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  • 1.
    Bratengeier, Cornelia
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Johansson, L.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi.
    Liszka, Aneta
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Bakker, A. D.
    Univ Amsterdam, Netherlands; Vrije Univ Amsterdam, Netherlands.
    Hallbeck, Martin
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för neurobiologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk patologi.
    Fahlgren, Anna
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Mechanical loading intensities affect the release of extracellular vesicles from mouse bone marrow-derived hematopoietic progenitor cells and change their osteoclast-modulating effect2024Ingår i: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 38, nr 1, artikel-id e23323Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Low-intensity loading maintains or increases bone mass, whereas lack of mechanical loading and high-intensity loading decreases bone mass, possibly via the release of extracellular vesicles by mechanosensitive bone cells. How different loading intensities alter the biological effect of these vesicles is not fully understood. Dynamic fluid shear stress at low intensity (0.7 +/- 0.3 Pa, 5 Hz) or high intensity (2.9 +/- 0.2 Pa, 1 Hz) was used on mouse hematopoietic progenitor cells for 2 min in the presence or absence of chemical compounds that inhibit release or biogenesis of extracellular vesicles. We used a Receptor activator of nuclear factor kappa-Beta ligand-induced osteoclastogenesis assay to evaluate the biological effect of different fractions of extracellular vesicles obtained through centrifugation of medium from hematopoietic stem cells. Osteoclast formation was reduced by microvesicles (10 000x g) obtained after low-intensity loading and induced by exosomes (100 000x g) obtained after high-intensity loading. These osteoclast-modulating effects could be diminished or eliminated by depletion of extracellular vesicles from the conditioned medium, inhibition of general extracellular vesicle release, inhibition of microvesicle biogenesis (low intensity), inhibition of ESCRT-independent exosome biogenesis (high intensity), as well as by inhibition of dynamin-dependent vesicle uptake in osteoclast progenitor cells. Taken together, the intensity of mechanical loading affects the release of extracellular vesicles and change their osteoclast-modulating effect. The intensity of mechanical loading strongly affects bone remodeling by either formation of bone or resorption of bone. Low-intensity loading on bone cells releases microvesicles that reduce formation of bone-resorbing osteoclasts, while high-intensity loading on bone cells releases exosomes that induce formation of bone-resorbing osteoclasts. The graphical abstract was created with image

  • 2.
    Lindahl, Gabriel
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Fjellander, Sebastian
    Linköpings universitet, Institutionen för hälsa, medicin och vård, Avdelningen för diagnostik och specialistmedicin. Linköpings universitet, Medicinska fakulteten. BioReper AB, Linkoping, Sweden.
    Selvaraj, Karthik
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för klinisk kemi och farmakologi. Linköpings universitet, Medicinska fakulteten.
    Vildeval, Malin
    BioReper AB, Linkoping, Sweden.
    Ali, Zaheer
    BioReper AB, Linkoping, Sweden.
    Almter, Rusul
    BioReper AB, Linkoping, Sweden.
    Erkstam, Anna
    BioReper AB, Linkoping, Sweden.
    Rodriguez, Gabriela Vazquez
    BioReper AB, Linkoping, Sweden.
    Abrahamsson, Annelie
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten.
    Rydmark Kersley, Asa
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten, Forum Östergötland. Region Östergötland, Barn- och kvinnocentrum, Kvinnokliniken US.
    Fahlgren, Anna
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. BioReper AB, Linkoping, Sweden.
    Kjölhede, Preben
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för barns och kvinnors hälsa. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Barn- och kvinnocentrum, Kvinnokliniken US.
    Linder, Stig
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för klinisk kemi och farmakologi. Linköpings universitet, Medicinska fakulteten.
    Dabrosin, Charlotta
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
    Jensen, Lasse
    Linköpings universitet, Institutionen för hälsa, medicin och vård, Avdelningen för diagnostik och specialistmedicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk farmakologi. BioReper AB, Linkoping, Sweden.
    Zebrafish tumour xenograft models: a prognostic approach to epithelial ovarian cancer2024Ingår i: npj Precision Oncology, E-ISSN 2397-768X, Vol. 8, nr 1, artikel-id 53Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Epithelial ovarian cancer (EOC) is the gynaecological malignancy with highest mortality. Although adjuvant treatment with carboplatin and paclitaxel leads to an objective response in similar to 80% of these patients, a majority will relapse within two years. Better methods for assessing long-term treatment outcomes are needed. To address this, we established safe and efficacious doses of carboplatin and paclitaxel using IGROV-1 zebrafish-CDX models. Then fluorescently-labelled cell suspensions from 83 tumour biopsies collected at exploratory laparotomy of women with suspected EOC were generated and 37 (45%) were successfully implanted in zebrafish larvae. Among these 19 of 27 pathology-confirmed EOC samples (70%) engrafted. These zebrafish patient-derived tumour xenograft (ZTX) models were treated with carboplatin or paclitaxel and tumour growth/regression and metastatic dissemination were recorded. In a subgroup of nine patients, four ZTX models regressed during carboplatin treatment. All four corresponding patients had > 24 months PFS. Furthermore, both ZTX models established from two patients having < 24 months PFS failed to regress during carboplatin treatment. Seven of eight models seeding < 6 metastatic cells were established from patients having > 24 months PFS. In eleven of fourteen patients, FIGO stage I + II or III tumours gave rise to ZTX models seeding < 4 or > 4 metastatic cells, respectively. In conclusion, ZTX models predicted patients having > 24 or < 24 months PFS, based on response/no response to carboplatin. Furthermore, high metastatic dissemination in ZTX models correlated to shorter PFS and more advanced disease at diagnosis. These preliminary results suggest that ZTX models could become a useful prognostic tool in EOC treatment planning.

  • 3.
    Kowald, Saskia
    et al.
    Linköpings universitet, Institutionen för hälsa, medicin och vård, Avdelningen för diagnostik och specialistmedicin. Linköpings universitet, Medicinska fakulteten.
    Huge, Ylva
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Urologiska kliniken i Östergötland.
    Tandiono, Decky
    BioReper AB, SE-58213 Linkoping, Sweden.
    Ali, Zaheer
    BioReper AB, SE-58213 Linkoping, Sweden.
    Vazquez-Rodriguez, Gabriela
    BioReper AB, SE-58213 Linkoping, Sweden.
    Erkstam, Anna
    BioReper AB, SE-58213 Linkoping, Sweden.
    Fahlgren, Anna
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. BioReper AB, SE-58213 Linkoping, Sweden.
    Sherif, Amir
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Umea Univ, Sweden.
    Cao, Yihai
    Karolinska Inst, Sweden.
    Jensen, Lasse
    Linköpings universitet, Institutionen för hälsa, medicin och vård, Avdelningen för diagnostik och specialistmedicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk farmakologi. BioReper AB, SE-58213 Linkoping, Sweden.
    Novel Zebrafish Patient-Derived Tumor Xenograft Methodology for Evaluating Efficacy of Immune-Stimulating BCG Therapy in Urinary Bladder Cancer2023Ingår i: Cells, E-ISSN 2073-4409, Vol. 12, nr 3, artikel-id 508Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Bacillus Calmette-Guerin (BCG) immunotherapy is the standard-of-care adjuvant therapy for non-muscle-invasive bladder cancer in patients at considerable risk of disease recurrence. Although its exact mechanism of action is unknown, BCG significantly reduces this risk in responding patients but is mainly associated with toxic side-effects in those facing treatment resistance. Methods that allow the identification of BCG responders are, therefore, urgently needed. Methods: Fluorescently labelled UM-UC-3 cells and dissociated patient tumor samples were used to establish zebrafish tumor xenograft (ZTX) models. Changes in the relative primary tumor size and cell dissemination to the tail were evaluated via fluorescence microscopy at three days post-implantation. The data were compared to the treatment outcomes of the corresponding patients. Toxicity was evaluated based on gross morphological evaluation of the treated zebrafish larvae. Results: BCG-induced toxicity was avoided by removing the water-soluble fraction of the BCG formulation prior to use. BCG treatment via co-injection with the tumor cells resulted in significant and dose-dependent primary tumor size regression. Heat-inactivation of BCG decreased this effect, while intravenous BCG injections were ineffective. ZTX models were successfully established for six of six patients based on TUR-B biopsies. In two of these models, significant tumor regression was observed, which, in both cases, corresponded to the treatment response in the patients. Conclusions: The observed BCG-related anti-tumor effect indicates that ZTX models might predict the BCG response and thereby improve treatment planning. More experiments and clinical studies are needed, however, to elucidate the BCG mechanism and estimate the predictive value.

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  • 4.
    Gunnarsson, Svante
    et al.
    Linköpings universitet, Institutionen för systemteknik, Reglerteknik. Linköpings universitet, Tekniska fakulteten.
    Fahlgren, Anna
    Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för cellbiologi.
    Fagrell, Per
    KTH Royal Institute of Technology, Stockholm, Sweden.
    Enhancing Interaction with External Stakeholders in Program Management2022Ingår i: Proceedings of the 18th International CDIO Conference, 2022, s. 61-71Konferensbidrag (Övrigt vetenskapligt)
    Abstract [en]

    Interaction with the surrounding society and external stakeholders is an important component when developing and managing high quality and relevant education programs. This paper presents some of the outcomes of the project MERUT which was carried out during 2018 – 2020 with support from the Swedish innovation agency Vinnova. The key outcome is a toolbox offering a structured way to describe and handle methods and tools for stakeholder interaction. The methods of interaction are organized in three categories, denoted A, B, and C, where category A includes methods for external stakeholders to influence the management and development of the education program. Category B consists of means for external stakeholders to have an active role in course modules, and category C contains methods and tools to evaluate the quality and relevance of the education from, for example, alumni or employer perspective. Examples from the different categories are presented, including the CDIO Syllabus Survey, alumni surveys, and reflection documents. 

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  • 5.
    Bratengeier, Cornelia
    et al.
    Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för cellbiologi.
    Bakker, Astrid D.
    Department of Oral Cell Biology, Academic Centre for Dentistry Amsterdam (ACTA), University of Amsterdam and Vrije Universiteit Amsterdam, Amsterdam Movement Sciences, Amsterdam, The Netherlands.
    Liszka, Aneta
    Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för cellbiologi.
    Schilcher, Jörg
    Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Ortopedkliniken i Linköping. Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi.
    Fahlgren, Anna
    Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för cellbiologi.
    The release of osteoclast-stimulating factors on supraphysiological loading by osteoprogenitors coincides with expression of genes associated with inflammation and cytoskeletal arrangement2022Ingår i: Scientific Reports, E-ISSN 2045-2322, Vol. 12, nr 1, artikel-id 21578Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Supraphysiological loading induced by unstable orthopedic implants initiates osteoclast formation, which results in bone degradation. We aimed to investigate which mechanosensitive cells in the peri-implant environment produce osteoclast-stimulating factors and how the production of these factors is stimulated by supraphysiological loading. The release of osteoclast-stimulating factors by different types of isolated bone marrow-derived hematopoietic and mesenchymal stem cells from six osteoarthritic patients was analyzed after one hour of supraphysiological loading (3.0 ± 0.2 Pa, 1 Hz) by adding their conditioned medium to osteoclast precursors. Monocytes produced factors that enhanced osteoclastogenesis by 1.6 ± 0.07-fold and mesenchymal stem cells by 1.4 ± 0.07-fold. Medium from osteoprogenitors and pre-osteoblasts enhanced osteoclastogenesis by 1.3 ± 0.09-fold and 1.4 ± 0.03-fold, respectively, where medium from four patients elicited a response and two did not. Next generation sequencing analysis of osteoprogenitors revealed that genes encoding for inflammation-related pathways and cytoskeletal rearrangements were regulated differently between responders and non-responders. Our data suggest that released osteoclast-stimulating soluble factors by progenitor cells in the bone marrow after supraphysiological loading may be related to cytoskeletal arrangement in an inflammatory environment. This connection could be relevant to better understand the aseptic loosening process of orthopedic implants.

