Thesis (MScPhysio)--Stellenbosch University, 2015. / ENGLISH ABSTRACT: Introduction: Iliotibial band syndrome (ITBS), an overuse injury, is the second most common running injury and the main cause of lateral knee pain in runners. Due to the increasing number of runners worldwide there has been an increase in its occurrence. Runners with ITBS typically experience symptoms just after heel strike at approximately 20°-30° of knee flexion (impingement zone) during the stance phase of running. A variety of intrinsic and extrinsic risk factors may be responsible for why some runners are more prone to developing symptoms during the impingement zone as opposed to others. Abnormalities in running biomechanics is an intrinsic risk factor which has been most extensively described in literature but little is known about its exact relationship to ITBS. Objectives: The purpose of this systematic review was to provide an up to date evidence synthesis of the biomechanical risk factors associated with ITBS. These risk factors may need to be considered in the prevention or management of ITBS in runners. A clinical algorithm is also presented. Methods: A systematic review with meta-analysis was conducted. An electronic search was performed in PubMed, PEDro, SPORTSDisc and Scopus of literature published up-until May 2014. Cross-sectional and cohort studies were eligible for inclusion if they evaluated the lower limb biomechanics of runners with ITBS or those who went onto developing it. All studies included in the review were methodologically appraised. Evidence was graded according to the level of evidence, consistency of evidence and the clinical impact. Data was described narratively using tables or narrative summaries where appropriate. A meta-analysis was conducted for biomechanical risk factors which were reported in at least two studies, provided that homogeneity in the outcomes and samples were present. Results: A total of 11 studies were included (1 prospective and 10 cross-sectional). Overall the methodological score of the studies was moderate. Increased peak hip adduction and knee internal rotation during the stance phase may predict the development of ITBS in female runners. These biomechanical risk factors may need to be screened for ITBS prevention, despite the evidence base being limited to a single study. Currently there is no conclusive evidence that any of the biomechanical parameters need to be considered when managing runners with ITBS. Stellenbosch University https://scholar.sun.ac.za iii Conclusion: Biomechanical differences may exist between runners with ITBS and those who may develop ITBS compared to healthy runners. Although a large variety of biomechanical risk factors were evaluated, the evidence base for screening or managing these risk factors for runners with ITBS is limited. This is due to a small evidence base, small clinical effect and heterogeneity between study outcomes and findings. Further prospective and cross-sectional research is required to ascertain if abnormalities in running biomechanics may be related to why runners develop ITBS or to ascertain which risk factors may be involved when managing these runners. / AFRIKAANSE OPSOMMING: Inleiding: Iliotibiale-band-sindroom (ITBS), ’n besering vanweë oormatige gebruik, is die tweede algemeenste hardloopbesering en die hoofoorsaak van laterale kniepyn by hardlopers. Namate die getal hardlopers wêreldwyd toeneem, neem die voorkoms van hierdie toestand ook toe. Hardlopers met ITBS ervaar tipies simptome ná die hakslag met die knie ongeveer 20-30° gebuig (die wrywingsone of “impingement zone”) gedurende die staanfase van hardloop. Verskeie intrinsieke en ekstrinsieke risikofaktore kan ’n rol speel in waarom sommige hardlopers meer geneig is as ander om gedurende die wrywingsone simptome te ervaar. Abnormaliteite in hardloopbiomeganika is ’n intrinsieke risikofaktor wat reeds omvattend in die literatuur beskryf is. Tog is weinig bekend oor presies hoe dit met ITBS verband hou. Oogmerke: Die doel van hierdie stelselmatige ondersoek was om ’n sintese te bied van die jongste bewyse van die biomeganiese risikofaktore van ITBS. Hierdie risikofaktore kan dalk oorweeg word om ITBS by hardlopers te voorkom of te bestuur. ’n Kliniese algoritme word ook aangebied. Metodes: ’n Stelselmatige ondersoek is met behulp van meta-ontleding onderneem. PubMed, PEDro, SPORTSDisc en Scopus is elektronies deurgesoek vir literatuur wat tot en met Mei 2014 verskyn het. Deursnee en kohortstudies is ingesluit indien dit gehandel