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  • 1.
    Ahmed, Tamer A. E.
    et al.
    University of Ottawa, Ontario, Canada.
    Giulivi, Antonio
    The Ottawa Hospital, Ontario, Canada.
    Griffith, May
    University of Ottawa, Ontario, Canada.
    Hincke, Max
    University of Ottawa, Ontario, Canada.
    Fibrin Glues in Combination with Mesenchymal Stem Cells to Develop a Tissue-Engineered Cartilage Substitute2011In: Tissue Engineering. Parts A, B and C, ISSN 2152-4947, E-ISSN 2152-4955, Vol. 17, no 3-4, p. 323-335Article in journal (Refereed)
    Abstract [en]

     Damage of cartilage due to traumatic or pathological conditions results in disability and severe pain. Regenerative medicine, using tissue engineering-based constructs to enhance cartilage repair by mobilizing chondrogenic cells, is a promising approach for restoration of structure and function. Fresh fibrin (FG) and platelet-rich fibrin (PR-FG) glues produced by the CryoSeal (R) FS System, in combination with human bone marrow-derived mesenchymal stem cells (BM-hMSCs), were evaluated in this study. We additionally tested the incorporation of heparin-based delivery system (HBDS) into these scaffolds to immobilize endogenous growth factors as well as exogenous transforming growth factor-beta(2). Strongly, CD90+ and CD105+ hMSCs were encapsulated into FG and PR-FG with and without HBDS. Encapsulation of hMSCs in PR-FG led to increased expression of collagen II gene at 2.5 weeks; however, no difference was observed between FG and PR-FG at 5 weeks. The incorporation of HBDS prevented the enhancement of collagen II gene expression. BM-hMSCs in FG initially displayed enhanced aggrecan gene expression and increased accumulation of Alcian blue-positive extracellular matrix; incorporation of HBDS into these glues did not improve aggrecan gene expression and extracellular matrix accumulation. The most significant effect on cartilage marker gene expression and accumulation was observed after encapsulation of hMSCs in FG. We conclude that FG is more promising than PR-FG as a scaffold for chondrogenic differentiation of hMSCs; however, immobilization of growth factors inside these fibrin scaffolds with the HBDS system has a negative impact on this process. In addition, BM-hMSCs are valid and potentially superior alternatives to chondrocytes for tissue engineering of articular cartilage.

  • 2.
    Ahmed, Tamer A. E.
    et al.
    Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
    Griffith, May
    Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
    Hincke, Max
    Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
    Characterization and inhibition of fibrin hydrogel-degrading enzymes during development of tissue engineering scaffolds2007In: Tissue engineering, ISSN 1076-3279, E-ISSN 1557-8690, Vol. 13, no 7, p. 1469-1477Article in journal (Refereed)
    Abstract [en]

    The goal of articular cartilage tissue engineering is to provide cartilaginous constructs to replace abnormal cartilage. We have evaluated the chondroprogenitor clonal cell line RCJ3.1C5.18 (C5.18) as a model to guide the development of appropriate scaffolds for tissue engineering. Rapid degradation of fibrin hydrogels was observed after encapsulation of C5.18 cells. The enzymes responsible for this fibrin gel breakdown were characterized to control their activity and regulate gel stability. Western blotting, confirming zymography, revealed bands due to matrix metalloproteinases (MMP-2, MMP-3) that are secreted concomitantly with fibrin hydrogels breakdown. High plasmin activity was detected in conditioned media during hydrogel breakdown but not in the confluent cells before encapsulation. Reverse transcriptase polymerase chain reaction indicated the expression of MMP-2, -3, and -9 and plasminogen in the cells. MMP-9 was 100 times higher at day 1, whereas MMP-2 started to increase and reached its maximum level by day 7. Aprotinin, a known serine protease inhibitor, and galardin (GM6001), a potent MMP inhibitor, in combination or separately, prevented the breakdown of fibrin-C5.18 hydrogels, whereas only the combination of both promoted the accumulation of extracellular matrix. These findings suggest that plasmin and MMPs contribute independently to fibrin hydrogel breakdown, but that either enzyme can achieve extracellular matrix breakdown.

  • 3.
    Ahn, Jae-Il
    et al.
    Ottawa Hospital, Canada .
    Kuffova, Lucia
    University of Aberdeen, Scotland .
    Merrett, Kimberley
    Ottawa Hospital, Canada .
    Mitra, Debbie
    Ottawa Hospital, Canada .
    Forrester, John V.
    University of Aberdeen, Scotland .
    Li, Fengfu
    Ottawa Hospital, Canada .
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Ottawa Hospital, Canada .
    Crosslinked collagen hydrogels as corneal implants: Effects of sterically bulky vs. non-bulky carbodiimides as crosslinkers2013In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 9, no 8, p. 7796-7805Article in journal (Refereed)
    Abstract [en]

    We have previously shown that recombinant human collagen can be crosslinked with N-(3-dimethylaminopropyl)-N-ethylcarbodiimide (EDC) to fabricate transparent hydrogels possessing the shape and dimensions of the human cornea. These corneal implants have been tested in a Phase I human clinical study. Although these hydrogels successfully promoted corneal tissue and nerve regeneration, the gelling kinetics were difficult to control during the manufacture of the implants. An alternative carbodiimide capable of producing hydrogels of similar characteristics as EDC in terms of strength and biocompatibility, but with a longer gelation time would be a desirable alternative. Here, we compared the crosslinking kinetics and properties of hydrogels crosslinked with a sterically bulky carbodiimide, N-Cyclohexyl-N-(2-morpholinoethyl) carbodiimide metho-p-toluenesulfonate (CMC), with that of EDC. CMC crosslinking was possible at ambient temperature whereas the EDC reaction was too rapid to control and had to be carried out at low temperatures. The highest tensile strength obtained using optimized formulations were equivalent, although CMC crosslinked hydrogels were found to be stiffer. The collagenase resistance of CMC crosslinked hydrogels was superior to that of EDC crosslinked hydrogels while biocompatibility was similar. We are also able to substitute porcine collagen with recombinant human collagen and show that the in vivo performance of both resulting hydrogels as full-thickness corneal implants is comparable in a mouse model of an orthotopic corneal graft. In conclusion, CMC is a viable alternative to EDC as a crosslinker for collagen-based biomaterials for use as corneal implants, and potentially for use in other tissue engineering applications.

  • 4.
    Alarcon, E I
    et al.
    Bio-nanomaterials Chemistry and Engineering Laboratory, Division of Cardiac Surgery, University of Ottawa Heart Institute, 40 Ruskin Street, Rm H5229, Ottawa, Canada.
    Vulesevic, B
    Bio-nanomaterials Chemistry and Engineering Laboratory, Division of Cardiac Surgery, University of Ottawa Heart Institute, 40 Ruskin Street, Rm H5229, Ottawa, Canada.
    Argawal, A
    Bio-nanomaterials Chemistry and Engineering Laboratory, Division of Cardiac Surgery, University of Ottawa Heart Institute, 40 Ruskin Street, Rm H5229, Ottawa, Canada.
    Ross, A
    Bio-nanomaterials Chemistry and Engineering Laboratory, Division of Cardiac Surgery, University of Ottawa Heart Institute, 40 Ruskin Street, Rm H5229, Ottawa, Canada.
    Bejjani, P
    Bio-nanomaterials Chemistry and Engineering Laboratory, Division of Cardiac Surgery, University of Ottawa Heart Institute, 40 Ruskin Street, Rm H5229, Ottawa, Canada.
    Podrebarac, J
    Bio-nanomaterials Chemistry and Engineering Laboratory, Division of Cardiac Surgery, University of Ottawa Heart Institute, 40 Ruskin Street, Rm H5229, Ottawa, Canada.
    Ravichandran, Ranjithkumar
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Phopase, Jaywant
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Suuronen, E J
    Bio-nanomaterials Chemistry and Engineering Laboratory, Division of Cardiac Surgery, University of Ottawa Heart Institute, 40 Ruskin Street, Rm H5229, Ottawa, Canada.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Coloured cornea replacements with anti-infective properties: expanding the safe use of silver nanoparticles in regenerative medicine.2016In: Nanoscale, ISSN 2040-3364, E-ISSN 2040-3372, Vol. 8, no 12, p. 6484-6489Article in journal (Refereed)
    Abstract [en]

    Despite the broad anti-microbial and anti-inflammatory properties of silver nanoparticles (AgNPs), their use in bioengineered corneal replacements or bandage contact lenses has been hindered due to their intense yellow coloration. In this communication, we report the development of a new strategy to pre-stabilize and incorporate AgNPs with different colours into collagen matrices for fabrication of corneal implants and lenses, and assessed their in vitro and in vivo activity.

  • 5.
    Alarcon, Emilio I.
    et al.
    University of Ottawa, Canada; University of Ottawa, Canada; University of Ottawa, Canada.
    Udekwu, Klas I.
    Karolinska Institute, Sweden.
    Noel, Christopher W.
    University of Ottawa, Canada; .
    Gagnon, Luke B. -P.
    University of Ottawa, Canada.
    Taylor, Patrick K.
    University of Ottawa, Canada.
    Vulesevic, Branka
    University of Ottawa, Canada.
    Simpson, Madeline J.
    University of Ottawa, Canada.
    Gkotzis, Spyridon
    Karolinska Institute, Sweden.
    Islam, Mohammed Mirazul
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
    Lee, Chyan-Jang
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics. Linköping University, The Institute of Technology.
    Richter-Dahlfors, Agneta
    Karolinska Institute, Sweden.
    Mah, Thien-Fah
    University of Ottawa, Canada.
    Suuronen, Erik J.
    University of Ottawa, Canada.
    Scaiano, Juan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. University of Ottawa, Canada.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
    Safety and efficacy of composite collagen-silver nanoparticle hydrogels as tissue engineering scaffolds2015In: Nanoscale, ISSN 2040-3364, E-ISSN 2040-3372, Vol. 7, no 44, p. 18789-18798Article in journal (Refereed)
    Abstract [en]

    The increasing number of multidrug resistant bacteria has revitalized interest in seeking alternative sources for controlling bacterial infection. Silver nanoparticles (AgNPs), are amongst the most promising candidates due to their wide microbial spectrum of action. In this work, we report on the safety and efficacy of the incorporation of collagen coated AgNPs into collagen hydrogels for tissue engineering. The resulting hybrid materials at [AgNPs] less than0.4 mu M retained the mechanical properties and biocompatibility for primary human skin fibroblasts and keratinocytes of collagen hydrogels; they also displayed remarkable anti-infective properties against S. aureus, S. epidermidis, E. coli and P. aeruginosa at considerably lower concentrations than silver nitrate. Further, subcutaneous implants of materials containing 0.2 mu M AgNPs in mice showed a reduction in the levels of IL-6 and other inflammation markers (CCL24, sTNFR-2, and TIMP1). Finally, an analysis of silver contents in implanted mice showed that silver accumulation primarily occurred within the tissue surrounding the implant.