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  • 6.
    Ali, Zaheer
    et al.
    BioReperia AB, Linkoping, Sweden.
    Vildevall, Malin
    BioReperia AB, Linkoping, Sweden.
    Rodriguez, Gabriela Vazquez
    BioReperia AB, Linkoping, Sweden.
    Tandiono, Decky
    BioReperia AB, Linkoping, Sweden.
    Vamvakaris, Ioannis
    Athens Chest Hosp Sotiria, Greece.
    Evangelou, Georgios
    Natl Kapodistrian Univ Athens, Greece.
    Lolas, Georgios
    Natl Kapodistrian Univ Athens, Greece; Catalan Inst Oncol ICO, Spain.
    Syrigos, Konstantinos N.
    Natl Kapodistrian Univ Athens, Greece.
    Villanueva, Alberto
    InCELLiA PC, Greece; Xenopat SL, Spain.
    Wick, Michael
    XenoSTART, TX USA.
    Omar, Shenga
    Linköpings universitet, Institutionen för hälsa, medicin och vård, Avdelningen för diagnostik och specialistmedicin. Linköpings universitet, Medicinska fakulteten.
    Erkstam, Anna
    BioReperia AB, Linkoping, Sweden.
    Schueler, Julia
    Charles River Labs, Germany.
    Fahlgren, Anna
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. BioReperia AB, Linkoping, Sweden.
    Jensen, Lasse
    Linköpings universitet, Institutionen för hälsa, medicin och vård, Avdelningen för diagnostik och specialistmedicin. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Diagnostikcentrum, Klinisk farmakologi. BioReperia AB, Linkoping, Sweden.
    Zebrafish patient-derived xenograft models predict lymph node involvement and treatment outcome in non-small cell lung cancer2022Ingår i: Journal of Experimental & Clinical Cancer Research, E-ISSN 1756-9966, Vol. 41, nr 1, artikel-id 58Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background Accurate predictions of tumor dissemination risks and medical treatment outcomes are critical to personalize therapy. Patient-derived xenograft (PDX) models in mice have demonstrated high accuracy in predicting therapeutic outcomes, but methods for predicting tumor invasiveness and early stages of vascular/lymphatic dissemination are still lacking. Here we show that a zebrafish tumor xenograft (ZTX) platform based on implantation of PDX tissue fragments recapitulate both treatment outcome and tumor invasiveness/dissemination in patients, within an assay time of only 3 days. Methods Using a panel of 39 non-small cell lung cancer PDX models, we developed a combined mouse-zebrafish PDX platform based on direct implantation of cryopreserved PDX tissue fragments into zebrafish embryos, without the need for pre-culturing or expansion. Clinical proof-of-principle was established by direct implantation of tumor samples from four patients. Results The resulting ZTX models responded to Erlotinib and Paclitaxel, with similar potency as in mouse-PDX models and the patients themselves, and resistant tumors similarly failed to respond to these drugs in the ZTX system. Drug response was coupled to elevated expression of EGFR, Mdm2, Ptch1 and Tsc1 (Erlotinib), or Nras and Ptch1 (Paclitaxel) and reduced expression of Egfr, Erbb2 and Foxa (Paclitaxel). Importantly, ZTX models retained the invasive phenotypes of the tumors and predicted lymph node involvement of the patients with 91% sensitivity and 62% specificity, which was superior to clinically used tests. The biopsies from all four patient tested implanted successfully, and treatment outcome and dissemination were quantified for all patients in only 3 days. Conclusions We conclude that the ZTX platform provide a fast, accurate, and clinically relevant system for evaluation of treatment outcome and invasion/dissemination of PDX models, providing an attractive platform for combined mouse-zebrafish PDX trials and personalized medicine.

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  • 7.
    Fagrell, Per
    et al.
    KTH.
    Fahlgren, Anna
    Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för cellbiologi.
    Gunnarsson, Svante
    Linköpings universitet, Institutionen för systemteknik, Reglerteknik. Linköpings universitet, Tekniska fakulteten.
    Relevans i högre utbildning2021Konferensbidrag (Refereegranskat)
    Abstract [sv]

    Betyder kvalitet och relevans samma sak inom högre utbildning? Medan begreppet kvalitet har studerats utförligt och används i utvärderings- och kvalitetssäkringssystem, är betydelsen och vikten av ordet relevans inte studerat i samma omfattning. Inom ramen för en nyligen genomförd studie gjordes ett försök att rama in begreppen kvalitet och relevans inom högre utbildning och klargöra eventuella likheter och skillnader i begreppens innebörd. Vidare belystes kopplingen till nyttiggörande och arbetsmarknad. Samtliga tillfrågade i studien såg kopplingar mellan kvalitet och relevans, och flera menade att en utbildning med hög kvalitet rimligtvis bör vara relevant, och av det följer att relevans bör vara en viktig komponent i kvalitetsbegreppet. Dessutom uppfattas kvalitet och relevans i många fall som delmängder av varandra, d.v.s. som kompletterande snarare än som motsatser. De tillfrågande såg ett tydligt samband mellan relevans och arbetsmarknad, men sambandet var inte lika starkt för begreppet kvalitet. 

  • 8.
    Blaus, Johan
    et al.
    KTH.
    Fagrell, Per
    KTH.
    Fahlgren, Anna
    Linköpings universitet, Medicinska fakulteten. Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för cellbiologi.
    Gunnarsson, Svante
    Linköpings universitet, Institutionen för systemteknik, Reglerteknik. Linköpings universitet, Tekniska fakulteten.
    Kiessling, Anna
    Karolinska Institutet.
    Structures, processes, and methods for collaboration with stakeholders on relevance assessment of higher education2021Konferensbidrag (Refereegranskat)
    Abstract [en]

    Introduction 

    Higher education institutions (HEIs) face challenges assessing the relevance of educational programmes. Upon graduation, the student should have acquired knowledge and understanding, competence and skills as well as good judgement and approaches to operate in a changing labour market. Ideas on new programmes and courses mainly emanate from research findings identified at the HEIs. Needs and expectations from external stakeholders have the potential to further contribute if room for collaboration is created. Extensive rapid societal changes increase this need for collaboration. 

    The Standards and Guidelines for Quality Assurance in the European Higher Education Area (ESG) state that higher education aims to fulfil multiple purposes, including preparing students for active citizenship, future careers, personal development and create a broad, advanced knowledge base and stimulate research and innovation (ENQA, 2015). However, different stakeholders may have other priorities. Therefore, quality assurance needs to take these different perspectives into account. 

    Relevance is considered an aspect of quality in higher education, but many HEIs in Sweden lack structures, processes, and methods for assessing relevance and involving stakeholders in these processes.

    This project aimed to increase the knowledge and provide methods to systematically assess relevance and use university-industry collaborations as tools for educational development. 

    Methods/Approach 

    This paper is a summary of the project MERUT focused on methods for assessment of relevance in higher education. The project was carried out during 2017-2020 with financial support from Vinnova (The Swedish Innovation Agency) and involved seven Swedish HEIs. The connection to future career paths is often stated as the primary factor to describe the relevance of educational programmes and was selected as the focus of MERUT. Data have been collected using workshops, meetings, literature reviews, interview studies, and surveys. Important parts of the work have been interviews with external stakeholders in different labour-market areas who, in various ways, are involved in higher education, most often in advisory boards. Also, interviews with quality coordinators at university programmes as well as at faculty and university management levels at each HEI have been carried out.

    The seven participating Swedish universities in MERUT have been Karolinska Institutet, Kristianstad University, KTH Royal Institute of Technology, Mälardalen University, Linköping University, Stockholm University, and Umeå University.

    Results The project resulted in knowledge, tools, and methods to work systematically with relevance in higher education. The results can be summarized as follows:

    ·         Interviews with HEIs showed that they collaborate with external stakeholders in many ways, primarily around teaching and learning and to a lesser extent around programme management and quality assurance. 

    ·         Further, the involvement of stakeholders varied both between and within the universities (faculties, subject areas, levels of education). Therefore, it is difficult to evaluate, in a systematic way, how collaboration is included in the quality systems of the HEIs. 

    ·         A toolbox with methods for how to involve external stakeholders in the process of assessing and developing the relevance of a study programme. These methods can be used in continuous quality work, in major curriculum revisions as well as in the establishment of new programmes.

    ·         A checklist for external stakeholders' involvement in educational development to facilitate and clarify roles, structures, and tasks in connection with external stakeholders in both the development and operational phases of a study programme. 

    The results show that there are many similarities between the HEIs in the study in terms of relevance assessment and dimensioning decisions. However, the potential of a systematic collaboration with stakeholders and society for relevance assessment and dimensioning of education is not yet fully being realised. 

    Conclusion 

    HEIs interact with external stakeholders in many ways within education. However, it is rare to find examples where external stakeholders are involved in the quality assurance process, at least not in a systematic way. The MERUT project has developed recommendations for collaboration perspectives and stakeholder participation in the governing of educational programmes. A systematic dialogue and interaction with stakeholders contribute to a mutual understanding of different stakeholder groups’ needs and expectations, and their view of quality of higher education. Furthermore, to consider relevance as a quality aspect creates a basis for a more methodical assessment process where external stakeholders can contribute in a clear role. MERUT has developed a toolbox and a checklist to facilitate such systematic interaction and collaboration with stakeholder groups. A conclusion of  this project is that a reciprocal, transparent, and systematic approach leads to a sustainable educational collaboration with improved quality and relevance of higher education.

    It would constitute a large gain for society if the HEIs are able to systematically and by efficient processes take external stakeholders’ and societal needs and expectations into account when building comprehensive and systematic relevance assessment processes and in dimensioning of education.  

    References

    European Association for Quality Assurance in Higher Education (ENQA). (2015). Standards and Guidelines for Quality Assurance in the European Higher Education Area (ESG). Brussels, EURASHE.

  • 9.
    Fagrell, Per
    et al.
    KTH, Sweden.
    Fahlgren, Anna
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Gunnarsson, Svante
    Linköpings universitet, Institutionen för systemteknik, Reglerteknik. Linköpings universitet, Tekniska fakulteten.
    Curriculum development and quality work in higher education in Sweden: The external stakeholder perspective2020Ingår i: Journal of Praxis in Higher Education, E-ISSN 2003-3605, Vol. 2, nr 1, s. 28-45Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This article provides an external stakeholder perspective on the influence of higher education in Sweden, exploring their views on curriculum development and qualitywork at the programme level. Semi-structured interviews with a selected number of representatives of external stakeholders involved in various educational areas were conducted at seven higher education institutions. The participants argued that changes intheir business sectors, and subsequent changes in the knowledge and skills in the labour needed, should encourage higher education institutions to adjust and develop their programmes. They did not anticipate or demand immediate changes in response to their comments, nor did they see themselves as a part of any quality assurance scheme. Uncertainties about the internal decision-making process and organisation in higher education institutions apparently do not facilitate external stakeholders’ understanding of their role in the larger scheme. However, all informants had comments on quality in higher education, perceiving it predominantly as something connected to the world of work. The practical implication of this study is that curriculum development at higher education institutions would benefit from communicating the internal decision-making processes to external stakeholders and agreeing on the expectations with them, in collaboration.

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  • 10.
    Vinther Madsen, Rune
    et al.
    Hosp Special Surg, NY 10021 USA; Zealand Univ Hosp, Denmark.
    Nam, Denis
    Rush Univ, IL USA.
    Schilcher, Jörg
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för kirurgi, ortopedi och onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Ortopedkliniken i Linköping.
    Dvorzhinskiy, Aleksey
    Hosp Special Surg, NY 10021 USA.
    Sutherland, James P.
    Hosp Special Surg, NY 10021 USA.
    Bostrom, F. Mathias
    Hosp Special Surg, NY 10021 USA.
    Fahlgren, Anna
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten. Hosp Special Surg, NY 10021 USA.
    Mechanical instability induces osteoclast differentiation independent of the presence of a fibrous tissue interface and osteocyte apoptosis in a rat model for aseptic loosening2020Ingår i: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 91, nr 1, s. 115-120Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background and purpose - Insufficient initial fixation or early micromotion of an implant is associated with a thin layer of fibrous tissue at the peri-implant interface. It is unknown if bone loss is induced by the fibrous tissue interface acting as an active biological membrane, or as a membrane that will produce supraphysiologic fluid flow conditions during gait, which activates the mechanosensitive osteocytes to mediate osteoclast differentiation. We investigated whether mechanically induced osteolysis is dependent on the fibrous tissue interface as a biologically active scaffold, or if it merely acts as a conduit for fluid flow, affecting the mechanosensitive osteocytes in the peri-prosthetic bone. Methods - Using a rat model of mechanically instability-induced aseptic loosening, we assessed whether the induction of osteoclast differentiation was dependent on the presence of a peri-implant fibrous interface. We analyzed the amount of osteoclast differentiation, osteocyte apoptosis, pro-resorptive cytokine expression and bone loss using immunohistochemistry, mRNA expression and micro-CT. Results - Osteoclast differentiation and bone loss were induced by mechanical instability but were not affected by the presence of the fibrous tissue membrane or associated with osteocyte apoptosis. There was no increased mRNA expression of any of the cytokines in the fibrous tissue membrane compared with the peri-implant bone. Interpretation - Our data show that the fibrous tissue membrane in the interface plays a minor role in inducing bone loss. This indicates that the peri-implant bone adjacent to loose bone implants might play an important role for osteoclast differentiation.