het oor die biomeganika in die onderste ledemate van hardlopers wat ITBS het of later ontwikkel het. Alle studies wat deel was van die ondersoek is metodologies geëvalueer. Bewyse is aan die hand van bewysvlak, bewyskonsekwentheid en kliniese impak beoordeel. Data is narratief beskryf met behulp van tabelle of narratiewe opsommings waar dit toepaslik was. ’n Meta-ontleding is onderneem waar biomeganiese risikofaktore in minstens twee studies aangemeld is, mits daar homogeniteit in die uitkomste sowel as die steekproewe was. Resultate: Altesaam 11 studies is ingesluit (een prospektief en tien deursnee). Die metodologiese telling van die studies was oorwegend gemiddeld. Verhoogde spitsheupadduksie en interne knierotasie gedurende die staanfase kan op die ontwikkeling van ITBS by vrouehardlopers dui. Hierdie biomeganiese risikofaktore kan dalk nagegaan word vir ITBS-voorkoming, al was die bewysbasis beperk tot ’n enkele studie. Daar is tans geen afdoende bewys dat enige van die biomeganiese parameters oorweeg behoort te word in die bestuur van langafstandatlete met ITBS nie. Gevolgtrekking: Daar bestaan dalk biomeganiese verskille tussen hardlopers wat ITBS het of kan ontwikkel en gesonde hardlopers. Hoewel ’n groot verskeidenheid biomeganiese risikofaktore beoordeel is, is die bewysbasis vir die toets of bestuur daarvan by atlete met ITBS beperk. Dít is vanweë die klein hoeveelheid bewyse, die klein kliniese impak, en heterogeniteit tussen studie-uitkomste en bevindinge. Verdere prospektiewe en deursneenavorsing word vereis om te bepaal of abnormaliteite in hardloopbiomeganika ’n rol kan speel in waarom langafstandhardlopers ITBS ontwikkel, of om vas te stel watter risikofaktore ter sprake kan wees in die bestuur van hierdie hardlopers.

Thesis (MScPhysio)--Stellenbosch University, 2015. / ENGLISH ABSTRACT: This review aims to present the available evidence for the effect of McConnell taping on knee biomechanics in individuals with Anterior Knee Pain (AKP). Pubmed, Medline, Cinahl, Sportdiscus, Pedro and Science Direct electronic databases were searched from inception until September 2014. Experimental research into knee biomechanical or EMG outcomes of McConnell taping compared to no tape or placebo tape were included. Two reviewers completed the searches, selected the full text articles and assessed the risk of bias of eligible studies. Authors were contacted for missing data. Eight heterogeneous studies with a total sample of 220 were included in this review. All of the studies had a moderate to low risk of bias and compared taping to no tape and/ or placebo tape. Pooling of data was possible for three outcomes; average knee extensor moment, average VMO/VL ratio and average VMO-VL onset timing. None of these outcomes revealed significant differences. The evidence is currently insufficient to justify the routine use of the McConnell Taping technique in the treatment of Anterior Knee Pain. There is a need for more evidence on the aetiological pathways of Anterior knee Pain; level one evidence and studies investigating other potential mechanisms of McConnell taping. / AFRIKAANSE OPSOMMING: Die objektief van hierdie resensie was om te bepaal wat die effekte van McConnell Patellar Vasbinding is op knie kinematika, kinetiek en spier aktivering in diegene met Voorafgaande Knie Pyn (VKP). Die navorsers het elektroniese databases soos Pubmed, Medline, Cinahl, Sportdiscus, Pedro en Science Direct, van aanvang tot September 2014, ondersoek. Eksperimenteel studie ontwerpe wat biomeganiese of EMG gevolge van McConnell Vasbinding vergelyk met geen vasbinding of placebo vasbinding, is ingesluit. Twee resente het die ondersoek voltooi, die volle tekse artikels gekies en die partydigheid risiko van die ingeslote studies, geskat. Skrywers is gekontak vir enige verlore data. Agt heterogeen studies uit ‘n totalle monster van 220 is in hierdie resensie ingesluit. Al die studies het ‘n gematigde tot laag risiko vir eensydigheid en vergelyk vasbinding met geen of placebo vasbinding. Data saamvoeging was moontlik vir drie uitslae, naamlik: gemiddelde knie ekstensor moment; gemiddelde VMO/VL ratio en gemiddelde aanval tydmeting. Geen gevolge het veelseggende verskille of afwykings vertoon. Tans is die bewys nie genoegsaam om die routiene gebruik van McConnell Vasbinding tegniek te regverdig nie in die behandeling van VKP. Meer bewyslewering op die etiologiese paaie van VKP; Graad een bewys en studies wat ander moontlike meganisme van Mc Connell Vasbinding ondersoek, is noodsaaklik.

