The Trapeziometacarpal Joint: Tissue Characterization and Surgical Techniques for Treatment of Osteoarthritis

The trapeziometacarpal (TMC) joint is one of the most important joints in the human body. It provides the thumb with the ability to cross over the palm of the hand, thus enabling motions of pinch and grip essential in performing routine daily activities. In the case of repeated use of this joint, the articular cartilage may wear through a progressive joint disease known as osteoarthritis (OA). This disease is characterized by pain at the base of the thumb, decreased range of motion, thumb instability, and decreased grip and pinch strength leading to impairment in vocational activities, significantly affecting quality of life. Much of the research surrounding the TMC joint has focused on development of non-surgical and surgical options for treatment of early and late stage OA. Unfortunately, the extent of research on characterizing the biophysical properties of the TMC joint and surrounding tissue is limited. The following research will seek to identify the ligamentous structures hypothesized to act as primary stabilizers of the TMC joint through advanced, high-resolution motion analyses. Mechanical properties of the primary ligamentous stabilizers will be obtained through uniaxial tensile testing of ligamentous tissue. This tissue will be further characterized through histology, staining for identification of the presence and orientation of essential proteins which may serve to support the argument for primary stabilizing tissue. Using results from the tissue characterization studies, two techniques are presented for the treatment of early and late stage TMC joint osteoarthris, which are designed to maintain and/or regain stability of this joint. The final section introduces a methodology for development of patient-specific computational finite element models of the hand and thumb. Input properties of these models are based on computed tomography data and outputs from the motion analysis and mechanical testing studies

The proprioception and neuromuscular stability of the basal thumb joint

OBJECTIVES The basal thumb joint, or the first carpometacarpal joint (CMC1) is an enigmatic construction. The concavo-convex shape of the CMC1 and wide range of movement, allows for both precision and power grips and is particularly susceptible to the development of osteoarthritis. Previous theories regarding the development of CMC1 osteoarthritis have focused on the role of gender, excessive joint load and ligament laxity as causative factors. An emerging theory is the role of proprioception and sensorimotor functions that act to maintain adequate joint equilibrium. This concept constitutes the basis of this thesis with the intent on examining both healthy and osteoarthritic joints. Using microscopic, biomechanical and neurophysiological methods, we address the hypothesis that CMC1 holds proprioceptive and neuromuscular properties that are integral for proper thumb function. METHODS Patients with CMC1 osteoarthritis that were treated surgically with complete trapeziectomy and suspension arthroplasty were included. Two CMC1 ligaments were collected from these subjects: the anterior oblique ligament (AOL) and the dorsal radial ligament (DRL). Following immunofluorescent triple staining techniques using markers p75, PGP9.5 and DAPI, the ligamentous innervation and mechanoreceptor populations were analyzed (study I-II). In study III, biomechanical assessment of the role of isometric muscle load on CMC1 was performed by a FASTRAK® motion tracking device. In study IV, two intrinsic (the first dorsal interosseous muscle; DI, abductor pollicis brevis; APB,) and two extrinsic muscles (extensor pollicis longus; EPL, abductor pollicis longus, APL) were examined in healthy subjects using electromyographic (EMG) analysis during functional thumb tasks. Post-stimulus reactions following stimulation of the DRL were analyzed for each muscle and each thumb position. RESULTS The CMC1 ligaments investigated displayed a varying degree of innervation. AOL presented with little innervation and was mainly composed of incoherent connective tissue and scarce collagen fibers, whereas DRL presented with abundant innervation and well-organized collagen (study I). Unclassifiable mechanoreceptors were the most frequent type of receptor found in AOL and DRL. No significant difference in the innervation between the proximal and distal portions of these osteoarthritic ligaments was identified (study II). The first dorsal interosseous muscle (FDI or DI) produced the highest level of distal migration and the least dorsoradial translation of the base of the first metacarpal. APL was identified as the main destabilizer as it increases dorsoradial misalignment (study III). Following stimulation of the DRL, significant (p<0.05) post-stimulus changes were found in all four muscles (DI, APB, APL, EPL) and positions tested. A mass inhibitory reaction was observed during tip pinch whilst key pinch produced rapid co-contractions. During palmar pinch a rapid inhibitory response was evoked in antagonistic muscles (study IV). CONCLUSIONS Ligaments from osteoarthritic patients displayed alterations in distribution and type of mechanoreceptors as compared to previous studies on normal joints. The results reinforce DRL’s proprioceptive and stabilizing role for the CMC1 joint. Isometric load of CMC1 indicates that DI promotes joint congruency by reducing dorsoradial translation, whereas APL acts in an opposing manner as a destabilizing force. Ligamento-muscular reflexes were observed following the stimulation of DRL. Thus, the dorsoradial ligament, in addition to being the primary static stabilizer of the joint, also possesses proprioceptive qualities. The post-stimulus reactions detected in DI, APB, APL and EPL are indicative of protective ligamento-muscular pathways, which facilitate neuromuscular functions and the maintenance of joint stability. CLINICAL RELEVANCE Patients with CMC1 osteoarthritis constitute a large group. Their symptoms are of varying severity, where some can be addressed within the scope of primary care units, whilst others are in need of operative treatment. Patients with CMC1 osteoarthritis often present with impaired neuromuscular functions, reduced range of motion, weakness, joint and ligamentous pathology as well as pain, which affect their daily activities. Understanding the proprioceptive and neuromuscular characteristics of the basal thumb joint is therefore essential in deciphering the complex pathophysiology of the basal thumb joint

