| 1. |
- Blaszczyk, Izabela, 1967-
(author)
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Upper limb assessment and treatment in cerebral palsy
- 2023
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Doctoral thesis (other academic/artistic)abstract
- Cerebral palsy (CP) is a heterogeneous group of neurological disorders caused by fetal or infant brain damage that often involves deficits in upper limb (UL) posture and function. Knowledge about effective methods of assessment and treatment of UL in CP is not extensive. In this thesis, different aspects of these two are explored.In Paper I we retrospectively investigated the effect of a long-term treatment regime developed in Västerbotten county habilitation service. The treatment regime included intramuscular injections of botulinum toxin type A (BoNT-A) combined with occupational therapy (OT) and movement training. The results of passive extension of the wrist with fingers extended and the assessment of hand function in children with severe hand function impairment (initially House functional classification 0-1) were analyzed over time. Twenty-five children were divided into 3 groups depending on the treatment regime start age (before or after the age of 7) and treatment regime availability. We found significantly worse passive extension of the wrist with fingers extended in children who did not have a chance to benefit from therapy in early childhood. Additionally, an improvement in the passive movement of the wrists was noted in children who completed the treatment regime before the age of 7. Regarding hand function, a significant difference was found between children who received treatment in early childhood and those who received treatment as adolescents.The injections of BoNT-A in CP are common, however the monitoring of eventual side effects and adverse events (AEs) after this treatment is difficult to perform in clinical practice. To facilitate this process, we created a new, no previously validated questionnaire (Paper II). The questionnaire was given to patients or their caregivers to be completed after each BoNT-A treatment. 94% of participants returned the questionnaire. 80 % were filled in completely which proves the effectiveness of the applied form and the ease of its use in clinical practice. 61% of patients reported one or more different AEs or sides effects. In addition, we analyzed the risk for generalized and focal distal AEs reported by 38% of patients. Those may indicate the spread of BoNT-A toxin to the whole body, therefore requiring special attention. We found that females had a 1.899 relative risk with significant association (p=0.029) of reporting generalized and focal delayed AEs compared to males. The use of the questionnaire helped to make the decision to change or discontinue BoNT-A injections in 8 cases (11%).In some patients with dyskinetic type of CP (DCP) treated with BoNT-A to diminish the external rotation posture of the shoulders, a loss of treatment effect was observed, which contributed to the need to look for another method of treatment. In paper III, a surgical method to manage the external rotation posture of the shoulders is presented. The surgical procedure consists of weakening the strength of the externally rotating muscles by cutting the attachment of one of them (release of the posterior deltoid) and complete denervation of the other (denervation of the infraspinatus). The third shoulder external rotator (teres minor) remains intact. The results of this procedure performed in 7 shoulders in 6 patients (age 14-24) were analyzed using satisfaction questionnaire and pre-/postoperative video-recordings. Five of 6 patients were very satisfied with the treatment, one was neither satisfied nor dissatisfied. Four patients had an obvious improvement in their shoulder position confirmed on video recordings. In one, overcorrection in the form of internal shoulder rotation was observed.Assessment of the thumb in CP is important as the thumb impairment plays a crucial role in hand grip function. Paper IV presents a new tool called CP-thumb score, which addresses the occupational therapists to follow the changes in the thumb function and its posture. CP-thumb score has two parts: descriptive and score of the thumb’s CMC joint radial abduction. Thirty thumbs in 19 patients with all types of CP were assessed with CP-thumb score. All assessments were made based on available video recordings. Additionally, all thumbs were assessed using the House’s thumb-in-palm classification which has been shown to be unreliable. These two thumb assessments were compared with each other.
