfaces with minimal cell attachment. The plasma-alginate treatment did not adversely affect the optical or swelling properties of the constructs. Contact angle measurement analysis revealed that the posterior surface hydrophilicity significantly increased after the treatment. The grafting of alginate to the implants surfaces was confirmed by fourier transform infrared spectroscopy. Both of the untreated and alginate grafted corneal materials were found to be superior to human cornea in optical and swelling properties.

  • 39.
    Rafat, Mehrdad
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Mondal, Debasish
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Islam, M.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Liedberg, Bo
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics. Linköping University, The Institute of Technology.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Nanoparticles incorporated collagen hydrogels for sustained release of EGF2013In: Acta Ophthalmologica; Special Issue: Abstracts from the 2013 European Association for Vision and Eye Research Conference, Volume 91, Issue Supplement s252, page 0, August 2013, John Wiley & Sons, 2013Conference paper (Refereed)
    Abstract [en]

    Therapeutic biomolecules such as growth factors are essential for enhancing the regeneration of damaged tissues by inducing cell signaling activities such as cell migration, proliferation, and differentiation. Nevertheless, they have short half-lives in physiological conditions due to fast deactivation and degradation by enzymes and other physical and chemical reactions. Therefore, there is a great need for the suitable target delivery of nanoparticles to improve the release kinetics of growth factors as well as their therapeutic effectiveness. The main objective of this study was to develope and characterize a sustained delivery system consisting of an EGF-encapslated chitosan nanoparticles and collagen hydrogel carrier system to achieve a sustained release of EGF. In this study, we made EGF-loaded chitosan nanoparticles, which could be incorporated into an engineered collagen hydrogel scaffold. The particles were spherical in the size range of 60–100 nm. The release kinetics of EGF showed the release of growth factors in a sustained manner. Live-dead staining of human corneal epithelial (HCEC) cells was done to evaluate the cytotoxicity of the nanoparticles.

  • 40.
    Rafat, Mehrdad
    et al.
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, Faculty of Science & Engineering.
    Xeroudaki, Maria
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping. Linköping University, Faculty of Medicine and Health Sciences.
    Koulikovska, Marina
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping. Linköping University, Faculty of Medicine and Health Sciences.
    Sherrell, Peter
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, Faculty of Science & Engineering.
    Groth, Fredrik
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping. Linköping University, Faculty of Medicine and Health Sciences.
    Fagerholm, Per
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping. Linköping University, Faculty of Medicine and Health Sciences.
    Lagali, Neil
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping.
    Composite core-and-skirt collagen hydrogels with differential degradation for corneal therapeutic applications2016In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 83, p. 142-155Article in journal (Refereed)
    Abstract [en]

    Scarcity of donor tissue to treat corneal blindness and the need to deliver stem cells or pharmacologic agents to ensure corneal graft survival are major challenges. Here, new composite collagen-based hydrogels are developed as implants to restore corneal transparency while serving as a possible reservoir for cells and drugs. The composite hydrogels have a centrally transparent core and embedded peripheral skirt of adjustable transparency and degradability, with the skirt exhibiting faster degradation in vitro. Both core and skirt supported human epithelial cell populations in vitro and the skirt merged homogeneously with the core material to smoothly distribute a mechanical load in vitro. After in vivo transplantation in rabbit corneas over three months, composites maintained overall corneal shape and integrity, while skirt degradation could be tracked in vivo and non-invasively due to partial opacity. Skirt degradation was associated with partial collagen breakdown, thinning, and migration of host stromal cells and macrophages, while the central core maintained integrity and transparency as host cells migrated and nerves regenerated.

    IMPACT:

    This study indicates the feasibility of a collagen-based composite hydrogel to maintain corneal stability and transparency while providing a degradable peripheral reservoir for cell or substance release.

  • 41.
    Shakeri, Raheleh
    et al.
    University of Tehran, Iran.
    Hosseinkhani, Saman
    Tarbiat Modares University, Iran.
    Los, Marek Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Davoodi, Jamshid
    University of Tehran, Iran.
    Jain, Mayur Vilas
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Cieslar-Pobuda, Artur
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Rafat, Mehrdad
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, Faculty of Science & Engineering.
    Kaboudanian Ardestani, Sussan
    University of Tehran, Iran.
    Role of the salt bridge between glutamate 546 and arginine 907 in preservation of autoinhibited form of Apaf-12015In: International Journal of Biological Macromolecules, ISSN 0141-8130, E-ISSN 1879-0003, Vol. 81, p. 370-374Article in journal (Refereed)
    Abstract [en]