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  • 11.
    Amirhosseini, Mehdi
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Bernhardsson, Magnus
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten.
    Lång, Pernilla
    Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden.
    Andersson, Göran
    Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden.
    Flygare, Johan
    Department of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden..
    Fahlgren, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Cyclin-dependent kinase 8/19 inhibition suppresses osteoclastogenesis by downregulating RANK and promotes osteoblast mineralization and cancellous bone healing.2019Ingår i: Journal of Cellular Physiology, ISSN 0021-9541, E-ISSN 1097-4652, Vol. 234, nr 9, s. 16503-16516Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Cyclin-dependent kinase 8 (CDK8) is a mediator complex-associated transcriptional regulator that acts depending on context and cell type. While primarily under investigation as potential cancer therapeutics, some inhibitors of CDK8-and its paralog CDK19-have been reported to affect the osteoblast lineage and bone formation. This study investigated the effects of two selective CDK8/19 inhibitors on osteoclastogenesis and osteoblasts in vitro, and further evaluated how local treatment with a CDK8/19 inhibitor affects cancellous bone healing in rats. CDK8/19 inhibitors did not alter the proliferation of neither mouse bone marrow-derived macrophages (BMMs) nor primary mouse osteoblasts. Receptor activator of nuclear factor κΒ (NF-κB) ligand (RANKL)-induced osteoclastogenesis from mouse BMMs was suppressed markedly by inhibition of CDK8/19, concomitant with reduced tartrate-resistant acid phosphatase (TRAP) activity and C-terminal telopeptide of type I collagen levels. This was accompanied by downregulation of PU.1, RANK, NF-κB, nuclear factor of activated T-cells 1 (NFATc1), dendritic cell-specific transmembrane protein (DC-STAMP), TRAP, and cathepsin K in RANKL-stimulated BMMs. Downregulating RANK and its downstream signaling in osteoclast precursors enforce CDK8/19 inhibitors as anticatabolic agents to impede excessive osteoclastogenesis. In mouse primary osteoblasts, CDK8/19 inhibition did not affect differentiation but enhanced osteoblast mineralization by promoting alkaline phosphatase activity and downregulating osteopontin, a negative regulator of mineralization. In rat tibiae, a CDK8/19 inhibitor administered locally promoted cancellous bone regeneration. Our data indicate that inhibitors of CDK8/19 have the potential to develop into therapeutics to restrict osteolysis and enhance bone regeneration.

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  • 12.
    Fahlgren, Anna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Larsson, Max
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelning för neurobiologi. Linköpings universitet, Medicinska fakulteten.
    Lindahl, Mats
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för neuro- och inflammationsvetenskap. Linköpings universitet, Medicinska fakulteten.
    Thorsell, Annika
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Centrum för social och affektiv neurovetenskap. Linköpings universitet, Medicinska fakulteten.
    Kågedal, Katarina
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Gunnarsson, Svante
    Linköpings universitet, Institutionen för systemteknik, Reglerteknik. Linköpings universitet, Tekniska fakulteten.
    Design and Outcome of a CDIO Syllabus Survey for a Biomedicine Program2019Ingår i: The 15th International CDIO Conference: Proceedings – Full Papers / [ed] Jens Bennedsen, Aage Birkkjær Lauritsen, Kristina Edström, Natha Kuptasthien, Janne Roslöf & Robert Songer, Aarhus: Aarhus University , 2019, s. 191-200Konferensbidrag (Refereegranskat)
    Abstract [en]

    The CDIO Syllabus survey has successfully been applied to the Bachelor’s and Master’s programs in Experimental and Medical Biosciences, within the Faculty of Medicine and Health Sciences at Linköping University, Sweden. The programs are and have been, subject to considerable redesign with strong influence from the CDIO framework. One of the main drivers for the redesign is a shift concerning the main job market after graduation, from an academic career to industry and healthcare. One of the steps in the development process has been to carry out a Syllabus survey based on an adapted version of the CDIO Syllabus. The survey was sent out to students and to various categories of professionals, and in total 87 responses were received. The adapted version of the Syllabus and the design, execution, and outcome of the survey is presented.

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    Design and Outcome of a CDIO Syllabus Survey for a Biomedicine Program
  • 13.
    Bratengeier, Cornelia
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Bakker, Astrid D.
    Univ Amsterdam, Netherlands; Vrije Univ Amsterdam, Netherlands.
    Fahlgren, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Mechanical loading releases osteoclastogenesis-modulating factors through stimulation of the P2X7 receptor in hematopoietic progenitor cells2019Ingår i: Journal of Cellular Physiology, ISSN 0021-9541, E-ISSN 1097-4652, Vol. 234, nr 8, s. 13057-13067Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Mechanical instability of bone implants stimulate osteoclast differentiation and peri-implant bone loss, leading to prosthetic loosening. It is unclear which cells at the periprosthetic interface transduce mechanical signals into a biochemical response, and subsequently facilitate bone loss. We hypothesized that mechanical overloading of hematopoietic bone marrow progenitor cells, which are located near to the inserted bone implants, stimulates the release of osteoclast-inducing soluble factors. Using a novel in vitro model to apply mechanical overloading, we found that hematopoietic progenitor cells released adenosine triphosphate (ATP) after only 2min of mechanical loading. The released ATP interacts with its specific receptor P2X7 to stimulate the release of unknown soluble factors that inhibit (physiological loading) or promote (supraphysiological loading) the differentiation of multinucleated osteoclasts derived from bone marrow cultures. Inhibition of ATP-receptor P2X7 by Brilliant Blue G completely abolished the overloading-induced stimulation of osteoclast formation. Likewise, stimulation of P2X7 receptor on hematopoietic cells by BzATP enhanced the release of osteoclastogenesis-stimulating signaling molecules to a similar extent as supraphysiological loading. Supraphysiological loading affected neither gene expression of inflammatory markers involved in aseptic implant loosening (e.g., interleukin-1 (IL-1), IL-6, tumor necrosis factor-, and PTGES2) nor expression of the osteoclast modulators receptor activator of nuclear factor -B ligandand osteoprotegerin. Our findings suggest that murine hematopoietic progenitor cells are a potential key player in local mechanical loading-induced bone implant loosening via the ATP/P2X7-axis. Our approach identifies potential therapeutic targets to prevent prosthetic loosening.

  • 14.
    Amirhosseini, Mehdi
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Madsen, Rune V.
    Hosp Special Surg, NY 10021 USA.
    Escott, K. Jane
    AstraZeneca, England.
    Bostrom, Mathias P.
    Hosp Special Surg, NY 10021 USA.
    Ross, F. Patrick
    Hosp Special Surg, NY 10021 USA.
    Fahlgren, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    GSK-3 beta inhibition suppresses instability-induced osteolysis by a dual action on osteoblast and osteoclast differentiation2018Ingår i: Journal of Cellular Physiology, ISSN 0021-9541, E-ISSN 1097-4652, Vol. 233, nr 3, s. 2398-2408Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Currently, there are no medications available to treat aseptic loosening of orthopedic implants. Using osteoprotegerin fusion protein (OPG-Fc), we previously blocked instability-induced osteoclast differentiation and peri-prosthetic osteolysis. Wnt/beta-catenin signaling, which regulates OPG secretion from osteoblasts, also modulates the bone tissue response to mechanical loading. We hypothesized that activating Wnt/beta-catenin signaling by inhibiting glycogen synthase kinase-3 beta (GSK-3 beta) would reduce instability-induced bone loss through regulation of both osteoblast and osteoclast differentiation. We examined effects of GSK-3 beta inhibition on regulation of RANKL and OPG in a rat model of mechanical instability-induced peri-implant osteolysis. The rats were treated daily with a GSK-3 beta inhibitor, AR28 (20 mg/kg bw), for up to 5 days. Bone tissue and blood serum were assessed by qRT-PCR, immunohistochemistry, and ELISA on days 3 and 5, and by micro-CT on day 5. After 3 days of treatment with AR28, mRNA levels of beta-catenin, Runx2, Osterix, Col1 alpha 1, and ALP were increased leading to higher osteoblast numbers compared to vehicle-treated animals. BMP-2 and Wnt16 mRNA levels were downregulated by mechanical instability and this was rescued by GSK-3 beta inhibition. Osteoclast numbers were decreased significantly after 3 days of GSK-3 beta inhibition, which correlated with enhanced OPG mRNA expression. This was accompanied by decreased serum levels of TRAP5b on days 3 and 5. Treatment with AR28 upregulated osteoblast differentiation, while osteoclastogenesis was blunted, leading to increased bone mass by day 5. These data suggest that GSK-3 beta inactivation suppresses osteolysis through regulating both osteoblast and osteoclast differentiation in a rat model of instability-induced osteolysis.

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  • 15.
    Fahlgren, Anna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Bratengeier, Cornelia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Semeins, Cornelis M.
    Univ Amsterdam, Netherlands; Vrije Univ Amsterdam, Netherlands.
    Klein-Nulend, Jenneke
    Univ Amsterdam, Netherlands; Vrije Univ Amsterdam, Netherlands.
    Bakker, Astrid D.
    Univ Amsterdam, Netherlands; Vrije Univ Amsterdam, Netherlands.
    Supraphysiological loading induces osteocyte-mediated osteoclastogenesis in a novel in vitro model for bone implant loosening2018Ingår i: Journal of Orthopaedic Research, ISSN 0736-0266, E-ISSN 1554-527X, Vol. 36, nr 5, s. 1425-1434Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We aimed to develop an in vitro model for bone implant loosening, allowing analysis of biophysical and biological parameters contributing to mechanical instability-induced osteoclast differentiation and peri-implant bone loss. MLO-Y4-osteocytes were mechanically stimulated for 1h by fluid shear stress using regimes simulating: (i) supraphysiological loading in the peri-prosthetic interface (2.9 +/- 2.9Pa, 1Hz, square wave); (ii) physiologic loading in the cortical bone (0.7 +/- 0.7Pa, 5Hz, sinusoidal wave); and (iii) stress shielding. Cellular morphological parameters, membrane-bound RANKL expression, gene expression influencing osteoclast differentiation, nitric oxide release and caspase 3/7-activity were determined. Either Mouse bone marrow cells were cultured on top of loaded osteocytes or osteocyte-conditioned medium was added to bone marrow cells. Osteoclast differentiation was assessed after 6 days. We found that osteocytes subjected to supraphysiological loading showed similar morphology and caspase 3/7-activity compared to simulated physiological loading or stress shielding. Supraphysiological stimulation of osteocytes enhanced osteoclast differentiation by 1.9-fold compared to physiological loading when cell-to-cell contact was permitted. In addition, it enhanced the number of osteoclasts using conditioned medium by 1.7-fold, membrane-bound RANKL by 3.3-fold, and nitric oxide production by 3.2-fold. The stimulatory effect of supraphysiological loading on membrane-bound RANKL and nitric oxide production was higher than that achieved by stress shielding. In conclusion, the in vitro model developed recapitulated the catabolic biological situation in the peri-prosthetic interface during instability that is associated with osteoclast differentiation and enhanced RANKL expression. The model thus provides a platform for pre-clinical testing of pharmacological interventions with potential to stop instability-induced bone implant loosening. (c) 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1425-1434, 2018.