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| 2. |
- Bourke, Grainne, 1970-
(author)
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Magnetic resonance imaging and diffusion tensor imaging after brachial plexus injury and repair : Experimental and clinical study
- 2022
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Doctoral thesis (other academic/artistic)abstract
- Brachial plexus injuries (BPI) cause permanent upper limb paralysis and serious disability in adults and children. Timely identification of the severity of nerve injury and early appreciation of the inane potential for recovery would revolutionise management. Radiology supports clinical assessment but is not an independent marker of disease severity. Surgical evaluation in severe closed nerve injuries defines the reconstructive potential. This thesis explores aspects of BPI assessment and treatment that remain unsolved. Conventional magnetic resonance imaging (MRI) and novel diffusion tensor imaging (DTI) are evaluated in adults to gain a better understanding of their current diagnostic accuracy in BPI and future value in assessing nerve health. In neonates, this thesis evaluates the preganglionic effects related to timing of injury and repair and socioeconomic factors that influence the incidence and presentation of neonates to specialist centres. These currently controversial factors are important prerequisites to designing and evaluating the optimal objective imaging modality in this age group. Data from 29 high energy trauma BPI patients were analysed. The diagnostic accuracy of 1.5T MRI for BP root avulsion was 79% (Index test MRI, Reference standard Surgery). The negative predictive value was 81% meaning there was one occult avulsion in every 5 cases. DTI data sets from 12 patients with unilateral BPI and seven matched adult controls were acquired. The test was considered positive for root avulsion when there was a visible lack of continuity between tracts in the spinal cord and the brachial plexus. The mean fractional anisotropy (FA) and mean diffusivity (MD) were calculated from a region of interest (ROI) - five 2.5mm2 pixels in the axial plane covering the lateral recess of the vertebral foramen. The overall diagnostic accuracy of DTI for determining root avulsion was 71% (95%CI 54, 85). The fractional anisotropy (FA) of avulsed roots was 10% lower than normal roots (95% [CI 7%,13%] p<0.001). The mean diffusivity (MD) of avulsed roots was 0.32x10-3mm2/s higher than normal intact roots (95%CI 0.11, 0.53; p><0.001). The T1 tracts were not clearly visualised in most BPI cases. The time course comparing survival of motoneurons in a neonatal rat BPI model, was evaluated at 2- 28 days after injury and repair. At day 10, the injury group survival of motoneurons was 22% and at 28 days only 9%of motoneurons remained. In the repair group the surviving neurons were 51% at 10 days and 20% at 28 days. The repair group had significantly reduced reactivity of macrophages and microglial cells in the C5/C6 ventral horn. In analysis (Index of Multiple Deprivation, IMD) of a 13 year, retrospective cohort series of 321 children with Obstetric Brachial Plexus injury (England), 109 (39%) were from the most deprived quintile. In Yorkshire and Humber 44% were from the most deprived quintile. No relationship was identified between severity of condition and IMD. These laboratory and clinical studies in adults, children and neonatal animals align with the real-time clinical conundrum in evaluating the injured nerve’s ability to recover to functional significance. ><0.001). The mean diffusivity (MD) of avulsed roots was 0.32x10-3mm2/s higher than normal intact roots (95%CI 0.11, 0.53;p<0.001). The T1 tracts were not clearly visualised in most BPI cases. The time course comparing survival ofmotoneurons in a neonatal rat BPI model, was evaluated at 2- 28 days after injury and repair. At day 10, the injury group survival of motoneurons was 22% and at 28 days only 9%of motoneurons remained. In the repair group the surviving neurons were 51% at 10 days and 20% at 28 days. The repair group had significantly reduced reactivity of macrophages and microglial cells in the C5/C6 ventral horn. In analysis (Index of Multiple Deprivation, IMD) of a 13 year, retrospective cohort series of 321 children with Obstetric Brachial Plexus injury (England), 109 (39%) were from the most deprived quintile. In Yorkshire and Humber 44% were from the most deprived quintile. No relationship was identified between severity of condition and IMD. These laboratory and clinical studies in adults, children and neonatal animals align with the real-time clinical conundrum in evaluating the injured nerve’s ability to recover to functional significance.