    Apaf-1, the key element of apoptotic mitochondrial pathway, normally exists in an auto-inhibited form inside the cytosol. WRD-domain of Apaf-1 has a critical role in the preservation of auto-inhibited form; however the underlying mechanism is unclear. It seems the salt bridges between WRD and NOD domains are involved in maintaining the inactive conformation of Apaf-1. At the present study, we have investigated the effect of E546-R907 salt bridge on the maintenance of auto-inhibited form of human Apaf-1. E546 is mutated to glutamine (Q) and arginine (R). Over-expression of wild type Apaf-1 and its E546Q and E546R variants in HEK293T cells does not induce apoptosis unlike - HL-60 cancer cell line. In vitro apoptosome formation assay showed that all variants are cytochrome c and dATP dependent to form apoptosome and activate endogenous procaspase-9 in Apaf-1-knockout MEF cell line. These results suggest that E546 is not a critical residue for preservation of auto-inhibited Apaf-1. Furthermore, the behavior of Apaf-1 variants for in vitro apoptosome formation in HEK293T cell is similar to exogenous wild type Apaf-1. Wild type and its variants can form apoptosome in HEK293T cell with different procaspase-3 processing pattern in the presence and absence of exogenous cytochrome c and dATP. (C) 2015 Elsevier B.V. All rights reserved.

  • 42.
    Sherrell, Peter
    et al.
    Linköping University, Department of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    Cieślar-Pobuda, Artur
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Institute of Automatic Control, Silesian University of Technology, Gliwice, Poland.
    Silverå Ejneby, Malin
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Sammalisto, Laura
    Linköping University, Department of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    Gelmi, Amy
    Linköping University, Department of Physics, Chemistry and Biology. Linköping University, Faculty of Science & Engineering.
    de Muinck, Ebo
    Linköping University, Department of Medical and Health Sciences, Division of Cardiovascular Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Heart and Medicine Center, Department of Cardiology in Linköping.
    Brask, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences.
    Jan Los, Marek
    Malopolska Centre of Biotechnology, Jagiellonian University, Kraków, Poland.
    Rafat, Mehrdad
    Linköping University, Department of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    Rational Design of a Conductive Collagen Heart Patch2017In: Macromolecular Bioscience, ISSN 1616-5187, E-ISSN 1616-5195, Vol. 17, no 7, article id 1600446Article in journal (Refereed)
    Abstract [en]

    Cardiovascular diseases, including myocardial infarction, are the cause of significant morbidity and mortality globally. Tissue engineering is a key emerging treatment method for supporting and repairing the cardiac scar tissue caused by myocardial infarction. Creating cell supportive scaffolds that can be directly implanted on a myocardial infarct is an attractive solution. Hydrogels made of collagen are highly biocompatible materials that can be molded into a range of shapes suitable for cardiac patch applications. The addition of mechanically reinforcing materials, carbon nanotubes, at subtoxic levels allows for the collagen hydrogels to be strengthened, up to a toughness of 30 J m-1 and a two to threefold improvement in Youngs' modulus, thus improving their viability as cardiac patch materials. The addition of carbon nanotubes is shown to be both nontoxic to stem cells, and when using single-walled carbon nanotubes, supportive of live, beating cardiac cells, providing a pathway for the further development of a cardiac patch.

  • 43.
    Sherrell, Peter
    et al.
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, The Institute of Technology.
    Elmén, Karin
    Linköping University, Department of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    Cieslar-Pobuda, Artur
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Silesian Technical University, Poland.
    Wiechec, Emilia
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Lemoine, Mark
    Linköping University, Department of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    Arzhangi, Zahra
    University of Ottawa, Canada.
    Silverå Ejneby, Malin
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Brask, Johan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Daka, Joseph N.
    Health Canada, Canada.
    Rafat, Mehrdad
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, Faculty of Science & Engineering. Health Canada, Canada; LinkoCare Life Science AB, Linkoping, Sweden.
    Cardiac and stem cell-cocooned hybrid microspheres: A multi factorial design approach2016In: Sensors and actuators. B, Chemical, ISSN 0925-4005, E-ISSN 1873-3077, Vol. 236, p. 480-489Article in journal (Refereed)
    Abstract [en]

