| 1. |
- Blaus, Johan, et al.
(författare)
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Structures, processes, and methods for collaboration with stakeholders on relevance assessment of higher education
- 2021
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Konferensbidrag (refereegranskat)abstract
- 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. ReferencesEuropean Association for Quality Assurance in Higher Education (ENQA). (2015). Standards and Guidelines for Quality Assurance in the European Higher Education Area (ESG). Brussels, EURASHE.
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| 2. |
- Amirhosseini, Mehdi
(författare)
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Aseptic Loosening of Orthopedic Implants : Osteoclastogenesis Regulation and Potential Therapeutics
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Aseptic loosening is the main cause of failure of orthopedic prostheses. With no pharmaceuticals to prevent or mitigate periprosthetic bone degradation, a surgery to replace the loose implant with a new one is the only choice to restore patients’ function. Most studies on mechanisms for aseptic loosening investigate wear debris particle-induced osteolysis. However, pathological loading conditions around unstable implants can also trigger osteoclast differentiation and bone loss.In the first study, global gene expression changes induced by mechanical instability of implants, and by titanium particles were compared in a validated rat model for aseptic loosening. Microarray analysis showed that similar signaling pathways and gene expression patterns are involved in particle- and instability-induced periprosthetic osteolysis with an early onset innate immune response as a hallmark of osteolysis induced by mechanical instability.Further, effects of potential therapeutics on restriction of excessive osteoclast differentiation were evaluated. Wnt signaling pathway is known to regulate bone remodeling. In the second study, effects of inactivation of glycogen synthase kinase 3 beta (GSK-3β), a negative regulator of canonical Wnt signaling, on instability-induced periprosthetic osteolysis were examined using our rat model for aseptic loosening. Inhibition of GSK-3β led to a decrease in osteoclast numbers in the periprosthetic bone tissue exposed to mechanical instability while osteoblast perimeter showed an increase. This was accompanied by higher bone volume fraction (BV/TV) in animals treated with the GSK-3β inhibitor.In the third study, potential beneficial effects of two selective inhibitors of cyclindependent kinase 8/19 (CDK8/19) on bone tissue were evaluated. CDK8/19 is a Mediator complex-associated transcriptional regulator involved in several signaling pathways. CDK8/19 inhibitors, mainly under investigation as treatments for tumors, are reported to enhance osteoblast differentiation and bone formation. We show in this study, for the first time, that inhibition of CDK8/19 led to marked suppression of osteoclast differentiation from bone marrow macrophages in vitro through disruption of the RANK signaling. In mouse primary osteoblasts downregulation of osteopontin mRNA, a negative regulator of mineralization, together with increased alkaline phosphatase activity and calcium deposition indicated that osteoblast mineralization was promoted by CDK8/19 inhibition. Moreover, local administration of a CDK8/19 inhibitor promoted cancellous bone regeneration in a rat model for bone healing.These studies contribute to better understanding of mechanisms behind mechanical instability-induced periprosthetic osteolysis and propose potential therapeutics to restrict bone loss with effects on both osteoclasts and osteoblasts.
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| 3. |
- Amirhosseini, Mehdi, et al.
(författare)
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Cyclin-dependent kinase 8/19 inhibition suppresses osteoclastogenesis by downregulating RANK and promotes osteoblast mineralization and cancellous bone healing.
- 2019
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Ingår i: Journal of Cellular Physiology. - : Wiley. - 0021-9541 .- 1097-4652. ; 234:9, s. 16503-16516
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Tidskriftsartikel (refereegranskat)abstract
- 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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| 4. |
- Amirhosseini, Mehdi, et al.
(författare)
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Mechanical instability and titanium particles induce similar transcriptomic changes in a rat model for periprosthetic osteolysis and aseptic loosening
- 2017
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Ingår i: Bone Reports. - : Elsevier. - 2352-1872. ; 7, s. 17-25
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Tidskriftsartikel (refereegranskat)abstract
- 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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| 5. |
- Aspenberg, Per, 1949-, et al.