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| 3. |
- Brohlin, Maria
(author)
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Mesenchymal stem cells for repair of the peripheral and central nervous system
- 2011
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Doctoral thesis (other academic/artistic)abstract
- Bone marrow-derived mesenchymal stem cells (MSC) have been shown to provide neuroprotection after transplantation into the injured nervous system. The present thesis investigates whether adult human and rat MSC differentiated along a Schwann cell lineage could increase their expression of neurotrophic factors and promote regeneration after transplantation into the injured peripheral nerve and spinal cord. Human and rat mesenchymal stem cells (hMSC and rMSC) expressed characteristic stem cell surface markers, mRNA transcripts for different neurotrophic factors and demonstrated multi-lineage differentiation potential. Following treatment with a cocktail of growth factors, the hMSC and rMSC expressed typical Schwann cells markers at both the transcriptional and translational level and significantly increased production of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF). Age and time in culture are of relevance for clinical settings and growth-promoting effects of hMSC from young donors (16-18 years) and old donors (67-75 years) were compared. Undifferentiated hMSC from both young and old donors increased total neurite length of cultured dorsal root ganglion (DRG) neurons. Differentiation of hMSC from the young donors, but not the eldery donors, further enhanced the neurite outgrowth. Undifferentiated hMSC were cultured for eleven weeks in order to examine the effect of in vitro expansion time on neurite outgrowth. hMSC from the young donors maintained their proliferation rate and their ability to enhance neurite outgrowth from DRG neurons. Using a sciatic nerve injury model, a 10mm gap was bridged with either an empty tubular fibrin glue conduit, or conduits containing hMSC, with and without cyclosporine treatment. Cells were labeled with PKH26 prior to transplantation. At 3 weeks after injury the conduits with cells and immunosuppression increased regeneration compared with an empty conduit. PKH26 labeled human cells survived in the rat model and the inflammatory reaction could be suppressed by cyclosporine. After cervical C4 hemisection, BrdU/GFP-labeled rMSC were injected into the lateral funiculus rostral and caudal to the spinal cord lesion site. Spinal cords were analyzed 2-8 weeks after transplantation. Transplanted MSC remained at the injection sites and in the trauma zone for several weeks and were often associated with numerous neurofilament-positive axons. Transplanted rMSC induced up-regulation of vascular endothelial growth factor in spinal cord tissue rostral to the injury site, but did not affect expression of brain-derived neurotrophic factor. Although rMSC provided neuroprotection for rubrospinal neurons and significantly attenuated astroglial and microglial reaction, cell transplantation caused aberrant sprouting of calcitonin gene-related peptide immunostained sensory axons in the dorsal horn. In summary these results demonstrate that both rat and human MSC can be differentiated towards the glial cell lineage, and show functional characteristics similar to Schwann cells. hMSC from the young donors represent a more favorable source for neurotransplantation since they maintain proliferation rate and preserve their growth-promoting effects in long-term cultures. The data also suggest that differentiated MSC increase expression of neurotrophic factors and support regeneration after peripheral nerve and spinal cord injury.
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| 4. |
- Karalija, Amar, 1984-
(author)
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Diagnostic and therapeutic strategies following spinal cord and brachial plexus injuries
- 2016
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Doctoral thesis (other academic/artistic)abstract
- Traumatic injuries to the spinal cord and brachial plexus induce a significant inflammatory response in the nervous tissue with progressive degeneration of neurons and glial cells, and cause considerable physical and mental suffering in affected patients. This thesis investigates the effects of the antioxidants N-acetyl-cysteine (NAC) and acetyl-L- carnitine (ALC) on the survival of motoneurons in the brainstem and spinal cord, the expression of pro-apoptotic and pro-inflammatory cell markers, axonal sprouting and glial cell reactions after spinal hemisection in adult rats. In addition, a novel MRI protocol has been developed to analyse the extent of neuronal degeneration in the spinal cord. Rubrospinal neurons and tibial motoneurons were pre-labelled with the fluorescent tracer Fast Blue one week before cervical C3 or lumbar L5 spinal cord hemisection. The intrathecal treatment with the antioxidants NAC (2.4mg/day) or ALC (0.9 mg/day) was initiated immediately after injury using Alzet2002 osmotic mini pumps. Spinal cord injury increased the expression of apoptotic cell markers BAX and caspase 3, induced significant degeneration of rubrospinal neurons and spinal motoneurons with associated decrease in immunoreactivity for microtubule-associated protein-2 (MAP2) in dendritic branches, synaptophysin in presynaptic boutons and neurofilaments in nerve fibers. Immunostaining for the astroglial marker glial fibrillary acidic