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  • 1.
    Kootala, Sujit
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. UPPA, France.
    Chitin Nanoforms Provide Mechanical and Topological Cues to Support Growth of Human Adipose Stem Cells in Chitosan Matrices2018In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602Article in journal (Refereed)
  • 2.
    Kootala, Sujit
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Evaluation of Functionalized Biopolymers as a Step Toward Targeted Therapy of Osteoporosis2015Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The work presented in this thesis focuses on the development of strategies and smart bioactive materials for the treatment of osteoporosis. High and low molecular weight soluble hyaluronic acid-bisphosphonate (HA-BP) derivatives were investigated for their ability to inhibit osteoclasts. Low molecular weight HA-BP (L-HA-BP) was most effective in inhibiting active resorption of both murine and human osteoclasts (without affecting osteoblasts) compared to free bisphosphonate (BP). Precursor monocytes were unaffected, suggesting the specificity of HA-BP towards osteoclasts. This new class of functionalized hyaluronic acid could lead to rapid development of tailor-made pro-drugs for targeted treatment of osteoporosis.

    Polyphosphoesters (PEP) have been widely studied for their pro-osteoblast effects, primarily due to their involvement in cellular energy production pathway leading to the formation of inorganic phosphates that contribute to mineralized bone. Given that the effect of PEP on human osteoclasts is little studied, this work on poly(ethylene sodium phosphate) (PEP.Na) explores the potential to use PEP.Na as an inhibitor of osteoclast activity for the first time. PEP.Na exposure led to a dose-dependent toxicity of osteoclasts with reduction in their capacity to form resorption pits over 24h.

    Currently, there is a dearth of in vitro cell-culture systems that can study osteoclast-related resorption and osteoblast-related mineralization in a single co-culture system, and to simultaneously quantify the effects of soluble factors on these processes. Described here, is the development of a novel and simple two-sided co-culture system that can overcome these limitations with reliable and quantifiable readouts. In comparison with traditional one-sided co-culture systems, the two-sided co-culture was able to generate similar readouts for alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP) markers. There is also the advantage of distinctly separate and quantifiable readouts for mineralization and resorption, which has been demonstrated using Pamidronate.

    Finally, HA-BP was synthesized with pre-determined amounts of BP groups. The BP groups attached to HA allowed the tunable incorporation of BMP-2 in hydrogels. The charge-based affinity of BMP-2 and BP allowed stable incorporation of specific amounts of BMP-2, which could be tuned by the ratio of BP groups. 125I-labelled BMP-2 was loaded into hydrogels and their release was studied. Radioactive measurements revealed the tunable sequestration and controlled release of protein over time. This result was corroborated by ALP measurements of cells exposed to released BMP-2. ALP production was found to be almost 5-fold higher in HA-BP hydrogels loaded with BMP-2 which suggested that the sequestered BMP-2 is not only available to cells but also remains highly potent, even in entrapped form, The release of BMP-2 is dependent upon the rate of diffusion, swelling in hydrogels and degradation pattern of the gels and may assist in the long-term and rapid regeneration of osteoblasts in vitro.

    List of papers
    1. Bisphosphonate-functionalized hyaluronic acid showing selective affinity for osteoclasts as a potential treatment for osteoporosis
    Open this publication in new window or tab >>Bisphosphonate-functionalized hyaluronic acid showing selective affinity for osteoclasts as a potential treatment for osteoporosis
    Show others...
    2015 (English)In: Biomaterials Science, ISSN 2047-4830, E-ISSN 2047-4849, Vol. 3, p. 1197-1207Article in journal (Refereed) Published
    Abstract [en]

    Current treatments for osteoporosis involve the administration of high doses of bisphosphonates (BPs) over a number of years. However, the efficiency of the absorption of these drugs and specificity towards targeted osteoclastic cells is still suboptimal. In this study, we have exploited the natural affinity of high (H) and low (L) molecular-weight hyaluronic acid (HA) towards a cluster of differentiation 44 (CD44) receptors on osteoclasts to use it as a biodegradable targeting vehicle. We covalently bonded BP to functionalised HA (HA–BP) and found that HA–BP conjugates were highly specific to osteoclastic cells and reduced mature osteoclast numbers significantly more than free BP. To study the uptake of HA–BP, we fluorescently derivatised the polymer–drug with fluorescein B isothiocyanate (FITC) and found that L-HA–BP could seamlessly enter osteoclastic cells. Alternatively, we tested polyvinyl alcohol (PVA) as a synthetic polymer delivery vehicle using similar chemistry to link BP and found that osteoclast numbers did not reduce in the same way. These findings could pave the way for biodegradable polymers to be used as vehicles for targeted delivery of anti-osteoporotic drugs.

