uu.seUppsala University Publications
Change search
Refine search result
1 - 13 of 13
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Disputation date (earliest first)
  • Disputation date (latest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the Create feeds function.
  • 1.
    Fransson, Anette E
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Kisiel, Marta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Pirttilä, Kristian
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Pettersson, Curt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Analytical Pharmaceutical Chemistry.
    Videhult Pierre, Pernilla
    Division of Audiology, Department of Clinical Science, Intervention and Technology, Karolinska Institutet, Stockholm, Sweden.
    Laurell, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Hydrogen Inhalation Protects against Ototoxicity Induced by Intravenous Cisplatin in the Guinea Pig2017In: Frontiers in Cellular Neuroscience, ISSN 1662-5102, E-ISSN 1662-5102, Vol. 11, article id 280Article in journal (Refereed)
    Abstract [en]

    Introduction: Permanent hearing loss and tinnitus as side-effects from treatment with the anticancer drug cisplatin is a clinical problem. Ototoxicity may be reduced by co-administration of an otoprotective agent, but the results in humans have so far been modest.

    Aim: The present preclinical in vivo study aimed to explore the protective efficacy of hydrogen (H2) inhalation on ototoxicity induced by intravenous cisplatin.

    Materials and Methods: Albino guinea pigs were divided into four groups. The Cispt (n = 11) and Cispt+H2 (n = 11) groups were given intravenous cisplatin (8 mg/kg b.w., injection rate 0.2 ml/min). Immediately after, the Cispt+H2 group also received gaseous H2 (2% in air, 60 min). The H2 group (n = 5) received only H2 and the Control group (n = 7) received neither cisplatin nor H2. Ototoxicity was assessed by measuring frequency specific ABR thresholds before and 96 h after treatment, loss of inner (IHCs) and outer (OHCs) hair cells, and by performing densitometry-based immunohistochemistry analysis of cochlear synaptophysin, organic transporter 2 (OCT2), and copper transporter 1 (CTR1) at 12 and 7 mm from the round window. By utilizing metabolomics analysis of perilymph the change of metabolites in the perilymph was assessed.

    Results: Cisplatin induced electrophysiological threshold shifts, hair cell loss, and reduced synaptophysin immunoreactivity in the synapse area around the IHCs and OHCs. H2 inhalation mitigated all these effects. Cisplatin also reduced the OCT2 intensity in the inner and outer pillar cells and in the stria vascularis as well as the CTR1 intensity in the synapse area around the IHCs, the Deiters' cells, and the stria vascularis. H2 prevented the majority of these effects.

    Conclusion: H2 inhalation can reduce cisplatin-induced ototoxicity on functional, cellular, and subcellular levels. It is proposed that synaptopathy may serve as a marker for cisplatin ototoxicity. The effect of H2 on the antineoplastic activity of cisplatin needs to be further explored.

  • 2.
    Kisiel, Marta
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Bone Enhancement with BMP-2 for Safe Clinical Translation2013Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Bone morphogenetic protein-2 (BMP-2) is considered a promising adjuvant for the treatment of bone regeneration. However, BMP-2 delivery in a conventional collagen scaffold needs a high dose to achieve an effective outcome. Moreover, such dosage may lead to serious side effects. The aim of the following thesis was to find clinically acceptable strategies reducing the required dose of BMP-2 by improving the delivery and optimizing the preclinical testing of the new approaches. In all the studies hyaluronic acid (HA) hydrogels was used as a carrier for BMP-2.

    The HA hydrogel/BMP-2 construct was modified with bioactive matrix components in order to obtain an effective release of BMP-2 and an enhanced bone formation. The most promising were two strategies. In the first one, BMP-2, precomplexed with the glycosaminoglycans dermatan sulfate or heparin prior to loading it into HA hydrogel, protected and prolonged the delivery of the protein, resulting in twofold larger bone formation in comparison to non-complexed BMP-2. In the second strategy, the fibronectin fragment integrin-binding domain (FN) was covalently incorporated into HA hydrogel. The FN remarkably improved the capacity of the material to support the cells attachment and spreading, providing the formation of twice as much bone in comparison to non-functionalized HA hydrogel/BMP-2.