  • 16.
    Amirhosseini, Mehdi
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Andersson, Göran
    Division of Pathology, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital, Huddinge, Sweden.
    Aspenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för Kirurgi, Ortopedi och Onkologi. Linköpings universitet, Medicinska fakulteten. Region Östergötland, Centrum för kirurgi, ortopedi och cancervård, Ortopedkliniken i Linköping.
    Fahlgren, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Mechanical instability and titanium particles induce similar transcriptomic changes in a rat model for periprosthetic osteolysis and aseptic loosening2017Ingår i: Bone Reports, ISSN 2352-1872, Vol. 7, s. 17-25Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Wear debris particles released from prosthetic bearing surfaces and mechanical instability of implants are two main causes of periprosthetic osteolysis. While particle-induced loosening has been studied extensively, mechanisms through which mechanical factors lead to implant loosening have been less investigated. This study compares the transcriptional profiles associated with osteolysis in a rat model for aseptic loosening, induced by either mechanical instability or titanium particles. Rats were exposed to mechanical instability or titanium particles. After 15 min, 3, 48 or 120 h from start of the stimulation, gene expression changes in periprosthetic bone tissue was determined by microarray analysis. Microarray data were analyzed by PANTHER Gene List Analysis tool and Ingenuity Pathway Analysis (IPA). Both types of osteolytic stimulation led to gene regulation in comparison to unstimulated controls after 3, 48 or 120 h. However, when mechanical instability was compared to titanium particles, no gene showed a statistically significant difference (fold change = ± 1.5 and adjusted p-value = 0.05) at any time point. There was a remarkable similarity in numbers and functional classification of regulated genes. Pathway analysis showed several inflammatory pathways activated by both stimuli, including Acute Phase Response signaling, IL-6 signaling and Oncostatin M signaling. Quantitative PCR confirmed the changes in expression of key genes involved in osteolysis observed by global transcriptomics. Inflammatory mediators including interleukin (IL)-6, IL-1ß, chemokine (C-C motif) ligand (CCL)2, prostaglandin-endoperoxide synthase (Ptgs)2 and leukemia inhibitory factor (LIF) showed strong upregulation, as assessed by both microarray and qPCR. By investigating genome-wide expression changes we show that, despite the different nature of mechanical implant instability and titanium particles, osteolysis seems to be induced through similar biological and signaling pathways in this rat model for aseptic loosening. Pathways associated to the innate inflammatory response appear to be a major driver for osteolysis. Our findings implicate early restriction of inflammation to be critical to prevent or mitigate osteolysis and aseptic loosening of orthopedic implants.

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  • 17.
    Fahlgren, Anna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Bratengeier, Cornelia
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Gelmi, Amy
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biosensorer och bioelektronik. Linköpings universitet, Tekniska fakulteten.
    Semeins, Cornelis M.
    ACTA University of Amsterdam, Netherlands; Vrije University of Amsterdam, Netherlands.
    Klein-Nulend, Jenneke
    ACTA University of Amsterdam, Netherlands; Vrije University of Amsterdam, Netherlands.
    Jager, Edwin
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Biosensorer och bioelektronik. Linköpings universitet, Tekniska fakulteten.
    Bakker, Astrid D.
    ACTA University of Amsterdam, Netherlands; Vrije University of Amsterdam, Netherlands.
    Biocompatibility of Polypyrrole with Human Primary Osteoblasts and the Effect of Dopants2015Ingår i: PLOS ONE, E-ISSN 1932-6203, Vol. 10, nr 7, artikel-id e0134023Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Polypyrrole (PPy) is a conducting polymer that enables controlled drug release upon electrical stimulation. We characterized the biocompatibility of PPy with human primary osteoblasts, and the effect of dopants. We investigated the biocompatibility of PPy comprising various dopants, i.e. p-toluene sulfonate (PPy-pTS), chondroitin sulfate (PPy-CS), or dodecylbenzenesulfonate (PPy-DBS), with human primary osteoblasts. PPy-DBS showed the roughest appearance of all surfaces tested, and its wettability was similar to the gold-coated control. The average number of attached cells was 45% higher on PPy-DBS than on PPyCS or PPy-pTS, although gene expression of the proliferation marker Ki-67 was similar in osteoblasts on all surfaces tested. Osteoblasts seeded on PPy-DBS or gold showed similar vinculin attachment points, vinculin area per cell area, actin filament structure, and Ferets diameter, while cells seeded on PPY-CS or PPY-pTS showed disturbed focal adhesions and were enlarged with disorganized actin filaments. Osteoblasts grown on PPy-DBS or gold showed enhanced alkaline phosphatase activity and osteocalcin gene expression, but reduced osteopontin gene expression compared to cells grown on PPy-pTS and PPy-CS. In conclusion, PPy doped with DBS showed excellent biocompatibility, which resulted in maintaining focal adhesions, cell morphology, cell number, alkaline phosphatase activity, and osteocalcin gene expression. Taken together, conducting polymers doped with DBS are well tolerated by osteoblasts. Our results could provide a basis for the development of novel orthopedic or dental implants with controlled release of antibiotics and pharmaceutics that fight infections or focally enhance bone formation in a tightly controlled manner.

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  • 18.
    Grosso, Matthew J.
    et al.
    Hospital Special Surg, NY 10021 USA; Cleveland Clin, OH 44195 USA.
    Courtland, Hayden-William
    Hospital Special Surg, NY 10021 USA.
    Yang, Xu
    Hospital Special Surg, NY 10021 USA.
    Sutherland, James P.
    Hospital Special Surg, NY 10021 USA.
    Stoner, Kirsten
    Hospital Special Surg, NY 10021 USA.
    Nguyen, Joseph
    Hospital Special Surg, NY 10021 USA.
    Fahlgren, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för cellbiologi. Linköpings universitet, Hälsouniversitetet. Hospital Special Surg, NY 10021 USA.
    Ross, F. Patrick
    Hospital Special Surg, NY 10021 USA.
    van der Meulen, Marjolein C. H.
    Hospital Special Surg, NY 10021 USA; Cornell University, NY 14853 USA.
    Bostrom, Mathias P.
    Hospital Special Surg, NY 10021 USA.
    Intermittent PTH Administration and Mechanical Loading Are Anabolic for Periprosthetic Cancellous Bone2015Ingår i: Journal of Orthopaedic Research, ISSN 0736-0266, E-ISSN 1554-527X, Vol. 33, nr 2, s. 163-173Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The purpose of this study was to determine the individual and combined effects on periprosthetic cancellous bone of intermittent parathyroid hormone administration (iPTH) and mechanical loading at the cellular, molecular, and tissue levels. Porous titanium implants were inserted bilaterally on the cancellous bone of adult rabbits beneath a loading device attached to the distal lateral femur. The left femur received a sham loading device. The right femur was loaded daily, and half of the rabbits received daily PTH. Periprosthetic bone was evaluated up to 28 days for gene expression, histology, and mu CT analysis. Loading and iPTH increased bone mass by a combination of two mechanisms: (1) Altering cell populations in a pro-osteoblastic/anti-adipocytic direction, and (2) controlling bone turnover by modulating the RANKL-OPG ratio. At the tissue level, BV/TV increased with both loading (+53%, pless than0.05) and iPTH (+54%, pless than0.05). Combined treatment showed only small additional effects at the cellular and molecular levels that corresponded to a small additive effect on bone volume (+13% compared to iPTH alone, pgreater than0.05). This study suggests that iPTH and loading are potential therapies for enhancing periprosthetic bone formation. The elucidation of the cellular and molecular response may help further enhance the combined therapy and related targeted treatment strategies.

  • 19.
    Nam, Denis
    et al.
    Hospital Special Surg, NY USA .
    Bostrom, Mathias P G.
    Hospital Special Surg, NY USA .
    Fahlgren, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi. Linköpings universitet, Hälsouniversitetet. Hospital Special Surg, NY USA .
    Emerging Ideas: Instability-induced Periprosthetic Osteolysis Is Not Dependent on the Fibrous Tissue Interface2013Ingår i: Clinical Orthopaedics and Related Research, ISSN 0009-921X, E-ISSN 1528-1132, Vol. 471, nr 6, s. 1758-1762Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Stable initial fixation of a total joint arthroplasty implant is critical to avoid the risk of aseptic loosening and premature clinical failure. With implant motion, a fibrous tissue layer forms at the bone-implant interface, leading to implant migration and periprosthetic osteolysis. At the time of implant revision surgery, proresorptive signaling cytokines are expressed in the periimplant fibrous membrane. However, the exact role of this fibrous tissue in causing periprosthetic osteolysis attributable to instability remains unknown. less thanbrgreater than less thanbrgreater thanWe propose an alternative mechanism of periprosthetic osteolysis independent of the fibrous tissue layer, where pressurized fluid flow along the bone-implant interface activates mechanosensitive osteocytes in the periprosthetic bone, causing the release of proresorptive cytokines and subsequent osteoclast differentiation and osteolysis. less thanbrgreater than less thanbrgreater thanAn animal model for instability-induced osteolysis that mimics the periprosthetic bone-implant interface will be used. In this model, a fibrous tissue membrane is allowed to form in the periprosthetic zone, and pressurized fluid flow transmitted through this membrane reliably creates osteolytic lesions in the periprosthetic bone. In this study, half of the rats will have the fibrous tissue present, while the other half will not. We will determine whether the fibrous tissue membrane is essential for the release of proosteoclastic cytokines, leading to osteoclast differentiation and periprosthetic bone loss, by measuring the volume of bone resorption and presence of proresorptive cytokines at the bone-implant interface. less thanbrgreater than less thanbrgreater thanWe will determine whether the fibrous tissue membrane is crucial for osteoclastogenic signaling in the setting of periimplant osteolysis. In the future, this will allow us to test therapeutic interventions, such as specific cytokine inhibitors or alterations in implant design, which may translate into new, clinically relevant strategies to prevent osteolysis.

  • 20.
    Fahlgren, Anna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi. Linköpings universitet, Hälsouniversitetet.
    Yang, Xu
    Hospital for Special Surgery, New York, USA.
    Ciani, Cesare
    Hospital for Special Surgery, New York, USA.
    Ryan, James A.
    Hospital for Special Surgery, New York, USA.
    Kelly, Natalie
    Hospital for Special Surgery, New York, USA.
    Ko, Frank C.
    Cornell University, Ithaca, USA.
    van der Meulen, Marjolein C. H.
    Hospital for Special Surgery, New York, USA.
    Boström, Mathias P. G.
    Linköpings universitet, Institutionen för fysik, kemi och biologi, Teoretisk Fysik. Linköpings universitet, Tekniska högskolan.
    The effects of PTH, loading and surgical insult on cancellous bone at the bone-implant interface in the rabbit2013Ingår i: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 52, nr 2, s. 718-724Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Enhancing the quantity and quality of cancellous bone with anabolic pharmacologic agents may lead to more successful outcomes of non-cemented joint replacements. Using a novel rabbit model of cancellous bone loading, we examined two specific questions regarding bone formation at the bone-implant interface: (1) does the administration of intermittent PTH, a potent anabolic agent, and mechanical loading individually and combined enhance the pen-implant cancellous bone volume fraction; and, (2) does surgical trauma enhance the anabolic effect of PTH on pen-implant bone volume fraction. In this model, PTH enhanced pen-implant bone volume fraction by 30% in loaded bone, while mechanical loading alone increased bone volume fraction modestly (+10%). Combined mechanical loading and PTH treatment had no synergistic effect on any cancellous parameters. However, a strong combined effect was found in bone volume fraction with combined surgery and PTH treatment (+34%) compared to intact control limbs. Adaptive changes in the cancellous bone tissue included increased ultimate stress and enhanced remodeling activity. The number of proliferative osteoblasts increased as did their expression of pro-collagen 1 and PTH receptor 1, and the number of TRAP positive osteoclasts also increased. In summary, both loading and intermittent PTH treatment enhanced pen-implant bone volume, and surgery and PTH treatment had a strong combined effect This finding is of clinical importance since enhancing early osseointegration in the post-surgical period has numerous potential benefits.