    Cell therapy is a promising approach for the treatment of patients suffering from myocardial infarction. Most recent therapies involve direct injection of cells into the damaged heart tissue to induce regeneration and help restore its functions, however, anoikis and the harsh environment at the sight of injection limit the therapeutic efficacy of current techniques. Biopolymeric microspheres such as alginate have been widely used for cells encapsulation and delivery for cell therapy applications. However, majority of these techniques are not standardized that is a big challenge for translation into clinically-relevant treatment options. In addition, purely-alginate base microspheres are limited by poor biodegradability and lack of strong interaction between the encapsulated cells and their surrounding alginate matrix. In this work, we have shown that the addition of type I collagen into alginate microspheres, systematically optimized by a multivariate experimental design, improves the biocompatibility of the microspheres towards induced pluripotent stem cells (iPS), cardiomyocytes, and blood outgrowth endothelial cells (BOEC), whilst improving diffusion between outside environment and the inner sphere. The addition of collagen allows for multiple routes for sphere degradation leading to potentially greater control over cell release once delivered. Mathematical models were developed and utilized to effectively evaluate and predict the influence of various factors such as polymer ratios, micronization air flow rate, and air-gap distance on spheres size and shape, which play a key role in cell viability, degradation rate of microspheres, as well as controlled production of the cell cocoons toward clinically-relevant cell therapies for treatment of myocardial infarction. (C) 2016 Elsevier B.V. All rights reserved.

  • 44.
    Spinozzi, Daniele
    et al.
    Netherlands Inst Innovat Ocular Surg, Netherlands.
    Miron, Alina
    Netherlands Inst Innovat Ocular Surg, Netherlands.
    Bruinsma, Marieke
    Netherlands Inst Innovat Ocular Surg, Netherlands.
    Dapena, Isabel
    Netherlands Inst Innovat Ocular Surg, Netherlands; Melles Cornea Clin Rotterdam, Netherlands.
    Lavy, Itay
    Netherlands Inst Innovat Ocular Surg, Netherlands; Melles Cornea Clin Rotterdam, Netherlands.
    Binder, Perry S.
    Univ Calif Irvine, CA USA.
    Rafat, Mehrdad
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering. LinkoCare Life Sci AB, Linkoping, Sweden.
    Oellerich, Silke
    Netherlands Inst Innovat Ocular Surg, Netherlands.
    Melles, Gerrit R. J.
    Netherlands Inst Innovat Ocular Surg, Netherlands; Melles Cornea Clin Rotterdam, Netherlands; Amnitrans EyeBank Rotterdam, Netherlands.
    Evaluation of the Suitability of Biocompatible Carriers as Artificial Transplants Using Cultured Porcine Corneal Endothelial Cells2019In: Current Eye Research, ISSN 0271-3683, E-ISSN 1460-2202, Vol. 44, no 3, p. 243-249Article in journal (Refereed)
    Abstract [en]

    Purpose/Aim: Evaluating the suitability of bioengineered collagen sheets and human anterior lens capsules (HALCs) as carriers for cultivated porcine corneal endothelial cells (pCECs) and in vitro assessment of the cell-carrier sheets as tissue-engineered grafts for Descemet membrane endothelial keratoplasty (DMEK). Materials and Methods: pCECs were isolated, cultured up to P2 and seeded onto LinkCell (TM) bioengineered matrices of 20 mu m (LK20) or 100 mu m (LK100) thickness, and on HALC. During expansion, pCEC viability and morphology were assessed by light microscopy. ZO-1 and Na+/K+-ATPase expression was investigated by immunohistochemistry. Biomechanical properties of pCEC-carrier constructs were evaluated by simulating DMEK surgery in vitro using an artificial anterior chamber (AC) and a human donor cornea without Descemet membrane (DM). Results: During in vitro expansion, cultured pCECs retained their proliferative capacity, as shown by the positive staining for proliferative marker Ki67, and a high cell viability rate (96 +/- 5%). pCECs seeded on all carriers formed a monolayer of hexagonal, tightly packed cells that expressed ZO-1 and Na+/K+-ATPase. During in vitro surgery, pCEC-LK20 and pCEC-LK100 constructs were handled like Descemet stripping endothelial keratoplasty (DSEK) grafts, i.e. folded like a "taco" for insertion because of challenges related to rolling and sticking of the grafts in the injector. pCEC-HALC constructs behaved similar to the DMEK reference model during implantation and unfolding in the artificial AC, showing good adhesion to the bare stroma. Conclusions: In vitro DMEK surgery showed HALC as the most suitable carrier for cultivated pCECs with good intraoperative graft handling. LK20 carrier showed good biocompatibility, but required a DSEK-adapted surgical protocol. Both carriers might be notional candidates for potential future clinical applications.