    Furthermore, the importance of a proper design of the preclinical study for BMP-2 delivery systems was highlighted. Firstly, proper physicochemical handling of BMP-2 showed the improvement in further in vivo activity.  The use of glass storage vials and an acidic formulation buffer was superior to plastic surfaces and physiological pH. Secondly, while regenerative medicine strategy testing required the use of animal models that matched the research questions related to clinical translation, two new animal models were developed. The subperiosteal mandibular and calvarial models in rats were found to be minimally invasive, convenient and rapid solution for the evaluation of a broad range of approaches including bone augmentation, replacement and regeneration. Both models are primarily relevant for the initial testing of the injectable bone engineering constructs. 

    Those clinically translatable approaches presented here could prove to be a powerful platform for a wider use of BMP-2 in orthopedic, plastic surgery and regenerative medicine research.

    List of papers
    1. Critical assessment of rhBMP-2 mediated bone induction: An in vitro and in vivo evaluation.
    Open this publication in new window or tab >>Critical assessment of rhBMP-2 mediated bone induction: An in vitro and in vivo evaluation.
    Show others...
    2012 (English)In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 162, no 3, p. 646-653Article in journal (Refereed) Published
    Abstract [en]

    Understanding the influence of formulation and storage conditions on rhBMP-2 bioactivity is extremely important for its clinical application. Reports in the literature show that different research groups employ different parameters such as formulation conditions, storage, doses for in vivo applications etc. that makes it difficult to correlate results from different experiments. We therefore decided to rationalize these anomalies by performing a basic study on such parameters using two commercially available BMPs. Our in vitro experiments suggest that BMPs from different sources have significant differences in their bioactivity. The clinically approved rhBMP-2 (InductOs®; BMP-P) showed superior stability, compared to rhBMP-2 from R&D Systems (BMP-R) at physiological pH (determined by ALP assay). This BMP-P also showed lower binding to polypropylene Eppendorf tube. The BMP-R almost lost its bioactivity within 30min at physiological pH and also shows more adhesion to plastic surfaces. This aggregation behavior was unequivocally ascertained by performing light scattering studies of the two BMPs, which revealed linear aggregation with time for BMP-R unlike BMP-P. The in vitro results were also reflected in the in vivo experiments, in a rat ectopic model with injectable hyaluronic acid (HA) hydrogel as BMP carrier. After 7weeks post-implantation we observed larger bone volume with oriented collagen in the BMP-P group but a smaller bone with disoriented collagen in the BMP-R case. Our results highlight the large difference in activity between seemingly identical substances and also the importance of proper handling of such sensitive proteins.

    National Category
    Natural Sciences Polymer Chemistry
    Research subject
    Chemistry with specialization in Polymer Chemistry
    Identifiers
    urn:nbn:se:uu:diva-181153 (URN)10.1016/j.jconrel.2012.08.004 (DOI)000310506900021 ()22902595 (PubMedID)
    Available from: 2012-09-17 Created: 2012-09-17 Last updated: 2017-12-07Bibliographically approved
    2. Smart design of stable hydrazone crosslinked extracellular matrix mimetic hydrogel for tissue engineering application
    Open this publication in new window or tab >>Smart design of stable hydrazone crosslinked extracellular matrix mimetic hydrogel for tissue engineering application
    Show others...
    2012 (English)In: Journal of Tissue Engineering and Regenerative Medicine, ISSN 1932-6254, Vol. 6, no suppl 1, p. 192-192Article in journal, Meeting abstract (Other academic) Published
    Abstract [en]

    Injectable hydrogels are important biomaterials with enormous applications. They are used for various biomedical applications such as diagnostics, 3D cell culture matrix, drug reservoir, encapsulation of bioactive compounds and growth factors, scaffold for tissue engineering etc. We here present our recent development in our efforts to develop hydrogel scaffolds with enhanced rigidity, stability, swelling characteristics. Hydrazone crosslinked gels are attractive due to its simplicity and versatility which could be formed by mixing appropriate aldehyde and hydrazide functionalized hyaluronan. By fine-tuning the electronic character around the hydrazone linkage, we succeeded in developing extremely stable hydrazone bond and utilized it for developing hyaluronan (HA) based synthetic extracellular matrix (ECM) hydrogel. Among the different hydrazides tested, we identified carbonyldihydrazide (CDH) as the best candidate to deliver stable hydrazone linkage. This stability is presumably due to extensive delocalization of the positive charge across neighboring amino groups of CDH. The hydrolytic stability imparted by this group was found to be several folds under acidic, basic and physiological pH when compared to other hydrazones. This tailored hydrogel with CDH also exhibited superior swelling and mechanical properties and enzymatic stability which makes it ideal for tissue engineering application.