  • 6.
    Alarcon, Emilio I
    et al.
    University of Ottawa.
    Udekwu, Klas
    Karolinska Institute.
    Skog, Mårten
    Linköping University, Department of Clinical and Experimental Medicine, Cell Biology. Linköping University, Faculty of Health Sciences.
    Pacioni, NataliL
    University of Ottawa.
    Stamplecoskie, Kevin G
    University of Ottawa.
    Gonzalez-Bejar, Maria
    University of Ottawa.
    Polisetti, Naresh
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Wickham, Abeni
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics. Linköping University, The Institute of Technology.
    Richter-Dahlfors, Agneta
    Karolinska Institute.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences.
    Scaiano, Juan C
    University of Ottawa.
    The biocompatibility and antibacterial properties of collagen-stabilized, photochemically prepared silver nanoparticles2012In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 33, no 19, p. 4947-4956Article in journal (Refereed)
    Abstract [en]

    Spherical 3.5 nm diameter silver nanoparticles (AgNP) stabilized in type I collagen (AgNP@collagen) were prepared in minutes (5-15 min) at room temperature by a photochemical method initiated by UVA irradiation of a water-soluble non-toxic benzoin. This biocomposite was examined to evaluate its biocompatibility and its anti-bacterial properties and showed remarkable properties. Thus, while keratinocytes and fibroblasts were not affected by AgNP@collagen, it was bactericidal against Bacillus megaterium and E. coli but only bacteriostatic against S. epidermidis. In particular, the bactericidal properties displayed by AgNP@collagen were proven to be due to AgNP in AgNP@collagen, rather than to released silver ions, since equimolar concentrations of Ag are about four times less active than AgNP@collagen based on total Ag content. This new biocomposite was stable over a remarkable range of NaCl, phosphate, and 2-(N-morpholino)ethanesulfonic acid concentrations and for over one month at 4 degrees C. Circular dichroism studies show that the conformation of collagen in AgNP@collagen remains intact. Finally, we have compared the properties of AgNP@collagen with a similar biocomposite prepared using alpha-poly-L-Lysine and also with citrate stabilized AgNP; neither of these materials showed comparable biocompatibility, stability, or anti-bacterial activity.

  • 7.
    Aucoin, L
    et al.
    Department of Chemical Engineering, McMaster University, Hamilton ON, Canada.
    Griffith, CM
    University of Ottawa Eye Institute, Ottawa ON, Canada.
    Pleizier, G
    ICPET, National Research Council of Canada, Ottawa ON, Canada.
    Deslandes, Y
    ICPET, National Research Council of Canada, Ottawa ON, Canada.
    Sheardown, H
    Department of Chemical Engineering, McMaster University, Hamilton ON, Canada.
    Interactions of corneal epithelial cells and surfaces modified with cell adhesion peptide combinations2002In: Journal of Biomaterials Science. Polymer Edition, ISSN 0920-5063, E-ISSN 1568-5624, Vol. 13, no 4, p. 447-462Article in journal (Refereed)
    Abstract [en]

    In order to facilitate the adhesion of corneal epithelial cells to a poly dimethyl siloxane (PDMS) substrate ultimately for the development of a synthetic keratoprosthesis, PDMS surfaces were modified by covalent attachment of combinations of cell adhesion and synergistic peptides derived from laminin and fibronectin. Peptides studied included YIGSR and its synergistic peptide PDSGR from laminin and the fibronectin derived RGDS and PHSRN. Surfaces were modified with combinations of peptides determined by an experimental design. Peptide surface densities, measured using 125-I labeled tyrosine containing analogs, were on the order of pmol/cm(2). Surface density varied as a linear function of peptide concentration in the reaction solution, and was different for the different peptides examined. The lowest surface density at all solution fractions was obtained with GYRGDS, while the highest density was consistently obtained with GYPDSGR. These results provide evidence that the surfaces were modified with multiple peptides. Water contact angles and XPS results provided additional evidence for differences in the chemical composition of the various surfaces. Significant differences in the adhesion of human corneal epithelial cells to the modified surfaces were noted. Statistical analysis of the experimental adhesion results suggested that solution concentration YIGSR, RGDS, and PHSRN as well as the interaction effect of YIGSR and PDSGR had a significant effect on cell interactions. Modification with multiple peptides resulted in greater adhesion than modification with single peptides only. Surface modification with a control peptide PPSRN in place of PHSRN resulted in a decrease in cell adhesion in virtually all cases. These results suggest that surface modification with appropriate combinations of cell adhesion peptides and synergistic peptides may result in improved cell surface interactions.

  • 8.
    Bentley, E
    et al.
    Univ Wisconsin, Dept Surg Sci, Sch Vet Med, Madison, WI 53706 USA.
    Murphy, CJ
    Univ Wisconsin, Dept Surg Sci, Sch Vet Med, Madison, WI 53706 USA.
    Li, FF
    Univ Ottawa, Inst Eye, Ottawa, ON Canada.
    Carlsson, DJ
    Univ Ottawa, Inst Eye, Ottawa, ON Canada.
    Griffith, May
    Univ Ottawa, Inst Eye, Ottawa, ON Canada.
    Biosynthetic Corneal Substitute Implantation in Dogs2010In: Cornea, ISSN 0277-3740, E-ISSN 1536-4798, Vol. 29, no 8, p. 910-916Article in journal (Refereed)
    Abstract [en]

    Purpose: To assess integration of a biosynthetic corneal implant in dogs.

    Methods: Three normal adult laboratory Beagles underwent ophthalmic examinations, including slit-lamp biomicroscopy, indirect ophthalmoscopy, applanation tonometry, and Cochet-Bonnet aesthesiometry. Biosynthetic corneas fabricated from glutaraldehyde crosslinked collagen and copolymers of collagen and poly (N-isopropylacrylamide-co-acrylic acid-co-acryloxysuccinimide, denoted as TERP) were implanted into dogs by a modified epikeratoplasty technique. Ophthalmic examinations and aesthesiometry were performed daily for 5 days and then weekly thereafter for 16 weeks. Corneal samples underwent histopathological and transmission electron microscopy examination at 16 weeks.

    Results: Implants were epithelialized by 7 days. Intraocular pressure was within normal range throughout the study. Aesthesiometry values dropped from an average of 3.67 cm preoperatively to less than 1 mm for all dogs for the first postoperative weeks. By week 16, the average Cochet-Bonnet value was 1.67 cm, demonstrating partial recovery of functional innervation of the implant. No inflammation or rejection of the implant occurred, and minimal haze formation was noted. Light microscopy revealed thickened but normal epithelium over the implant with fibroblast migration into the scaffold. On transmission electron microscopy, the basement membrane was irregular but present and adhesion complexes were noted.

    Conclusion: Biosynthetic corneal implantation is well tolerated in dogs, and the collagen-polymer hybrid construct holds promise for clinical application in animals and humans.

  • 9.
    Blais, David R.
    et al.
    Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
    Vascotto, Sandy G.
    Eye Institute, University of Ottawa, Ottawa, Ontario, Canada..
    Griffith, May
    Eye Institute, and the Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
    Altosaar, Illimar
    Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, Ontario, Canada.
    LBP and CD14 secreted in tears by the lacrimal glands modulate the LPS response of corneal epithelial cells2005In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 46, no 11, p. 4235-4244Article in journal (Refereed)
    Abstract [en]

    PURPOSE. Lipopolysaccharide (LPS) is one of the most powerful bacterial virulence factors in terms of proinflammatory properties and is likely to contribute to corneal bacterial keratitis. Better understanding of the spatial expression of the LPS receptor components at the tear - corneal interface might facilitate enhanced functions of the LPS receptor complex in ocular defense against Gram-negative infections. METHODS. The expression of LPS-binding protein (LBP), CD14, toll-like receptor (TLR)-4, and MD-2 in human lacrimal glands, reflex tears, and corneal epithelia was examined by ELISA, RT-PCR, Western blot analysis, and immunofluorescence. The release of proinflammatory cytokines after the activation of primary and immortalized corneal epithelial cells with LPS and human tears was measured by ELISA. RESULTS. LBP and CD14 proteins were detected in reflex human tears. Human lacrimal glands and corneal epithelia expressed LBP, CD14, TLR4, and MD-2 mRNAs and proteins. In the corneal epithelium, LBP was mainly expressed by superficial and basal epithelial cells, whereas CD14, TLR4, and MD-2 expression were limited to the wing and basal epithelial cells. In a dose-dependant manner, tear CD14 and LBP mediated the secretion of interleukin (IL)-6 and IL-8 by corneal epithelia cells when challenged with LPS. CONCLUSIONS. Tear CD14 and LBP complemented the LPS receptor complex expressed by the corneal epithelia to trigger an immune response in the presence of LPS. The complementation of these tear and corneal immune proteins could play an important role in LPS recognition and signaling and, therefore, could modulate ocular innate immunity.

  • 10.
    Blake, Jessie A
    et al.
    University of Ottawa.
    Bareiss, Bettina
    University of Ottawa.
    Jimenez, Liliana
    University of Ottawa.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences.
    Scaiano, J C
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences.
    Design of xanthone propionate photolabile protecting group releasing acyclovir for the treatment of ocular herpes simplex virus2012In: Photochemical and Photobiological Sciences, ISSN 1474-905X, E-ISSN 1474-9092, Vol. 11, no 3, p. 539-547Article in journal (Refereed)
    Abstract [en]

    We have attached the antiviral drug acyclovir (ACV) to a xanthone photolabile protecting group (or photocage) through the O6 position of acyclovir, a procedure designed for the treatment of ocular herpes simplex virus infections. Acyclovir is photoreleased from the photocage, under physiological conditions, with a quantum yield (Phi(ACV release)) of 0.1-0.3 and an uncaging cross section (Phi.epsilon) of 450-1350 M cm(-1). We demonstrate that this photorelease method outcompetes alternative reaction pathways, such as protonation. Furthermore, complete release of the drug is theoretically possible given a sufficient dose of light. Surprisingly the acyclovir photocage, also showed some antiviral activity towards HSV-1.

  • 11.
    Brunette, Isabelle
    et al.
    University of Montreal, Canada.
    Alarcon, Emilio
    University of Ottawa Heart Institute, Canada.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Cornea Regeneration as an Alternative to Human Donor Transplantation2015In: European Ophthalmic Review, ISSN 1756-1795, Vol. 9, no 2, p. 111-114Article in journal (Refereed)
    Abstract [en]

    There is a need for an alternative to human donor corneas as the availability of good-quality tissues remains limited, with this situation potentially worsening as the population in many countries is progressively ageing. There have been numerous attempts to develop corneal equivalent as alternatives to donated human corneas as well as prostheses. In this short review, we focus on the efforts in bioengineering implants that promote regeneration by Canadian researchers, including our current team of authors. The examples of technologies developed that we describe include biomaterials that allow for partial regeneration of corneal tissue, self-assembled cornea constructs and cell-free corneal implants that promoted regeneration when evaluated in clinical trials in Europe.

