In our aging population, arthritis is becoming an increasingly common problem. Pain, loss of joint function and other negative affects make arthritis a major health problem. The most common form of arthritis, osteoarthritis, is caused by the "wear and tear" of articular cartilage on the surface of bones in synovial joints. It is a chronic problem that is slowed with different types of therapies, including pharmaceutical, nutritional and surgical, but to date the wearing down of the cartilage cannot be stopped or reversed. Normal, mature, articular cartilage does not spontaneously repair itself after an injury. In light of this, several surgical techniques are being developed to repair degenerate and/or osteoarthritic cartilage. One such approach uses Autologous Chondrocyte Implantation (ACI). Dr. Mats Brittberg, and associates at Goteborg University in Sweden began using this cartilage repair procedure in 1987. Other techniques attempt to stimulate the subchondral bone to generate cartilage, such as Abrasion Arthroplasty. Still others use tissue grafts to attempt to repair lesions in cartilage. The surface biomechanics of these repaired tissues have not yet been studied. How well does the repaired cartilage resist wear? How long will it last? How does the repaired cartilage compare to "normal" cartilage in terms of wear-resistance? It is the goal of this research to gain initial knowledge to help answer these questions. Dr. Brittberg has provided 17 sample of cartilage, from 9 Swedish patients, including repaired and normal pairs using the aforementioned repair techniques and others, as well as a degenerate and normal cartilage pair. The intention of this paper is to report the findings of experiments performed using these samples, and compare the wear-resistance of repaired and degenerate cartilage to that of normal cartilage. Wear and friction tests were carried out on 2 mm diameter specimens using a biotribology device and a new, modified technique developed specifically for these small samples. The cartilage samples were mounted, using specially designed adapters, in our biotribology device for oscillating contact against polished stainless steel disks at a constant applied normal load, oscillating frequency, and test time. A buffered saline solution was used as the lubricant. Cartilage wear was determined from hydroxyproline analysis of the test fluid and washings from the wear test. Thin layers of transferred cartilage-like films to the stainless steel disks were also analyzed. Also, friction data was recorded throughout the tests. The results of these experiments show that: 1) For the two pairs of ACI repaired cartilage, the repaired cartilage gave substantially less wear than that of normal cartilage. 2) For all other repair techniques tested, the repaired cartilage produced more wear than normal cartilage. 3) The single osteoarthritic cartilage tested produced similar wear to that of normal cartilage. This is surprising since the current thought is osteoarthritic cartilage is more susceptible to wear. 4) The hydroxyproline concentration, by weight, of cartilage increases after the wear test. 5) Friction levels were in the boundary lubrication regime, and had no correlation with the amount of wear. To our knowledge, this research represents the first controlled "in vitro" study of an important unknown in cartilage repair, i.e., the wear-resistance of the repaired cartilage. It shows that ACI produces a cartilage with very good wear-resistance, better than that of other repair techniques, and possibly better than normal, healthy cartilage. ACI and its applications to the treatment of degenerate and osteoarthritic joints are promising, and studies will continue to investigate this and other types of cartilage repair. / Master of Science

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京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21012号 / 医博第4358号 / 新制||医||1028(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 戸口田 淳也, 教授 鈴木 茂彦, 教授 開 祐司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Patient expectations have been shown to be a major predictor of outcomes. Furthermore, fulfilled expectations have been linked to increased patient satisfaction and rehabilitation adherence. Expectations may be influenced by a variety of factors, including patient characteristics, pre-operative function, or disease characteristics. However, it is currently unknown what factors and to what degree they may influence patient expectations prior to knee surgery. Furthermore, understanding the importance and values of those expectations for recovery using qualitative methods has not previously been conducted in this patient population. A mixed methods design was used. Twenty-one participants scheduled to undergo cartilage repair of the knee, including autologous chondrocyte implantation, osteochondral allograft transplantation, or meniscal transplant were included. During their pre-operative visit, participants completed an expectations survey (Hospital for Special Surgery (HSS) Knee Surgery Expectations Survey) and the Knee Injury and Osteoarthritis Outcome Score (KOOS) as a measure of functional ability. At their first post-operative visit, patients completed the Self-Efficacy for Rehabilitation Scale (SER). Rehabilitation adherence was collected by the participant’s rehabilitation provider. A selected sample of 6 participants participated in a semi-structured interview 6 months following surgery to better understand their expectations for recovery. Pearson correlation coefficients were used to determine relationships between expectations and KOOS scores, SER scores, and measures of adherence. Results demonstrated that patients have moderate expectations for recovery and these expectations were positively associated with pre-operative pain, activities of daily living, and knee-related quality of life as measured by the KOOS. In addition, a negative relationship was found between patient expectations and adherence with home exercises, use of a brace, and weight-bearing restrictions. Four qualitative themes emerged as participants’ described how previous recovery experiences shaped their recovery following cartilage repair of the knee. Patient education, pre-habilitation, and the use of psychological skills during rehabilitation may help to manage patient expectations, improve rehabilitation adherence, and assist clinicians in providing more focused and individualized patient care.