    National Category
    Medical and Health Sciences Polymer Chemistry
    Research subject
    Chemistry with specialization in Polymer Chemistry
    Identifiers
    urn:nbn:se:uu:diva-182412 (URN)10.1002/term.1586 (DOI)000308313001311 ()
    Available from: 2012-10-12 Created: 2012-10-10 Last updated: 2013-02-11Bibliographically approved
    3. Complexation and sequestration of BMP-2 from an ECM mimetic hyaluronan gel for improved bone formation
    Open this publication in new window or tab >>Complexation and sequestration of BMP-2 from an ECM mimetic hyaluronan gel for improved bone formation
    Show others...
    2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 10, article id e78551Article in journal (Refereed) Published
    Abstract [en]

    Bone morphogenetic protein-2 (BMP-2) is considered a promising adjuvant for the treatment of skeletal non-union and spinal fusion. However, BMP-2 delivery in a conventional collagen scaffold necessitates a high dose to achieve an efficacious outcome. To lower its effective dose, we precomplexed BMP-2 with the glycosaminoglycans (GAGs) dermatan sulfate (DS) or heparin (HP), prior to loading it into a hyaluronic acid (HA) hydrogel. In vitro release studies showed that BMP-2 precomplexed with DS or HP had a prolonged delivery compared to without GAG. BMP-2-DS complexes achieved a slightly faster release in the first 24 h than HP; however, both delivered BMP-2 for an equal duration. Analysis of the kinetic interaction between BMP-2 and DS or HP showed that HP had approximately 10 times higher affinity for BMP-2 than DS, yet it equally stabilized the protein, as determined by alkaline phosphatase activity. Ectopic bone formation assays at subcutaneous sites in rats demonstrated that HA hydrogel-delivered BMP-2 precomplexed with GAG induced twice the volume of bone compared with BMP-2 delivered uncomplexed to GAG.

    Keywords
    Bone morphogenetic protein-2, Bone repair, BMP-2 release, Heparin, Dermatan sulfate
    National Category
    Orthopaedics Biomaterials Science
    Research subject
    Orthopaedics; Engineering Science with specialization in Materials Science
    Identifiers
    urn:nbn:se:uu:diva-188175 (URN)10.1371/journal.pone.0078551 (DOI)000326034500093 ()
    Available from: 2012-12-13 Created: 2012-12-13 Last updated: 2018-01-12Bibliographically approved
    4. Improving the osteogenic potential of BMP-2 with hyaluronic acid hydrogel modified with integrin-specific fibronectin fragment
    Open this publication in new window or tab >>Improving the osteogenic potential of BMP-2 with hyaluronic acid hydrogel modified with integrin-specific fibronectin fragment
    Show others...
    2013 (English)In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 34, no 3, p. 704-712Article in journal (Refereed) Published
    Abstract [en]

    While human bone morphogenetic protein-2 (rhBMP-2) is a promising growth factor for bone regeneration, its clinical efficacy has recently shown to be below expectation. In order to improve the clinical translation of rhBMP-2, there exists strong motivation to engineer better delivery systems. Hyaluronic acid (HA) hydrogel is a suitable carrier for the delivery of rhBMP-2, but a major limitation of this scaffold is its low cell adhesive properties. In this study, we have determined whether covalent grafting of an integrin-specific ligands into HA hydrogel could improve cell attachment and further enhance the osteogenic potential of rhBMP-2. A structurally stabilized fibronectin (FN) fragment containing the major integrin-binding domain of full-length FN (FN III9 *-10) was engineered, in order to be incorporated into HA hydrogel. Compared to non-functionalized HA hydrogel, HA-FN hydrogel remarkably improved the capacity of the material to support mesenchymal stem cell attachment and spreading. In an ectopic bone formation model in the rat, delivery of rhBMP-2 with HA-FN hydrogel resulted in the formation of twice as much bone with better organization of collagen fibers compared to delivering the growth factor in non-functionalized HA hydrogel. This engineered hydrogel carrier for rhBMP-2 can be relevant in clinical bone repair.