  • 12.
    Buznyk, Oleksiy
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. National Academic Medical Science Ukraine, Ukraine.
    Pasyechnikova, Nataliya
    National Academic Medical Science Ukraine, Ukraine.
    Islam, Mohammad Mirazul
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
    Iakymenko, Stanislav
    National Academic Medical Science Ukraine, Ukraine.
    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.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
    Bioengineered Corneas Grafted as Alternatives to Human Donor Corneas in Three High-Risk Patients2015In: Clinical and Translational Science, ISSN 1752-8054, E-ISSN 1752-8062, Vol. 8, no 5, p. 558-562Article in journal (Refereed)
    Abstract [en]

    Corneas with severe pathologies have a high risk of rejection when conventionally grafted with human donor tissues. In this early observational study, we grafted bioengineered corneal implants made from recombinant human collagen and synthetic phosphorylcholine polymer into three patients for whom donor cornea transplantation carried a high risk of transplant failure. These patients suffered from corneal ulcers and recurrent erosions preoperatively. The implants provided relief from pain and discomfort, restored corneal integrity by promoting endogenous regeneration of corneal tissues, and improved vision in two of three patients. Such implants could in the future be alternatives to donor corneas for high-risk patients, and therefore, merits further testing in a clinical trial.

  • 13.
    Cheung Mak, Wing
    et al.
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, Faculty of Science & Engineering.
    Kwan Yee, Cheung
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Orban, Jenny
    Linköping University, Faculty of Science & Engineering. Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics.
    Lee, Chyan-Jang
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics. Linköping University, The Institute of Technology.
    Turner, Anthony
    Linköping University, Department of Physics, Chemistry and Biology, Biosensors and Bioelectronics. Linköping University, Faculty of Science & Engineering.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Surface-Engineered Contact Lens as an Advanced Theranostic Platform for Modulation and Detection of Viral Infection2015In: ACS Applied Materials and Interfaces, ISSN 1944-8244, E-ISSN 1944-8252, Vol. 7, no 45, p. 25487-25494Article in journal (Refereed)
    Abstract [en]

    We have demonstrated an entirely new concept of a wearable theranostic device in the form of a contact lens (theranostic lens) with a dual-functional hybrid surface to modulate and detect a pathogenic attack, using a the corneal HSV serotype-1 (HSV-1) model. The theranostic lenses were constructed using a facile layer-by-layer surface engineering technique, keeping the theranostic lenses with good surface wettability, optically transparency, and nontoxic toward human corneal epithelial cells. The theranostic lenses were used to capture and concentrate inflammatory cytokines such as interleukin-1 alpha (IL-1 alpha), which is upregulated during HSV-1 reactivation, for sensitive, noninvasive diagnostics. The theranostic lens also incorporated an antiviral coating to serve as a first line of defense to protect patients against disease. Our strategy tackles major problems in tear diagnostics that are mainly associated with the sampling of a relatively small volume of fluid and the low concentration of biomarkers. The theranostic lenses show effective anti-HSV-1 activity and good analytical performance for the detection of IL-1a, with a limit of detection of 1.43 pg mL(-1) and a wide linear range covering the clinically relevant region. This work offers a new paradigm for wearable noninvasive healthcare devices combining diagnosis and protection against disease, while supporting patient compliance. We believe that this approach holds immense promise as a next-generation point-of-care and decentralized diagnostic/theranostic platform for a range of biomarkers.

  • 14.
    Coutu, Daniel L
    et al.
    McGill University, Montreal, Canada.
    Cuerquis, Jessica
    McGill University, Montreal, Canada.
    El Ayoubi, Rouwayda
    Natl Res Council Canada, Boucherville, Canada.
    Forner, Kathy-Ann
    McGill University, Montreal, Canada.
    Roy, Ranjan
    McGill University, Montreal, Canada.
    Francois, Moira
    McGill University, Montreal, Canada.
    Griffith, May
    Ottawa Health Research Institute, Ottawa, Canada.
    Lillicrap, David
    Queen’s University, Kingston, Canada.
    Yousefi, Azizeh-Mitra
    Natl Res Council Canada, Boucherville, Canada.
    Blostein, Mark D
    McGill University, Montreal, Canada.
    Galipeau, Jacques
    McGill University, Montreal, Canada.
    Hierarchical scaffold design for mesenchymal stem cell-based gene therapy of hemophilia B2011In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 32, no 1, p. 295-305Article in journal (Refereed)
    Abstract [en]

    Gene therapy for hemophilia B and other hereditary plasma protein deficiencies showed great promise in pre-clinical and early clinical trials. However, safety concerns about in vivo delivery of viral vectors and poor post-transplant survival of ex vivo modified cells remain key hurdles for clinical translation of gene therapy. We here describe a 3D scaffold system based on porous hydroxyapatite PLGA composites coated with biomineralized collagen 1. When combined with autologous gene-engineered factor IX (hFIX) positive mesenchymal stem cells (MSCs) and implanted in hemophilic mice, these scaffolds supported long-term engraftment and systemic protein delivery by MSCs in vivo. Optimization of the scaffolds at the macro-, micro- and nanoscales provided efficient cell delivery capacity, MSC self-renewal and osteogenesis respectively, concurrent with sustained delivery of hFIX. In conclusion, the use of gene-enhanced MSC-seeded scaffolds may be of practical use for treatment of hemophilia B and other plasma protein deficiencies.

  • 15.
    Dare, Emma V.
    et al.
    Department of Cellular and Molecular Medicine, University of Ottawa, ON, Canada.
    Griffith, May
    Department of Cellular and Molecular Medicine, University of Ottawa, ON, Canada.
    Poitras, Philippe
    Orthopaedic Biomechanics Laboratory, CHEO Research Institute, Ottawa, ON, Canada.
    Kaupp, James A.
    Department of Mechanical and Materials Engineering, Queen’s University, Kingston, ON, Canada.
    Waldman, Stephen D.
    Department of Mechanical and Materials Engineering, Queen’s University, Kingston, ON, Canada.
    Carlsson, David J.
    National Research Council Canada.
    Dervin, Geoffrey
    Division of Orthopaedic Surgery, The Ottawa Hospital, Ottawa, ON, Canada.
    Mayoux, Christine
    National Research Council Canada.
    Hincke, Maxwell T.
    Department of Cellular and Molecular Medicine, University of Ottawa, ON, Canada.
    Genipin Cross-Linked Fibrin Hydrogels for in vitro Human Articular Cartilage Tissue-Engineered Regeneration2009In: Cells Tissues Organs, ISSN 1422-6405, E-ISSN 1422-6421, Vol. 190, no 6, p. 313-325Article in journal (Refereed)
    Abstract [en]

    Our objective was to examine the potential of a genipin cross-linked human fibrin hydrogel system as a scaffold for articular cartilage tissue engineering. Human articular chondrocytes were incorporated into modified human fibrin gels and evaluated for mechanical properties, cell viability, gene expression, extracellular matrix production and subcutaneous biodegradation. Genipin, a naturally occurring compound used in the treatment of inflammation, was used as a cross-linker. Genipin cross-linking did not significantly affect cell viability, but significantly increased the dynamic compression and shear moduli of the hydrogel. The ratio of the change in collagen II versus collagen I expression increased more than 8-fold over 5 weeks as detected with real-time RT-PCR. Accumulation of collagen II and aggrecan in hydrogel extracellular matrix was observed after 5 weeks in cell culture. Overall, our results indicate that genipin appeared to inhibit the inflammatory reaction observed 3 weeks after subcutaneous implantation of the fibrin into rats. Therefore, genipin cross-linked fibrin hydrogels can be used as cell-compatible tissue engineering scaffolds for articular cartilage regeneration, for utility in autologous treatments that eliminate the risk of tissue rejection and viral infection.

  • 16.
    Dare, Emma V.
    et al.
    Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada..
    Griffith, May
    Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada..
    Poitras, Philippe
    Orthopaedic Biomechanics Laboratory, CHEO Research Institute, Ottawa, Ontario, Canada.
    Wang, Tao
    Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada..
    Dervin, Geoffrey F.
    Division of Orthopaedic Surgery, The Ottawa Hospital, Ottawa, Ontario, Canada.
    Giulivi, Antonio
    Department of Pathology and Laboratory Medicine, The Ottawa Hospital, Ottawa, Ontario, Canada.
    Hincke, Maxwell T.
    Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada..
    Fibrin Sealants from Fresh or Fresh/Frozen Plasma as Scaffolds for In Vitro Articular Cartilage Regeneration2009In: TISSUE ENGINEERING PART A, ISSN 1937-3341, Vol. 15, no 8, p. 2285-2297Article in journal (Refereed)
    Abstract [en]

    Our objective was to evaluate human CryoSeal (R) fibrin glue derived from single units of plasma as scaffolds for articular cartilage tissue engineering. Human articular chondrocytes were encapsulated into genipin cross-linked fibrin glue derived from individual units of fresh or frozen plasma using the CryoSeal (R) fibrin sealant (FS) system. The constructs were cultured for up to 7 weeks in vitro under low (5%) or normal (21%) oxygen. Chondrocyte viability was greater than90% within the fibrin gels. Hypoxia induced significant increases in collagen II and Sox9 gene expression and a significant decrease in collagen I. A significant increase in collagen II was detected in fresh plasma-derived cultures, while only collagen I was significantly increased in frozen plasma cultures. Significant increases in total glycosaminoglycan and collagen were detected in the extracellular matrix secreted by the encapsulated chondrocytes. A significant increase in compression modulus was only observed for fresh plasma-derived gels, which is likely explained by a greater amount of collagen type I detected after 7 weeks in frozen compared to fresh plasma gels. Our results indicate that CryoSeal (R) fibrin glue derived from fresh plasma is suitable as a tissue engineering scaffold for human articular chondrocytes, and therefore should be evaluated for autologous articular cartilage regeneration.

  • 17.
    Dare, E.V.
    et al.
    Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
    Vascotto, S.G.
    University of Ottawa Eye Institute, Ottawa, Ontario, Canada.
    Carlsson, D.J.
    National Research Council Canada, Ottawa, Ontario, Canada.
    Hincke, M.T.
    Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
    Griffith, M.
    Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada.
    Differentiation of a fibrin gel encapsulated chondrogenic cell line2007In: International Journal of Artificial Organs, ISSN 0391-3988, E-ISSN 1724-6040, Vol. 30, no 7, p. 619-627Article in journal (Refereed)
    Abstract [en]

    Hyaline cartilage has very limited regenerative capacity following damage. Therefore engineered tissue substitutes have been the focus of much research. Our objective was to develop a fibrin-based scaffold as a cell delivery vehicle and template for hyaline cartilage regeneration, and compare its cellular properties against monolayer and pellet culture for chondrogenic cells. The chondrogenic precursor cell line, RCJ 3.1C5.18 (C5.18), was chosen as a test system for evaluating the effect of various culture conditions, including cell encapsulation, on articular chondrogenic cell differentiation. The C5.18 cells in monolayer showed elevated expression of collagen II, an articular chondrogenic marker, but also markers for fibrocartilage differentiation (collagen I and versican) when cultured with chondrogenic medium as compared to basic maintenance medium. Pellets of C5.18 cells cultured in chondrogenic medium were histologically more organized in structure than pellets cultured in control maintenance medium. The chondrogenic medium cultured pellets also secreted an extracellular matrix that was comprised of type II with very little type I collagen, indicating a trend towards a more hyaline-like cartilage. Moreover, when cultured in chondrogenic medium, fibrin-encapsulated C5.18 cells elaborated an extracellular matrix containing type II collagen, as well as aggrecan, which are both components of hyaline cartilage. This indicated a more articular-like chondrogenic differentiation for fibrin encapsulated C5.18 cells. The results of these experiments provide evidence that the C5.18 cell line can be used as a tool to evaluate potential scaffolds for articular cartilage tissue engineering.