Articular cartilage defects in the knee are common, and can result in pain, decreased function and decreased quality of life. Untreated defects are considered to be a risk factor for developing osteoarthritis, a progressive degenerative joint disease with minimal treatment options. To address these issues, various surgical procedures are available to treat articular cartilage defects in the knee. While these procedures overall have positive results, after surgery patients experience large and persistent deficits in quadriceps strength. A contributing factor to this post-surgical weakness is believed to be the extended post-operative non-weight bearing period, with full weight bearing not initiated until approximately 4 – 6 weeks after surgery. During this non-weight bearing period a minimal amount of demand is placed upon the muscle. Subsequently, the quadriceps muscle undergoes a large degree of atrophy with a significant decrease in muscle strength. Muscular strength deficits reduce the knee joint stability, also increasing the risk of osteoarthritis development. Interventions that can be used to facilitate quadriceps strength while protecting the articular cartilage repair are needed. Neuromuscular electrical stimulation (NMES) is an effective post-knee surgery rehabilitation technique to regain quadriceps musculature. In recent years manufactures have been developing knee sleeve garments integrated with NMES allowing for portability of the NMES treatment. The primary aim of this study was to evaluate the effectiveness of a 12-week home-based neuromuscular electrical stimulation treatment on post-surgical clinical outcomes (quadriceps strength, lower extremity function, and patient reported outcomes) after articular cartilage knee surgery. Patients were randomized between a standard of care home-treatment group and a NMES home-treatment group. Patients completed isometric quadriceps strength testing, the Y-balance test, and the Knee Injury and Osteoarthritis Outcome Score (KOOS) before surgery and at 3-months after surgery. The secondary aims of this study were to determine the most effective NMES parameters for post-surgical quadriceps strength; and to develop a framework to identify factors that may influence a patient’s adherence to a prescribed therapy program. From our results we can make several conclusions. First, we found only a small number of studies utilize similar parameters for post-surgical quadriceps strength treatments. The majority of the parameters reported in the literature were highly variable between studies. Second, clinicians can utilize the expanded Health Belief Model to identify situational and personal factors unique to a patient that may impact adherence to a prescribed treatment. Clinicians can then implement the proposed interventional strategies to address the identified situational and personal factors. Finally, there was no difference in quadriceps strength, lower extremity function, or self-reported scores at 3-month between a home-based NMES treatment and a standard of care home-based treatment. Patients’ adherence to the treatment protocols may have been a major factor contributing to these results. Utilizing a model, such as the proposed expanded Health Belief Model, may assist clinicians in improving a patients’ adherence to future prescribed home-treatment programs.