  • 21.
    Fahlgren, Anna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet.
    Johansson, Lars
    Linköpings universitet, Institutionen för ekonomisk och industriell utveckling, Mekanik. Linköpings universitet, Tekniska högskolan.
    Edlund, Ulf
    Linköpings universitet, Institutionen för ekonomisk och industriell utveckling, Mekanik. Linköpings universitet, Tekniska högskolan.
    Aspenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för inflammationsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Ortopedkliniken i Linköping.
    Direct ex vivo measurement of the fluid permeability of loose scar tissue2012Ingår i: Acta of Bioengineering and Biomechanics, ISSN 1509-409X, Vol. 14, nr 2, s. 47-51Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Fluid flow is important in many biomechanical models, but there is a lack of experimental data that quantifies soft tissue permeability. We measured the tissue permeability in fibrous soft tissue, using a novel technique to obtain specimens by allowing soft tissue to grow into coralline hydroxyapatite scaffoldings implanted between the abdominal muscle layers of rats.

  • 22.
    Nilsson, Anna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi. Linköpings universitet, Hälsouniversitetet.
    Norgard, Maria
    Karolinska Institute, Sweden Karolinska University Hospital Huddinge, Sweden .
    Andersson, Goran
    Karolinska Institute, Sweden Karolinska University Hospital Huddinge, Sweden .
    Fahlgren, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi. Linköpings universitet, Hälsouniversitetet. Hospital for Special Surgery, New York, New York.
    Fluid pressure induces osteoclast differentiation comparably to titanium particles but through a molecular pathway only partly involving TNFa2012Ingår i: Journal of Cellular Biochemistry, ISSN 0730-2312, E-ISSN 1097-4644, Vol. 113, nr 4, s. 1224-1234Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    In contrast to the well-understood inflammatory pathway driven by TNFa, by which implant-derived particles induce bone resorption, little is known about the process in which loosening is generated as a result of force-induced mechanical stimulus at the boneimplant interface. Specifically, there is no knowledge as to what cells or signaling pathways couple mechanical stimuli to bone resorption in context of loosening. We hypothesized that different stimuli, i.e., fluid flow versus wear particles, act through different cytokine networks for activation and localization of osteoclasts. By using an animal model in which osteoclasts and bone resorption were induced by fluid pressure or particles, we were able to detect distinct differences in osteoclast localization and inflammatory gene expression between fluid pressure and titanium particles. Fluid pressure recruits and activates osteoclasts with bone marrow contact away from the fluid pressure exposure zone, whereas titanium particles recruit and activate osteoclasts in areas in direct contact to particles. Fluid pressure induced weaker expression of the selected inflammatory related genes, although the eventual degree of osteoclast induction was similar in both models. Using TNFaRa (4?mg/kg) (Enbrel) and dexamethasone (2?mg/kg) as specific and more general suppressors of inflammation we showed that the TNFaRa failed to generate statistically impaired osteoclast generation while dexamethasone was much more potent. These results demonstrate that fluid pressure induces osteoclasts at a different localization than titanium particles by a molecular pathway less associated with TNFa and the innate system, which open up for other pathways controlling pressure induced osteoclastogenesis.

  • 23.
    Fahlgren, Anna
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi.
    Nilsson, Anna
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi.
    Norgard, Maria
    Karolinska University Hospital, Stockholm.
    Andersson, Goran
    Karolinska University Hospital, Stockholm.
    FLUID PRESSURE AND TITANIUM PARTICLES INDUCES OSTEOCLAST ACTIVATION VIA ALTERNATIVE PATHWAYS in OSTEOPOROSIS INTERNATIONAL, vol 22, issue , pp 33-332011Ingår i: OSTEOPOROSIS INTERNATIONAL, Springer Science Business Media , 2011, Vol. 22, s. 33-33Konferensbidrag (Refereegranskat)
    Abstract [en]

    n/a

  • 24.
    Johansson, Lars
    et al.
    Linköpings universitet, Institutionen för ekonomisk och industriell utveckling, Mekanik. Linköpings universitet, Tekniska högskolan.
    Edlund, Ulf
    Linköpings universitet, Institutionen för ekonomisk och industriell utveckling, Mekanik. Linköpings universitet, Tekniska högskolan.
    Fahlgren, Anna
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi.
    Aspenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Ortopedkliniken i Linköping.
    Fluid-induced osteolysis: modelling and experiments2011Ingår i: COMPUTER METHODS IN BIOMECHANICS AND BIOMEDICAL ENGINEERING, ISSN 1025-5842, Vol. 14, nr 4, s. 305-318Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A model to calculate bone resorption driven by fluid flow at the bone-soft tissue interface is developed and used as a basis for computer calculations, which are compared to experiments where bone is subjected to fluid flow in a rat model. Previous models for bone remodelling calculations have been based on the state of stress, strain or energy density of the bone tissue as the stimulus for remodelling. We believe that there is experimental support for an additional pathway where an increase in the amount of the cells directly involved in bone removal, the osteoclasts, is caused by fluid pressure, flow velocity or other parameters related to fluid flow at the bone-soft tissue interface, resulting in bone resorption.

  • 25.
    Aspenberg, Per
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Ortopedicentrum, Ortopedkliniken Linköping.
    Agholme, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Fahlgren, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Magnusson, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Klinisk kemi. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Diagnostikcentrum, Klinisk kemi.
    Targeting RANKL for reduction of bone loss around unstable implants: OPG-Fc compared to alendronate in a model for mechanically induced loosening2011Ingår i: BONE, ISSN 8756-3282, Vol. 48, nr 2, s. 225-230Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Orthopedic joint prostheses may loosen because of localized bone resorption. Despite initial optimism, there are no reports showing that bisphosphonates can stop the progression of prosthetic loosening once it has begun. This might be due to the strong resorptive stimulus, which continuously recruits new osteoclasts. Therefore, we hypothesized that a treatment targeting osteoclast recruitment would be more efficacious than a treatment reducing osteoclast activity. We used a previously described rat model for instability-induced bone resorption, and compared OPG-Fc with alendronate at a clinically relevant or an extreme dose. A titanium plate was osseointegrated at the rat tibial surface. Instability was simulated by a piston, moving perpendicularly to the bone surface. Piston movement induced bone loss via hydrostatic pressure or fluid flow. Rats were randomized to 5 groups (total n = 56), of which 4 were subjected to instability and one was stable. The unstable groups were injected with either high-dose OPG-Fc (10 mg/kg, twice weekly), a high dose of alendronate (20 mu g /kg/day), an extreme dose of alendronate (200 mu g/kg/day) or saline. Significant protection against resorption could only be shown for OPG-Fc and the extreme alendronate dose. Both alendronate doses reduced serum levels of tartrate-resistant acid phosphatase isoform 5b to a similar extent, demonstrating that the lower dose was able to reduce resorption in the normally remodeling skeleton, although not in the osteolytic lesions caused by instability. Osteoclast numbers in the lesion were increased by the lower bisphosphonate dose and reduced by OPG-Fc. The results suggest the possibility of targeting osteoclast recruitment via the RANKL system in patients with impending prosthetic loosening.

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  • 26.
    Schizas, Nikos
    et al.
    Karolinska University Hospital.
    Li, Jian
    Karolinska University Hospital.
    Andersson, Therese
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Fahlgren, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin. Linköpings universitet, Hälsouniversitetet.
    Aspenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Ortopedicentrum, Ortopedkliniken Linköping.
    Ahmed, Mahmood
    Karolinska University Hospital.
    W. Ackermann, Paul
    Karolinska University Hospital.
    Compression Therapy Promotes Proliferative Repair during Rat Achilles Tendon Immobilization2010Ingår i: Journal of Orthopaedic Research, ISSN 0736-0266, E-ISSN 1554-527X, Vol. 28, nr 7, s. 852-858Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Achilles tendon ruptures are treated with an initial period of immobilization, which obstructs the healing process partly by a reduction of blood circulation. Intermittent pneumatic compression (IPC) has been proposed to enhance tendon repair by stimulation of blood flow. We hypothesized that daily IPC treatment can counteract the deficits caused by 2 weeks of immobilization post tendon rupture. Forty-eight Sprague-Dawley SD) rats, all subjected to blunt Achilles tendon transection, were divided in three equal groups. Group A was allowed free cage activity, whereas groups B C were immobilized at the operated hindleg. Group C received daily IPC treatment. Two weeks post-rupture the rats were euthanatized and the tendons analyzed with tensile testing and histological assessments of collagen organization and collagen III-LI occurrence. Immobilization significantly reduced maximum force, energy uptake, stiffness, tendon length, transverse area, stress, organized collagen diameter and collagen III-LI occurrence by respectively 80, 75, 77, 22, 47, 65, 49, and 83% compared to free mobilization. IPC treatment improved maximum force 65%, energy 168%, organized collagen diameter 50%, tendon length 25%, and collagen III-LI occurrence 150% compared to immobilization only. The results confirm that immobilization impairs healing after tendon rupture and furthermore demonstrate that IPC-treatment can enhance proliferative tendon repair by counteracting biomechanical and morphological deficits caused by immobilization.

  • 27.
    Fahlgren, Anna
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Bostrom, Mathias Pg
    Hospital for Special Surgery, New York, NY, USA.
    Yang, Xu
    Hospital for Special Surgery, New York, NY, USA.
    Johansson, Lars
    Linköpings universitet, Institutionen för ekonomisk och industriell utveckling, Mekanik. Linköpings universitet, Tekniska högskolan.
    Edlund, Ulf
    Linköpings universitet, Institutionen för ekonomisk och industriell utveckling, Mekanik. Linköpings universitet, Tekniska högskolan.
    Agholme, Fredrik
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Aspenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Ortopedicentrum, Ortopedkliniken Linköping.
    Fluid pressure and flow as a cause of bone resorption2010Ingår i: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 81, nr 4, s. 508-516Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background Unstable implants in bone become surrounded by an osteolytic zone. This is seen around loose screws, for example, but may also contribute to prosthetic loosening. Previous animal studies have shown that such zones can be induced by fluctuations in fluid pressure or flow, caused by implant instability. Method To understand the roles of pressure and flow, we describe the 3-dimensional distribution of osteolytic lesions in response to fluid pressure and flow in a previously reported rat model of aseptic loosening. 50 rats had a piston inserted in the proximal tibia, designed to produce 20 local spikes in fluid pressure of a clinically relevant magnitude (700 mmHg) twice a day. The spikes lasted for about 0.3 seconds. After 2 weeks, the pressure was measured in vivo, and the osteolytic lesions induced were studied using micro-CT scans. Results Most bone resorption occurred at pre-existing cavities within the bone in the periphery around the pressurized region, and not under the piston. This region is likely to have a higher fluid flow and less pressure than the area just beneath the piston. The velocity of fluid flow was estimated to be very high (roughly 20 mm/s). Interpretation The localization of the resorptive lesions suggests that high-velocity fluid flow is important for bone resorption induced by instability.

  • 28.
    Aspenberg, Per
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Ortopedicentrum, Ortopedkliniken Linköping.
    Schilcher, Jörg
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Fahlgren, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Histology of an undisplaced femoral fatigue fracture in association with bisphosphonate treatment2010Ingår i: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 81, nr 4, s. 460-462Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    n/a

  • 29.
    Johansson, Lars
    et al.
    Linköpings universitet, Institutionen för ekonomisk och industriell utveckling, Mekanik. Linköpings universitet, Tekniska högskolan.
    Edlund, Ulf
    Linköpings universitet, Institutionen för ekonomisk och industriell utveckling, Mekanik. Linköpings universitet, Tekniska högskolan.
    Fahlgren, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Aspenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Bone Resorption Induced by Fluid Flow2009Ingår i: Journal of Biomechanical Engineering, ISSN 0148-0731, E-ISSN 1528-8951, Vol. 131, nr 9, s. 094505-1-094505-5Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    A model where bone resorption is driven by stimulus from fluid flow is developed and used as a basis for computer simulations, which are compared with experiments. Models for bone remodeling are usually based on the state of stress, strain, or energy density of the bone tissue as the stimulus for remodeling. We believe that there is experimental support for an additional pathway, where an increase in the amount of osteoclasts, and thus osteolysis, is caused by the time history of fluid flow velocity, fluid pressure, or other parameters related to fluid flow at the bone/soft tissue interface of the porosities in the bone.