protein and microglial markers OX42 and ED1 was markedly increased. Treatment with NAC and ALC attenuated levels of BAX, caspase 3, OX42 and ED1 expression after 2 weeks postoperatively. After 4-8 weeks of continuous intratheca ltreatment, NAC and ALC rescued approximately half of the rubrospinal neurons and spinal motoneurons destined to die, promoted axonal sprouting, restored the density of MAP2 and synaptophysin immunoreactivity and reduced the microglial reaction. However, antioxidant therapy did not affect the reactive astrocytes in the trauma zone. The inflammation modulating properties of ALC were also studied using cultures of human microglial cells. ALC increased the microglial production of interleukin IL-6 and BDNF, thereby possibly mediating the anti-inflammatory and pro-regenerative effects shown in vivo. To study degeneration in the spinal cord following pre-ganglionic and post-ganglionic brachial plexus injuries, adult rat models of ventral root avulsion and peripheral nerve injury were used. A novel MRI protocol was employed and the images were compared to morphological changes found in histological preparations. Ventral root avulsion caused degeneration of dendritic branches and axonal terminals in the spinal cord, followed by significant shrinkage of the ventral horn. Extensive astroglial and microglial reactions were detected in the histological preparations. Peripheral nerve injury reduced the density of dendritic branches but did not cause shrinkage of the ventral horn. Quantitative analysis of MRI images demonstrated changes in the ventral horn following ventral root avulsion only, thus validating the developed MRI technique as a possible tool for the differentiation of pre-ganglionic and post-ganglionic nerve injuries.
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| 5. |
- Kolar, Mallappa K., 1981-
(author)
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Transplantation of mesenchymal stem cells and injections of microRNA as therapeutics for nervous system repair
- 2016
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Doctoral thesis (other academic/artistic)abstract
- Traumatic injuries to the spinal cord (SCI) and peripheral nerve (PNI) affect several thousand people worldwide every year. At present, there is no effective treatment for SCI and despite continuous improvements in microsurgical reconstructive techniques for PNI, many patients are still left with permanent, devastating neurological dysfunction. This thesis investigates the effects of mesenchymal stem cells (MSC) derived from adipose (ASC) and dental (DSC) tissue and chitosan/microRNA-124 polyplex particles on regeneration after spinal cord and peripheral nerve injury in adult rats. Dental stem cells were obtained from apical papilla, dental pulp, and periodontal ligament. ASC and DSC expressed MSC surface markers (CD73, CD90, CD105 and CD146) and various neurotrophic molecules including BDNF, GDNF, NGF, VEGF-A and angiopoietin-1. Growth factor stimulation of the stem cells resulted in increased secretion of these proteins. Both ASC and DSC supported in vitro neurite outgrowth and in contrast to Schwann cells, ASC did not induce activation of astrocytes. Stimulated ASC also showed an enhanced ability to induce capillary-like tube formation in an in vitro angiogenesis assay. In a peripheral nerve injury model, ASC and DSC were seeded into a fibrin conduit, which was used to bridge a 10 mm rat sciatic nerve gap. After 2 weeks, both ASC and DSC promoted axonal regeneration in the conduit and reduced caspase-3 expression in the dorsal root ganglion (DRG). ASC also enhanced GAP-43 and ATF-3 expression in the spinal cord, reduced c-jun expression in the DRG and increased the vascularity of the implant. After transplantation into injured C3-C4 cervical spinal cord, ASC continued to express neurotrophic factors and laminin and stimulated extensive ingrowth of 5HT-positive raphaespinal axons into the trauma zone. In addition, ASC induced sprouting of raphaespinal terminals in C2 contralateral ventral horn and C6 ventral horn on both sides. Transplanted cells also changed the structure and the density of the astroglial scar. Although the transplanted cells had no effect on the density of capillaries around the lesion site, the reactivity of OX42-positive microglial cells was markedly reduced. However, ASC did not enhance recovery of forelimb function. In order to reduce activation of microglia/macrophages and the secondary tissue damage after SCI, the role of microRNA-124 was investigated. In vitro transfection of chitosan/microRNA-124 polyplex particles into rat microglia resulted in the reduction of reactive oxygen species and TNF-α levels and lowered expression of MHC-II. Upon microinjection into uninjured rat spinal cords, particles formed with Cy3-labeled control sequence RNA, were specifically internalized by OX42 positive macrophages and microglia. Alternatively, particles injected in the peritoneum were transported by macrophages to the site of spinal cord injury. Microinjections of chitosan/microRNA-124 particles significantly reduced the number of ED-1 positive macrophages after SCI. In summary, these results show that human MSC produce functional neurotrophic and angiogenic factors, creating a more desirable microenvironment for neural regeneration after spinal cord and peripheral nerve injury. The data also suggests that chitosan/microRNA-124 particles could be potential treatment technique to reduce neuroinflammation.