    Place, publisher, year, edition, pages
    United Kingdom: , 2015
    Keywords
    Bisphosphonates, Osteoporosis, Hyaluronic acid, Osteoclasts, Osteoblasts, Bone
    National Category
    Materials Chemistry
    Research subject
    Chemistry with specialization in Materials Chemistry; Chemistry with specialization in Polymer Chemistry
    Identifiers
    urn:nbn:se:uu:diva-258090 (URN)10.1039/C5BM00096C (DOI)000357937400003 ()26222035 (PubMedID)
    Projects
    MultiTERM
    Funder
    EU, European Research Council
    Note

    Erratum in Biomaterials Science 2015:3, issue 10, doi: 10.1039/c5bm90034d

    Available from: 2015-07-10 Created: 2015-07-10 Last updated: 2017-12-04Bibliographically approved
    2. Anti-Resorptive Functions of Poly(ethylene sodium phosphate) on Human Osteoclasts
    Open this publication in new window or tab >>Anti-Resorptive Functions of Poly(ethylene sodium phosphate) on Human Osteoclasts
    2015 (English)In: Macromolecular Bioscience, ISSN 1616-5187, E-ISSN 1616-5195, Vol. 15, no 12, p. 1634-1640Article in journal (Refereed) Published
    Keywords
    osteoclasts, osteoblasts, osteoporosis, poly(ethylene sodium phosphate)
    National Category
    Natural Sciences Chemical Sciences
    Research subject
    Chemistry with specialization in Materials Chemistry
    Identifiers
    urn:nbn:se:uu:diva-259078 (URN)10.1002/mabi.201500166 (DOI)000368456500001 ()26222677 (PubMedID)
    Funder
    Swedish Research Council, 2014-6009
    Available from: 2015-07-27 Created: 2015-07-27 Last updated: 2017-12-04Bibliographically approved
    3. Co-culture model using human osteoblasts and osteoclasts on bone discs for in situ monitoring of surface remodeling
    Open this publication in new window or tab >>Co-culture model using human osteoblasts and osteoclasts on bone discs for in situ monitoring of surface remodeling
    (English)In: Biomatter, ISSN 2159-2535Article in journal (Other academic) Submitted
    Abstract [en]

    Osteoporosis is marked by accelerated bone resorption than bone formation and is currently treated with suboptimal drugs associated with severe off-target effects. More robust in vitro models are needed to investigate the precise pharmacokinetic effects of new drug formulations on bone cells in coculture conditions. This would promote targeted drug development and could reduce the number of animals needed in pre-clinical trials. However, existing coculture models do not address the effect of soluble factors released from cells in coculture. To address this challenge, we developed a two-sided co-culture model comprising human osteoclasts and osteoblasts on opposite sides of a thin decellurized bone chip. Essential cellular functions such as resorption by osteoclasts and mineralization by osteoblasts were not disrupted in the two-sided co-culture, even though the bone chip physically separated the two cell types. In this model, we freshly quantified resorption pits and mineralization on opposite sides of the same material through microscopy assisted image analysis and histological staining, respectively. Mineralization by osteoblasts was assessed with alizarin red and showed downregulation by 25% in the presence of osteoclasts (relative to osteoblasts alone) on the bone chip. The drug Pamidronate reduced the osteoclast population by 10% without affecting the number of osteoblasts. Thus, this co-culture model significantly simplifies allows in-situ monitoring of the effect of soluble bone signaling factors and anti-osteoporotic drugs.