  • 30.
    Aspenberg, Per
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Östergötlands Läns Landsting, Ortopedicentrum, Ortopedkliniken Linköping.
    Wermelin, Karin
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin.
    Tengwall, Pentti
    Laboratory of Applied Physics, Department of Physics, Chemistry and Biology Linköping University.
    Fahlgren, Anna
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin.
    Additive effects of PTH and bisphosphonates on the bone healing response to metaphyseal implants in rats2008Ingår i: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 79, nr 1, s. 111-115Artikel i tidskrift (Refereegranskat)
    Abstract [en]

     BACKGROUND: When PTH is used to increase the amount of bone in osteoporotic patients, combination with bisphosphonates is known to attenuate the response. This might be explained by the reduced number of remodeling sites after bisphosphonate treatment, which reduces the number of cells able to respond to PTH. However, in a repair situation after trauma, a large number of osteoblasts reside in the wound site. If their activity is no longer coupled to osteoclasts, decreased resorption by bisphosphonates and stimulation of osteoblastic activity by PTH should both (independently) increase bone formation. Thus, we hypothesized that in contrast to the case in osteoporosis treatment, PTH and bisphosphonates have an additive effect in situations involving bone regeneration. MATERIAL AND METHODS: Stainless steel screws, either coated with biphosphonates or uncoated, were inserted in 46 rat tibias. This normally elicits a bone repair response, leading to a gradual increase in the strength of screw fixation. Half of the rats also received daily injections of teriparatide (PTH). Thus, there were 4 groups: control, bisphosphonate, PTH, and bisphosphonate plus PTH. Pull-out force and energy were measured after 2 weeks. RESULTS: The combined treatment had the strongest effect. It doubled the pull-out force and tripled the pull-out energy, compared to untreated controls. Also, bisphosphonate or PTH alone increased the pull-out force and energy, although less. No treatment cross-dependency was observed. INTERPRETATION: Because bisphosphonates mainly influence osteoclasts, and intermittent administration of PTH mainly influences osteoblasts, our findings indicate that to a large extent these cells work without coupling in this model. It appears that bisphosphonates are unlikely to attenuate the response to PTH during the formation of new bone.

  • 31.
    Virchenko, Olena
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Östergötlands Läns Landsting, Ortopedicentrum, Ortopedkliniken Linköping.
    Fahlgren, Anna
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin.
    Rundgren, Mats
    Department of Physiology and Pharmacology Karolinska Institutet, Stockholm.
    Aspenberg, Per
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Östergötlands Läns Landsting, Ortopedicentrum, Ortopedkliniken Linköping.
    Early Achilles tendon healing in sheep2008Ingår i: Archives of Orthopaedic and Trauma Surgery, ISSN 0936-8051, E-ISSN 1434-3916, Vol. 128, nr 9, s. 1001-1006Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Introduction: The biomechanics of early tendon healing is important for designing post-injury training, but this has not been described in an animal model, similar to humans in size. We measured elastic and viscoelastic properties of a tendon regenerate in sheep, in a study designed to see the effects of exogenously applying the growth and differentiation factor CDMP-2. This is the first description of early tendon healing in sheep Achilles tendons. Materials and methods: Twenty female sheep underwent Achilles tendon transection without suturing or immobilization. Two hours after the operation, 100 μg of CDMP-2 or placebo was injected into the hematoma. The sheep were slaughtered after 3 weeks, and tendon regenerates tested for viscoelastic properties by cyclical loading, before a destructive tensile test. Thereafter, all specimens were examined by high resolution computerized tomography (CT), and histology. Results: The tendon regenerate formed a sleeve, around the tendon stumps. Failure occurred between the regenerate sleeve and the tendon stumps. There was an unexpectedly large variation in force at failure. In the CDMP-2 group, force correlated with regenerate transverse area, but not in the controls. Thus, the variation in maximum stress was smaller in the CDMP-2 group (P = 0.009). Although the force at failure was only a tenth of normal, the capacity to store elastic energy was already near normal (hysteresis 16%). The mean transverse area, force at failure and stiffness were all about 30% larger in the CDMP-2 group, but this was not significant. There were no signs of bone or cartilage formation on CT or histology. Conclusions: Results are compatible with a positive effect of CDMP-2, but the power was too low to demonstrate any such effect. Considering that spontaneous ruptures in humans are likely to have a more variable geometry than in this model, humans can also be expected to vary a lot in early mechanical characteristics. This emphasizes the importance of individualized rehabilitation programs. The low hysteresis suggests that the energy storing capacity is rather easy for the tissues to develop, possibly it is harder to create appropriate energy dissipation, in order to avoid re-rupture. © Springer-Verlag 2008.

  • 32.
    Eliasson, Pernilla
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Fahlgren, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Aspenberg, Per
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Östergötlands Läns Landsting, Ortopedicentrum, Ortopedkliniken Linköping.
    Mechanical load and BMP signaling during tendon repair: A role for follistatin?2008Ingår i: Clinical Orthopaedics and Related Research, ISSN 0009-921X, E-ISSN 1528-1132, Vol. 466, nr 7, s. 1592-1597Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Healing of the rat Achilles tendon is sensitive to mechanical loading, and the callus strength is reduced by 3/4 after 14 days, if loading is prevented. Exogenous GDFs stimulate tendon healing. This response is influenced by loading: without loading, cartilage and bone formation is initiated. This implies BMP signaling is crucial during tendon healing and influenced by mechanical loading. We therefore asked if mechanical loading influences the gene expression of the BMP signaling system in intact and healing tendons, and how the BMP signaling system changes during healing. The genes were four BMPs (OP-1/BMP-7, GDF-5/CDMP-1/BMP-14, GDF-6/CDMP2/BMP-13, and GDF-7/CDMP-3/BMP-12), two receptors (BMPR1b and BMPR2), and the antagonists follistatin and noggin. The Achilles tendon was transected in rats and left to heal. Half of the rats had one Achilles tendon unloaded by injection of Botox in the calf muscles. Ten tendons were analyzed before transection and for each of four time points. All genes except noggin were expressed at all points, but followed different patterns during healing. Loading strongly decreased the expression of follistatin, which could lead to increased signaling. The BMP system appears involved in tendon maintenance and healing, and may respond to mechanical loading.

  • 33.
    Eliasson, Pernilla
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Fahlgren, Anna
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Ortopedi och Idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Pasternak, Björn
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Ortopedi och Idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Aspenberg, Per
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Ortopedi och Idrottsmedicin. Östergötlands Läns Landsting, Ortopedicentrum, Ortopedkliniken Linköping.
    Unloaded rat Achilles tendons continue to grow, but lose viscoelasticity2007Ingår i: Journal of applied physiology, ISSN 8750-7587, E-ISSN 1522-1601, Vol. 103, nr 2, s. 459-463Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Tendons can function as springs and thereby preserve energy during cyclic loading. They might also have damping properties, which, hypothetically, could reduce risk of microinjuries due to fatigue at sites of local stress concentration within the tendon. At mechanical testing, damping will appear as hysteresis. How is damping influenced by training or disuse? Does training decrease hysteresis, thereby making the tendon a better spring, or increase hysteresis and thus improve damping? Seventy-eight female 10-wk-old Sprague-Dawley rats were randomized to three groups. Two groups had botulinum toxin injected into the calf muscles to unload the left Achilles tendon through muscle paralysis. One of these groups was given doxycycline, as a systemic matrix metalloproteinase inhibitor. The third group served as loaded controls. The Achilles tendons were harvested after 1 or 6 wk for biomechanical testing. An increase with time was seen in tendon dry weight, wet weight, water content, transverse area, length, stiffness, force at failure, and energy uptake in all three groups (P < 0.001 for each parameter). Disuse had no effect on these parameters. Creep was decreased with time in all groups. The only significant effect of disuse was on hysteresis (P = 0.004) and creep (P = 0.007), which both decreased with disuse compared with control, and on modulus, which was increased (P = 0.008). Normalized glycosaminoglycan content was unaffected by time and disuse. No effect of doxycycline was observed. The results suggest that in growing animals, the tendons continue to grow regardless of mechanical loading history, whereas maintenance of damping properties requires mechanical stimulation.

  • 34.
    Fahlgren, Anna
    et al.
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Ortopedi och Idrottsmedicin.
    Chubinskaya, S
    Messner, Karola
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Ortopedi och Idrottsmedicin. Östergötlands Läns Landsting, Ortopedicentrum, Ortopedkliniken Linköping.
    Aspenberg, Per
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Ortopedi och Idrottsmedicin. Östergötlands Läns Landsting, Ortopedicentrum, Ortopedkliniken Linköping.
    A capsular incision leads to a fast osteoarthritic response, but also elevated levels of activated osteogenic protein-1 in rabbit knee joint cartilage2006Ingår i: Scandinavian Journal of Medicine and Science in Sports, ISSN 0905-7188, E-ISSN 1600-0838, Vol. 16, nr 6, s. 456-462Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We studied whether a small capsular incision alone, or combined with meniscectomy could induce early osteoarthritic changes in the rabbit knee. Thirty-one rabbits were operated on with a capsular incision in the left knee and meniscectomy in the right knee. Another 12 rabbits were used as controls. The rabbits were killed 3, 6 and 12 weeks after surgery. Osteoarthritic changes in the articular cartilage were evaluated by the modified Mankin score. The subchondral bone was evaluated by scintimetry (99mTc-HDP) and semiquantitative grading of histological changes. Osteogenic protein (OP-1) in its mature and pro-form was examined by immunohistochemistry. Both a capsular incision and meniscectomy induced articular cartilage fibrillation and increased bone metabolic activity during the initial weeks after surgery. Capsular incision led to lesser changes than meniscectomy. Mature OP-1 was elevated, and its pro-form reduced, in meniscectomized knees. A similar pattern was observed in knees with capsular incision. Already 3 weeks after surgery, the articular cartilage and subchondral bone showed typical signs of early osteoarthritis (OA), and a reparative response was suggested by increased intensity of OP-1 staining. As these signs were also found in knees with capsular incision only, it appears that trauma-related factors such as increased bleeding and inflammation are critical for the development of OA. Copyright © Blackwell Munksgaard 2006.

  • 35.
    Johansson, Lars
    et al.
    Linköpings universitet, Institutionen för ekonomisk och industriell utveckling, Mekanik. Linköpings universitet, Tekniska högskolan.
    Edlund, Ulf
    Linköpings universitet, Institutionen för ekonomisk och industriell utveckling, Mekanik. Linköpings universitet, Tekniska högskolan.
    Fahlgren, Anna
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Ortopedi och Idrottsmedicin.
    Aspenberg, Per
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Ortopedi och Idrottsmedicin. Östergötlands Läns Landsting, Ortopedicentrum, Ortopedkliniken Linköping.
    A model for bone resorption2006Ingår i: ESDA 2006, 8th Biennial ASME Conference on Engineering Systems Design and Analysis,2006, ASME Press, 2006, s. 487-495Konferensbidrag (Refereegranskat)
  • 36. Khoschnau, Shwan
    et al.
    Fahlgren, Anna
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Ortopedi och Idrottsmedicin.
    Aspenberg, Per
    Linköpings universitet, Hälsouniversitetet. Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Ortopedi och Idrottsmedicin. Östergötlands Läns Landsting, Ortopedicentrum, Ortopedkliniken Linköping.
    Rahme, Hans
    Improved healing of ligament to bone with point fixation in rabbits2006Ingår i: Acta Orthopaedica, ISSN 1745-3674, E-ISSN 1745-3682, Vol. 77, nr 6, s. 967-972Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Background: Secure healing of soft tissue to bone is a prerequisite for many orthopedic operations. This healing can be achieved either by pressing the tissue against the bone (press fixation) or by suturing the soft tissue to the bone (point fixation). Experiments and findings: We tested the hypothesis that point fixation of soft tissue to bone results in better mechanical properties than press fixation. 10 skeletally mature New Zealand White rabbits were operated on bilaterally at the knees. The medial collateral ligaments were fixated to the bone just above the original insertion on the tibia. Two types of plates were used for this purpose, one with flat undersurface (left knee) and the other one with a pegged undersurface (right knee). The pegged plate was thought to mimic fixation achieved with suture anchors. After 4 weeks, mechanical testing revealed an almost doubled force at failure, stiffness and energy uptake in the knees operated with the pegged plates. Interpretation: Suture anchors or devices with a pegged undersurface are better for soft tissue fixation to bone than devices with a flat surface, such as screws with washers or staples. Copyright© Taylor & Francis 2006.