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| 6. |
- Mantovani, Maria Cristina, 1974-
(author)
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Schwann cells and mesenchymal stem cells as promoter of peripheral nerve regeneration
- 2011
-
Doctoral thesis (other academic/artistic)abstract
- The transplantation of primary Schwann cells (SC) has been shown to improve nerve regeneration. However, to monitor the survival of transplanted cells within the host, a stable labelling method is required. The in vitro characteristics of green fluorescent protein labelled SC (GFP SC) and their effects in an in vivo peripheral nerve injury model were investigated. The GFP-SC were readily visualised ex vivo and stimulated significantly better axonal regeneration compared to controls. Clinical use of autologous SC for the treatment of nerve injuries is of limited use due to difficulty in obtaining clinically useful numbers. However, bone marrow mesenchymal stem cells (MSC) can trans-differentiate into SC like cells (dMSC). The in vitro and in vivo differentiation of MSC was explored, and the study extended to include the easily-accessible adipose stem cells (ASC). In vitro, glial growth factor stimulated MSC express S100, a SC marker, and its expression is maintained following in vivo transplantation. Similarly, untreated MSC transplanted in vivo also expressed S100, which indicates glial differentiation in response to local cytokines and growth factors. Using an in vitro model, comprising dMSC or dASC co-cultured with adult dorsal root ganglia (DRG) neurons, the capacity of the dMSC and SC like differentiated ASC (dASC) to promote axon myelination was verified: both cell types expressed transcripts for protein zero, peripheral myelin protein-22 and myelin basic protein.The potential of stem cells in nerve repair may be limited by innate cellular senescence or donor age affecting cell functionality thus it was essential to determine the effects of donor age on morphology and functionality of stem cells. The proliferation rates, expression of senescence markers (p38 and p53) and the stimulation of neurite outgrowth from DRG neurons by stem cells isolated from neonatal, young or old rats were very similar. However, the distribution and ultrastructure of mitochondria in dMSC and dASC from young and old rats were quite different, and seem to indicate physiological senescence of the aged cells. Given the wide-ranging influence of Notch signalling in cell differentiation, including the neural crest to a glial cell type switch, and self-renewal in mammals, its role in the differentiation of stem cells to SC was investigated. The mRNA for notch-1 and -2 receptors were expressed in the dASC, blockage of notch signaling did not affect the neurotrophic and myelination potential of dASC. In conclusion, these findings show that GFP labelling has no deleterious effect on SC survival and function. MSC and ASC differentiated into glial-type cells acquire SC morphology, and express characteristic SC markers, and the differentiation process was independent of the Notch signaling pathway. Also, following transplantation into a nerve gap injury dMSC improve regeneration. This study established that following co-culture with DRG neurons, dMSC and dASC were able to express peripheral myelin proteins. Also, the functional bioactivity of these cells is independent of the donor animal age. Finally, although the glial lineage differentiated aged cells characterized in this study expressed markers typical of senescence they retained the potential to support axon regeneration.