    Keywords
    Bone regeneration, Cell adhesion, Fibronectin, Hyaluronic acid hydrogel, Integrins, RhBMP-2
    National Category
    Natural Sciences
    Identifiers
    urn:nbn:se:uu:diva-184869 (URN)10.1016/j.biomaterials.2012.10.015 (DOI)000312759800011 ()
    Available from: 2012-11-21 Created: 2012-11-15 Last updated: 2017-12-07Bibliographically approved
    5. Bone Engineering by Biomimetic Injectable Hydrogel
    Open this publication in new window or tab >>Bone Engineering by Biomimetic Injectable Hydrogel
    Show others...
    2012 (English)In: Molecular Crystals and Liquid Crystals, ISSN 1542-1406, Vol. 555, no 1, p. 177-188Article in journal (Refereed) Published
    Abstract [en]

    Osteoporosis is a multifactorial bone disease characterized by low bone mineral density (BMD) and deterioration of micro-architecture of cancellous bone leading to bone fragility and risk of fractures. In the current work, a novel tissue engineering strategy was experimented to enhance bone architecture in the risk areas via local injection of a biomimetic/osteoinductive injectable hyaluronan based hydrogel loaded with nano-hydroxyapatite crystals (Hya/HA) with/without bone morphogenetic protein (BMP-2), in distal femur of normal and ovariectomized New Zealand white rabbits. Our results revealed the osteoinductive effect of the Hya/HA composite that enhanced bone density and architecture of the rabbit distal femur.

    Keywords
    Bone engineering, hyaluronic acid, hydroxyapatite, injectable hydrogels, osteoinduction, osteoporosis
    National Category
    Medical and Health Sciences Polymer Chemistry
    Research subject
    Chemistry with specialization in Polymer Chemistry
    Identifiers
    urn:nbn:se:uu:diva-174215 (URN)10.1080/15421406.2012.635530 (DOI)000302300400019 ()
    Conference
    11th International Conference on Frontiers of Polymers and Advanced Materials (ICFPAM 2011)
    Available from: 2012-05-15 Created: 2012-05-14 Last updated: 2013-02-11Bibliographically approved
    6. Minimally invasive mandibular bone augmentation using injectable hydrogels
    Open this publication in new window or tab >>Minimally invasive mandibular bone augmentation using injectable hydrogels
    Show others...
    2012 (English)In: Journal of Tissue Engineering and Regenerative Medicine, ISSN 1932-6254, Vol. 6, no S3, p. s15-s23Article in journal (Refereed) Published
    Abstract [en]

    Hyaluronic acid-based hydrogels are proven biocompatible materials and excellent carriers of bone morphogenetic protein-2 (BMP-2) that have been successfully tested for bone generation in vivo. Different formulations, with or without nanohydroxyapatite, have shown promise for craniofacial applications. In this study, 28 rats were used to investigate whether it is possible to achieve mandibular bone augmentation upon injection of novel hyaluronic acid-based hydrogels containing nanohydroxyapatite and different concentrations of BMP-2 (0, 5 and 150ÎŒg/ml). The biomaterials were injected subperiosteally through fine needles into the innate mandibular diastema, imitating a clinical procedure for resorbed mandibles. No incisions, flaps or sutures were necessary. After 8weeks the mandibles were evaluated by peripheral quantitative computed tomography (pQCT), micro-computed tomography (ÎŒCT), histology, immunohistochemistry and fluorochrome labelling. As a result, engineered bone was observed in all treated mandibles, with a statistically significant increase in mandibular bone volume correlated with the amount of BMP-2 loaded in the hydrogel formula. We therefore demonstrated that minimally invasive mandibular bone augmentation is possible upon injection in rats, when using the appropriate injectable scaffolds. This represents an attractive clinical alternative for oral implantology patients.

    Keywords
    Bone morphogenetic protein-2, Bone tissue engineering, Hyaluronic acid, Hydroxyapatite, Injectable hydrogel, Mandible, Minimally invasive, Rat animal model
    National Category
    Natural Sciences Polymer Chemistry
    Research subject
    Chemistry with specialization in Polymer Chemistry
    Identifiers
    urn:nbn:se:uu:diva-181021 (URN)10.1002/term.1593 (DOI)000313431100003 ()
    Note

    Correspondence Address: Hilborn, J.; Polymer Chemistry, Department of Chemistry - Ņngström Laboratory, Science for Life Laboratory email: hilborn@mkem.uu.se

    Available from: 2012-09-14 Created: 2012-09-14 Last updated: 2013-02-19Bibliographically approved
    7. Evaluation of injectable constructs for bone repair with a subperiosteal cranial model in the rat
    Open this publication in new window or tab >>Evaluation of injectable constructs for bone repair with a subperiosteal cranial model in the rat
    Show others...
    2013 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 8, p. 140p. e71683-Article in journal (Refereed) Published
    Abstract [en]