The purpose of this study was to determine the effectiveness of a modified sitting position straight leg raise on vastus medialis oblique (VMO) strength and EMG activity as compared to a traditional straight leg raise. A total of twenty-three subjects were recruited for this study. The subjects were randomly assigned to one of the following groups: (group I) modified straight leg raise (MSLR), and (group II) straight leg raise (SLR). The exercise program was three weeks long. University procedures for the protection of human subjects were followed. The subjects began with a 5 minute warm-up on a Cybex stationary bike set at 90 revolutions / minute. The subject then had electrodes placed on the Vastus Lateralis (VL) and Vastus Medialis Oblique (VMO). A Macintosh computer was used to record the EMG data. The subject then performed a standard Cybex test for knee flexion and extension. The Cybex dynamometer was placed at the knee joint line, the chair back tilt was at 85 degrees, the hip, chest, and thigh restraints were all fastened. The subjects in group I (Modified sitting SLR) and II (SLR) then returned the next day for their first rehabilitation lesson. Each subject group then participated in their respected exercise program for a total of three weeks. After three weeks of rehabilitation, the subjects retested using the same procedures followed in the pretest. A two tailed t-test was used to determine significance of the difference between means of the two groups. No significant differences were found between the two groups. / School of Physical Education

The purpose of this study was to determine the vastus medialis oblique muscular electromyographical (EMG) activity during two therapeutic exercises: the modified straight leg raise and the traditional straight leg raise. Two subject groups of 10 subjects each, one with anterior knee pain (PHY) and the other group with no history of patellofemoral pathology (NORM), performed the traditional straight leg raise (SLR) and a modified straight leg raise with external hip rotation (MOD). Each subject performed an isometric maximum voluntary contraction and three trials of each of the two therapeutic exercises. The EMG variables analyzed were the percent of the maximum voluntary contraction for each muscle, vastus medialis oblique, vastus lateralis, and rectus femoris: the percent of the maximum voluntary contraction of the ratio between the vastus medialis oblique and the vastus lateralis; the percent of the maximum voluntary contraction for the integrated EMG for each muscle; and the percent of the maximum voluntary contraction for the root mean square for each muscle. The statistical analysis was conducted with two-way analysis of variance procedures. The statistical analysis revealed no significant differences; however, the data appeared to illustrate a trend toward more electromyographical activity in the vastus medialis oblique in the PHY subject group during the MOD therapeutic exercise. This suggests that the MOD therapeutic exercise may be able to isolate the vastus medialis oblique muscle in persons with anterior knee pain and allow them to regain strength and normal function earlier than with the use of the SLR therapeutic exercise. / School of Physical Education

The primary purpose of this study was to determine the ratio of activation between the VMO and VL while performing three selected knee exercises (drop squat, modified lateral squat, Muncie Method). Additionally, the data was analyzed to determine if a correlation existed between the muscle's activation rate per set and whether or not the rates are affected by Q-angle or gender. Twenty Ball State University subjects (10 male, 10 female) who were asymptomatic to Patellofemoral Syndrome (PFS), provided electroymyographic (EMG) data while performing the three selected exercises. A one-way ANOVA found no statistical significance (p=0.500) on any of the tested variables except the Drop Squat VL Root Mean Square (RMS). Significant correlations were found between: VL RMS to set number during drop squat, and VMO and VL RMS to set number during Muncie Method performance. Based on the results of this study, each of these exercises could be used to selectively strengthen the VMO in treatment of PFS. / School of Physical Education