  • 45.
    Wasik, Agata M.
    et al.
    Karolinska Institute, Stockholm, Sweden.
    Grabarek, Jerzy
    Pomeranian Medical University, Szczecin, Poland.
    Pantovic, Aleksandar
    University of Belgrade, Serbia.
    Cieslar-Pobuda, Artur
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Silesian Technical University, Gliwice, Poland.
    Asgari, Hamid R.
    Tehran University of Medical Sciences, Iran.
    Bundgaard-Nielsen, Caspar
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Aalborg University, Denmark .
    Rafat, Mehrdad
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering.
    Dixon, Ian M.
    University of Manitoba, Winnipeg, Canada.
    Ghavami, Saeid
    University of Manitoba, Winnipeg, Canada.
    Los, Marek Jan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Pomeranian Medical University, Szczecin, Poland; BioApplications Enterprises, Winnipeg, Canada.
    Reprogramming and Carcinogenesis-Parallels and Distinctions2014In: International Review of Cell and Molecular Biology / [ed] Kwang W Jeon, Elsevier, 2014, Vol. 308, p. 167-203Chapter in book (Refereed)
    Abstract [en]

    Rapid progress made in various areas of regenerative medicine in recent years occurred both at the cellular level, with the Nobel prize-winning discovery of reprogramming (generation of induced pluripotent stem (iPS) cells) and also at the biomaterial level. The use of four transcription factors, Oct3/4, Sox2, c-Myc, and Klf4 (called commonly "Yamanaka factors") for the conversion of differentiated cells, back to the pluripotent/embryonic stage, has opened virtually endless and ethically acceptable source of stem cells for medical use. Various types of stem cells are becoming increasingly popular as starting components for the development of replacement tissues, or artificial organs. Interestingly, many of the transcription factors, key to the maintenance of stemness phenotype in various cells, are also overexpressed in cancer (stem) cells, and some of them may find the use as prognostic factors. In this review, we describe various methods of iPS creation, followed by overview of factors known to interfere with the efficiency of reprogramming. Next, we discuss similarities between cancer stem cells and various stem cell types. Final paragraphs are dedicated to interaction of biomaterials with tissues, various adverse reactions generated as a result of such interactions, and measures available, that allow for mitigation of such negative effects.

  • 46.
    Wassmer, Sarah
    et al.
    Ottawa Hospital Research Institute, Vision Sciences Program, Ottawa, Canada.
    Rafat, Mehrdad
    Ottawa Hospital Research Institute, Vision Sciences Program, Ottawa, ON, Canada; University of Ottawa, Department of Cellular and Molecular Medicine, Ottawa, ON, Canada.
    Fong, Wai Gin
    Ottawa Hospital Research Institute, Vision Sciences Program, Ottawa, Canada.
    Baker, Adam N.
    Ottawa Hospital Research Institute, Vision Sciences Program, Ottawa, Canada.
    Tsilfidis, Catherine
    Ottawa Hospital Research Institute, Vision Sciences Program, Ottawa, Canada; University of Ottawa, Department of Cellular and Molecular Medicine, Ottawa, ON, Canada; University of Ottawa, Department of Ophthalmology, Ottawa, ON, Canada.
    Chitosan microparticles for delivery of proteins to the retina2013In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 9, no 8, p. 7855-7864Article in journal (Refereed)
    Abstract [en]

    Chitosan microparticles (CMPs) have previously been developed for topical applications to the eye, but their safety and efficacy in delivering proteins to the retina have not been adequately evaluated. This study examines the release kinetics of CMPs in vitro, and assesses their biocompatibility and cytotoxicity on retinal cells in vitro and in vivo. Two proteins were used in the encapsulation and release studies: BSA (bovine serum albumin) and tat-EGFP (enhanced green fluorescent protein fused to the transactivator of transcription peptide). Not surprisingly, the in vitro release kinetics were dependent on the protein encapsulated, with BSA showing higher release than tat-EGFP. CMPs containing encapsulated tat-EGFP were tested for cellular toxicity in photoreceptor-derived 661W cells. They showed no signs of in vitro cell toxicity at a low concentration (up to 1 mg ml 1), but at a higher concentration of 10 mg ml1 they were associated with cytotoxic effects. In vivo, CMPs injected into the subretinal space were found beneath the photoreceptor layer of the retina, and persisted for at least 8 weeks. Similar to the in vitro studies, the lower concentration of CMPs was generally well tolerated, but the higher concentration resulted in cytotoxic effects and in reduced retinal function, as assessed by electroretinogram amplitudes. Overall, this study suggests that CMPs are effective long-term delivery agents to the retina, but the concentration of chitosan may affect cytotoxicity.

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