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| 7. |
- Moradi, Fatemeh, 1985-
(author)
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Working out work : from personal informatics to redesigning work
- 2016
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Doctoral thesis (other academic/artistic)abstract
- "Personal Informatics" (PI) and "Quantified Self" (QS) are two contemporary notions in the field of Human–Computer Interaction. Such hardware and software systems gather personalized quantified data and visualize them for the purpose of supporting self-reflection. Many of these systems focus on breaking the habit of prolonged sitting and increasing physical activity in our daily lives. The problems associated with the sedentary lifestyle and prolonged hours of sitting have been noted in many studies. In fact, stationary behavior is a risk factor for cardiovascular disease, diabetes and certain types of type of cancer. Nowadays we, as adults, spend more than 8 hours a day on work and work-related activities. As a consequence, the time spent sitting in office workspaces contributes to the majority of stationary behavior in our daily lives. Throughout history, designers and technocrats have constantly redesigned workspaces in attempts to increase work productivity and efficiency. Thus "modern" office work configuration includes desks and stationary computers and so office workers have become accustomed to prolonged sitting in their workplaces. In relation to this research problem, I have worked on my PhD thesis within the context of a four-year cross disciplinary research project in which we have been exploring ways of increasing physical activity and breaking the habit of prolonged sitting among office workers. This is a thesis in informatics and closely allied to medicine and it focuses on studying how contemporary office work affects the body and how to redesign this context. For this thesis, I conducted three empirical studies and designed and developed two prototypes - the "NEAT Lamp" and the "Talking Tree". The "Sport Co." study was the first quantitative study, and was followed by two qualitative observational ethnographic studies – the "Housing Co." study and the "Health Co." study. The research process adopted during the work can be described as an intertwined process consisting of three methodological approaches: observational ethnographic studies, concept development and prototyping. These three came together to form a coherent contextual design process for tackling the research question, "How can we approach the design of work in today's offices in order to make office workers more physically active in their workspaces?" This process resulted in five papers presenting various aspects and results of the research conducted. The results cover the role of bodies at work by considering the history of work design, knowledge about the local movement and mobility patterns of office workers in modern office spaces and eventually the design and evaluation of the two prototypes introduced in this thesis. Finally, I conclude this thesis by highlighting my overall contributions. The first contribution targets designers willing to design for increasing physical activity and breaking the habit of prolonged sitting in workspaces. In relation to this I introduce a design space as a tool for understanding the design of work in relation to worker’s bodies. The second contribution highlights how observational ethnographic studies, concept development, and prototyping can be combined when exploring the context of physical activity in office environments and it shows how contextual design might be a suitable approach for such studies. In addition, it emphasizes ways for how we can redesign work and expand our contextual knowledge. This, by examining and evaluating interactive prototypes in real office settings.
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| 8. |
- Pettersson, Jonas, 1979-
(author)
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Biosynthetic conduits and cell transplantation for neural repair
- 2011
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Doctoral thesis (other academic/artistic)abstract
- Spinal cord injury results in complete failure of the central neurons to regenerate and is associated with cyst formation and enlargement of the trauma zone. In contrast to the spinal cord, axons in the injured peripheral nerve have the capacity to undergo some spontaneous regeneration. However, significant post-traumatic loss of nervous tissue causing long nerve gap is one of the main reasons for the poor restoration of function following microsurgical repair of injured nerves. The present thesis investigates the effects of biodegradable conduits prepared from fibrin glue and poly-beta-hydroxybutyrate (PHB) in combination with cultured Schwann cells, mesenchymal stem cells and extracellular matrix molecules on regeneration after spinal cord and peripheral nerve injury in adult rats. At 4-8 weeks after transplantation into the injured spinal cord, the PHB conduit was well integrated into the cavity but regenerating axons were found mainly outside the PHB. When suspension of BrdU-labeled Schwann cells was added to the PHB, regenerating axons filled the conduit