    While testing regenerative medicine strategies, the use of animal models that match the research questions and that are related to clinical translation is crucial. During the initial stage of evaluating new strategies for bone repair, the main goal is to state whether the strategies efficiently induce the formation of new bone tissue at an orthotopic site. Here, we present a subperiosteal model in rat calavria that allow the evaluation of a broad range of approaches including bone augmentation, replacement and regeneration. Easy and fast to perform, the model is minimally invasive and no defect are created. The procedure enables to evaluate the outcomes quantitatively using micro-computed tomography and qualitatively by histology and immunohistochemistry. For establishing the model, we used bone morphogenetic protein-2 as an osteoinductive factor and hyaluronic acid hydrogel as injectable biomaterial. We showed that this subperiosteal cranial model offers a minimally invasive and promising solution for a rapid evaluation of bone tissue engineering strategies, even for investigator with limited experience in orthopedic surgery. We believe that this approach could be a powerful platform for orthopedic research and regenerative medicine.

    Publisher
    p. 140
    Keywords
    Subperiosteal rat model, Minimally invasive surgery, Regenerative medicine, Bone repairr matrix, Hyaluronan, Animal model
    National Category
    Biomaterials Science Orthopaedics
    Research subject
    Orthopaedics; Surgery; Engineering Science; Engineering Science
    Identifiers
    urn:nbn:se:uu:diva-188001 (URN)10.1371/journal.pone.0071683 (DOI)000323115800075 ()
    Available from: 2012-12-13 Created: 2012-12-12 Last updated: 2018-01-12Bibliographically approved
  • 3.
    Kisiel, Marta
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Klar, Agnieszka S
    Martino, Mikaël M
    Ventura, Manuela
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Evaluation of injectable constructs for bone repair with a subperiosteal cranial model in the rat2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 8, p. 140p. e71683-Article in journal (Refereed)
    Abstract [en]

    While testing regenerative medicine strategies, the use of animal models that match the research questions and that are related to clinical translation is crucial. During the initial stage of evaluating new strategies for bone repair, the main goal is to state whether the strategies efficiently induce the formation of new bone tissue at an orthotopic site. Here, we present a subperiosteal model in rat calavria that allow the evaluation of a broad range of approaches including bone augmentation, replacement and regeneration. Easy and fast to perform, the model is minimally invasive and no defect are created. The procedure enables to evaluate the outcomes quantitatively using micro-computed tomography and qualitatively by histology and immunohistochemistry. For establishing the model, we used bone morphogenetic protein-2 as an osteoinductive factor and hyaluronic acid hydrogel as injectable biomaterial. We showed that this subperiosteal cranial model offers a minimally invasive and promising solution for a rapid evaluation of bone tissue engineering strategies, even for investigator with limited experience in orthopedic surgery. We believe that this approach could be a powerful platform for orthopedic research and regenerative medicine.

  • 4.
    Kisiel, Marta
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Martino, Mikaël M.
    Ventura, Manuela
    Hubbell, Jeffrey A.
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Ossipov, Dmitri A.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Improving the osteogenic potential of BMP-2 with hyaluronic acid hydrogel modified with integrin-specific fibronectin fragment2013In: Biomaterials, ISSN 0142-9612, E-ISSN 1878-5905, Vol. 34, no 3, p. 704-712Article in journal (Refereed)
    Abstract [en]

    While human bone morphogenetic protein-2 (rhBMP-2) is a promising growth factor for bone regeneration, its clinical efficacy has recently shown to be below expectation. In order to improve the clinical translation of rhBMP-2, there exists strong motivation to engineer better delivery systems. Hyaluronic acid (HA) hydrogel is a suitable carrier for the delivery of rhBMP-2, but a major limitation of this scaffold is its low cell adhesive properties. In this study, we have determined whether covalent grafting of an integrin-specific ligands into HA hydrogel could improve cell attachment and further enhance the osteogenic potential of rhBMP-2. A structurally stabilized fibronectin (FN) fragment containing the major integrin-binding domain of full-length FN (FN III9 *-10) was engineered, in order to be incorporated into HA hydrogel. Compared to non-functionalized HA hydrogel, HA-FN hydrogel remarkably improved the capacity of the material to support mesenchymal stem cell attachment and spreading. In an ectopic bone formation model in the rat, delivery of rhBMP-2 with HA-FN hydrogel resulted in the formation of twice as much bone with better organization of collagen fibers compared to delivering the growth factor in non-functionalized HA hydrogel. This engineered hydrogel carrier for rhBMP-2 can be relevant in clinical bone repair.