[Truncated abstract] Articular cartilage has no vascular, neural, or lymphatic supply, and hence no intrinsic capacity to self-repair following injury. These physiological limitations, combined with the inability of local chondrocytes to contribute to the repair process, translate to poor structural and functional outcomes in these troublesome defects, and osteoarthritic deterioration with time. Subsequently, many surgical therapies have been trialed to stimulate cartilage repair, but none have produced reliable outcomes. Hence, cartilage repair research has been broadened, with many investigators now focused on cell-based treatment. Smith began a revolution of autologous cell research when in 1965 she isolated chondrocytes from articular cartilage and transplanted them into fresh cartilage nodules (Smith, 1965). Since, new technologies and improved techniques have seen autologous chondrocyte implantation (ACI) widely accepted for use in clinical orthopaedics (Bentley et al., 2003; Brittberg et al., 1994; Grande et al., 1989; Peterson et al., 2002). At present, matrix-induced autologous chondrocyte implantation (MACI) is the most surgically simple form of ACI, boasting clinical outcomes comparable to any technique on the market, and far less complications compared to the first generation of ACI - periosteal ACI (Bartlett et al., 2005; Behrens et al., 2006; Gigante et al., 2006; Henderson et al., 2004; Marlovits et al., 2005; Minas, 2001; Willers et al., 2007; Zheng et al., 2007). But whilst MACI has been adopted by the orthopaedic surgeon for articular cartilage repair, many of the molecular, histological, and clinical factors governing patient outcomes are still largely understudied. Firstly we assessed the bioactivity of fibrin sealant (FS - Tisseel®), a critical component of MACI, on the migration and proliferation of human articular chondrocytes in vitro. We also looked to elucidate the associated molecular mechanisms of thrombin, a key active ingredient in FS, by examining the expression and activation of proteaseactivated receptors (PARs), established thrombin receptors. All four PAR isoforms were detected in human chondrocytes, with PAR-1 being the major isoform expressed. '...' This thesis has demonstrated biological, histological, and clinical features of the MACI technique. Our in vitro has supported the use of fibrin sealant and collagen membrane as the major material components of MACI, illustrating improved chondrocyte proliferation, migration, and chondrogenic differentiation. We have evidenced that MACI stimulates successful production of hyaline-like cartilage by 6 months, while also showing that revised and clinically failed repair tissues are predominantly hyaline-like and fibrocartilage with inferior composition. Clinically, we have documented significant improvements in patient repair structure, function, symptoms, quality of life, and satisfaction, whilst concurrently confirming sentiment within the literature regarding the importance of exercise/ rehabilitation for maximising MACI outcome. In summary, the findings presented in this thesis suggest that MACI is a biologically sound and clinically efficacious cell-based treatment option for repairing articular cartilage defects.

[Truncated abstract] Articular cartilage (AC) covers the surface of synovial joints providing a nearly frictionless bearing surface and distributing mechanical load. Joint trauma can damage the articular surface causing pain, loss of mobility and deformation. Currently there is no uniform treatment protocol for managing focal cartilage defects, with most treatment options targeted towards symptomatic relief but not limiting the progression into osteoarthritis (OA). Autologous chondrocyte implantation (ACI) and more recently matrix-induced autologous chondrocyte implantation (MACI), have emerged as promising methods for producing hyaline or hyaline-like repair tissue, however there remains some controversy regarding the exact histological nature of the tissue formed. Histological characterisation of AC repairs requires destructive tissue biopsy potentially inducing further joint pathology thereby negating the treatment effect. OA is recognised as a major cause of pain, loss of function and disability in Western populations, however the exact aetiology is yet to be elucidated. The assessment of both OA and cartilage repair has been limited to macroscopic observation, radiography, magnetic