and became associated with the implanted cells. Modification of the PHB surface with extracellular matrix molecules significantly increased Schwann cell attachment and proliferation but did not alter axonal regeneration. To improve the labeling technique of the transplanted cells, the efficacy of fluorescent cell tracers Fast Blue, PKH26, Vibrant DiO and Cell Tracker™ Green CMFDA was evaluated. All tested dyes produced very efficient initial labeling of olfactory ensheathing glial cells in culture. The number of Fast Blue-labeled cells remained largely unchanged during the first 4 weeks whereas the number of cells labeled with other tracers was significantly reduced after 2 weeks. After transplantation into the spinal cord, Fast Blue-labeled glial cells survived for 8 weeks but demonstrated very limited migration from the injection sites. Additional immunostaining with glial and neuronal markers demonstrated transfer of the dye from the transplanted cells to the host tissue. In a sciatic nerve injury model, the extent of axonal regeneration through a 10mm gap bridged with tubular PHB conduit was compared with a fibrin glue conduit. At 2 weeks after injury, the fibrin conduit supported similar axonal regeneration and migration of the host Schwann cells compared with the PHB conduit augmented with a diluted fibrin matrix and GFP-labeled Schwann cells or mesenchymal stem cells. The long-term regenerative response was evaluated using retrograde neuronal labeling. The fibrin glue conduit promoted regeneration of 60% of sensory neurons and 52% of motoneurons when compared with the autologous nerve graft. The total number of myelinated axons in the distal nerve stump in the fibrin conduit group reached 86% of the nerve graft control and the weight of gastrocnemius and soleus muscles recovered to 82% and 89%, respectively. When a fibrin conduit was used to bridge a 20mm sciatic nerve gap, the weight of gastrocnemius muscle reached only 43% of the nerve graft control. The morphology of the muscle showed more chaotic appearance and the mean area and diameter of fast type fibers were significantly worse than those of the corresponding 10mm gap group. In contrast, both gap sizes treated with nerve graft showed similar fiber size. In summary, these results show that a PHB conduit promotes attachment, proliferation and survival of adult Schwann cells and supports marked axonal growth after transplantation into the injured spinal cord. The data suggest an advantage of the fibrin conduit for the important initial phase of peripheral nerve regeneration and demonstrate potential of the conduit to promote long-term neuronal regeneration and muscle recovery.
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| 9. |
- Poikolainen Rosén, Anton, 1992-
(author)
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Noticing nature : exploring more-than-human-centred design in urban farming
- 2022
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Doctoral thesis (other academic/artistic)abstract
- This thesis articulates, theorises and furthers the concept of “more-than-human-centred design” by studying the use and design of technology for noticing nature and caring for nature. The emerging field of more-than-human-centred design focuses on the mutual interdependence between humans and non-humans (e.g. organisms such as animals, plants and microbes, as well as autonomous technologies). It is a step away from seeing other organisms as inferior to humans or valuable only as resources. This implies that design research frameworks and methods need to be remade. How can we design for and with other organisms? What needs to be accommodated in a paradigm that allows for more-than-human-centred design? What are concrete design examples and implications of this kind of thinking? In short, there is a need to investigate what it means to design for more-than-human worlds.This is investigated in the thesis through a series of studies and design experiments, including ethnography (participant observation, interviews, surveys and workshops), design projects (design ideation, development and analysis of prototypes) and design critique of existing artefacts. Most of these studies are conducted within a four-year ethnography of a regenerative urban farming community in Stockholm, Sweden.The thesis draws on posthuman theory. This theory examines the implications of expanding concern and subjectivities beyond the human, and aims to understand the human subject and its relationship to the world in a non-anthropocentric light. Phenomenological analysis is further applied to articulate and understand the human-technology-nature relationship as it is experienced first-person.The thesis contributes an articulation of a more-than-human-centred design programme. Here, two design implications are suggested, “expanding the sensible” and “design for sensory-rich experiences”. Methods for noticing the more-than-human world are suggested, along with principles for designing for and with other organisms, such as finding leverage points in systems and providing a scaffold for naturally occurring processes. The meaning of “design”, “the designer” and “the user” is discussed. Lastly, a manifesto for more-than-human-centred design is proposed.