  • 5.
    Kisiel, Marta
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Ventura, M.
    George, Anu
    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.
    Varghese, Oommen P.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Critical Assessment of rhBMP-2 Mediated Bone Induction: an In Vitro and In Vivo Evaluation2012In: Journal of Tissue Engineering and Regenerative Medicine, ISSN 1932-6254, Vol. 6, no SI, p. 39-39Article in journal (Other academic)
  • 6.
    Kisiel, Marta
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ventura, Manuela
    Podiyan, Oommen
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    George, Anu
    Walboomers, X Frank
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Varghese, Oommen P
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Critical assessment of rhBMP-2 mediated bone induction: An in vitro and in vivo evaluation.2012In: Journal of Controlled Release, ISSN 0168-3659, E-ISSN 1873-4995, Vol. 162, no 3, p. 646-653Article in journal (Refereed)
    Abstract [en]

    Understanding the influence of formulation and storage conditions on rhBMP-2 bioactivity is extremely important for its clinical application. Reports in the literature show that different research groups employ different parameters such as formulation conditions, storage, doses for in vivo applications etc. that makes it difficult to correlate results from different experiments. We therefore decided to rationalize these anomalies by performing a basic study on such parameters using two commercially available BMPs. Our in vitro experiments suggest that BMPs from different sources have significant differences in their bioactivity. The clinically approved rhBMP-2 (InductOs®; BMP-P) showed superior stability, compared to rhBMP-2 from R&D Systems (BMP-R) at physiological pH (determined by ALP assay). This BMP-P also showed lower binding to polypropylene Eppendorf tube. The BMP-R almost lost its bioactivity within 30min at physiological pH and also shows more adhesion to plastic surfaces. This aggregation behavior was unequivocally ascertained by performing light scattering studies of the two BMPs, which revealed linear aggregation with time for BMP-R unlike BMP-P. The in vitro results were also reflected in the in vivo experiments, in a rat ectopic model with injectable hyaluronic acid (HA) hydrogel as BMP carrier. After 7weeks post-implantation we observed larger bone volume with oriented collagen in the BMP-P group but a smaller bone with disoriented collagen in the BMP-R case. Our results highlight the large difference in activity between seemingly identical substances and also the importance of proper handling of such sensitive proteins.

  • 7.
    Martinez-Sanz, Elena
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Varghese, Oommen
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Kisiel, Marta
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Engstrand, Thomas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Reich, Karoline
    Bohner, Marc
    Jonsson, Kenneth B
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Köhler, Thomas
    Müller, Ralph
    Ossipov, Dmitri
    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.
    Minimally invasive mandibular bone augmentation using injectable hydrogels2012In: Journal of Tissue Engineering and Regenerative Medicine, ISSN 1932-6254, Vol. 6, no S3, p. s15-s23Article in journal (Refereed)
    Abstract [en]

    Hyaluronic acid-based hydrogels are proven biocompatible materials and excellent carriers of bone morphogenetic protein-2 (BMP-2) that have been successfully tested for bone generation in vivo. Different formulations, with or without nanohydroxyapatite, have shown promise for craniofacial applications. In this study, 28 rats were used to investigate whether it is possible to achieve mandibular bone augmentation upon injection of novel hyaluronic acid-based hydrogels containing nanohydroxyapatite and different concentrations of BMP-2 (0, 5 and 150ÎŒg/ml). The biomaterials were injected subperiosteally through fine needles into the innate mandibular diastema, imitating a clinical procedure for resorbed mandibles. No incisions, flaps or sutures were necessary. After 8weeks the mandibles were evaluated by peripheral quantitative computed tomography (pQCT), micro-computed tomography (ÎŒCT), histology, immunohistochemistry and fluorochrome labelling. As a result, engineered bone was observed in all treated mandibles, with a statistically significant increase in mandibular bone volume correlated with the amount of BMP-2 loaded in the hydrogel formula. We therefore demonstrated that minimally invasive mandibular bone augmentation is possible upon injection in rats, when using the appropriate injectable scaffolds. This represents an attractive clinical alternative for oral implantology patients.