(författare)
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Additive effects of PTH and bisphosphonates on the bone healing response to metaphyseal implants in rats
- 2008
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Ingår i: Acta Orthopaedica. - : Medical Journals Sweden AB. - 1745-3674 .- 1745-3682. ; 79:1, s. 111-115
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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| 6. |
- Bernhardsson, Magnus, 1989-
(författare)
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Healing Processes in Cancellous Bone
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Most of what is known about the biological response during fracture healing comes from numerous animal studies with shaft fractures in the long bone. However, most patients suffer from fractures closer to the ends of the long bones, in the hip, or in the vertebrae. These types of fractures mainly involve cancellous bone, while shaft fractures concern cortical bone. Compared to cortical bone whose structure is dense and compact, cancellous bone is of spongy and porous structure. A growing number of studies point towards that cortical and cancellous bone heal differently. To even this imbalance in knowledge between these two types of bone tissue, further studies in cancellous bone are justified.In this thesis we delved into the quiet unknown processes behind cancellous bone healing.In the first study we characterized and compared two models for cancellous bone healing in mice and rats: the first model can be used to analyze the morphology and morphometry of the regenerating bone; the second model can measure the mechanical properties of cancellous bone. The two models correspond in their developing patterns during the first week before they diverge. This suggests that these models can be utilized together to evaluate the initial healing in cancellous bone. Furthermore, we saw in the drill hole model that the bone formation is strictly restricted to the traumatized region, with a distinct interface to the adjacent uninjured tissue.The second study characterized the cellular response during the initial healing phase in cancellous bone. The focus was to follow the spatial location of inflammatory and osteogenic cells over time in a cancellous bone injury. In contrast to shaft fractures (cortical bone), where healing is described as sequential events where inflammatory cells are the first to arrive to the trauma before osteogenic cells are recruited and initiate healing, we could see how inflammatory and osteogenic cells appeared early, simultaneously after a cancellous bone injury. This study showed that cancellous bone differs from how fracture healing is normally described.In the third study we explored the role of a subpopulation of lymphocytes (CD8 positive cells), earlier studied in shaft fractures. We wanted to see how their absence would affect the healing in a cancellous bone injury. Without CD8+ cells, cancellous bone healing was impaired as expressed via poorer mechanical properties of the regenerated bone tissue.The fourth and last study issued the influence of uninjured bone marrow on cortical bone healing. We developed a cortical defect model which blocked uninjured marrow from reaching the defect. Without the presence of marrow, the cortical defects ability to regenerate was significantly impaired. This implies that the marrow is important for cortical bone healing.In conclusion, cancellous bone healing is different from its cortical counterpart and the general perception of fracture healing. We have briefly discerned healing mechanisms in cancellous bone that might be of clinical importance: the restricted cancellous bone formation is something to take into consideration when performing arthrodeses; and importance of marrow in skeletal defects (e.g. pseudarthroses). With this thesis, we hope to promote that further investigating on cancellous bone healing is necessary.