resonance imaging (MRI) or destructive biopsy. The development of non-destructive AC assessment modalities will facilitate further development of AC repair techniques and enable early monitoring of OA changes in both experimental animal models and clinical subjects. Confocal laser scanning microscopy (CLSM) is a type of fluorescence microscopy that generates high-resolution three-dimensional images from relatively thick sections of tissue. ... Biomechanical analysis suggested that the mechanical properties of MACI tissue remain inferior for at least three months. This study showed the potential of a multi-site sheep model of articular cartilage defect repair and validated its assessment via LSCA. Finally, the LSCA was used to arthroscopically image the cartilage of an intact fresh frozen cadaveric knee from a patient with clinically diagnosed OA. Images were correlated to ICRS (Outerbridge) Grades I-IV and histology. The LSCA gave excellent visualization of cell morphology and cell density to a depth of up to 200'm. Classical OA changes including clustering chondrocytes, surface fibrillation and fissure formation were imaged. Fair to moderate agreement was demonstrated with statistically significant correlations between all modalities. This study confirmed the viability of the LSCA for non-destructive imaging of the microstructure of the OA cartilage. In conclusion, the LSCA identified histological features of orthopaedic tissues, accurately quantified chondrocyte morphology and demonstrated classical OA changes. While the development and investigation of an ovine model of cartilage repair showed the treatment benefit of MACI, some biomechanical issues remain. Ultimately, the LSCA has been demonstrated as a reliable nondestructive imaging modality capable of providing optical histology without the need for mechanical biopsy. Medical Subject Headings (MESH): articular cartilage; autologous chondrocyte implantation; matrix-induced autologous chondrocyte implantation; biomechanics; cartilage; confocal microscopy; diagnosis; histology; image analysis; immunohistochemistry; magnetic resonance imaging; microscopy; osteoarthritis

Knorpeldefekte des Kniegelenks zeichnen sich durch eine sehr begrenzte spontane Heilungstendenz aus und führen im Verlauf häufig zur Arthrose. Trotz intensiver Forschungsbemühungen konnte bisher keine neue Therapieoption eine zufrieden-stellende Alternative zu den bisherigen Therapien hervorbringen. Eine ACI in Kombination mit einem künstlich hergestellten Knorpel-Knochen-Ersatzmaterial scheint jedoch großes Potential für die Therapie von Knorpel-Knochen-Schäden zu besitzen. Im vorliegenden Langzeittierversuch mit Kaninchen wurde eine einzeitige ACI mit einem biphasischen Ersatzmaterial (TruFit®) und platelet-rich-plasma (PRP) kombiniert. Zu diesem Zweck wurde in der medialen Femurkondyle ein critical-size-Defekt mit einem Durchmesser von 4,5 mm gesetzt. In der ersten Versuchsgruppe blieb der Defekt unbehandelt (Leer). Bei der zweiten Gruppe wurde die Defekthöhle mit einem TruFit®-Zylinder aufgefüllt (TFP). Gruppe drei erhielt zusätzlich PRP (TFP+PRP) und Gruppe vier wurde darüber hinaus mit einer einzeitigen ACI kombiniert (TFP+PRP+C), bei der Chondrozyten mit Hilfe eines speziellen Kollagenase-Schnellverdaus isoliert werden konnten. Die Auswertung der Knorpel-Knochen-Regeneration erfolgte nach 12 Monaten durch eine Mikroradiographie, eine intravitale Fluoreszenzmarkierung des Knochens und durch Toluidinblau-O- und Safranin-O-Färbungen. Verwendet wurden die Scores nach Wakitani und O’Driscoll. Dabei konnte gezeigt werden, dass eine TruFit®-Therapie die Knochenregeneration positiv beeinflussen kann. Die Zugabe von PRP bewirkte die Bildung von zahlreichen dünnen Trabekeln mit einer erhöhten Anzahl trabekulärer Verbindungen, allerdings auch eine schlechtere Rekonvaleszenz der subchondralen Knochenschicht. Bezüglich der Knorpelheilung schnitt die Gruppe TFP+PRP+C am besten ab, wobei die Unterschiede nicht signifikant waren. Insgesamt zeigten alle Versuchsgruppen eine unzureichende osteochondrale Regeneration, so dass für die Therapie am Menschen zunächst weitere Studien nötig sind, die sowohl ossär als auch chondral eine verbesserte Heilungspotenz demonstrieren können. Bisher fehlen groß angelegte Studien um Therapieempfehlungen bezüglich des Ersatzmaterials, der genauen Durchführung der einzeitigen ACI und Zusätzen wie Wachstumsfaktoren zu machen.