Ligament tears are more prevalent than all other knee injury pathologies, and contribute significantly to musculoskeletal joint pain and disability reported worldwide. Despite current soft tissue reconstruction techniques, the injured ligament fails to regenerate due to dysregulated cell-extracellular matrix (ECM) interactions that culminate in scar formation. Hallmarks of scar formation, or fibrotic healing include disorganized ECM, pathological stiffness or tissue rigidity, and the accumulation and persistence of myofibroblasts. A primary driver of fibrosis, myofibroblasts are characterized by high contractility, excessive deposition of collagen type I, coupled with inflammatory and fibrotic signaling. Notably these cells are critical early on in the response to injury, by aiding in the contracture of the wound bed and depositing collagen to repair the injury site. However, myofibroblasts are not capable of fully regenerating the native ligamentous matrix, and resolution of the phenotype is necessary in order to cue surrounding cells, prevent chronic inflammation and aberrant tissue remodeling. Persistence of the myofibroblast phenotype thus leads to a ligament scar that is functionally weaker than the healthy tissue matrix, characterized by significantly different histological, biochemical, and biomechanical properties. The consequential instability of this scar disrupts load distribution within the knee joint and increases the risk of subsequent injury, osteochondral degeneration, and ultimately, the development of post-traumatic osteoarthritis. Therefore, there is a critical need for strategies that target the inflammatory and fibrotic myofibroblast phenotypes for soft tissue healing. It follows that the overarching goal of this thesis is to engineer an immunomodulatory matrix to regulate myofibroblast activation and downstream fibrogenic signaling. To this end, models of soft tissue fibrotic repair are explored in order to test the central hypothesis that cues from the repairing ECM play an important role in regulating myofibroblast activation and persistence. Specifically, this thesis will compare myofibroblast differentiation and signaling in three in vitro models of tissue repair: 1) 2D on tissue culture polystyrene (TCPS), and two 3D models namely 2) collagen hydrogel and 3) electrospun collagen fiber matrices. As expected, on the 2D model, a persistent myofibroblast phenotype could be generated over time with an optimized transforming growth factor beta 1 (TGF-β1) stimulation protocol. To create repair-relevant 3D matrix models, we engineered collagen hydrogels with controlled mechanical properties, as well as electrospun fiber platforms that isolate key matrix factors including, collagen content, stiffness, fiber diameter, and alignment. These models emulate the connective tissue repair process via recapitulating the increasing matrix stiffness and fiber assembly of the early (granulation tissue), proliferative, and remodeling stages of the repair. Myofibroblast differentiation potential, parallel inflammatory and fibrotic cytokine secretion, as well as matrix remodeling potential were observed to be dependent on matrix model parameters. Moreover, single-cell resolution RNA sequencing revealed heterogenous myofibroblast populations within the context of response to engineered collagenous substrates. Specifically, myofibroblast accumulation was observed on hydrogel substrates that recapitulate the pathologically stiff mechanics and disorganization of fibrotic scar tissue while architectural cues of engineered fiber substrates prevented myofibroblast differentiation in a diameter and alignment-dependent manner. Moreover, nanoscale fibers elicited the greatest anti-fibrotic and anti-inflammatory properties compared to microscale fibers and stiff collagen-based hydrogels. Throughout, this thesis also explores the contribution of NF-κB signaling to myofibroblast