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| 7. |
- Bratengeier, Cornelia, 1983-
(författare)
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Mechanisms of mechanically induced Osteoclastogenesis : in a novel in vitro model for bone implant loosening
- 2019
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Total joint arthroplasty is the primary intervention in the treatment of end-stage osteoarthritis. Despite the high success rate, in some patients, the replacement will fail during their lifetime requiring a revision of the implant. These revisions are strenuous for the patient and costly for health care. Joint replacement at a younger age, in combination with a more active lifestyle, increases the need for an early revision of the joint prosthesis. The main reason for revision surgeries is aseptic loosening, a condition where the prosthesis is loosening due to bone degradation at the peri-prosthetic interface in the absence of infections. The most well-established pathological mechanism for aseptic loosening is related to wear particles, generated from different parts of the prosthesis that will trigger bone degradation and bone loss. In addition, early micromotions of the prosthesis and resulting local pressurized fluid flow in the peri-prosthetic interface (supraphysiological loading) have also been identified as a cause for aseptic loosening. However, it remains unknown what cells are the primary responders to supraphysiological loading, and what underlying physical, cellular and molecular mechanism that triggers osteoclast differentiation and osteolysis.In this thesis, we intended to shed light on three currently unknown aspects of mechanical loading-induced peri-prosthetic osteolysis, leading to aseptic loosening of orthopedic prostheses: (1)Which cells are the primary responder to supraphysiological loading? (2)What characteristics of the mechanical stimulus induce an osteo-protective or osteo-destructive response? (3)Which cellular mechano-sensing mechanisms are involved in an osteo-destructive response?We successfully implemented supraphysiological mechanical loading, mimicking the periprosthetic pressurized fluid flow around a loosening implant, in an in vitro model for bone implant loosening. Using this model, we uncovered the involvement of mesenchymal stem cells and myeloid progenitor cells (monocytes) in mechanical loading-induced peri-prosthetic osteolysis. Applying supraphysiological loading on cells from patients undergoing primary hip arthroplasty, successfully validated the in vitro model for the use of cells of human origin. We further identified in murine myeloid progenitor cells that a combination of high loading amplitude (3.0±0.2Pa), prolonged active loading duration per cycle (duty cycle 22%-50%), and rapid alterations in minimum/maximum values of the loading profile (square wave) is necessary to induce an osteo-destructive response. Further, the loading-induced ATP release and subsequent activation of the P2X7 receptor was essential for the release of soluble factors modulating osteoclastogenesis.In conclusion, we expect that the proposed new in vitro model is a helpful tool to further advance the knowledge in aseptic loosening, by uncovering the mechanoresponsive cellular mechanism to supraphysiological mechanical loading. The identification of the respondent cells in mechanical loading-induced prosthetic loosening gives the opportunity to deliver targeted treatment strategies. Furthermore, identifying the physical parameters that define the shift towards an osteo-destructive response emphasizes the importance of the prosthetic design and surgical technique to reduce mechanical loading-induced bone degradation around a prosthesis.
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| 8. |
- Bratengeier, Cornelia, 1983-, et al.
(författare)
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The release of osteoclast-stimulating factors on supraphysiological loading by osteoprogenitors coincides with expression of genes associated with inflammation and cytoskeletal arrangement
- 2022
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Ingår i: Scientific Reports. - : Springer. - 2045-2322. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- 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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| 9. |
- Bögl, Hans Peter, 1969-
(författare)
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Atypical femoral fractures: Another brick in the wall : On aspects of healing, treatment strategies and surveillance
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Atypical femoral fractures are stress fractures of the femoral subtrochanteric and diaphyseal region. It is a common notion that these fractures heal poorly, if at all. In this thesis we show that patients with atypical femoral fractures have a good capacity to generate bone and therefore heal fractures. In daily practice, these patients have a higher risk for reoperation when compared with patients with a normal femoral fracture. However, this risk is less likely to be dependent on the type of fracture than other factors such as age, gender, comorbidities and survival. Using an implant that protects the fragile proximal femur, the risk for reoperations can be attenuated dramatically. An intramedullary nail with fixation of the femoral neck protects the femur from subsequent hip fractures – the most common complication in elderly patients with any type of femoral shaft fracture.Atypical femoral fractures are difficult to identify in the population. Erroneous diagnosis coding, poor reporting of adverse drug reactions and low accuracy of radiology reports make the identification and surveillance a difficult task. The Swedish Fracture Register has provided the option to register this special fracture since 2015. With its physician-based registration process, it enables researchers and treating physicians to identify and follow these rare fractures longitudinally.
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| 10. |
- Eliasson, Pernilla, et al.
(författare)
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Unloaded rat Achilles tendons continue to grow, but lose viscoelasticity
- 2007
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Ingår i: Journal of applied physiology. - : American Physiological Society. - 8750-7587 .- 1522-1601. ; 103:2, s. 459-463
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Tidskriftsartikel (refereegranskat)abstract
- 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.
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