    Place, publisher, year, edition, pages
    Taylor & Francis Group
    National Category
    Chemical Sciences
    Research subject
    Chemistry with specialization in Polymer Chemistry; Chemistry with specialization in Materials Chemistry; Biology with specialization in Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-259080 (URN)
    Projects
    MultiTERM
    Funder
    EU, FP7, Seventh Framework Programme, 238551Swedish Research Council, 2014-6099
    Available from: 2015-07-27 Created: 2015-07-27 Last updated: 2015-09-01Bibliographically approved
    4. Spatio-Temporal Control of Growth Factor Binding and Release in Bisphosphonate Functionalized Hydrogels Guides Rapid Differentiation of Precursor Cells in vitro
    Open this publication in new window or tab >>Spatio-Temporal Control of Growth Factor Binding and Release in Bisphosphonate Functionalized Hydrogels Guides Rapid Differentiation of Precursor Cells in vitro
    Show others...
    (English)In: Journal of materials chemistry. B, ISSN 2050-750X, E-ISSN 2050-7518Article in journal (Refereed) Submitted
    Abstract [en]

    An in situ cross-linkable hyaluronan hydrogel functionalized with bisphosphonate (BP) groups allows tunable release of bone morphogenetic protein-2 (BMP-2) determined by the amount of BP groups. Sequestration of BMP-2 in the hydrogel permits guided differentiation of entrapped progenitor cells in 3-D cultures. 

    Place, publisher, year, edition, pages
    Royal Society of Chemistry
    Keywords
    bisphosphonates, hydrogels, growth factors, tissue engineering, biomaterials
    National Category
    Polymer Chemistry
    Research subject
    Chemistry with specialization in Polymer Chemistry; Chemistry with specialization in Materials Chemistry
    Identifiers
    urn:nbn:se:uu:diva-259081 (URN)
    Funder
    EU, European Research Council, 262948-2EU, FP7, Seventh Framework Programme, 238551
    Available from: 2015-07-27 Created: 2015-07-27 Last updated: 2017-12-04Bibliographically approved
    Download full text (pdf)
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  • 3.
    Kootala, Sujit
    et al.
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Chem, Div Glycosci, Stockholm, Sweden.
    Filho, Luimar
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Srivastava, Vaibhav
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Chem, Div Glycosci, Stockholm, Sweden.
    Linderberg, Victoria
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Chem, Div Glycosci, Stockholm, Sweden.
    Moussa, Amani
    Univ Claude Bernard Lyon 1, Univ Lyon, CNRS UMR 5223, IMP, Villeurbanne, France.
    David, Laurent
    Univ Claude Bernard Lyon 1, Univ Lyon, CNRS UMR 5223, IMP, Villeurbanne, France.
    Trombotto, Stephane
    Univ Claude Bernard Lyon 1, Univ Lyon, CNRS UMR 5223, IMP, Villeurbanne, France.
    Crouzier, Thomas
    KTH Royal Inst Technol, Sch Engn Sci Chem Biotechnol & Hlth, Dept Chem, Div Glycosci, Stockholm, Sweden.
    Reinforcing Mucus Barrier Properties with Low Molar Mass Chitosans2018In: Biomacromolecules, ISSN 1525-7797, E-ISSN 1526-4602, Vol. 19, no 3, p. 872-882Article in journal (Refereed)
    Abstract [en]

    The mucus gel covers the wet epithelia that forms the inner lining of the body. It constitutes our first line of defense protecting the body from infections and other deleterious molecules. Failure of the mucus barrier can lead to the inflammation of the mucosa such as in inflammatory bowel diseases. Unfortunately, there are no effective strategies that reinforce the mucus barrier properties to recover or enhance its ability to protect the epithelium. Herein, we describe a mucus engineering approach that addresses this issue where we physically cross-link the mucus gel with low molar mass chitosan variants to reinforce its barrier functions. We tested the effect of these chitosans on mucus using in-lab purified porcine gastric mucins, which mimic the native properties of mucus, and on mucus-secreting HT29-MTX epithelial cell cultures. We found that the lowest molar mass chitosan variant (degree of polymerization of 8) diffuses deep into the mucus gels while physically cross-linking the mucin polymers, whereas the higher molar mass chitosan variants (degree of polymerization of 52 and 100) interact only superficially. The complexation resulted in a tighter mucin polymer mesh that slowed the diffusion of dextran polymers and of the cholera toxin B subunit protein through the mucus gels. These results uncover a new use for low molar mass mucoadhesive polymers such as chitosans as noncytotoxic mucosal barrier enhancers that could be valuable in the prevention and treatment of mucosal diseases.