plasticity and persistence using engineered collagen-based platforms, highlighting the dynamic role of myofibroblasts as critical immunoregulating cells. The NF-κB signaling pathway is implicated in a broad array of fibrotic and chronic inflammatory conditions, and more recently has been associated with survival of persistent myofibroblast populations in soft-tissue fibrosis and tendon degeneration models. In this thesis, NF-κB activation was seen to be related to the persistent myofibroblast phenotype and increase over time in both 2D TCPS and 3D collagenous hydrogel matrices that mimic pathologically stiff scar tissue, while a temporally dependent activation pattern was observed in electrospun collagen fiber-based models. At the transcriptional level, NF-κB survival signaling was significantly enriched in myofibroblast populations supported by TCPS and stiff collagen-based hydrogels but downregulated on soft hydrogels and fibers with decreasing fiber diameter that prevented robust myofibroblast differentiation at single cell resolution. Building upon these new insights regarding matrix cues that drive myofibroblast activation, we designed an immunomodulatory matrix that mediates small molecule release targeting NF-κB inhibition. The immunomodulatory matrix achieved robust amelioration of the myofibroblast phenotype as well as reduced the secretion of key inflammatory and fibrotic cytokines by these cells. Moreover, a similar anti-fibrotic response was seen for human ligament fibroblasts treated with these matrices. Collectively, this thesis work presents a systematic evaluation of myofibroblast plasticity and persistence within the context of 2D (TCPS), 3D (collagen-based hydrogels), and finally 3D with defined microarchitectural cues (electrospun collagen-based fibers) that recapitulate the progressive stages of scar-mediated healing, and reveals NF-κB as a promising target for reducing myofibroblast persistence. Moreover, the immunomodulatory control of myofibroblast plasticity and persistence via matrix cues coupled with NF-κB inhibition informs future strategies for true ligament healing.

[Truncated abstract] Hyaline articular cartilage is a highly specialised tissue consisting of chondrocytes embedded in a matrix of proteoglycan and collagens. Hyaline articular cartilage withstands high levels of mechanical stress and continuously renews its extracellular matrix. Despite this durability, mature articular cartilage is vulnerable to injury and disease processes that cause irreparable tissue damage. Native hyaline articular cartilage has poor regenerative capacity following injury, largely due to the tissue's lack of blood and lymphatic supply, as well as the inability of native chondrocytes to migrate through the dense extracellular matrix into the defect site. Articular cartilage injuries that fail to penetrate the subchondral bone plate evoke only a short-lived metabolic and enzymatic response, which fails to provide sufficient new cells or matrix to repair even minimal damage. Clinically, it has previously been accepted that treatment of such defects does not result in the restoration of normal hyaline articular cartilage, which is able to withstand the mechanical demands that are placed on the joint during every day activities of daily living. ... Historically, rehabilitation following ACI has not kept pace with the advances in cell culture and surgical technique. Subsequently, there exists a significant gap in knowledge regarding `best practice' in post operative rehabilitation following ACI. The importance of structured rehabilitation in ACI should not be underestimated when evaluating the clinical success of this chondral treatment. Patients should not be left to their own devices following ACI surgery, as the risk of damage to their implant (via delamination) is high if immediate postoperative movement is not controlled. Furthermore, the biological longevity and clinical success of the graft is dependent on a controlled and graduated return to ambulation and physical activity, and the biomechanical stimulation of the implanted chondrocytes.