  • 8. Nageeb, Mohamad
    et al.
    Nouh, Samir R.
    Bergman, Kristoffer
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Nagy, Naglaa B.
    Khamis, Dalia
    Kisiel, Marta
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Engstrand, Thomas
    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.
    Marei, Mona K.
    Bone Engineering by Biomimetic Injectable Hydrogel2012In: Molecular Crystals and Liquid Crystals, ISSN 1542-1406, Vol. 555, no 1, p. 177-188Article in journal (Refereed)
    Abstract [en]

    Osteoporosis is a multifactorial bone disease characterized by low bone mineral density (BMD) and deterioration of micro-architecture of cancellous bone leading to bone fragility and risk of fractures. In the current work, a novel tissue engineering strategy was experimented to enhance bone architecture in the risk areas via local injection of a biomimetic/osteoinductive injectable hyaluronan based hydrogel loaded with nano-hydroxyapatite crystals (Hya/HA) with/without bone morphogenetic protein (BMP-2), in distal femur of normal and ovariectomized New Zealand white rabbits. Our results revealed the osteoinductive effect of the Hya/HA composite that enhanced bone density and architecture of the rabbit distal femur.

  • 9.
    Oommen, Oommen P.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Wang, Shujiang
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Kisiel, Marta
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Sloff, Marije
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Varghese, Oommen P.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Smart Design of Stable Extracellular Matrix Mimetic Hydrogel: Synthesis, Characterization, and In Vitro and In Vivo Evaluation for Tissue Engineering2013In: Advanced Functional Materials, ISSN 1616-301X, E-ISSN 1616-3028, Vol. 23, no 10, p. 1273-1280Article in journal (Refereed)
    Abstract [en]

    The simplicity and versatility of hydrazone crosslinking has made it a strategy of choice for the conjugation of bioactive molecules. However, the labile nature of hydrazone linkages and reversibility of this coupling reaction restricts its full potential. Based on the fundamental understanding of hydrazone stability, this problem is circumvented by resonance-stabilization of a developing N2 positive charge in a hydrazone bond. A novel chemistry is presented to develop a resilient hydrazone bond that is stable and non- reversible under physiological conditions. A carbodihydrazide (CDH) type hydrazide derivative of the biomolecule forms intrinsically stabilized hydrazone-linkages that are nearly 15-fold more stable at pH 5 than conventional hydrazone. This chemoselective coupling reaction is catalyst-free, instantaneous, and virtually non-cleavable under physiological conditions, therefore can serve as a catalyst-free alternative to click chemistry. This novel crosslinking reaction is used to tailor a hyaluronan hydrogel, which delivered exceptional hydrolytic stability, mechanical properties, low swelling, and controlled enzymatic degradation. These desired characteristics are achieved without increasing the chemical crosslinking. The in vivo evaluation of this hydrogel revealed neo-bone with highly ordered collagen matrix mimicking natural bone regeneration. The proximity ligation assay or PLA is used to detect blood vessels, which highlighted the quality of engineered tissue.

  • 10.
    Pierre, Pernilla Videhult
    et al.
    Karolinska Inst, Dept Clin Sci Intervent & Technol, Div Audiol, Stockholm, Sweden.
    Fransson, Anette
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Kisiel, Marta Alina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Damberg, Peter
    Karolinska Univ Hosp, Karolinska Expt Res & Imaging Ctr, Stockholm, Sweden.
    Aski, Sahar Nikkhou
    Karolinska Univ Hosp, Karolinska Expt Res & Imaging Ctr, Stockholm, Sweden.
    Andersson, Mats
    RISE Res Inst Sweden, Div Biosci & Mat, Sodertalje, Sweden.
    Hallgren, Lotta
    RISE Res Inst Sweden, Div Biosci & Mat, Sodertalje, Sweden.
    Laurell, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Otolaryngology and Head and Neck Surgery.
    Middle Ear Administration of a Particulate Chitosan Gel in an in vivo Model of Cisplatin Ototoxicity2019In: Frontiers in Cellular Neuroscience, ISSN 1662-5102, E-ISSN 1662-5102, Vol. 13, article id 268Article in journal (Refereed)
    Abstract [en]