  • 4.
    Kootala, Sujit
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Ossipov, Dmitri
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Zhang, Yu
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Hyaluronic acid linked bisphosphonates as a step towards targeted therapy for osteoporosis2014In: Journal of Tissue Engineering and Regenerative Medicine, ISSN 1932-6254, E-ISSN 1932-7005, Vol. 8, p. 420-421Article in journal (Other academic)
  • 5.
    Kootala, Sujit
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ossipov, Dmitri
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    van den Beucken, Jeroenn
    Leeuwenburgh, Sander
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bisphosphonate-functionalized hyaluronic acid showing selective affinity for osteoclasts as a potential treatment for osteoporosis2015In: Biomaterials Science, ISSN 2047-4830, E-ISSN 2047-4849, Vol. 3, p. 1197-1207Article in journal (Refereed)
    Abstract [en]

    Current treatments for osteoporosis involve the administration of high doses of bisphosphonates (BPs) over a number of years. However, the efficiency of the absorption of these drugs and specificity towards targeted osteoclastic cells is still suboptimal. In this study, we have exploited the natural affinity of high (H) and low (L) molecular-weight hyaluronic acid (HA) towards a cluster of differentiation 44 (CD44) receptors on osteoclasts to use it as a biodegradable targeting vehicle. We covalently bonded BP to functionalised HA (HA–BP) and found that HA–BP conjugates were highly specific to osteoclastic cells and reduced mature osteoclast numbers significantly more than free BP. To study the uptake of HA–BP, we fluorescently derivatised the polymer–drug with fluorescein B isothiocyanate (FITC) and found that L-HA–BP could seamlessly enter osteoclastic cells. Alternatively, we tested polyvinyl alcohol (PVA) as a synthetic polymer delivery vehicle using similar chemistry to link BP and found that osteoclast numbers did not reduce in the same way. These findings could pave the way for biodegradable polymers to be used as vehicles for targeted delivery of anti-osteoporotic drugs.

  • 6.
    Kootala, Sujit
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Rojas, Ramiro
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Novel hyaluronic acid hydrogels for spinal cord repair2012In: Journal of Tissue Engineering and Regenerative Medicine, ISSN 1932-6254, Vol. 6, no suppl 1, p. 190-190Article in journal (Other academic)
    Abstract [en]

    Spinal cord injury and repair is one of the important focus areas in tissue regeneration. Mechanical trauma caused due to factors such as contusion, compression or involuntary stretching induce post-traumatic secondary tissue damage in many Spinal Cord Injury (SCI) patients. Therefore, there is a need for scaffolds that provide a conducive threedimensionsal (3D) environment for injured cells to attach and grow. In this study we propose to synthesize 3D polymeric scaffolds in order to study the mechanical and adhesive properties & the nature of the interactions between hyaluronan-based (HY) biomaterials and cells and tissues both in vitroandin vivo. Here we have synthesized 3D HY-based hydrogels with robust mechanical and adhesive properties and demonstrate the use of this material for neuronal-related applications such as the treatment of SCI. Cell culture and survivability studies were done with NSC-34 cells. Live/Dead assay performed on the cells revealed significant differences in the staining of live cells and showed increased viability and proliferation. The number of live cells in the HY-based hydrogels with 0.1% collagen showed higher cell numbers compared with the other hydrogels. In this study we show that Injectable HYbased hydrogels with high elasticity, comparable to the mechanical properties of nervous tissue have been used in this study to study their biocompatibility and neuroprotective properties and they show better affinity for neuronal cells.