Post-traumatic osteoarthritis (PTOA) of the knee is a complication resulting from direct injury to the joint, such as anterior cruciate ligament and meniscus tears, and accounts for approximately 12% of all OA cases. The economic and clinical impact of PTOA is also greater than idiopathic OA, as patients are younger and often more active, requiring treatments for symptomatic OA over a greater fraction of their lifetime. A common strategy to manage pain and inflammation associated with PTOA is the intraarticular administration of corticosteroids. However, these injections are limited due to the requirement of high-doses imposed by synovial joint clearance rates and their resulting systemic side effects. In addition, currently used broad-spectrum corticosteroids are palliative and not curative, stemming from incomplete knowledge of specific mechanisms that drive cartilage degeneration and other joint pathologies. Thus, most patients with PTOA eventually undergo surgical procedures such as osteochondral graft transplantation for focal defects and in more severe cases, total knee arthroplasty. As such, the studies presented in this dissertation (i) offer specific insights into mechanisms by which traumatic injury can drive joint degeneration and (ii) present novel strategies to modulate joint responses to pathological factors by leveraging sustained drug-delivery platforms. In Part I, mechanistic assessments of human cartilage and synovium responses to insults are conducted to identify novel pathways that may lead to impaired joint homeostasis. First, a direct consequence of traumatic injury, hemarthrosis, is explored as a potential contributor to the development of PTOA specifically through contributions by red blood cells. We demonstrate for the first time the differential roles of erythrocytes in their intact and lysed states through measures of oxidative stress and changes to metabolomic profiles in the context of ferroptosis. Furthermore, we demonstrate the therapeutic potential of Ferrostatin-1, a lipophilic radical scavenger in inhibiting pathological changes to cartilage and its crosstalk with the neighboring synovium in an in vitro model of hemophilic arthropathy. Second, a strategy to prevent an indirect consequence of traumatic injury, arthrofibrosis, is presented in an in vitro model of joint contraction. Fibrosis and the presence of hyperplastic synovium are implicated in the progression of OA through pathological shifts in tissue composition as well as secreted factors that promote cartilage degeneration and the maintenance of a pro-inflammatory joint environment. A type I transforming growth factor beta-1 receptor inhibitor, SB-431542, is encapsulated in polymeric microspheres for the prophylactic treatment of arthrofibrosis through sustained low-dose drug delivery to circumvent the challenges associated with resident joint clearance rates. Utilizing human-based in vitro models of cartilage and synovium pathology, we present novel mechanisms and therapeutic strategies to prevent pathological changes following traumatic joint injury that may contribute to the development of PTOA. In Part II, the sustained delivery platform introduced in Part I is extended to the treatment of PTOA. Osteochondral graft transplantation is currently the clinical gold standard for large focal cartilage lesions. However, allograft procedures are limited due to the lack of available donor tissues and autografts are associated with complications due to donor-site morbidity. In both cases, grafts are subject to failure, potentially in part due to the continual presence of pro-inflammatory factors following surgical procedure. In this section, we present cellular agarose hydrogels embedded with dexamethasone-releasing microspheres that are integrated with a titanium base as a functional tissue-engineered alternative to native osteochondral allografts. These allogenic tissue-engineered grafts were assessed in an in vivo preclinical canine model in their ability to maintain clinical function and to modulate the inflammatory response over the course of 12 months. We successfully demonstrated the feasibility of using engineered grafts by comparing clinical measures of range of motion, function, lameness, and pain, as well as modified cartilage graft scores, against native osteochondral allograft controls. In addition, improvements in the histopathological scoring of neighboring synovial and meniscal tissues indicate the therapeutic capacity of dexamethasone released from within the joint to modulate the inflammatory response up to one-year post-implantation. Taken together, the studies presented in this dissertation identify novel mechanisms behind pathological changes to the cartilage and synovium that may contribute to the development of PTOA following injury. Potential therapeutic targets, inhibitory compounds, and delivery strategies are also assessed using human-based in vitro models of disease and further validated in an in vivo canine model through a clinically relevant timeframe. Ultimately, we demonstrate for the first time, the use of dual-function tissue-engineered grafts in a weight-bearing region of the knee joint to circumvent limitations associated with the clinical gold standard for the treatment of large focal cartilage defects.