  • 37.
    Virchenko, Olena
    et al.
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Skoglund, Björn
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Fahlgren, Anna
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Aspenberg, Per
    Linköpings universitet, Institutionen för klinisk och experimentell medicin, Ortopedi och idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    CDMP-2 injection improves early tendon healing in a rabbit model for surgical repair2005Ingår i: Scandinavian Journal of Medicine and Science in Sports, ISSN 0905-7188, Vol. 15, nr 4, s. 260-264Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    This study examines the hypothesis that cartilage-derived morphogenic protein-2 (CDMP-2) can improve tendon healing after surgical repair. We have previously found improved tendon healing by applying CDMP-2 in models for conservative treatment with mechanically loaded Achilles tendon defects in rats and rabbits. In this study, the patellar tendon was unloaded by patello- tibial cerclage and cut transversely in 40 rabbits. Two hours post-operative, the rabbits received a dose of 20 μg of CDMP-2 or vehicle injected into the hematoma. Specimens were harvested after 14 and 28 days and evaluated by biomechanical testing, radiography and histology. At 14 days, CDMP-2 caused a 65% increase in force at failure, a 50% increase in ultimate stress and a 57% increase in stiffness, as compared with controls. There was no effect on callus size. At 28 days, no differences between the treatment groups could be demonstrated. No bone or cartilage was found in any tendon or regenerated tissue at any time point. Thus, early tendon repair can be stimulated by CDMP-2 in an unloaded model. These results suggest that CDMP-2 might be of interest for clinical use as a complement to surgical treatment of tendon ruptures.

  • 38.
    Fahlgren, Anna
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Ortopedi och Idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Early knee osteoarthrosis after meniscectomy: studies in rabbits2003Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
    Abstract [en]

    Post-traumatic osteoarthrosis develops after intraarticular injuries. It is a disease, which affects both articular cartilage and subchondral bone, and progresses over 10-20 years. Irreversible damage has often occurred by the time clinical diagnosis is possible. More knowledge about the early phase of the disease might yield measures to detect and delay or even prevent progression. This thesis evaluates changes in articular cartilage and subchondral bone at an early stage of post-traumatic osteoarthrosis.

    Simultaneous changes in articular cartilage and subchondral bone were evaluated 3 to 40 weeks post-operatively in a rabbit meniscectomy model for post-traumatic osteoarthrosis. Rabbits were meniscectomized in the right knee and sham-operated in the left knee. Osteoarthrotic cartilage changes were evaluated by histology. Changes in the subchondral bone were evaluated by histology, scintimetry and dual-energy X-ray absorptiometry (DEXA). Joint space narrowing, and its utility as diagnostic tool at early stages of osteoarthrosis, was assessed with weight-bearing radiographs. The prognostic value of transforming growth factor-ßI (TGF-ß1) and proteoglycan fragment concentrations in the joint fluid at an early stage was also assessed.

    We found slight cartilage changes and an increased metabolic activity in the subchondral bone as early as 3 weeks after meniscectomy. However, sham-operated knees displayed similar changes, although to a lesser degree. Cartilage fibrillation progressed at areas of high load within the meniscectomized knee joint. The subchondral bone showed a general response such as high scintimetric activity 3 weeks after surgery, and a decreased bone mineral density at later time points. Local adaptation in areas of high load within the subchondral bone was also seen. There was an increased osteoid content at the border between the cancellous bone and the marrow cavity already 3 weeks after meniscectomy, and at 13 weeks the subchondral bone plate was thickened. This thickening of the bone plate persisted up to 40 weeks. Joint space narrowing occurred after removal of the meniscus, but weight-bearing radiographs were not sensitive enough to measure early cartilage changes. Increased concentration of TGF-ß1 in the joint fluid at 3 weeks after surgery was associated with a higher degree of histological osteoarthrotic changes at a later time point.

    Simultaneous changes in both cartilage and bone were apparent already 3 weeks after surgery, indicating that both tissues are involved from a very early stage. The localisation of cartilage changes illustrates that mechanical consequences of meniscectomy play a crucial role in progression of the disease. Surgical trauma resulted in increased release of TGF-ß1 at 3 weeks after surgery. This was found to be indicative for the severity of later osteoarthrosis. Thus, factors solely associated with the surgical trauma may also be important for the progression of osteoarthrosis.

    Delarbeten
    1. Simultaneous changes in bone mineral density and articular cartilage in a rabbit meniscectomy model of knee osteoarthrosis
    Öppna denna publikation i ny flik eller fönster >>Simultaneous changes in bone mineral density and articular cartilage in a rabbit meniscectomy model of knee osteoarthrosis
    2000 (Engelska)Ingår i: Osteoarthritis and Cartilage, ISSN 1063-4584, E-ISSN 1522-9653, Vol. 8, nr 3, s. 197-206Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Objective It was hypothesized that increased bone mineral density of the medial proximal tibia would precede or coincide with the development of more severe cartilage changes after meniscectomy.

    Methods In a rabbit knee model, mineral density of subchondral bone and changes of articular cartilage were monitored 13 to 40 weeks after medial meniscectomy or a sham operation.

    Results Both procedures resulted in a decrease of bone mineral density, especially of the medial proximal tibia, which persisted up to 40 weeks (P< 0.02–0.0007). Meniscectomy induced cartilage changes typical for osteoarthrosis (P< 0.009), which progressed over time on the posterior aspect of the medial tibial plateau (P< 0.009), which is physiologically covered by the meniscus, but the procedure also induced iatrogenic changes which were located mainly on the anterior aspect of the concerned compartment, and which did not progress or develop to osteoarthrosis.

    Conclusions The data suggest that the cartilage changes after meniscectomy in this animal model are caused by the surgical trauma, subsequent limb misuse, and altered load distribution, and initially associated by a decrease not an increase in bone mineral density of the proximal tibia. Moreover, the cartilage changes progressed without a simultaneous increase of the bone mineral density at corresponding sites.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-27749 (URN)10.1053/joca.1999.0290 (DOI)12490 (Lokalt ID)12490 (Arkivnummer)12490 (OAI)
    Tillgänglig från: 2009-10-08 Skapad: 2009-10-08 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
    2. Meniscectomy leads to an early increase in subchondral bone plate thickness in the rabbit knee
    Öppna denna publikation i ny flik eller fönster >>Meniscectomy leads to an early increase in subchondral bone plate thickness in the rabbit knee
    2003 (Engelska)Ingår i: Acta Orthopaedica Scandinavica, ISSN 0001-6470, Vol. 74, nr 4, s. 437-441Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    We evaluated morphological changes in the tibial bone after meniscectomy in a rabbit model. 15 rabbits subjected to a medial meniscectomy in the right knee and a sham-operation in the left. Histomorphometric parameters were evaluated in the subchondral bone plate and the underlying trabecular bone, 13, 25 and 40 weeks after surgery. 5 rabbits were used as unoperated controls.Meniscectomized knees had a thicker subchondral bone plate than sham-operated contralateral ones in 13 of the 15 rabbits (p= 0.01), but the trabecular bone showed no morphological differences. The meniscectomized knees of these rabbits developed mild osteoarthrosis, described elsewhere, which may have been partly due to a change in the mechanical properties of the thickened subchondral bone plate. Our findings suggest that the first bony response after meniscectomy occurs in the subchondral bone plate rather than in the trabecular bone.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-27640 (URN)10.1080/00016470310017758 (DOI)12376 (Lokalt ID)12376 (Arkivnummer)12376 (OAI)
    Tillgänglig från: 2009-10-08 Skapad: 2009-10-08 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
    3. Meniscectomy in the rabbit knee leads to increased bone remodelling and cartilage degeneration within three weeks
    Öppna denna publikation i ny flik eller fönster >>Meniscectomy in the rabbit knee leads to increased bone remodelling and cartilage degeneration within three weeks
    (Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Increased knowledge about the early cartilaginous and osseous responses to meniscectomy may elucidate processes behind development of osteoarthrosis. The purpose of the present study was to evaluate tibial bone and cartilage changes during the first months after meniscectomy.

    Thirty-one skeletally mature New Zealand white rabbits were operated on with meniscectomy in the right knee and a sham-operation in the left knee. Another 12 rabbits were used as controls. The knee joints were evaluated 3, 6 and 12 weeks after surgery by radiolabelled bisphosphonate uptake (99mTc-HDP) and semiquantitative grading of histological changes in the subchondral bone and cartilage.

    Already 3 weeks after meniscectomy, there was increased metabolic activity in the subchondral bone, and articular cartilage fibrillation. Similar changes were seen in shamoperated knees, but to a lesser extent. This appears to be caused both by the new loading situation in the joint after meniscectomy and the operative trauma.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-84496 (URN)
    Tillgänglig från: 2012-10-10 Skapad: 2012-10-10 Senast uppdaterad: 2012-10-10Bibliografiskt granskad
    4. Radiographic joint space narrowing and histologic changes in a rabbit meniscectomy model of early knee osteoarthrosis
    Öppna denna publikation i ny flik eller fönster >>Radiographic joint space narrowing and histologic changes in a rabbit meniscectomy model of early knee osteoarthrosis
    2001 (Engelska)Ingår i: American Journal of Sports Medicine, ISSN 0363-5465, E-ISSN 1552-3365, Vol. 29, nr 2, s. 151-160Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    The purpose of this study was to compare weightbearing radiographs with histologic cartilage evaluation in a rabbit meniscectomy model of the early stage of osteoarthrosis. Fifteen rabbits had a medial meniscectomy performed in one knee and a sham operation in the other knee. Five rabbits each were sacrificed at 13, 25, and 40 weeks after surgery. Radiographic joint space width and histologic cartilage changes of the medial knee compartment were quantified. Five nonoperated knees and five knees in which the meniscus had been removed immediately before the evaluations served as control specimens. Overall, the joint space of the peripheral part of the medial knee compartment was narrower in knees operated on for meniscus removal than in sham-operated knees (P < 0.003). In the knees with the meniscus removed, more cartilage changes were seen at the joint surface area of contact on radiographs than in the sham-operated knees (P < 0.0015). Indeed, the area of contact had cartilage changes similar to those in the whole medial compartment. However, there was no correlation between the degree of histologic cartilage change and the corresponding joint space measurements. Joint space width as measured on weightbearing radiographs is reduced after meniscectomy in the rabbit, but it does not reflect the degree of cartilage damage of the loaded joint surfaces in early stages of osteoarthrosis.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-25901 (URN)10342 (Lokalt ID)10342 (Arkivnummer)10342 (OAI)
    Tillgänglig från: 2009-10-08 Skapad: 2009-10-08 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
    5. TGF-β1 as a prognostic factor in the process of early osteoarthrosis in the rabbit knee
    Öppna denna publikation i ny flik eller fönster >>TGF-β1 as a prognostic factor in the process of early osteoarthrosis in the rabbit knee
    2001 (Engelska)Ingår i: Osteoarthritis and Cartilage, ISSN 1063-4584, E-ISSN 1522-9653, Vol. 9, nr 3, s. 195-202Artikel i tidskrift (Refereegranskat) Published
    Abstract [en]

    Objective To assess changes in knee joint fluid concentrations of transforming growth factor-β1 (TGF-β1) and proteoglycan (PG) fragments during the early course of post-traumatic osteoarthrosis (OA) after meniscectomy in the rabbit knee, and to ascertain whether the concentrations of these substances shortly after operation could be used as prognostic markers for the OA process.

    Design In 15 rabbits with medial meniscectomy in one knee and a sham operation in the other knee, synovial lavage fluid samples were taken repeatedly, before operation, every third week post-operatively until 12 weeks, thereafter every sixth week, and at death. Five rabbits each were killed at 13, 25 and 40 weeks. Synovial lavage fluid samples from five non-operated rabbits served as controls. At death, two histological scores were formed that characterized the highest (MAX) and the overall (ALL) degree of OA changes in each joint.