  • 18.
    Deng, C
    et al.
    Univ Ottawa, Inst Eye, Ottawa, ON K1H 8L6 Canada.
    Li, FF
    Univ Ottawa, Inst Eye, Ottawa, ON K1H 8L6 Canada.
    Hackett, JM
    Univ Ottawa, Inst Eye, Ottawa, ON K1H 8L6 Canada.
    Chaudhry, SH
    Univ Ottawa, Inst Eye, Ottawa, ON K1H 8L6 Canada.
    Toye, B
    Univ Ottawa, Inst Eye, Ottawa, ON K1H 8L6 Canada.
    Hodge, W
    Univ Ottawa, Inst Eye, Ottawa, ON K1H 8L6 Canada.
    Griffith, May
    Univ Ottawa, Inst Eye, Ottawa, ON K1H 8L6 Canada.
    Collagen and glycopolymer based hydrogel for potential corneal application2010In: ACTA BIOMATERIALIA, ISSN 1742-7061, Vol. 6, no 1, p. 187-194Article in journal (Refereed)
    Abstract [en]

    6-Methacryloyl-alpha-D-galactopyranose (MG) was synthesized, and characterized by Fourier transform infrared (FTIR) and nuclear magnetic resonance (NMR) spectrometry, and single-crystal X-ray diffraction. A series of interpenetrating polymer network (IPN) hydrogels was fabricated by simultaneously photo-curing MG crosslinked by poly(ethylene glycol) diacrylate and chemically crosslinking type I collagen with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide and N-hydroxysuccinimide. The successful incorporation of the glycopolymer, polymer MG, into collagen hydrogel was confirmed by FTIR and solid-state C-13 NMR. The optical characteristics of the IPN hydrogels are comparable to those of human corneas. The tensile strength and modulus of the hydrogels are enhanced by incorporation of polymer MG in comparison to that of the control collagen hydrogel. Biodegradation results indicated that polymer MG enhanced the stability of the composite hydrogels against collagenase. In vitro results demonstrated that the IPN hydrogel supported the adhesion and proliferation of human corneal epithelial cells and outperformed human cornea in blocking bacteria adhesion. Taken together, the IPN hydrogel might be a promising material for use in corneal lamellar keratoplasty. (C) 2009 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

  • 19.
    Deng, C
    et al.
    Univ Ottawa, Inst Heart, Div Cardiac Surg, Ottawa, ON K1Y 4W7 Canada.
    Zhang, PC
    Univ Ottawa, Inst Heart, Div Cardiac Surg, Ottawa, ON K1Y 4W7 Canada.
    Vulesevic, B
    Univ Ottawa, Inst Heart, Div Cardiac Surg, Ottawa, ON K1Y 4W7 Canada.
    Kuraitis, D
    Univ Ottawa, Inst Heart, Div Cardiac Surg, Ottawa, ON K1Y 4W7 Canada.
    Li, FF
    Univ Ottawa, Inst Eye, Ottawa, ON K1Y 4W7 Canada.
    Yang, AF
    Agr & Agri Food Canada, Ottawa, ON Canada.
    Griffith, May
    Univ Ottawa, Inst Eye, Ottawa, ON K1Y 4W7 Canada.
    Ruel, M
    Univ Ottawa, Inst Heart, Div Cardiac Surg, Ottawa, ON K1Y 4W7 Canada.
    Suuronen, EJ
    Univ Ottawa, Inst Heart, Div Cardiac Surg, Ottawa, ON K1Y 4W7 Canada.
    A Collagen-Chitosan Hydrogel for Endothelial Differentiation and Angiogenesis2010In: TISSUE ENGINEERING PART A, ISSN 1937-3341, Vol. 16, no 10, p. 3099-3109Article in journal (Refereed)
    Abstract [en]

     Cell therapy for the treatment of cardiovascular disease has been hindered by low cell engraftment, poor survival, and inadequate phenotype and function. In this study, we added chitosan to a previously developed injectable collagen matrix, with the aim of improving its properties for cell therapy and neovascularization. Different ratios of collagen and chitosan were mixed and chemically crosslinked to produce hydrogels. Swell and degradation assays showed that chitosan improved the stability of the collagen hydrogel. In culture, endothelial cells formed significantly more vascular-like structures on collagen-chitosan than collagen-only matrix. While the differentiation of circulating progenitor cells to CD31(+) cells was equal on all matrices, vascular endothelial-cadherin expression was increased on the collagen-chitosan matrix, suggesting greater maturation of the endothelial cells. In addition, the collagen-chitosan matrix supported a significantly greater number of CD133(+) progenitor cells than the collagen-only matrix. In vivo, subcutaneously implanted collagen-chitosan matrices stimulated greater vascular growth and recruited more von Willebrand factor (vWF(+)) and CXCR4(+) endothelial/angiogenic cells than the collagen-only matrix. These results indicate that the addition of chitosan can improve the physical properties of collagen matrices, and enhance their ability to support endothelial cells and angiogenesis for use in cardiovascular tissue engineering applications.

  • 20.
    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.

  • 21.
    Doillon, CJ
    et al.
    CHUL Research Center, Laval University, Quebec City, Quebec, Canada.
    Watsky, MA
    Department of Physiology, University of Tennessee, Health Science Center, Memphis, TN, USA.
    Hakim, M
    University of Ottawa Eye Institute, University of Ottawa, Ottawa, Canada.
    Wang, J
    Department of Physiology, University of Tennessee, Health Science Center, Memphis, TN, USA.
    Munger, R
    University of Ottawa Eye Institute, University of Ottawa, Ottawa, Canada.
    Laycock, N
    University of Ottawa Eye Institute, University of Ottawa, Ottawa, Canada.
    Osborne, R
    The Procter and Gamble Company, Miami Valley Laboratories, Cincinnati, OH, USA.
    Griffith, M
    University of Ottawa Eye Institute, University of Ottawa, Ottawa, Canada.
    A collagen-based scaffold for a tissue engineered human cornea: Physical and physiological properties2003In: International Journal of Artificial Organs, ISSN 0391-3988, E-ISSN 1724-6040, Vol. 26, no 8, p. 764-773Article in journal (Refereed)
    Abstract [en]

    Stabilized collagen-glycosaminoglycan scaffolds for tissue engineered human corneas were characterized. Hydrated matrices were constructed by blending type I collagen with chondroitin sulphates (CS), with glutaraldehyde crosslinking. A corneal keratocyte cell line was added to the scaffolds with or without corneal epithelial and endothelial cells. Constructs were grown with or without ascorbic acid. Wound-healing was evaluated in chemical-treated constructs. Native, noncrosslinked gels were soft with limited longevity. Crosslinking strengthened the matrix yet permitted cell growth. CS addition increased transparency. Keratocytes grown within the matrix had higher frequencies of K+ channel expression than keratocytes grown on plastic. Ascorbic acid increased uncrosslinked matrix degradation in the presence of keratocytes, while it enhanced keratocyte growth and endogenous collagen synthesis in crosslinked matrices. Wounded constructs showed recovery from exposure to chemical irritants. In conclusion, this study demonstrates that our engineered, stabilized matrix is well-suited to function as an in vitro corneal stroma.

  • 22.
    Dravida, Subhadra
    et al.
    University of Ottawa Eye Institute, Ottawa, ON, Canada.
    Gaddipati, Subhash
    Sudhakar and Sreekant Ravi Stem Cell Laboratory, L. V. Prasad Eye Institute, Hyderabad Eye Research Foundation, Hyderabad, India.
    Griffith, May
    University of Ottawa Eye Institute, Ottawa, ON, Canada and Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada.
    Merrett, Kim
    University of Ottawa Eye Institute, Ottawa, ON, Canada.
    Lakshmi Madhira, Soundarya
    Sudhakar and Sreekant Ravi Stem Cell Laboratory, L. V. Prasad Eye Institute, Hyderabad Eye Research Foundation, Hyderabad, India.
    Sangwan, Virender S.
    Cornea and Anterior Segment Services, L. V. Prasad Eye Institute, Hyderabad Eye Research Foundation, Hyderabad, India.
    Vemuganti, Geeta K.
    Sudhakar and Sreekant Ravi Stem Cell Laboratory and Ophthalmic Pathology Services, L. V. Prasad Eye Institute, Hyderabad Eye Research Foundation, Hyderabad, India.
    A biomimetic scaffold for culturing limbal stem cells: a promising alternative for clinical transplantation2008In: JOURNAL OF TISSUE ENGINEERING AND REGENERATIVE MEDICINE, ISSN 1932-6254, Vol. 2, no 5, p. 263-271Article in journal (Refereed)
    Abstract [en]

    Limbal tissues can be cultured on various types of scaffolds to create a sheet of limbal-corneal epithelium for research as well as clinical transplantation. An optically clear, biocompatible, biomimetic scaffold would be an ideal replacement graft for transplanting limbal stem cells. in this study, we evaluated the physical and culture characteristics of the recombinant human cross-linked collagen scaffold (RHC-III scaffold) and compared it with denuded human amniotic membrane (HAM). Optical/mechanical properties and microbial susceptibility were measured for the scaffolds. With the approval of the institutional review board, 2 mm. fresh human limbal tissues were cultured on 2.5 x 2.5 cm(2) scaffolds in a medium containing autologous serum in a feeder cell-free submerged system. The cultured cell systems were characterized by morphology and immunohistochemistry for putative stem cells and differentiated cell markers. The refractive index (RI) and tensile strength of the RHC-III scaffold were comparable to human cornea, with delayed in vitro degradation compared to HAM. RHC-III scaffolds were 10-fold less susceptible to microbial growth. Cultures were initiated on day 1, expanded to form a monolayer by day 3 and covered the entire growth surface in 10 days. Stratified epithelium on the scaffolds was visualized by transmission electron microscopy. The cultured cells showed p63 and ABCG2 positivity in the basal layer and were immunoreactive for cytokeratin K3 and K12 in the suprabasal layers. RHC-III scaffold supports and retains the growth and stemness of limbal stem cells, in addition to resembling human cornea; thus, it could be a good replacement scaffold for growing cells for clinical transplantation.