    Background: Middle ear (intratympanic, IT) administration is a promising therapeutic method as it offers the possibility of achieving high inner ear drug concentrations with low systemic levels, thus minimizing the risk of systemic side effects and drug-drug interactions. Premature elimination through the Eustachian tube may be reduced by stabilizing drug solutions with a hydrogel, but this raises the secondary issue of conductive hearing loss. Aim: This study aimed to investigate the properties of a chitosan-based particulate hydrogel formulation when used as a drug carrier for IT administration in an in vivo model of ototoxicity. Materials and Methods: Two particulate chitosan-based IT delivery systems, Thio-25 and Thio-40, were investigated in albino guinea pigs (n = 94). Both contained the hearing protecting drug candidate sodium thiosulfate with different concentrations of chitosan gel particles (25% vs. 40%). The safety of the two systems was explored in vivo. The most promising system was then tested in guinea pigs subjected to a single intravenous injection with the anticancer drug cisplatin (8 mg/kg b.w.), which has ototoxic side effects. Hearing status was evaluated with acoustically evoked frequency-specific auditory brainstem response (ABR) and hair cell counting. Finally, in vivo magnetic resonance imaging was used to study the distribution and elimination of the chitosan-based system from the middle ear cavity in comparison to a hyaluronan-based system. Results: Both chitosan-based IT delivery systems caused ABR threshold elevations (p < 0.05) that remained after 10 days (p < 0.05) without evidence of hair cell loss, although the elevation induced by Thio-25 was significantly lower than for Thio-40 (p < 0.05). Thio-25 significantly reduced cisplatin-induced ABR threshold elevations (p < 0.05) and outer hair cell loss (p < 0.05). IT injection of the chitosan- and hyaluronan-based systems filled up most of the middle ear space. There were no significant differences between the systems in terms of distribution and elimination. Conclusion: Particulate chitosan is a promising drug carrier for IT administration. Future studies should assess whether the physical properties of this technique allow for a smaller injection volume that would reduce conductive hearing loss.

  • 11.
    Podiyan, Oommen
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Wang, Shujiang
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Kisiel, Marta
    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.
    Varghese, Oommen P.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Smart design of stable hydrazone crosslinked extracellular matrix mimetic hydrogel for tissue engineering application2012In: Journal of Tissue Engineering and Regenerative Medicine, ISSN 1932-6254, Vol. 6, no suppl 1, p. 192-192Article in journal (Other academic)
    Abstract [en]

    Injectable hydrogels are important biomaterials with enormous applications. They are used for various biomedical applications such as diagnostics, 3D cell culture matrix, drug reservoir, encapsulation of bioactive compounds and growth factors, scaffold for tissue engineering etc. We here present our recent development in our efforts to develop hydrogel scaffolds with enhanced rigidity, stability, swelling characteristics. Hydrazone crosslinked gels are attractive due to its simplicity and versatility which could be formed by mixing appropriate aldehyde and hydrazide functionalized hyaluronan. By fine-tuning the electronic character around the hydrazone linkage, we succeeded in developing extremely stable hydrazone bond and utilized it for developing hyaluronan (HA) based synthetic extracellular matrix (ECM) hydrogel. Among the different hydrazides tested, we identified carbonyldihydrazide (CDH) as the best candidate to deliver stable hydrazone linkage. This stability is presumably due to extensive delocalization of the positive charge across neighboring amino groups of CDH. The hydrolytic stability imparted by this group was found to be several folds under acidic, basic and physiological pH when compared to other hydrazones. This tailored hydrogel with CDH also exhibited superior swelling and mechanical properties and enzymatic stability which makes it ideal for tissue engineering application.

  • 12.
    Varghese, Oommen P.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Kisiel, Marta
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Martinez-Sanz, Elena
    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.
    Hilborn, Jöns
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Materials Chemistry, Polymer Chemistry.
    Synthesis of Guanidinium-Modified Hyaluronic Acid Hydrogel2010In: Macromolecular rapid communications, ISSN 1022-1336, E-ISSN 1521-3927, Vol. 31, no 13, p. 1175-1180Article in journal (Refereed)
    Abstract [en]

    In this report, a new guanidinylating reagent is presented, which was developed without any protection/deprotection strategy and was successfully employed for linking to hyaluronan in aqueous solution. The dually functionalised HA biopolymer bearing guanidinium and hydrazide groups was synthesised to form hydrogel in Ho less than a minute when mixed with aldehyde-modified HA. This hydrogel exhibited higher storage modulus with enhanced stability in PBS when compared to the non-guanidine-containing gel. The gel shift assay showed that this biopolymer formed a stable complex with DNA as well as efficient gene transfection to cells that express HA-receptor CD44. The toxicity studies of this polymer with fibroblast cells revealed that the cells were almost 80% viable after 4 d of incubation at high HA concentration (2.5 x 10(-3) m).

  • 13.
    Varghese, Oommen P.
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Podiyan, Oommen
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - Ångström, Polymer Chemistry.
    Wang, S
    Kisiel, Marta
    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.
    Injectable hyaluronic acid hydrogel for bone tissue engineering2012In: European Cells and Materials, ISSN 1473-2262, E-ISSN 1473-2262, Vol. 23, no supplement 3, p. 2-Article in journal (Refereed)
1 - 13 of 13
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf