| 1. |
- Abtahi, Jahan, 1965-
(författare)
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Bisphosphonates and implants in the jaw bone
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Insertion of metal implants in bone is one of the commonest of all surgical procedures. The success of these operations is dependent on the fixation of the implants, which, in turn, depends on the strength of the bone that holds them. If the quality of the bone holding the implant could be improved locally, surgical procedures would become simpler and rehabilitation would become faster. Bisphosphonates are anti-resorptive drugs that act specifically on osteoclasts, thereby maintaining bone density and strength. Once released from the surface of a coated implant, bisphosphonates reduce osteoclast activity, thereby changing the balance of bone turnover in favor of bone formation, leading to a net gain in local bone density. During the last decades, the effects of bisphosphonate treatment on the stability of implants have been tested in several clinical and animal studies, but not in human jaws. This may be because it has been suggested that there is a link between the use of bisphosphonates (especially those given intravenously) and a condition called osteonecrosis of the jaw (ONJ). The pathophysiology and treatment of ONJ is controversial. The difficulty in treating ONJ has highlighted the importance of prevention.The overall aim of the present thesis was to evaluate the effect of local and systemic use of bisphosphonates on bone tissue. Could a thin, bisphosphonate-eluting fibrinogen coating improve the fixation of metal implants in the human jaw? Would it be possible to reproduce ONJ and prevent the development of this condition in an animal model?In two clinical studies, a total number of 96 implants were inserted in 21 patients. In a randomized trial with a paired design, one implant in each pair was coated with a thin fibrinogen layer containing two bisphosphonates (pamidronate and ibandronate). The bisphosphonate-coated implants showed better stability as measured by resonancefrequency analysis. Radiographic intraoral films also showed less bone loss. Three animal models were developed. In a study comparing local and systemic effects of bisphosphonates, zoledronate-coated screws inserted in rats showed better fixation in spite of a drug treatment that is known to induce ONJ-like lesions when given systemically. In another rat model, ONJ-like lesions were reproducibly induced at sites of tooth extraction whereas there were no signs of bone cell death in uninjured sites. Finally, rat experiments showed that the development of ONJ-like lesions after tooth extraction could be prevented by early mucoperiosteal coverage.In conclusion, a thin, bisphosphonate-eluting fibrinogen coating can improve the fixation of dental implants in human bone. This may lead to new possibilities in orthopaedic surgery and dentistry. The pathophysiology of ONJ is strongly linked to bone exposure in combination with drugs that reduce resorption.
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| 2. |
- Agholme, Fredrik
(författare)
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Wnt signaling and metaphyseal bone healing
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis relates to some new aspects on the regulation of bone healing. In the last few years, Wnt-signaling has been shown to play a central role in bone biology. As well as being involved in bone maintenance and repair, Wnt-signaling has been presented as one of the key pathways through which bone responds to mechanical load. Two secreted extracellular inhibitors of Wnt-signaling, sclerostin and dickkopf-1 are potent negative regulators of bone formation.Using a rat fracture model we investigated how metaphyseal bone healing is influenced by changes in Wnt-signaling.Antibodies were used to suppress levels of sclerostin and dickkopf-1, and thereby increase Wnt-signaling. Primarily, we investigated if those antibody treatments lead to improved bone healing. Also, we investigated if the response was coupled to the loading conditions of the bone.Our findings suggest that suppression of either sclerostin or dickkopf-1 leads to increased bone formation and improved bone healing. Apart from just having an effect on healing, the treatment also improved bone formation in other parts of the skeleton. Depending on the loading conditions, the effects were different. Dickkopf-1 appeared to have a stronger effect on bone volume density in unloaded bone, implying a role mainly in mechano-transduction, while sclerostin had similar effect in both loaded and unloaded bone. To confirm these findings, we studied how the expression of several Wnt-related genes changed due to trauma and unloading in metaphyseal bone. We found that trauma led to upregulation of most of the genes with the largest effect seen in the unloaded bone. In untraumatized bone, there was mainly an effect on the sclerostin gene.In conclusion, antibodies against sclerostin and dickkopf-1 appear to be able to improve metaphyseal bone healing. There appear to be some differences in how the effect of the two antibodies manifests itself, especially if the loading conditions of the bone are altered. These findings suggest a potential for clinical use to shorten fracture healing time.
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| 3. |
- Blomgran, Parmis, 1985-
(författare)
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Inflammation and tendon healing
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Tendons heal through three different overlapping phases; the inflammatory, proliferative and remodeling phase. Many studies have investigated what factors influence healing of tendons. However, little was known about inflammation and the immune cells present during Achilles tendon healing by the time this thesis started. We developed a flow cytometry method for our rat model of tendon healing, which enabled us to study different leukocyte subpopulations during Achilles tendon healing.The general aim of this thesis was to understand more about inflammation and the immune cell populations present during tendon healing and how the immune cell composition changes during normal tendon healing. Moreover, we investigated how different factors that are known to influence tendon healing affected the composition of the immune cell population.First, we described the immune cells during the time course of tendon healing focusing on different subpopulations of macrophages and T cells. Then, we studied how these cells were influenced by reduced mechanical loading. Mechanical loading prolonged the presence of M1 macrophages and delayed the switch to regulatory T cells and M2 macrophages compared to reduced mechanical loading. Next, the effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on the leukocyte composition revealed that, even though NSAIDs influence the mechanical properties of healing tendon, this effect was not mediated via changes in the leukocyte sub-populations during early and mid-time tendon healing. Further, the effect of corticosteroids during the inflammatory and remodeling phases of tendon healing was an improved healing of tendons and a reduction of CD8a T cells when corticosteroid was administered after the inflammatory phase. Lastly, we investigated if impairment of tendon healing by NSAIDs was related to mechanotransduction or microdamage during mechanical loading and showed that NSAIDs impair tendon healing by reducing the response to microdamage.In conclusion, these studies show that inflammation plays an important role during Achilles tendon healing, and factors that influence healing can also alter the presence or polarization of immune cell populations.
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| 4. |
- 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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| 5. |
- 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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| 6. |
- Eliasson, Pernilla
(författare)
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Response to mechanical loading in healing tendons
- 2011
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Ruptured tendons heal faster if they are exposed to mechanical loading. Loading creates deformation of the extracellular matrix and cells, which give rise to intracellular signalling, increased gene expression and protein synthesis. The effects of loading have been extensively studied in vitro, and in intact tendons in vivo. However, the response to loading in healing tendons is less known.The general aim of this thesis was to understand more about the response to mechanical loading during tendon healing. The specific aims were to find out how short daily loading episodes could influence tendon healing, and to understand more about genes involved in tendon healing.The studies were performed using rat models. Unloading of healing tendons resulted in a weaker callus tissue. This could be reversed to some extent by short daily loading episodes. Loading induced more matrix production, making the tendons thicker and stronger, but there was no improvement in the material properties of the matrix. Lengthening is one potential adversity with early loading, during tendon healing in patients. This was also seen with continuous loading in the rat models. However, short loading episodes did not result in any lengthening, not even when loading was applied during the inflammatory phase of healing. It also appeared as loading once daily was enough to make healing tendons stronger, while loading twice daily with 8 hours interval did not give any additional effect. The strongest gene expression response to one loading episode was seen after 3 hours. The gene expression changes persisted 12 hours after the loading episode but had disappeared by 24 hours. Loading appeared to regulate genes involved in inflammation, wound healing and coagulation, angiogenesis, and production of reactive oxygen species. Inflammation-associated genes were regulated both by continuous loading and by one short loading episode. Inflammation is an important part of the healing response, but too much can be harmful. Loading might therefore have a role in fine-tuning the inflammatory response during healing.In conclusion, these studies show that short daily loading episodes during early tendon healing could potentially be beneficial for rehabilitation. Loading might have a role in regulating the inflammatory response during healing.
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| 7. |
- Hammerman, Malin, 1984-
(författare)
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Tendon Healing : Mechanical Loading, Microdamage and Gene Expression
- 2018
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Mechanical loading and the inflammatory response during tendon healing might be important for the healing process. Mechanical loading can improve the healing tendon but the mechanism is not fully understood. The aim of this thesis was to further clarify the effect of mechanical loading on tendon healing and how mechanical loading affects the inflammatory response during the healing process.We used a rat Achilles tendon model to study healing. The rats were exposed to different degrees of loading by unloading methods such as paralysis of the calf muscles with Botox, tail suspension, and an orthosis (a boot). Full loading was achieved by free cage activity or treadmill walking. Microdamage in tendons, unloaded with Botox, was also investigated by needling. The healing tendons were evaluated in a materials testing machine (to analyze the mechanical properties), by gene expression analysis (microarray and PCR), or histology.Our results show that moderate loading (unloading with Botox) improves the mechanical properties of healing tendons compared to minimal loading (unloading with Botox in combination with tail suspension or a boot), especially the material properties. In accordance to these findings, expression of extracellular matrix genes were also increased by moderate compared to minimal loading.Full loading improved all mechanical properties and the expression of extracellular matrix genes was further increased compared to moderate loading. However, structural properties, such as the strength and the size of the healing tendon, were more affected by full loading. Full loading also affected the expression of inflammation-related genes during the early healing phase, 3 and 5 days after tendon injury, and increased the number of immune cells in the healing tendon tissue. Also microdamage of the healing tendon (detected by blood leakage) was increased by full loading compared to moderate loading during the early healing phase.Induced microdamage by repeated needling in the healing tendon tissue increased the structural properties of the healing tendon. The gene expression after needling was similar to the gene expression after full loading.The improvement of mechanical properties by loading in healing tendons was decreased by an anti-inflammatory drug called parecoxib, which decreases the production of prostaglandins by inhibiting COX-2 activity. The effect of parecoxib was reduced when loading was reduced but we could not confirm that the effect of parecoxib was related to the degree of loading. However, parecoxib abolished the stimulatory effect of microdamage.In conclusion, these studies show that moderate loading improves the quality of the healing tendon whereas full loading also increases the quantity of the healing tendon tissue. Full loading creates microdamage and increases inflammation during the early healing phase. The strong effect of full loading on the structural properties might be due to microdamage. Indeed, the anti-inflammatory drug parecoxib seems to impair mechanical stimulation of healing tendons by reducing the response to microdamage.
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| 8. |
- Ledin, Håkan, 1962-
(författare)
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Fixation of total knee replacement : Effects of bone specific drugs and tourniquet use
- 2024
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Knee and hip replacements are among the most common surgical procedures in today's healthcare. Joint replacement is effective for treating pain and disability from osteoarthritis. Although most patients are satisfied with their operation, two percent are reoperated within two years. A common cause for reoperation is aseptic loosening. Almost three thousand reoperations of hip and knee prostheses are performed annually in Sweden. The most common reason for a reoperation is aseptic loosening. Such interventions are technically difficult, associated with poor patient satisfaction, greater risks of complications, and involving larger costs for society. The primary mechanism of aseptic loosening is debated, but it has been convincingly shown that a well-fixed implant in the first two years after the operation is important for the long-term survival of the prosthesis. Even well-integrated prostheses can loosen over time if the fixation is impaired. The use of a tourniquet, to obtain a bloodless field in knee replacement surgery is very common but can have serious side effects. The bloodless field during the operation theoretically creates a blood-free bone bed for cementation, which might lead to better fixation because the bone cement can penetrate into the trabecular bone structure. In this thesis, we show that surgery performed with tourniquet did not improve fixation but may cause more postoperative pain and decreased range of motion (Study I). We also explored using bone specific drugs to improve fixation: parathyroid hormone (Study II) stimulates bone-forming cells (osteoblasts), and denosumab (Study III) inhibits bone-resorbing cells (osteoclasts). We found that patients who received parathyroid hormone after total knee replacement did not experience improved fixation, whereas those treated with denosumab showed enhanced fixation. Similar to denosumab, bisphosphonates—widely used in the treatment of osteoporosis—also inhibit osteoclast function. Study IV is a protocol publication of an ongoing, double-blinded, randomised controlled clinical trial involving 1000 patients. We are investigating whether a single intravenous dose of bisphosphonate given immediately after surgery improves prosthesis fixation and patient satisfaction after primary total hip and knee joint replacement.
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| 9. |
- Lindgren, Christer
(författare)
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On healing of titanium implants in biphasic calcium phosphate
- 2012
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Previously, autogenous bone was considered the gold standard for grafting procedures in implant surgery. Today, the use of bone graft substitutes is an alternative for sinus lift procedures. Nevertheless, only a few bone substitutes are well documented and can be recommended as an alternative to autogenous bone grafts. Both deproteinized bovine bone (DBB) and tricalcium phosphate (TCP) are materials that are frequently used and well documented. During the last years a novel biphasic calcium phosphate (BCP) has been introduced to the market. Until now only a few studies have been published.Aims: Studies I, II, III and IV. The overall aim of the present thesis was to evaluate a new biphasic calcium phosphate for bone augmentation of the maxillary sinus. Deproteinized bovine bone was used as a control.Study V. The aim of this in vitro study was to evaluate the response of human osteoblast-like cells (HOB) to nano-crystalline-diamond-particle-modified (nDP-modified) and un-modified (control) deproteinized bovine bone (DBB) and biphasic calcium phosphate (BCP) scaffolds.Materials and Methods: Studies I, II, III and IV. The studies were based on 11 patients (six women, five men) with a mean age of 67 years (range; 50 to 79 years). All patients showed severe maxillary resorption with less than 5mm of residual alveolar bone in the floor of the maxillary sinus, which excluded conventional implant treatment. Twenty-two maxillary sinuses were augmented with BCP on one side and with DBB acting as a control at the contralateral side. Simultaneously with the augmentation procedure 22 microimplants were placed inside the augmented materials. After 8 months of graft healing the microimplants and a surrounding bone core were retrieved for histomorphometrical analysis (Paper I) and for energy dispersive spectroscopy (Paper II). After retrieval of the microimplants, 62 conventional implants were placed and left to heal for 8 weeks before rehabilitation with fixed prosthetic constructions. The conventional implants were evaluated clinically at baseline, after 1- and 3 years of loading (Papers III and IV). After 3 years of graft healing 18 biopsies were harvested from 9 patients for histomorphometrical analysis (Paper IV).Computerized tomography (CT) of the maxillary sinuses was performed after 3 years of graft healing to allow examination of the recipient sites.Study V. Nano-crystalline-diamond particle-modification of DBB and BCP particles was carried out through different steps of preparation including grinding and ultrasonic techniques. Scanning electron microscopy (SEM) was carried out after 24 hours and 3 days. Real time-polymerase chain reaction (PCR) was carried out after 3 days, 1 week and 2 weeks of incubation. The following osteoblast differentiation markers were analyzed: alkaline phosphatase (ALP), osteocalcin (OC), bone morphogenetic protein type 2 (BMP-2) and integrin alpha 10 (ITGA 10).Results: In paper I, the results revealed a similar degree of bone formation and bone-to-implant contact around sandblasted and acid-etched microimplants placed in sinuses augmented with BCP or DBB. No obvious signs of resorption of the BCP and DBB particles were noticed. There was a significantly higher amount of DBB particles in contact with newly formed bone compared to BCP (p=.007).In paper II, the median Ca/P ratios (atomic %), determined from >200 discreet sites within residual graft particles and adjacent bone were analysed. The difference between the median values for BCP and DBB and for BCP-augmented bone compared with DBB-augmented bone were statistical significant (p=.028 in each case). The reduction in Ca/P ratio for BCP over the healing period is consistent with the dissolution of β-TCP and reprecipitation on the surface of calcium-deficient hydroxyapatite.In paper III, the results revealed that no implant placed in residual bone was lost, one implant placed in BCP was lost after 3 months of functional loading due to infection, and one implant placed in DBB was lost only a few weeks after insertion due to lack of initial instability. The overall implant survival rate was 96.8%. Success rates for implants placed in BCP and DBB were 91.7% and 95.7% respectively. No significant differences in marginal bone loss were found around implants placed in BCP, DBB or residual bone respectively.In paper IV, it was shown that after 36 months (range; 36 to 37 months) of functional loading the overall implant survival rate was 96.8%. Success rates for implants placed in BCP, DBB and residual bone were 91.7%, 95.7% and 86.7% respectively. No