  • 23.
    Duan, X
    et al.
    Department of Chemical Engineering, University of Ottawa, Canada.
    Griffith, CM
    University of Ottawa Eye Institute, Ottawa, Canada.
    Dube, MA
    Department of Chemical Engineering, University of Ottawa, Canada.
    Sheardown, H
    Departments of Chemical Engineering and Pathology and Molecular Medicine, McMaster University, Hamilton, Canada.
    Novel dendrimer based polynrethanes for PEO incorporation2002In: Journal of Biomaterials Science. Polymer Edition, ISSN 0920-5063, E-ISSN 1568-5624, Vol. 13, no 6, p. 667-689Article in journal (Refereed)
    Abstract [en]

    A series of segmented polyurethanes based on methylene diisocyanate/ poly (tetramethylene oxide) and chain extended with either ethylene diamine or butane diol in combination with a generation 2 polypropylenimine octaamine dendrimer were synthesized. For polymer synthesis, the dendrimers were protected with either t-boc or Fmoc groups and were incorporated into the polyurethane microstructure to permit further functionalization with biologically active groups. Following deprotection, the dendrimers were reacted with succinimidyl propionate polyethylene oxide (SPA-PEO) to improve the protein resistance of the polymers and to examine the potential of this technique for polymer functionalization. Different synthesis techniques were examined to optimize the incorporation of the PEO into the polymer microstructure. Incorporation of the dendrimers and the PEO were confirmed by NMR and FTIR. Gel permeation chromatography was used to examine the molecular weights of the various polyurethanes. The dendrimer incorporated polymers had significantly lower molecular weights than the ED or BDO chain extended controls, likely due to lower reactivity of the dendrimers as a result of steric factors. Following PEO reaction, the molecular weights of the resultant polymers were consistent with the levels of PEO incorporation noted by comparison of peak intensities in the NMR spectra. Due to the highly hydrophilic nature of the PEO, some migration to the polymer surface was expected. Water contact angles and XPS, used to characterize the surfaces, suggest that there was some PEO enrichment at the surface of the polymers. Adsorption of radiolabeled fibrinogen to the polymer surfaces was decreased by a factor of approximately 40% in some of the PEO incorporated polymers. There were also differences in the patterns of plasma protein adsorption on the various surfaces as evaluated by SDS PAGE and immunoblotting. Therefore, the use of dendrimers in biomaterials for incorporation of a large number of functional groups seems to be promising.

  • 24.
    Duan, Xiaodong
    et al.
    Department of Chemical Engineering, McMaster University, Hamilton, Ont., Canada.
    McLaughlin, Christopher
    Department of Ophthalmology, University of Ottawa, Ottawa, Ont., Canada.
    Griffith, May
    Department of Ophthalmology, University of Ottawa, Ottawa, Ont., Canada.
    Sheardown, Heather
    Department of Chemical Engineering, McMaster University, Hamilton, Ont., Canada.
    Biofunctionalization of collagen for improved biological response: Scaffolds for corneal tissue engineering2007In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 28, no 1, p. 78-88Article in journal (Refereed)
    Abstract [en]

    Residual dendrimer amine groups were modified with incorporate COOH group containing biomolecules such as cell adhesion peptides into collagen scaffolds. YIGSR, as a model cell adhesion peptide, was incorporated into both the bulk structure of the gels and onto the gel surface. The effects of the peptide modified collagen gets on corneal epithelial cell behavior were examined with an aim of improving the potential of these materials as tissue-engineering scaffolds. YIGSR was first chemically attached to dendrimers and the YIGSR attached dendrimers were then used as collagen crosslinkers, incorporating the peptide into the bulk structure of the collagen gels. YIGSR was also attached to the surface of dendrimer crosslinked collagen gels through reaction with excess amine groups. The YIGSR modified dendrimers were characterized by H-NMR and MALDI mass spectra. The amount of YIGSR incorporated into collagen gels was determined by (125)1 radiolabelling at maximum to be 3.1-3.4 x 10(-2)mg/mg collagen when reacted with the bulk and 88.9-95.6 mu g/cm(2) when attached to the surface. The amount of YIGSR could be tuned by varying the amount of peptide reacted with the dendrimer or the amount of modified dendrimer used in the crosslinking reaction. It was found that YIGSR incorporation into the bulk and YIGSR modification of surface promoted the adhesion and proliferation of human corneal epithelial cells as well as neurite extension from dorsal root ganglia. (c) 2006 Elsevier Ltd. All rights reserved.

  • 25.
    Fagerholm, Per
    et al.
    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.
    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.
    Carlsson, David J.
    National Research Council of Canada, Ottawa, Ontario; University of Ottawa Eye Institute, Ontario, Canada.
    Merrett, Kimberley
    University of Ottawa Eye Institute, Ontario, Canada.
    Griffith, May
    University of Ottawa Eye Institute, Ontario, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Canada.
    Corrigendum to “Corneal Regeneration Following Implantation of a Biomimetic Tissue-Engineered Substitute”  [vol 2, Issue 2, pg 162-164, 2009]2014In: Clinical and Translational Science, ISSN 1752-8054, E-ISSN 1752-8062, Vol. 7, no 4, p. 347-347Article in journal (Other academic)
    Abstract [en]

    n/a

  • 26.
    Fagerholm, Per
    et al.
    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.
    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.
    Ong, Jeb A.
    Maisonneuve Rosemont Hospital, Montreal, Canada .
    Merrett, Kimberley
    Östergötlands Läns Landsting, Anaesthetics, Operations and Specialty Surgery Center, Department of Ophthalmology in Linköping. Ottawa Hospital Research Institute, Canada.
    Jackson, W. Bruce
    Ottawa Hospital Research Institute, Canada .
    Polarek, James W.
    FibroGen Inc, San Francisco, CA, USA.
    Suuronen, Erik J.
    University of Ottawa Heart Institute, Canada .
    Liu, Yuwen
    CooperVision Inc, Pleasanton, CA, USA.
    Brunette, Isabelle
    Maisonneuve Rosemont Hospital, Montreal, Canada .
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Stable corneal regeneration four years after implantation of a cell-free recombinant human collagen scaffold2014In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 35, no 8, p. 2420-2427Article in journal (Refereed)
    Abstract [en]

    We developed cell-free implants, comprising carbodiimide crosslinked recombinant human collagen (RHC), to enable corneal regeneration by endogenous cell recruitment, to address the worldwide shortage of donor corneas. Patients were grafted with RHC implants. Over four years, the regenerated neo-corneas were stably integrated without rejection, without the long immunosuppression regime needed by donor cornea patients. There was no recruitment of inflammatory dendritic cells into the implant area, whereas, even with immunosuppression, donor cornea recipients showed dendritic cell migration into the central cornea and a rejection episode was observed. Regeneration as evidenced by continued nerve and stromal cell repopulation occurred over the four years to approximate the micro-architecture of healthy corneas. Histopathology of a regenerated, clear cornea from a regrafted patient showed normal corneal architecture. Donor human cornea grafted eyes had abnormally tortuous nerves and stromal cell death was found. Implanted patients had a 4-year average corrected visual acuity of 20/54 and gained more than 5 Snellen lines of vision on an eye chart. The visual acuity can be improved with more robust materials for better shape retention. Nevertheless, these RHC implants can achieve stable regeneration and therefore, represent a potentially safe alternative to donor organ transplantation.

  • 27.
    Fagerholm, Per
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of Ophthalmology UHL/MH.
    Lagali, Neil S
    Östergötlands Läns Landsting, Reconstruction Centre, Department of Ophthalmology UHL/MH. Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences.
    Carlsson, David J
    Natl Res Council Canada, Ottawa, ON K1A 0R6, Canada.
    Merrett, Kimberley
    Univ Ottawa, Inst Eye, Ottawa, ON K1H 8L6, Canada.
    Griffith, May
    Univ Ottawa, Inst Eye, Ottawa, ON K1H 8L6, Canada.
    Corneal Regeneration Following Implantation of a Biomimetic Tissue-Engineered Substitute2009In: CTS-CLINICAL AND TRANSLATIONAL SCIENCE, ISSN 1752-8054, Vol. 2, no 2, p. 162-164Article in journal (Refereed)
    Abstract [en]

    n/a

  • 28.
    Fagerholm, Per
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of Ophthalmology UHL/MH.
    Lagali, Neil S
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of Ophthalmology UHL/MH.
    Merrett, Kimberley
    University of Ottawa Eye Institute.
    Jackson, W Bruce
    University of Ottawa Eye Institute.
    Munger, Rejean
    University of Ottawa Eye Institute.
    Liu, Yuwen
    CooperVision Inc, Pleasanton, USA .
    Polarek, James W
    FibroGen Inc, San Francisco.
    Söderqvist, Monica
    Synsam Opticians, Linköping.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences.
    A biosynthetic alternative to human donor tissue for inducing corneal regeneration: 24-month follow-up of a phase 1 clinical study2010In: Science translational medicine, ISSN 1946-6234, Vol. 2, no 46, p. 46-61Article in journal (Refereed)
    Abstract [en]

    Corneas from human donors are used to replace damaged tissue and treat corneal blindness, but there is a severe worldwide shortage of donor corneas. We conducted a phase 1 clinical study in which biosynthetic mimics of corneal extracellular matrix were implanted to replace the pathologic anterior cornea of 10 patients who had significant vision loss, with the aim of facilitating endogenous tissue regeneration without the use of human donor tissue. The biosynthetic implants remained stably integrated and avascular for 24 months after surgery, without the need for long-term use of the steroid immunosuppression that is required for traditional allotransplantation. Corneal reepithelialization occurred in all patients, although a delay in epithelial closure as a result of the overlying retaining sutures led to early, localized implant thinning and fibrosis in some patients. The tear film was restored, and stromal cells were recruited into the implant in all patients. Nerve regeneration was also observed and touch sensitivity was restored, both to an equal or to a greater degree than is seen with human donor tissue. Vision at 24 months improved from preoperative values in six patients. With further optimization, biosynthetic corneal implants could offer a safe and effective alternative to the implantation of human tissue to help address the current donor cornea shortage.

  • 29.
    Ghani, Mozhdeh
    et al.
    Nanotechnology Institute, Amirkabir University of Technology, Tehran, Iran.
    Mak, Wing Cheung
    Linköping University, Department of Physics, Chemistry and Biology, Sensor and Actuator Systems. Linköping University, Faculty of Science & Engineering.
    Cheung, Kwan Yee
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Montazer, M.
    Nanotechnology Institute, Amirkabir University of Technology, Tehran, Iran.
    Rezaei, B.
    Nanotechnology Institute, Amirkabir University of Technology, Tehran, Iran.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Cross-linked superfine electrospun tragacanth-based biomaterial as scaffolds for tissue engineering2016In: European Cells and Materials, ISSN 1473-2262, E-ISSN 1473-2262, Vol. 31, no Suppl. 1, p. 204-204Article in journal (Refereed)
    Abstract [en]

    Natural polymer-based nanofibrous structures promote cell adhesion and proliferation due to their high surface area/volume ratio, high porosity, and similarity to native extracellular matrix in terms of both chemical composition and physical structure. Gum tragacanth (Tg) is a natural polysaccharides obtained from plants. It is a biocompatible, biodegradable and anionic polysaccharides that has been used extensively as an emulsifier in food and pharmaceutical industries. Despite, its good rheological properties and compatibility, the potential biomedical applications of Tg have not been fully investigated. The objective of the present study was to explore the feasibility of combining Tg with gelatin to fabricate a scaffold that serves as a simple collagen-glycosaminoglycans analog for tissue engineering applications, e.g. as a scaffold for human skin epithelial cells.