  • 7.
    Kootala, Sujit
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Tokunaga, Masahiro
    Kansai University.
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Iwasaki, Yasuhiko
    Kansai University, Faculty of Chemistry, Materials and Bioengineering.
    Anti-Resorptive Functions of Poly(ethylene sodium phosphate) on Human Osteoclasts2015In: Macromolecular Bioscience, ISSN 1616-5187, E-ISSN 1616-5195, Vol. 15, no 12, p. 1634-1640Article in journal (Refereed)
  • 8.
    Kootala, Sujit
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zhang, Yu
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ghalib, Sara
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tolmachev, Vladmir
    Rudbeck Laboratory-Biomedical Radiation Sciences.
    Hilborn, Jöns
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Ossipov, Dmitri
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Spatio-Temporal Control of Growth Factor Binding and Release in Bisphosphonate Functionalized Hydrogels Guides Rapid Differentiation of Precursor Cells in vitroIn: Journal of materials chemistry. B, ISSN 2050-750X, E-ISSN 2050-7518Article in journal (Refereed)
    Abstract [en]

    An in situ cross-linkable hyaluronan hydrogel functionalized with bisphosphonate (BP) groups allows tunable release of bone morphogenetic protein-2 (BMP-2) determined by the amount of BP groups. Sequestration of BMP-2 in the hydrogel permits guided differentiation of entrapped progenitor cells in 3-D cultures. 

  • 9.
    Kootala, Sujit
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Zhang, Yu
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Co-culture model using human osteoblasts and osteoclasts on bone discs for in situ monitoring of surface remodelingIn: Biomatter, ISSN 2159-2535Article in journal (Other academic)
    Abstract [en]

    Osteoporosis is marked by accelerated bone resorption than bone formation and is currently treated with suboptimal drugs associated with severe off-target effects. More robust in vitro models are needed to investigate the precise pharmacokinetic effects of new drug formulations on bone cells in coculture conditions. This would promote targeted drug development and could reduce the number of animals needed in pre-clinical trials. However, existing coculture models do not address the effect of soluble factors released from cells in coculture. To address this challenge, we developed a two-sided co-culture model comprising human osteoclasts and osteoblasts on opposite sides of a thin decellurized bone chip. Essential cellular functions such as resorption by osteoclasts and mineralization by osteoblasts were not disrupted in the two-sided co-culture, even though the bone chip physically separated the two cell types. In this model, we freshly quantified resorption pits and mineralization on opposite sides of the same material through microscopy assisted image analysis and histological staining, respectively. Mineralization by osteoblasts was assessed with alizarin red and showed downregulation by 25% in the presence of osteoclasts (relative to osteoblasts alone) on the bone chip. The drug Pamidronate reduced the osteoclast population by 10% without affecting the number of osteoblasts. Thus, this co-culture model significantly simplifies allows in-situ monitoring of the effect of soluble bone signaling factors and anti-osteoporotic drugs.

  • 10.
    Ossipov, Dmitri A.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Yang, Xia
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Varghese, Oommen
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Kootala, Sujit
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Modular approach to functional hyaluronic acid hydrogels using orthogonal chemical reactions2010In: Chemical Communications, ISSN 1359-7345, E-ISSN 1364-548X, Vol. 46, no 44, p. 8368-8370Article in journal (Refereed)
    Abstract [en]

    A modular approach for the synthesis of hyaluronic acid hydrogels using orthogonal chemoselective reactions for subsequent enzymatic decomposition to nanoparticles is described.

  • 11.
    Ossipov, Dmitri
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Kootala, Sujit
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Yi, Zheyi
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Yang, Xia
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Orthogonal Chemoselective Assembly of Hyaluronic Acid Networks and Nanogels for Drug Delivery2013In: Macromolecules, ISSN 0024-9297, E-ISSN 1520-5835, Vol. 46, no 10, p. 4105-4113Article in journal (Refereed)
    Abstract [en]

    Functionalization of hyaluronic acid (HA) with orthogonally reactive aldehyde and thiol groups permitted simultaneous bioconjugation and networking/nanostructuring of the HA chains for potential use as local and systemic delivery vehicles for medical therapies. In one experiment, the thiol-disulfide exchange reaction and carbazone chemistry were employed to construct a disulfide hydrogel matrix of HA macromolecules with the carbazone-linked poly(vinyl alcohol) prodrug of doxorubicin (PVA-DOX). In another experiment, orthogonal chemoselective reactions were utilized to prepare nanogel particles through conjugation of the polymeric PVA-DOX prodrug to HA and simultaneous attachment of hydrophobic fluorescent groups to the HA chains. The effect of the prodrug nanostructuring and functionalization with HA on the in vitro drug release and uptake by cancer cells was preliminary verified.