    Results TGF-β1 and PG fragment concentrations in synovial lavage fluid correlated highly (R=0.81, P< 0.001). Both OA scores were higher in meniscectomized than controls (P< 0.05). The synovial lavage fluid concentration of TGF-β1 at 3 weeks, but no other time point, correlated to the histological scores (ALL, R=0.58; MAX, R=0.52;P< 0.001).

    Conclusion Higher concentrations of TGF-β1 in synovial lavage fluid early after surgery seemed indicative for the later development of more severe OA changes in contrast to lower concentrations. The association between TGF-β1 and the changes found later in the cartilage was underlined by the high correlations between this substance and PG fragment concentrations in synovial lavage fluid at all time points.

    Nationell ämneskategori
    Medicin och hälsovetenskap
    Identifikatorer
    urn:nbn:se:liu:diva-27601 (URN)10.1053/joca.2000.0376 (DOI)12331 (Lokalt ID)12331 (Arkivnummer)12331 (OAI)
    Tillgänglig från: 2009-10-08 Skapad: 2009-10-08 Senast uppdaterad: 2017-12-13Bibliografiskt granskad
  • 39.
    Fahlgren, Anna
    et al.
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Ortopedi och Idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Messner, Karola
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Ortopedi och Idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Aspenberg, Per
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Ortopedi och Idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Meniscectomy leads to an early increase in subchondral bone plate thickness in the rabbit knee2003Ingår i: Acta Orthopaedica Scandinavica, ISSN 0001-6470, Vol. 74, nr 4, s. 437-441Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    We evaluated morphological changes in the tibial bone after meniscectomy in a rabbit model. 15 rabbits subjected to a medial meniscectomy in the right knee and a sham-operation in the left. Histomorphometric parameters were evaluated in the subchondral bone plate and the underlying trabecular bone, 13, 25 and 40 weeks after surgery. 5 rabbits were used as unoperated controls.Meniscectomized knees had a thicker subchondral bone plate than sham-operated contralateral ones in 13 of the 15 rabbits (p= 0.01), but the trabecular bone showed no morphological differences. The meniscectomized knees of these rabbits developed mild osteoarthrosis, described elsewhere, which may have been partly due to a change in the mechanical properties of the thickened subchondral bone plate. Our findings suggest that the first bony response after meniscectomy occurs in the subchondral bone plate rather than in the trabecular bone.

  • 40.
    Messner, Karola
    et al.
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Ortopedi och Idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Fahlgren, Anna
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Ortopedi och Idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Persliden, Jan
    Linköpings universitet, Institutionen för medicin och vård, Radiofysik. Linköpings universitet, Hälsouniversitetet.
    Andersson, Britt-Marie
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Ortopedi och Idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Radiographic joint space narrowing and histologic changes in a rabbit meniscectomy model of early knee osteoarthrosis2001Ingår i: American Journal of Sports Medicine, ISSN 0363-5465, E-ISSN 1552-3365, Vol. 29, nr 2, s. 151-160Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    The purpose of this study was to compare weightbearing radiographs with histologic cartilage evaluation in a rabbit meniscectomy model of the early stage of osteoarthrosis. Fifteen rabbits had a medial meniscectomy performed in one knee and a sham operation in the other knee. Five rabbits each were sacrificed at 13, 25, and 40 weeks after surgery. Radiographic joint space width and histologic cartilage changes of the medial knee compartment were quantified. Five nonoperated knees and five knees in which the meniscus had been removed immediately before the evaluations served as control specimens. Overall, the joint space of the peripheral part of the medial knee compartment was narrower in knees operated on for meniscus removal than in sham-operated knees (P < 0.003). In the knees with the meniscus removed, more cartilage changes were seen at the joint surface area of contact on radiographs than in the sham-operated knees (P < 0.0015). Indeed, the area of contact had cartilage changes similar to those in the whole medial compartment. However, there was no correlation between the degree of histologic cartilage change and the corresponding joint space measurements. Joint space width as measured on weightbearing radiographs is reduced after meniscectomy in the rabbit, but it does not reflect the degree of cartilage damage of the loaded joint surfaces in early stages of osteoarthrosis.

  • 41.
    Fahlgren, Anna
    et al.
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Ortopedi och Idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Andersson, Britt-Marie
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Ortopedi och Idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Messner, Karola
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Ortopedi och Idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    TGF-β1 as a prognostic factor in the process of early osteoarthrosis in the rabbit knee2001Ingår i: Osteoarthritis and Cartilage, ISSN 1063-4584, E-ISSN 1522-9653, Vol. 9, nr 3, s. 195-202Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective To assess changes in knee joint fluid concentrations of transforming growth factor-β1 (TGF-β1) and proteoglycan (PG) fragments during the early course of post-traumatic osteoarthrosis (OA) after meniscectomy in the rabbit knee, and to ascertain whether the concentrations of these substances shortly after operation could be used as prognostic markers for the OA process.

    Design In 15 rabbits with medial meniscectomy in one knee and a sham operation in the other knee, synovial lavage fluid samples were taken repeatedly, before operation, every third week post-operatively until 12 weeks, thereafter every sixth week, and at death. Five rabbits each were killed at 13, 25 and 40 weeks. Synovial lavage fluid samples from five non-operated rabbits served as controls. At death, two histological scores were formed that characterized the highest (MAX) and the overall (ALL) degree of OA changes in each joint.

    Results TGF-β1 and PG fragment concentrations in synovial lavage fluid correlated highly (R=0.81, P< 0.001). Both OA scores were higher in meniscectomized than controls (P< 0.05). The synovial lavage fluid concentration of TGF-β1 at 3 weeks, but no other time point, correlated to the histological scores (ALL, R=0.58; MAX, R=0.52;P< 0.001).

    Conclusion Higher concentrations of TGF-β1 in synovial lavage fluid early after surgery seemed indicative for the later development of more severe OA changes in contrast to lower concentrations. The association between TGF-β1 and the changes found later in the cartilage was underlined by the high correlations between this substance and PG fragment concentrations in synovial lavage fluid at all time points.

  • 42.
    Messner, Karola
    et al.
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Ortopedi och Idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Fahlgren, Anna
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Ortopedi och Idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Ross, I.
    Linköpings universitet, Institutionen för medicin och hälsa, Endokrinologi. Linköpings universitet, Hälsouniversitetet.
    Andersson, Britt-Marie
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Ortopedi och Idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Simultaneous changes in bone mineral density and articular cartilage in a rabbit meniscectomy model of knee osteoarthrosis2000Ingår i: Osteoarthritis and Cartilage, ISSN 1063-4584, E-ISSN 1522-9653, Vol. 8, nr 3, s. 197-206Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    Objective It was hypothesized that increased bone mineral density of the medial proximal tibia would precede or coincide with the development of more severe cartilage changes after meniscectomy.

    Methods In a rabbit knee model, mineral density of subchondral bone and changes of articular cartilage were monitored 13 to 40 weeks after medial meniscectomy or a sham operation.

    Results Both procedures resulted in a decrease of bone mineral density, especially of the medial proximal tibia, which persisted up to 40 weeks (P< 0.02–0.0007). Meniscectomy induced cartilage changes typical for osteoarthrosis (P< 0.009), which progressed over time on the posterior aspect of the medial tibial plateau (P< 0.009), which is physiologically covered by the meniscus, but the procedure also induced iatrogenic changes which were located mainly on the anterior aspect of the concerned compartment, and which did not progress or develop to osteoarthrosis.

    Conclusions The data suggest that the cartilage changes after meniscectomy in this animal model are caused by the surgical trauma, subsequent limb misuse, and altered load distribution, and initially associated by a decrease not an increase in bone mineral density of the proximal tibia. Moreover, the cartilage changes progressed without a simultaneous increase of the bone mineral density at corresponding sites.

  • 43.
    Bratengeier, Cornelia
    et al.
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Liszka, Aneta
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    Hoffman, Johan
    KTH Royal Inst Technol, Sweden.
    Bakker, Astrid D.
    Univ Amsterdam, Netherlands; Vrije Univ Amsterdam, Netherlands.
    Fahlgren, Anna
    Linköpings universitet, Institutionen för biomedicinska och kliniska vetenskaper, Avdelningen för cellbiologi. Linköpings universitet, Medicinska fakulteten.
    High shear stress amplitude in combination with prolonged stimulus duration determine induction of osteoclast formation by hematopoietic progenitor cellsIngår i: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860Artikel i tidskrift (Refereegranskat)
    Abstract [en]

    To date, it is unclear how fluid dynamics stimulate mechanosensory cells to induce an osteoprotective or osteodestructive response. We investigated how murine hematopoietic progenitor cells respond to 2 minutes of dynamic fluid flow stimulation with a precisely controlled sequence of fluid shear stresses. The response was quantified by measuring extracellular adenosine triphosphate (ATP), immunocytochemistry of Piezo1, and sarcoplasmic/endoplasmic Ca2+ reticulum ATPase 2 (SERCA2), and by the ability of soluble factors produced by mechanically stimulated cells to modulate osteoclast differentiation. We rejected our initial hypothesis that peak wall shear stress rate determines the response of hematopoietic progenitor cells to dynamic fluid shear stress, as it had only a minor correlation with the abovementioned parameters. Low stimulus amplitudes corresponded to activation of Piezo1, SERCA2, low concentrations of extracellular ATP, and inhibition of osteoclastogenesis and resorption area, while high amplitudes generally corresponded to osteodestructive responses. At a given amplitude (3 Pa) and waveform (square), the duration of individual stimuli (duty cycle) showed a strong correlation with the release of ATP and osteoclast number and resorption area. Collectively, our data suggest that hematopoietic progenitor cells respond in a viscoelastic manner to loading, since a combination of high shear stress amplitude and prolonged duty cycle is needed to trigger an osteodestructive response. Plain Language Summary In case of painful joints or missing teeth, the current intervention is to replace them with an implant to keep a high-quality lifestyle. When exercising or chewing, the cells in the bone around the implant experience mechanical loading. This loading generally supports bone formation to strengthen the bone and prevent breaking, but can also stimulate bone loss when the mechanical loading becomes too high around orthopedic and dental implants. We still do not fully understand how cells in the bone can distinguish between mechanical loading that strengthens or weakens the bone. We cultured cells derived from the bone marrow in the laboratory to test whether the bone loss response depends on (i) how fast a mechanical load is applied (rate), (ii) how intense the mechanical load is (amplitude), or (iii) how long each individual loading stimulus is applied (duration). We mimicked mechanical loading as it occurs in the body, by applying very precisely controlled flow of fluid over the cells. We found that a mechanosensitive receptor Piezo1 was activated by a low amplitude stimulus, which usually strengthens the bone. The potential inhibitor of Piezo1, namely SERCA2, was only activated by a low amplitude stimulus. This happened regardless of the rate of application. At a constant high amplitude, a longer duration of the stimulus enhanced the bone-weakening response. Based on these results we deduce that a high loading amplitude tends to be bone weakening, and the longer this high amplitude persists, the worse it is for the bone.

  • 44.
    Fahlgren, Anna
    et al.
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Ortopedi och Idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Messner, Karola
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Ortopedi och Idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Aspenberg, Per
    Linköpings universitet, Institutionen för nervsystem och rörelseorgan, Ortopedi och Idrottsmedicin. Linköpings universitet, Hälsouniversitetet.
    Meniscectomy in the rabbit knee leads to increased bone remodelling and cartilage degeneration within three weeksManuskript (preprint) (Övrigt vetenskapligt)
    Abstract [en]

    Increased knowledge about the early cartilaginous and osseous responses to meniscectomy may elucidate processes behind development of osteoarthrosis. The purpose of the present study was to evaluate tibial bone and cartilage changes during the first months after meniscectomy.

    Thirty-one skeletally mature New Zealand white rabbits were operated on with meniscectomy in the right knee and a sham-operation in the left knee. Another 12 rabbits were used as controls. The knee joints were evaluated 3, 6 and 12 weeks after surgery by radiolabelled bisphosphonate uptake (99mTc-HDP) and semiquantitative grading of histological changes in the subchondral bone and cartilage.

    Already 3 weeks after meniscectomy, there was increased metabolic activity in the subchondral bone, and articular cartilage fibrillation. Similar changes were seen in shamoperated knees, but to a lesser extent. This appears to be caused both by the new loading situation in the joint after meniscectomy and the operative trauma.

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