  • 30.
    Gian Vascotto, Sandy
    et al.
    University of Ottawa Eye Institute, Ottawa, Ontario, Canada.
    Griffith, May
    University of Ottawa Eye Institute, Ottawa, Ontario, Canada.
    Localization of candidate stem and progenitor cell markers within the human cornea, limbus, and bulbar conjunctiva in vivo and in cell culture2006In: Anatomical Record Part A-discoveries in Molecular Cellular and Evolutionary Biology, ISSN 1552-4884, E-ISSN 1932-8494, Vol. 288A, no 8, p. 921-931Article in journal (Refereed)
    Abstract [en]

    Corneal diseases are some of the most prevalent causes of blindness worldwide. While the most common treatment for corneal blindness is the transplantation of cadaver corneas, expanded limbal stem cells are finding recent application. Unknown, however, is the identity of the actual repopulating stem cell fraction utilized in both treatments and the critical factors governing successful engraftment and repopulation. In order to localize potential stem cell populations in vivo, we have immunohistochemically mapped a battery of candidate stem and progenitor cell markers including c-Kit and other growth factor receptors, nuclear markers including Delta Np63, as well as adhesion factors across the cornea and distal sclera. Cell populations that differentially and specifically stained for some of these markers include the basal and superficial limbal/conjunctival epithelium and scattered cells within the substantia propria of the bulbar conjunctiva. We have also determined that the culture of differentiated cornea epithelial cells as dissociated and explant cultures induces the expression of several markers previously characterized as candidate limbal stem cell markers. This study provides a foundation to explore candidate corneal stem cell populations. As well, we show that expression of traditional stem cell markers may not be reliable indicator of stem cell content during limbal stem cell expansion in vitro and could contribute to the variable success rates of corneal stem cell transplantation.

  • 31.
    Griffith, May
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Maisonneuve Rosemont Hospital, Canada.
    Alarcon, E. I.
    University of Ottawa, Canada.
    Brunette, I.
    Maisonneuve Rosemont Hospital, Canada; University of Montreal, Canada.
    Regenerative approaches for the cornea2016In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 280, no 3, p. 276-286Article, review/survey (Refereed)
    Abstract [en]

    The cornea is the transparent front part of the eye that transmits light to the back of the eye to generate vision. Loss of corneal transparency, if irreversible, leads to severe vision loss or blindness. For decades, corneal transplantation using human donor corneas has been the only option for treating corneal blindness. Despite recent improvement in surgical techniques, donor cornea transplantation remains plagued by risks of suboptimal optical results and visual acuity, immune rejection and eventually graft failure. Furthermore, the demand for suitable donor corneas is increasing faster than the number of donors, leaving thousands of curable patients untreated worldwide. Here, we critically review the state of the art of biomaterials for corneal regeneration. However, the lessons learned from the use of the cornea as a disease model will allow for extension of the biomaterials and techniques for regeneration of more complex organs such as the heart.

  • 32.
    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.

  • 33.
    Griffith, May
    et al.
    University of Ottawa Eye Institute, Ottawa, Ontario, Canada.
    Hakim, Malik
    University of Ottawa Eye Institute, Ottawa, Ontario, Canada and National Research Council of Canada - ICPET, Ottawa, Ontario, Canada.
    Shimmura, Shigeto
    Dental College, Ichikawa General Hospital Cornea Center, Ichikawa, Chiba, Japan.
    Watsky, Mitchell A.
    Department of Physiology, University of Tennessee Health Science Center, Memphis, Tennessee, USA.
    Li, Fengfu
    University of Ottawa Eye Institute, Ottawa, Ontario, Canada and National Research Council of Canada - ICPET, Ottawa, Ontario, Canada.
    Carlsson, David
    National Research Council of Canada - ICPET, Ottawa, Ontario, Canada.
    Doillon, Charles J.
    Oncology and Molecular Endocrinology Research Center, Laval University, Quebec, Canada.
    Nakamura, Masatsugu
    Santen Pharmaceutical Co. Ltd., Nara R&D Center, Ikoma-shi, Nara, Japan.
    Suuronen, Erik
    University of Ottawa Eye Institute, Ottawa, Ontario, Canada.
    Shinozaki, Naoshi
    Dental College, Ichikawa General Hospital Cornea Center, Ichikawa, Chiba, Japan.
    Nakata, Katsuhiko
    Santen Pharmaceutical Co. Ltd., Nara R&D Center, Ikoma-shi, Nara, Japan.
    Sheardown, Heather
    Department of Chemical Engineering, McMaster University, Hamilton, Ontario, Canada.
    Artificial human corneas - Scaffolds for transplantation and host regeneration2002In: Cornea, ISSN 0277-3740, E-ISSN 1536-4798, Vol. 21, no 7, p. S54-S61Article in journal (Refereed)
    Abstract [en]

    Purpose. To review the development of artificial corneas (prostheses and tissue equivalents) for transplantation, and to provide recent updates on our tissue-engineered replacement corneas. Methods. Modified natural polymers and synthetic polymers were screened for their potential to replace damaged portions of the human cornea or the entire corneal thickness. These polymers, combined with cells derived from each of the three main corneal layers or stem cells, were used to develop artificial corneas. Functional testing was performed in vitro. Trials of biocompatibility and immune and inflammatory reactions were performed by implanting the most promising polymers into rabbit corneas. Results. Collagen-based biopolymers, combined with synthetic crosslinkers or copolymers, formed effective scaffolds for developing prototype artificial corneas that could be used as tissue replacements in the future. We have previously developed an artificial cornea that mimicked key morphologic and functional properties of the human cornea. The addition of synthetic polymers increased its toughness as it retained transparency and low light scattering, making the matrix scaffold more suitable for transplantation. These new composites were implanted into rabbits without causing any acute inflammation or immune response. We have also fabricated full-thickness composites that can be fully sutured. However, the long-term effects of these artificial corneas need to be evaluated. Conclusions. Novel tissue-engineered corneas that comprise composites of natural and synthetic biopolymers together with corneal cell lines or stem cells will, in the future, replace portions of the cornea that are damaged. Our results provide a basis for the development of both implantable temporary and permanent corneal replacements.

  • 34.
    Griffith, May
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Harkin, Damien G.
    Queensland University of Technology, and Queensland Eye Institute, South Brisbane, QLD, Australia.
    Recent advances in the design of artificial corneas2014In: Current Opinion in Ophthalmology, ISSN 1040-8738, E-ISSN 1531-7021, Vol. 25, no 3, p. 240-247Article, review/survey (Refereed)
    Abstract [en]

    PURPOSE OF REVIEW:

    Artificial corneas are being developed to meet a shortage of donor corneas and to address cases in which allografting is contraindicated. A range of artificial corneas has been developed. Here we review several newer designs and especially those inspired by naturally occurring biomaterials found with the human body and elsewhere.

    RECENT FINDINGS:

    Recent trends in the development of artificial corneas indicate a move towards the use of materials derived from native sources including decellularized corneal tissue and tissue substitutes synthesized by corneal cells in vitro when grown either on their own or in conjunction with novel protein-based scaffolds. Biologically inspired materials are also being considered for implantation on their own with the view to promoting endogenous corneal tissue.

    SUMMARY:

    More recent attempts at making artificial corneas have taken a more nature-based or nature-inspired approach. Several will in the near future be likely to be available clinically.

  • 35.
    Griffith, May
    et al.
    University of Ottawa.
    Jackson, W B
    University of Ottawa.
    Lagali, Neil
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of Ophthalmology UHL/MH.
    Merrett, K
    University of Ottawa.
    Li, F
    University of Ottawa.
    Fagerholm, Per
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of Ophthalmology UHL/MH.
    Artificial corneas: a regenerative medicine approach2009In: EYE, ISSN 0950-222X, Vol. 23, no 10, p. 1985-1989Article in journal (Refereed)
    Abstract [en]

    Corneal substitutes are being developed to address the shortage of human donor tissues as well as the current disadvantages in some clinical indications, which include immune rejection. In the past few years, there have been significant developments in bioengineered corneas that are designed to replace part or the full thickness of damaged or diseased corneas that range from keratoprostheses that solely address the replacement of the corneas function, through tissue-engineered hydrogels that permit regeneration of host tissues. We describe examples of corneal substitutes that encourage regeneration of the host tissue. We also contend that it is unlikely that there will be a single "one-size-fits-all corneal substitute for all indications. Instead, there will most likely be a small range of corneal substitutes ranging from prostheses to tissue-engineered matrix substitutes that are tailored to different clusters of clinical indications. The tissue-engineered matrices can either be produced as sterile acellular matrices, or complete with functional cells, ready for implantation.

  • 36.
    Griffith, May
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Lee, Chyan-Jang
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Buznyk, Oleksiy
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Filatov Inst Eye Dis and Tissue Therapy, Ukraine.
    Artificial Corneas, and Reinforced Composite Implants for High Risk Donor Cornea Transplantation2017In: The Stem Cell Microenvironment and its Role in Regenerative Medicine and Cancer Pathogenesis, RIVER PUBLISHERS , 2017, Vol. 7, p. 93-102Conference paper (Refereed)
    Abstract [en]

    Here, we review examples of artificial corneas that have been developed as alternatives to donor cornea transplantation. These consist of artificial corneas developed as prostheses and regenerative scaffolds. Examples of reinforced and composite implants developed within our group are profiled.

  • 37.
    Griffith, May
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences.
    Polisetti, Naresh
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Kuffova, Lucia
    University of Aberdeen, Scotland .
    Gallar, Juana
    University of Miguel Hernandez, Spain .
    Forrester, John
    University of Aberdeen, Scotland .
    Vemuganti, Geeta K
    University of Hyderabad, India .
    Armin Fuchsluger, Thomas
    University of Hyderabad, India University of Dusseldorf, Germany .
    Regenerative Approaches as Alternatives to Donor Allografting for Restoration of Corneal Function2012In: The Ocular Surface, ISSN 1542-0124, Vol. 10, no 3, p. 170-183Article in journal (Refereed)
    Abstract [en]

    A range of alternatives to human donor tissue for corneal transplantation are being developed to address the shortfall of good quality tissues as well as the clinical conditions for which allografting is contraindicated. Classical keratoprostheses, commonly referred to as artificial corneas, are being used clinically to replace minimal corneal function. However, they are used only as last resorts, as they are associated with significant complications, such as extrusion/rejection, glaucoma, and retinal detachment. The past few years have seen significant developments in technologies designed to replace part or the full thickness of damaged or diseased corneas with materials that encourage regeneration to different extents. This review describes selected examples of these corneal substitutes, which range from cell-based regenerative strategies to keratoprostheses with regenerative capabilities via tissue-engineered scaffolds pre-seeded with stem cells. It is unlikely that one corneal substitute will be best for all indications, but taken together, the various approaches may soon be able to supplement the supply of human donor corneas for transplantation or allow restoration of diseased or damaged corneas that cannot be treated by currently available techniques.