significant difference was found between implants placed in BCP, DBB and residual bone. The corresponding histological evaluation after 3 years of graft healing showed BCP particles under different levels of dissolution. Dissolution was mostly observed on the edges of the BCP particles but in some cases the entire particle was dissolving. In contrast, DBB particles showed no signs of resorption. The percentage of graft particles in contact with newly formed bone was not significantly different after 3 years of healing for BCP and DBB.In paper V, cellular responses were evaluated in terms of attachment and differentiation. SEM after 24 hours and 3 days of incubation disclosed similar cell attachment and spreading for nDP-modified and non-modified DBB and BCP particles. Real-time PCR revealed significant up-regulation of mRNA expression of ALP and OC and by HOB grown on nDP-modified DBB and BCP-particles after 1 and 2 weeks compared to non-modified particles. A significant down-regulation of BMP-2 on nDP-modified DBB and a significant up-regulation of BMP-2 on DP-modified BCP was disclosed for HOB in relation to un-modified particles. Cell adhesion marker ITGA 10 showed significant down-regulation in the mRNA level for both nDP-modified groups after 2 weeks of incubation (mDP-BCP (p<.01) and nDP-DBB (p<.05) compared to the non-modified materials.Conclusion: It is concluded that BCP can be used for maxillary floor augmentation and later placement of dental implants producing equal results to those for DBB. Nevertheless, the initial HA/β-TCP ratio in BCP might not be optimized for cell adhesion, which can affect the early healing phase. Furthermore, the results indicate that BCP is not optimized for gene expression in its present form and that nDP-modified BCP enhances the osteoblast phenotype suggesting that these scaffolds are appropriate cell carriers, superior to non-modified BCP particles. Surface modification of bone substitutes is a new interesting field in bone tissue engineering (BTE). Nevertheless, it´s still unclear if the modification will have any clinical impact.
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| 10. |
- Lundin, Anna-Carin
(författare)
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Tendinosis in Trigger Finger
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Trigger finger is one of the most common hand conditions, with a prevalence of almost 3%. The aetiology remains unclear even though many causes have been suggested. The prevailing paradigm is that the pathogenesis of trigger finger is ascribed to primary changes in the first fibrous condensation of the tendon sheath (A1-pulley). Several studies have investigated pathology in the pulley, but few have investigated the tendon. The general aim of this thesis was to find out if there is pathology in the trigger finger tendon and to define it.We first looked at trigger finger tendon biopsies in a light microscope, and found that they were histologically different from healthy tendons. They showed signs of micro-ruptures, collagen degradation, increased amounts of ground substance, both hyper- and hypo-cellular areas, round active cell nuclei and absence of inflammatory cells, all similar to tendinosis. The histological picture was further assessed by using a scoring system for Achilles tendinosis. The trigger finger tendons scored high, suggesting a similar histopathology.Next, we performed a quantitative real-time polymerase chain reaction (qPCR) on trigger finger tendons. We assessed the mRNA expression of 10 genes, which have been described to be differently expressed in Achilles tendinosis (collagen 1 and 3, versican, decorin, biglycan, aggrecan, MMP-2, MMP-3, ADAMTS-5, and TIMP-3). The overall expression pattern agreed with previous studies on Achilles tendinosis, suggesting that the cellular function in trigger finger tendons is disturbed in a similar way as in Achilles tendinosis.Recent experimental and observational research has suggested potential side effects of statin treatment on tendons, but firm evidence was lacking. We performed an epidemiological study on two large population-based cohorts. Statin use was found to increase the risk of both trigger finger and tendinosis in the shoulder and Achilles tendons, especially among men. This suggests a similar pathology in trigger finger and tendinosis.We have also studied the time to treatment effect after a single injection of glucocorticoid in trigger finger. Our results suggest that 60-80% of patients can expect resolution of the triggering within 14 days, and half of them within seven days. This result allows correct information to be given to the patient and proper planning of follow-ups.In conclusion, the pathology in trigger finger tendons is similar to tendinosis in other tendons.
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