  • 12.
    Schizas, Nikos
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Rojas, Ramiro
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Kootala, Sujit
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Andersson, Brittmarie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Pettersson, Jennie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Hailer, Nils P
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Hyaluronic acid-based hydrogel enhances neuronal survival in spinal cord slice cultures from postnatal mice2014In: Journal of biomaterials applications, ISSN 0885-3282, E-ISSN 1530-8022, Vol. 28, no 6, p. 825-836Article in journal (Refereed)
    Abstract [en]

    Numerous biomaterials based on extracellular matrix-components have been developed. It was our aim to investigate whether a hyaluronic acid-based hydrogel improves neuronal survival and tissue preservation in organotypic spinal cord slice cultures. Organotypic spinal cord slice cultures were cultured for 4 days in vitro (div), either on hyaluronic acid-based hydrogel (hyaluronic acid-gel group), collagen gel (collagen group), directly on polyethylene terephthalate membrane inserts (control group), or in the presence of soluble hyaluronic acid (soluble hyaluronic acid group). Cultures were immunohistochemically stained against neuronal antigen NeuN and analyzed by confocal laser scanning microscopy. Histochemistry for choline acetyltransferance, glial fibrillary acidic protein, and Griffonia simplicifolia isolectin B4 followed by quantitative analysis was performed to assess motorneurons and different glial populations. Confocal microscopic analysis showed a 4-fold increase in the number of NeuN-positive neurons in the hyaluronic acid-gel group compared to both collagen (p < 0.001) and control groups (p < 0.001). Compared to controls, organotypic spinal cord slice cultures maintained on hyaluronic acid-based hydrogel showed 5.9-fold increased survival of choline acetyltransferance-positive motorneurons (p = 0.008), 2-fold more numerous resting microglial cells in the white matter (p = 0.031), and a 61.4% reduction in the number of activated microglial cells within the grey matter (p = 0.05). Hyaluronic acid-based hydrogel had a shear modulus (G') of ≈1200 Pascals (Pa), which was considerably higher than the ≈25 Pa measured for collagen gel. Soluble hyaluronic acid failed to improve tissue preservation. In conclusion, hyaluronic acid-based hydrogel improves neuronal and - most notably - motorneuron survival in organotypic spinal cord slice cultures and microglial activation is limited. The positive effects of hyaluronic acid-based hydrogel may at least in part be due to its mechanical properties.

  • 13.
    Yang, Xia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Dogan, Ilyas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Pannala, Vasudeva Reddy
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Kootala, Sujit
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Ossipov, Dmitri
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    A hyaluronic acid-camptothecin nanoprodrug with cytosolic mode of activation for targeting cancer2013In: POLYM CHEM-UK, ISSN 1759-9954, Vol. 4, no 17, p. 4621-4630Article in journal (Refereed)
    Abstract [en]

    We have developed a nanoprodrug that enables the uptake by cancer cells and the subsequent intracellular activation. The nanoprodrug is composed of a cancer cell-targeting biopolymer, hyaluronic acid (HA), and an anti-cancer drug, camptothecin (CPT). The chemical linkage between the polymer and the drug is stable outside the cells, thus maintaining the drug in an "off" state. The specific uptake of the nanoprodrug by cancer cells should then lead to an environmental change that results in the cleavage of the linkage, liberating the drug and thus entering the "on" state. The natural cancer-targeting biopolymer HA was modified with aldehyde "click" groups. This "clickable" HA was then conjugated to CPT modified with a hydrazide linker using a mild hydrazone-coupling reaction. The linker consists of a thiol-activated self-immolative dithioethoxycarbonyl spacer, which is stable in PBS buffer but should be rapidly cleaved in the reductive cytosolic environment of cancer cells. The resulting HA-CPT nanoprodrug released CPT only at low levels in PBS buffer. However, the drug was efficiently cleaved after the addition of dithiothreitol (DTT). Consistent with these data, the HA-CPT nanoprodrug showed a 3-fold greater cytotoxicity to cancer cells compared to free CPT. Fluorescence microscopy confirmed the rapid and efficient uptake of the HA-CPT nanoprodrug by the cancer cells.