  • 38.
    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.

  • 39.
    Hackett, JM
    et al.
    Ottawa Hosp, Res Inst, Ottawa, ON K1H 8L6 Canada.
    Ferguson, C
    Univ Ottawa, Dept Cellular & Mol Med, Ottawa, ON K1H 8M5 Canada .
    Dare, E
    Univ Ottawa, Dept Cellular & Mol Med, Ottawa, ON K1H 8M5 Canada .
    McLaughlin, CR
    Univ Ottawa, Dept Cellular & Mol Med, Ottawa, ON K1H 8M5 Canada .
    Griffith, May
    Univ Ottawa, Inst Eye, Ottawa, ON K1H 8L6 Canada.
    Optimal neural differentiation and extension of hybrid neuroblastoma cells (NDC) for nerve-target evaluations using a multifactorial approach2010In: Toxicology in Vitro, ISSN 0887-2333, E-ISSN 1879-3177, Vol. 24, no 2, p. 567-577Article in journal (Refereed)
    Abstract [en]

    In vitro models of tissues, such as the cornea, represent systems for modeling cell-to-cell interactions and tissue function. The objective of this study was to develop an optimized nerve differentiation medium to incorporate into a 3D in vitro model to study innervation and cell targeting. A hybrid neuroblastoma cell line (NDC) was examined for its ability to differentiate into neurons, produce neurites, and functionally contact target cells. Neuronal differentiation of NDCs was optimized through a combinatorial approach which involved culturing cells in the presence of various extracellular matrices and soluble factors. A serum-free medium containing nerve growth factor (NGF), dimethyl sulfoxide (DMSO), or dexamethasone resulted in the greatest proportion of NDCs demonstrating a neuronal morphology. Similarly, with supplementation of cyclic AMP (cAMP) or NGF, neurite extension was optimized. Combining these factors generated an optimized differentiation and extension medium, relative to the individual components alone. In co-culture with epithelial cells, NDC neurites generated in the optimized medium formed contacts with epithelial targets and produced substance P. Similarly, NDCs seeded into a collagen matrix produced neurites that projected through the matrix to target epithelial cells, promoted epithelial stratification, and increased the rate of epithelial wound healing. As well, differentiated NDCs could target and alter acetylcholine receptor clustering in mouse C2C12 myotubes, demonstrating synaptic plasticity. Our data supports the use of NDCs, in combination with optimized medium, for generating an innervated in vitro model. (C) 2009 Elsevier Ltd. All rights reserved.

  • 40.
    Hackett, Joanne M.
    et al.
    Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology.
    Lagali, Neil
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of Ophthalmology UHL/MH.
    Merrett, Kimberley
    University of Ottawa Eye Institute.
    Edelhauser, Henry
    Emory University School of Medicine.
    Sun, Yifei
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Gan, Lisha
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences.
    Fagerholm, Per
    Linköping University, Department of Clinical and Experimental Medicine, Ophthalmology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Reconstruction Centre, Department of Ophthalmology UHL/MH.
    Biosynthetic corneal implants for replacement of pathologic corneal tissue: performance in a controlled rabbit alkali burn model2011In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 52, no 2, p. 651-657Article in journal (Refereed)
    Abstract [en]

    Purpose: To evaluate the performance of structurally reinforced, stabilized recombinant human collagen-phosphorylcholine (RHCIII-MPC) hydrogels as corneal substitutes in a rabbit model of severe corneal damage.

    Methods: One eye each of 12 rabbits received a deep corneal alkali wound. Four corneas were implanted with RHCIII-MPC hydrogels. The other eight control corneas were implanted with either allografts or a simple crosslinked RHCIII hydrogel. In all cases, 6.25 mm diameter, 350 µm thick buttons were implanted by anterior lamellar keratoplasty to replace damaged corneal tissue. Implants were followed for nine months by clinical examination and in vivo confocal microscopy, after which implanted corneas were removed and processed for histopathological and ultrastructural examination.

    Results: Alkali exposure induced extensive central corneal scarring, ocular surface irregularity, and neovascularization in one case. All implants showed complete epithelial coverage by four weeks post-operative, but with accompanying suture-induced vascularization in 6/12 cases. A stable, stratified epithelium with hemidesmosomal adhesion complexes regenerated over all implants, and subbasal nerve regeneration was observed in allograft and RHCIII-MPC implants. Initially acellular biosynthetic implants were populated with host-derived keratocytes as stromal haze subsided and stromal collagen was remodeled. Notably, RHCIII-MPC implants exhibited resistance to vascular ingrowth while supporting endogenous cell and nerve repopulation.

    Conclusion: Biosynthetic implants based on RHC promoted cell and nerve repopulation in alkali burned rabbit eyes. In RHCIII-MPC implants, evidence of an enhanced resistance to neovascularization was additionally noted.

  • 41.
    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.

  • 42.
    Hayes, Sally
    et al.
    Cardiff University, Wales; Cardiff University, Wales.
    Lewis, Phillip
    Cardiff University, Wales; Cardiff University, Wales.
    Islam, Mohammad Mirazul
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
    Doutch, James
    Diamond Light Source, England.
    Sorensen, Thomas
    Diamond Light Source, England.
    White, Tomas
    Cardiff University, Wales; Cardiff University, Wales.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
    Meek, Keith M.
    Cardiff University, Wales; Cardiff University, Wales.
    The structural and optical properties of type III human collagen biosynthetic corneal substitutes2015In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 25, p. 121-130Article in journal (Refereed)
    Abstract [en]

    The structural and optical properties of clinically biocompatible, cell-free hydrogels comprised of synthetically cross-linked and moulded recombinant human collagen type III (RHCIII) with and without the incorporation of 2-methacryloyloxyethyl phosphorylcholine (MPC) were assessed using transmission electron microscopy (TEM), X-ray scattering, spectroscopy and refractometry. These findings were examined alongside similarly obtained data from 21 human donor corneas. TEM demonstrated the presence of loosely bundled aggregates of fine collagen filaments within both RHCIII and RHCIII-MPC implants, which X-ray scattering showed to lack D-banding and be preferentially aligned in a uniaxial orientation throughout. This arrangement differs from the predominantly biaxial alignment of collagen fibrils that exists in the human cornea. By virtue of their high water content (90%), very fine collagen filaments (2-9 nm) and lack of cells, the collagen hydrogels were found to transmit almost all incident light in the visible spectrum. They also transmitted a large proportion of UV light compared to the cornea which acts as an effective UV filter. Patients implanted with these hydrogels should be cautious about UV exposure prior to regrowth of the epithelium and in-growth of corneal cells into the implants. (C) 2015 Acta Materialia Inc. Published by Elsevier Ltd.

  • 43.
    He, Min
    et al.
    Harvard Medical Sch, MA USA; Shanxi Medical University, Peoples R China.
    Storr-Paulsen, Thomas
    Harvard Medical Sch, MA USA; Aarhus University Hospital NBG, Denmark.
    Wang, Annie L.
    Harvard Medical Sch, MA USA.
    Ghezzi, Chiara E.
    Tufts University, MA 02155 USA.
    Wang, Siran
    Tufts University, MA 02155 USA.
    Fullana, Matthew
    Case Western Reserve University, OH 44106 USA.
    Karamichos, Dimitrios
    University of Oklahoma, OK USA.
    Utheim, Tor P.
    Harvard Medical Sch, MA USA; University of Oslo, Norway; Vestre Viken Hospital Trust, Norway; University of Coll Southeast Norway, Norway.
    Islam, Rakibul
    Harvard Medical Sch, MA USA; University of Oslo, Norway.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
    Islam, Mohammad Mirazul Mirazul
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
    Hodges, Robin R.
    Harvard Medical Sch, MA USA.
    Wnek, Gary E.
    Case Western Reserve University, OH 44106 USA.
    Kaplan, David L.
    Tufts University, MA 02155 USA.
    Dartt, Darlene A.
    Harvard Medical Sch, MA USA.
    Artificial Polymeric Scaffolds as Extracellular Matrix Substitutes for Autologous Conjunctival Goblet Cell Expansion2016In: Investigative Ophthalmology and Visual Science, ISSN 0146-0404, E-ISSN 1552-5783, Vol. 57, no 14, p. 6134-6146Article in journal (Refereed)
    Abstract [en]

    PURPOSE. We fabricated and investigated polymeric scaffolds that can substitute for the conjunctival extracellular matrix to provide a substrate for autologous expansion of human conjunctival goblet cells in culture. METHODS. We fabricated two hydrogels and two silk films: (1) recombinant human collagen (RHC) hydrogel, (2) recombinant human collagen 2-methacryloylxyethyl phosphorylcholine (RHC-MPC) hydrogel, (3) arginine-glycine-aspartic acid (RGD) modified silk, and (4) poly-D-lysine (PDL) coated silk, and four electrospun scaffolds: (1) collagen, (2) poly(acrylic acid) (PAA), (3) poly(caprolactone) (PCL), and (4) poly(vinyl alcohol) (PVA). Coverslips and polyethylene terephthalate (PET) were used for comparison. Human conjunctival explants were cultured on scaffolds for 9 to 15 days. Cell viability, outgrowth area, and the percentage of cells expressing markers for stratified squamous epithelial cells (cytokeratin 4) and goblet cells (cytokeratin 7) were determined. RESULTS. Most of cells grown on all scaffolds were viable except for PCL in which only 3.6 +/- 2.2% of the cells were viable. No cells attached to PVA scaffold. The outgrowth was greatest on PDL-silk and PET. Outgrowth was smallest on PCL. All cells were CK7-positive on RHCMPC while 84.7 +/- 6.9% of cells expressed CK7 on PDL-silk. For PCL, 87.10 +/- 3.17% of cells were CK7-positive compared to PET where 67.10 +/- 12.08% of cells were CK7-positive cells. CONCLUSIONS. Biopolymer substrates in the form of hydrogels and silk films provided for better adherence, proliferation, and differentiation than the electrospun scaffolds and could be used for conjunctival goblet cell expansion for eventual transplantation once undifferentiated and stratified squamous cells are included. Useful polymer scaffold design characteristics have emerged from this study.

  • 44.
    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.