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| 10. |
- Schaakxs, Dominique, 1979-
(author)
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Stem cells for nerve repair and prevention of muscle atrophy
- 2015
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Doctoral thesis (other academic/artistic)abstract
- Peripheral nerve injury (PNI) is common and despite modern microsurgical techniques of repair, functional restoration is always incomplete. This results in impaired sensation and reduced motor function alongside pain and cold intolerance. Traumatic PNI are often associated with loss of nerve tissue, creating a gap, and direct repair of the two damaged nerve stumps is not possible. These types of injuries are reconstructed using autologous nerve grafts but this is far from ideal since it necessitates the sacrifice of a functional nerve from elsewhere in the body. Chronic muscle atrophy because of the prolonged delay in nerve regeneration across gaps is a significant impediment to an optimal functional recovery. Tissue engineering and regenerative medicine approaches to nerve repair might one day replace the need for autologous nerve grafts. This thesis investigates the effects of adipose derived stem cells (ASC) on nerve regeneration and muscle recovery by using the stem cells for intramuscular injection and combined with a biomaterial, poly-3-hydroxybutyrate (PHB), to create a bioengineered artificial nerve repair construct. The mechanisms of interaction between the stem cells and neuromuscular system cells were investigated and with a view to translating this work into clinical practice, an optimal source of cells was investigated from human donors. It was hypothesized that injecting regenerative cells into muscle would reduce nerve injury induced muscle atrophy. A rat sciatic nerve lesion was performed and three different types of cells were injected into the denervated gastrocnemius muscle; either (1) undifferentiated ASC, (2) ASC induced to a ‘Schwann cell-like’ phenotype (dASC) or (3) primary Schwann cells. Nerves were either repaired by direct end-end suture or capped to prevent muscle reinnervation. One month later, functionality was measured using a walking track test, and muscle atrophy was assessed by examining muscle weight and histology. The Schwann cells and dASC groups showed significantly better scores on functional tests when compared with control injections of growth medium alone. Muscle weight and histology were also significantly improved in the cell groups in comparison with the control group. PHB strips seeded with either primary Schwann cells or dASC suspended in a fibrin glue matrix were used to bridge a 10mm rat sciatic nerve gap. After 12 weeks, functional and morphological analysis (walking track test, electromyography, muscle weight and muscle and nerve histology) was performed. The results showed significantly better functional results for the PHB strips seeded with cells versus the control group with fibrin matrix only. This correlated with less muscle atrophy and greater distal axon myelination in the cell groups. To further optimize the nerve regeneration and muscle recovery, the nerve gap lesion was repaired by treatment with the bioengineered constructs seeded with dASC or nerve autograft in combination with stem cell injection in the muscle. After 6 weeks, the best results were obtained in the nerve graft group combined with intramuscular dASC injection which showed significantly less atrophy than the other groups. The results also showed that using the stem cells in a matrix on a PHB strip in combination with intramuscular injections could significantly reduce muscle atrophy. In vitro experiments showed that dASC expressed a wide range of neurotrophic and myogenic factors including BDNF, VEGF-A, IGF-1 and HGF. Stem cell conditioned medium enhanced the proliferation of myoblast cell lines and primary Schwann cells. Various signaling pathways (PKA, MAP kinase) were involved in these effects dependent on the cell type investigated. Furthermore, in direct co-culture with myoblast cells, a small population of the cells fused together to form myotube-like structures and expressed myogenic markers. Human ASC were isolated from the deep and superficial layers of abdominal fat tissue obtained during abdominoplasty procedures. Cells from the superficial layer proliferated significantly faster than those from the deep layer. Superficial layer ASC induced significantly enhanced neurite outgrowth from neuronal cell lines when compared with the deep layer cells. However, RT-PCR and ELISA analysis showed that ASC isolated from both layers expressed similar levels of the neurotrophic factors NGF, BDNF and GDNF. In summary, these results show that stem cell therapy at both levels (the nerve lesion site and in the target denervated muscle) offers a promising approach for clinical application for treatment of peripheral nerve lesions. The bioengineered artificial nerve construct, combining PHB strip with cells, also provides a beneficial environment for nerve regeneration. Many of the benefits of the ASC are likely to be mediated through their secretome, a rich source of neurotrophic and myogenic factors. Thus adipose tissue contains a pool of regenerative stem cells which have significant potential application to tissue engineering and regenerative medicine for nerve repair.
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