  • 14.
    Yang, Xia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Kootala, Sujit
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Ossipov, Dmitri A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Preparation of hyaluronic acid nanoparticles via hydrophobic association assisted chemical cross-linking: an orthogonal modular approach2011In: Soft Matter, ISSN 1744-683X, E-ISSN 1744-6848, Vol. 7, no 16, p. 7517-7525Article in journal (Refereed)
    Abstract [en]

    The objective of this study was to develop an efficient and stable drug delivery nanocarrier based on a dually functionalized hyaluronic acid (HA) derivative which could be used as a long circulating drug delivery vehicle. Self-assembled HA nanoparticles (HA NPs) were prepared by attaching pyrene to the HA backbone and the obtained physical NPs were stabilized by chemical cross-linking of the HA chains to form hydrophobic core-hydrophilic shell NPs. Orthogonal chemoselective reactions were applied for conversion of HA into its amphiphilic derivative and subsequent cross-linking of the formed micellar-type associates. Chemical stabilization of the physical HA associates afforded therefore very stable nanoparticles that could easily be re-suspended in aqueous media after freeze-drying. In contrast, freeze-drying of the uncross-linked physically associated particles resulted in a non-soluble material. Doxorubicin (DOX), a typical anticancer drug, was entrapped into HA NPs via ionic and/or hydrophobic interactions and used for in vitro drug release. Higher loading efficiency and the slower release profile of DOX from HA NPs were obtained with the hydrophobically encapsulated drug. We have shown that free HA NPs were readily taken up by NIH 3T3 cells without causing any toxicity to the cells, while the DOX-loaded HA NPs resulted in increased cell death comparable to the free drug. This study clearly showed the applicability of orthogonal chemoselective modifications for the synthesis of stable HA nanogel particles as a potential cancer-targeted drug delivery system.

  • 15.
    Yang, Xia
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Yi, Sun
    Radboud University Nijmegen Medical Centre.
    Kootala, Sujit
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Heerschap, Arend
    Radboud University Nijmegen Medical Centre.
    Ossipov, Dmitri
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Injectable hyaluronic acid hydrogel for F-19 magnetic resonance imaging2014In: Carbohydrate Polymers, ISSN 0144-8617, E-ISSN 1879-1344, Vol. 110, p. 95-99Article in journal (Refereed)
    Abstract [en]

    We report on a19F labeled injectable hyaluronic acid (HA) hydrogel that can be monitored by both 1H and 19F MR imaging. The HA based hydrogel formed via carbazone reaction can be obtained within a minute by simple mixing of HA-carbazate and HA-aldehyde derivatized polymers. 19F contrast agent was linked to with carbazate and thiol dually functionalized HA via orthogonal Michael addition reaction which afforded cross-linkable and 19F labeled HA. The 19F labeling of HA polymer did not affect the mechanical properties of the formed hydrogel. As a result, the shape of a hydrogel sample could be imaged very well by both 1H MRI and high resolution19F MRI. This hydrogel has high potential in clinical applications since it is injectable, biocompatible, and can be tracked in a minimally invasive manner. The present approach can be applied in preparation of injectable 19F labeled hydrogel biomaterials from other natural biomacromolecules.

  • 16.
    Yi, Zheyi
    et al.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Zhang, Yu
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Kootala, Sujit
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Hilborn, Jöns
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Ossipov, Dmitri A.
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Hydrogel Patterning by Diffusion through the Matrix and Subsequent Light-Triggered Chemical Immobilization2015In: ACS Applied Materials and Interfaces, ISSN 1944-8244, E-ISSN 1944-8252, Vol. 7, no 2, p. 1194-1206Article in journal (Refereed)
    Abstract [en]

    A novel approach to hyaluronic acid (HA) hydrogel with a chemical gradient of the matrix-linked bisphosphonate (BP) groups is presented. The method consists of two steps, including initial generation of physical gradient patterns of BPs by diffusion of BP acrylamide reagent into HA matrix carrying thiol groups and subsequent chemical immobilization of the BP groups by UV light-triggered thiolene addition reaction. This gradient hydrogel permits spatial three-dimensional regulation of secondary interactions of different molecules with the polymer matrix. In particular, graded amounts of cytochrome c (cyt c) were reversibly absorbed in the hydrogel, thus enabling the subsequent spatially controlled release of the therapeutic protein. The obtained patterned hydrogel acts also as a unique reactor in which peroxidase-catalyzed oxidation of a substrate is determined by spatial position of the enzyme (cyt c) in the matrix resulting in a range of product concentrations. As an example, matrix template-assisted oxidation of 3,3',5,5'-tetarmethylbenzydine (TMB) in the presence of H2O2 occurs simultaneously at different rates within the gradient hydrogel. Moreover, calcium binding to the gradient HABP hydrogel reflects the pattern of immobilized BP groups eventually leading to the graded biomineralization of the matrix. This approach opens new possibilities for use of hydrogels as dynamic models for biologic three-dimensional structures such as extracellular matrix.