  • 45.
    Islam, Mohammad Mirazul
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Harvard Medical School, Boston, MA USA.
    Buznyk, Oleksiy
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Filatov Institute of Eye Diseases and Tissue Therapy of the NAMS of Ukraine, Odessa, Ukraine.
    Reddy, Jagadesh C
    Tej Kohli Cornea Institute, LV Prasad Eye Institute, Hyderabad, India.
    Pasyechnikova, Nataliya
    Filatov Institute of Eye Diseases and Tissue Therapy of the NAMS of Ukraine, Odessa, Ukraine.
    Alarcon, Emilio I
    Division of Cardiac Surgery, University of Ottawa Heart Institute, Ottawa, ON Canada.
    Hayes, Sally
    School of Optometry and Vision Sciences College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK; 7Cardiff Institute for Tissue Engineering and Repair (CITER), Cardiff University, Cardiff, UK.
    Lewis, Philip
    School of Optometry and Vision Sciences College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK; 7Cardiff Institute for Tissue Engineering and Repair (CITER), Cardiff University, Cardiff, UK.
    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.
    He, Chaoliang
    Key Laboratory of Polymer Eco-materials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, China.
    Iakymenko, Stanislav
    Filatov Institute of Eye Diseases and Tissue Therapy of the NAMS of Ukraine, Odessa, Ukraine.
    Liu, Wenguang
    School of Materials Science and Engineering, Tianjin University, Tianjin, China.
    Meek, Keith M
    School of Optometry and Vision Sciences College of Biomedical and Life Sciences, Cardiff University, Cardiff, UK; 7Cardiff Institute for Tissue Engineering and Repair (CITER), Cardiff University, Cardiff, UK.
    Sangwan, Virender S
    Tej Kohli Cornea Institute, LV Prasad Eye Institute, Hyderabad, India.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. University of Montreal, Montreal, Canada.
    Biomaterials-enabled cornea regeneration in patients at high risk for rejection of donor tissue transplantation2018In: NPJ Regenerative medicine, ISSN 2057-3995, Vol. 3, article id 2Article in journal (Refereed)
    Abstract [en]

    The severe worldwide shortage of donor organs, and severe pathologies placing patients at high risk for rejecting conventional cornea transplantation, have left many corneal blind patients untreated. Following successful pre-clinical evaluation in mini-pigs, we tested a biomaterials-enabled pro-regeneration strategy to restore corneal integrity in an open-label observational study of six patients. Cell-free corneal implants comprising recombinant human collagen and phosphorylcholine were grafted by anterior lamellar keratoplasty into corneas of unilaterally blind patients diagnosed at high-risk for rejecting donor allografts. They were followed-up for a mean of 24 months. Patients with acute disease (ulceration) were relieved of pain and discomfort within 1-2 weeks post-operation. Patients with scarred or ulcerated corneas from severe infection showed better vision improvement, followed by corneas with burns. Corneas with immune or degenerative conditions transplanted for symptom relief only showed no vision improvement overall. However, grafting promoted nerve regeneration as observed by improved touch sensitivity to near normal levels in all patients tested, even for those with little/no sensitivity before treatment. Overall, three out of six patients showed significant vision improvement. Others were sufficiently stabilized to allow follow-on surgery to restore vision. Grafting outcomes in mini-pig corneas were superior to those in human subjects, emphasizing that animal models are only predictive for patients with non-severely pathological corneas; however, for establishing parameters such as stable corneal tissue and nerve regeneration, our pig model is satisfactory. While further testing is merited, we have nevertheless shown that cell-free implants are potentially safe, efficacious options for treating high-risk patients.

  • 46.
    Islam, Mohammad Mirazul
    et al.
    Swedish Medical Nanoscience Center, Karolinska Institute, Stockholm, Sweden.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Merrett, Kimberley
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Fabrication of a human recombinant collagen-based corneal substitute using carbodiimide chemistry2013In: Methods in Molecular Biology, ISSN 1064-3745, E-ISSN 1940-6029, Vol. 1014, p. 157-164Article in journal (Refereed)
    Abstract [en]

    Human recombinant collagen can be cross-linked with a variety of chemical cross-linking agents. Cross-linking methods can be tuned to confer collagen-based scaffolds with specific physical properties, improved antigenicity and thermal stability without impeding the ability of the material to integrate into the surrounding tissue and to promote regeneration. Here, we describe a method to cross-link human recombinant collagen using a water soluble carbodiimide. Carbodiimides are referred to as zero-length cross-linking agents as they are not incorporated into the final cross-link and thus pose minimal risk with respect to cytotoxicity. The resulting collagen-based scaffold possesses properties comparable to that of the human cornea and is thus suitable for use as a corneal substitute.

  • 47.
    Islam, Mohammad Mirazul
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
    Ravichandran, Ranjithkumar
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Olsen, D.
    FibroGen Inc, CA 94158 USA.
    Kozak Ljunggren, Monika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    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.
    Lee, Chyan-Jang
    Linköping University, Department of Physics, Chemistry and Biology, Sensor Science and Molecular Physics. Linköping University, The Institute of Technology. Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Karolinska Institute, Sweden.
    Phopase, Jaywant
    Linköping University, Department of Physics, Chemistry and Biology, Molecular Physics. Linköping University, Faculty of Science & Engineering.
    Self-assembled collagen-like-peptide implants as alternatives to human donor corneal transplantation2016In: RSC Advances, ISSN 2046-2069, E-ISSN 2046-2069, Vol. 6, no 61, p. 55745-55749Article in journal (Refereed)
    Abstract [en]

    Extracellular matrix proteins like collagen promote regeneration as implants in clinical studies. However, collagens are large and unwieldy proteins, making small functional peptide analogs potentially ideal substitutes. Self-assembling collagen-like-peptides conjugated with PEG-maleimide were assembled into hydrogels. When tested pre-clinically as corneal implants in mini-pigs, they promoted cell and nerve regeneration, forming neo-corneas structurally and functionally similar to natural corneas.

  • 48.
    Islam, Rakibul
    et al.
    University of Oslo, Norway; Oslo University Hospital, Norway; Harvard University, MA USA.
    Jackson, Catherine
    Oslo University Hospital, Norway.
    Eidet, Jon R.
    Oslo University Hospital, Norway.
    Messelt, Edward B.
    University of Oslo, Norway.
    Maria Corraya, Rima
    Oslo University Hospital, Norway; Harvard University, MA USA.
    Lyberg, Torstein
    Oslo University Hospital, Norway.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Dartt, Darlene A.
    Harvard University, MA USA.
    Utheim, Tor P.
    University of Oslo, Norway; Oslo University Hospital, Norway; Harvard University, MA USA.
    Effect of Storage Temperature on Structure and Function of Cultured Human Oral Keratinocytes2015In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 10, no 6, p. e0128306-Article in journal (Refereed)
    Abstract [en]

    Purpose/Aims To assess the effect of storage temperature on the viability, phenotype, metabolism, and morphology of cultured human oral keratinocytes (HOK). Materials and Methods Cultured HOK cells were stored in HEPES- and sodium bicarbonate-buffered Minimum Essential Medium (MEM) at nine temperatures in approximately 4 degrees C increments from 4 degrees C to 37 degrees C for seven days. Cells were characterized for viability by calcein fluorescence, phenotype retention by immunocytochemistry, metabolic parameters (pH, glucose, lactate, and O-2) within the storage medium by blood gas analysis, and morphology by scanning electron microscopy and light microscopy. Results Relative to the cultured, but non-stored control cells, a high percentage of viable cells were retained only in the 12 degrees C and 16 degrees C storage groups (85%+/- 13% and 68%+/- 10%, respectively). Expression of ABCG2, Bmi1, C/EBP delta, PCNA, cytokeratin 18, and caspase-3 were preserved after storage in the 5 groups between 4 degrees C and 20 degrees C, compared to the non-stored control. Glucose, pH and pO(2) in the storage medium declined, whereas lactate increased with increasing storage temperature. Morphology was best preserved following storage of the three groups between 12 degrees C, 16 degrees C, and 20 degrees C. Conclusion We conclude that storage temperatures of 12 degrees C and 16 degrees C were optimal for maintenance of cell viability, phenotype, and morphology of cultured HOK. The storage method described in the present study may be applicable for other cell types and tissues; thus its significance may extend beyond HOK and the field of ophthalmology.

  • 49.
    Islam, Rakibul
    et al.
    Harvard Medical Sch, MA USA; University of Oslo, Norway; Oslo University Hospital, Norway.
    Roger Eidet, Jon
    Oslo University Hospital, Norway.
    Badian, Reza A.
    Harvard Medical Sch, MA USA; University of Coll Southeast Norway, Norway; Innlandet Hospital Trust, Norway.
    Lippestad, Marit
    Harvard Medical Sch, MA USA; Oslo University Hospital, Norway; University of Oslo, Norway.
    Messelt, Edward
    University of Oslo, Norway.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Dartt, Darlene A.
    Harvard Medical Sch, MA USA; University of Oslo, Norway.
    Paaske Utheim, Tor
    Harvard Medical Sch, MA USA; University of Oslo, Norway; Oslo University Hospital, Norway; Innlandet Hospital Trust, Norway.
    Tissue Harvesting Site and Culture Medium Affect Attachment, Growth, and Phenotype of Ex Vivo Expanded Oral Mucosal Epithelial Cells2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 674Article in journal (Refereed)
    Abstract [en]

    Transplantation of cultured oral mucosal epithelial cells (OMECs) is a promising treatment strategy for limbal stem cell deficiency. In order to improve the culture method, we investigated the effects of four culture media and tissue harvesting sites on explant attachment, growth, and phenotype of OMECs cultured from Sprague-Dawley rats. Neither choice of media or harvesting site impacted the ability of the explants to attach to the culture well. Dulbeccos modified Eagles medium/Hams F12 (DMEM) and Roswell Park Memorial Institute 1640 medium (RPMI) supported the largest cellular outgrowth. Fold outgrowth was superior from LL explants compared to explants from the buccal mucosa (BM), HP, and transition zone of the lower lip (TZ) after six-day culture. Putative stem cell markers were detected in cultures grown in DMEM and RPMI. In DMEM, cells from TZ showed higher colony-forming efficiency than LL, BM, and HP. In contrast to RPMI, DMEM both expressed the putative stem cell marker Bmi-1 and yielded cell colonies. Our data suggest that OMECs from LL and TZ cultured in DMEM give rise to undifferentiated cells with high growth capacity, and hence are the most promising for treatment of limbal stem cell deficiency.

  • 50.
    Jangamreddy, Jaganmohan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. LV Prasad Eye Inst, India.
    Haagdorens, Michel K. C.
    Antwerp Univ Hosp, Belgium; Univ Antwerp, Belgium.
    Mirazul Islam, Mohammad Mirazul
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Lewis, Philip
    Cardiff Univ, Wales.
    Samanta, Ayan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    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.
    Liszka, Aneta
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Kozak Ljunggren, Monika
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Buznyk, Oleksiy
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences.
    Alarcon, Emilio I.
    Univ Ottawa, Canada.
    Zakaria, Nadia
    Antwerp Univ Hosp, Belgium; Univ Antwerp, Belgium.
    Meek, Keith M.
    Cardiff Univ, Wales.
    Griffith, May
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Univ Montreal, Canada; Univ Montreal, Canada.
    Correction: Short peptide analogs as alternatives to collagen in pro-regenerative corneal implants (vol 69, pg 120, 2018)2018In: Acta Biomaterialia, ISSN 1742-7061, E-ISSN 1878-7568, Vol. 81, p. 330-331Article in journal (Other academic)
    Abstract [en]

    n/a

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