  • 17.
    Zhou, Bo
    et al.
    Guangxi Med Univ, Guangxi Engn Ctr Biomed Mat Tissue & Organ Regene, Affiliated Hosp 1, Nanning 530021, Peoples R China;Guangxi Med Univ, Affiliated Hosp 1, Guangxi Collaborat Innovat Ctr Biomed, Nanning 530021, Peoples R China.
    Gao, Ming
    Guangxi Med Univ, Guangxi Engn Ctr Biomed Mat Tissue & Organ Regene, Affiliated Hosp 1, Nanning 530021, Peoples R China;Guangxi Med Univ, Affiliated Hosp 1, Guangxi Collaborat Innovat Ctr Biomed, Nanning 530021, Peoples R China.
    Feng, Xianjing
    Guangxi Med Univ, Guangxi Engn Ctr Biomed Mat Tissue & Organ Regene, Affiliated Hosp 1, Nanning 530021, Peoples R China;Guangxi Med Univ, Affiliated Hosp 1, Guangxi Collaborat Innovat Ctr Biomed, Nanning 530021, Peoples R China;Guangxi Med Univ, Pharmaceut Coll, Nanning 530021, Peoples R China.
    Huang, Lanli
    Guangxi Med Univ, Affiliated Hosp 1, Guangxi Collaborat Innovat Ctr Biomed, Nanning 530021, Peoples R China;Guangxi Med Univ, Pharmaceut Coll, Nanning 530021, Peoples R China.
    Huang, Quanxin
    Guangxi Med Univ, Guangxi Engn Ctr Biomed Mat Tissue & Organ Regene, Affiliated Hosp 1, Nanning 530021, Peoples R China;Guangxi Med Univ, Affiliated Hosp 1, Guangxi Collaborat Innovat Ctr Biomed, Nanning 530021, Peoples R China.
    Kootala, Sujit
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Larsson, Tobias E.
    Karolinska Inst, Dept Clin Sci Intervent & Technol, SE-14186 Stockholm, Sweden;Karolinska Univ Hosp, Dept Nephrol, Stockholm, Sweden.
    Zheng, Li
    Guangxi Med Univ, Guangxi Engn Ctr Biomed Mat Tissue & Organ Regene, Affiliated Hosp 1, Nanning 530021, Peoples R China;Guangxi Med Univ, Affiliated Hosp 1, Guangxi Collaborat Innovat Ctr Biomed, Nanning 530021, Peoples R China.
    Bowden, Tim
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Carbazate modified dextrans as scavengers for carbonylated proteins2020In: Carbohydrate Polymers, ISSN 0144-8617, E-ISSN 1879-1344, Vol. 232, article id 115802Article in journal (Refereed)
    Abstract [en]

    A series of biocompatible and non- toxic polysaccharide molecules have been successfully fabricated and explored their potential application for scavenging the carbonyl species in vitro. These macromolecules were dextrans with different hydrazide substitution ratios determined by TNBS assay, NMR and FTIR characterization. The colorimetric assay had demonstrated that these macromolecules could effectively scavenge acrolein, oxidized bovine serum albumin (BSA) in buffer solutions as well as carbonyl proteins from serum. The scavengers could achieve twice more scavenging effects for modified dextrans with high molecular weight (Mw=100,000) than those of low ones (Mw=40,000) with the same substitution ratio. Protein gel electrophoresis confirmed that the formation of the complex between carbonyls and modified dextrans resulted in appearance of slower bands. It also revealed that such macromolecules could protect cultured cells against the toxicity of acrolein or its derivatives. The proposed macromolecules indicated a very promising capability as scavengers for oxidative stress plus its derivatives without side effects.

1 - 17 of 17
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