Osteoarthritis

Osteoarthritis is one of the most debilitating diseases affecting millions of people worldwide. However, there is no FDA approved disease modifying drug specifically for OA. Surgery remains an effective last resort to restore the function of the joints. As the aging populations increase worldwide, the number of OA patients increases dramatically in recent years and is expected to increase in many years to come. This is a book that summarizes recent advance in OA diagnosis, treatment, and surgery. It includes wide ranging topics from the cutting edge gene therapy to alternative medicine. Such multifaceted approaches are necessary to develop novel and effective therapy to cure OA in the future. In this book, different surgical methods are described to restore the function of the joints. In addition, various treatment options are presented, mainly to reduce the pain and enhance the life quality of the OA patients

Active Latent Space Shape Model: A Bayesian Treatment of Shape Model Adaptation with an Application to Psoriatic Arthritis Radiographs

Shape models have been used extensively to regularise segmentation of objects of interest in images, e.g. bones in medical x-ray radiographs, given supervised training examples. However, approaches usually adopt simple linear models that do not capture uncertainty and require extensive annotation effort to label a large number of set template landmarks for training. Conversely, supervised deep learning methods have been used on appearance directly (no explicit shape modelling) but these fail to capture detailed features that are clinically important.We present a supervised approach that combines both a non-linear generative shape model and a discriminative appearance-based convolutional neural network whilst quantifying uncertainty and relaxes the need for detailed, template based alignment for the training data. Our Bayesian framework couples the uncertainty from both the generator and the discriminator; our main contribution is the marginalisation of an intractable integral through the use of radial basis function approximations. We illustrate this model on the problem of segmenting bones from Psoriatic Arthritis hand radiographs and demonstrate that we can accurately measure the clinically important joint space gap between neighbouring bones

Imaging-Based Biomarkers for Evaluating Musculoskeletal Pain in the Hand and Wrist

The defining symptom, and often the major reason for seeking medical treatment associated with most clinical disorders of the hand and wrist, is pain. However, pain mechanisms following MSK trauma are complex, multifactorial, and remain largely unknown.As such, this thesis sought to understand pain mechanisms in hand and wrist MSK pathologies, using imaging-based biomarkers and gold-standard pain evaluation techniques. Chapter 2 presents an exploratory analysis on the interacting influences of sex on multi-modal pain evaluation techniques that tap different pain domains. Our results highlight the importance of multiple pain measures when creating sex-specific intervention strategies, as the accuracy of predicting ones’ clinical pain evaluation scores did not show true difference greater than chance. Chapter 3 explores the use of imaging-based biomarkers, namely subchondral volumetric bone mineral density (vBMD) and static joint contact area (JCA), to differentiate between two study cohorts. On average, our healthy cohort had a higher vBMD for all measured depths from the subchondral surface of the distal radius. Chapter 4 presents the relationship between subchondral vBMD and kinematic JCA throughout a range of motion in a healthy cohort of adults to understand the impact of joint contact on subchondral bone. In deep regions of subchondral bone, a higher vBMD was significantly correlated to a larger JCA, most notably during wrist extension. Lastly, Chapter 5 explores the preliminary association between structural and clinical disease progression, using pain evaluation measures and our imaging-based biomarkers, in a cohort of thumb carpometacarpal osteoarthritis (CMC OA) patients. Our preliminary results demonstrated that structural severity was significantly associated with a higher pain score and pain presentation was heterogeneous

Regulation of lipocalin prostaglandin-D synthase expression by interleukin-1β in human chondrocytes

L'arthrose est une maladie multifactorielle complexe. Parmi les facteurs impliqués dans sa pathogénie, les certains prostaglandines exercent un rôle inflammatoire et d’autres un rôle protecteur. La prostaglandine D2 (PGD2) est bien connue comme une PG anti-inflammatoire, qui est régulée par l’enzyme «Lipocalin prostaglandine D-synthase». Avec l’inflammation de l'arthrose, les chondrocytes essaient de protéger le cartilage en activant certaines voies de récupération dont l'induction du gène L-PGDS. Dans cette étude, nous étudions la voie de signalisation impliquée dans la régulation de l'expression du (L-PGDS) sur les chondrocytes traités avec différents médiateurs inflammatoires. Le but de projet: Nous souhaitons étudier la régulation de la L-PGDS dans le but de concevoir des approches thérapeutiques qui peuvent activer la voie intrinsèque anti-inflammatoire. Méthode et conclusions: In vivo, l'arthrose a été suivie en fonction de l’âge chez la souris ou chirurgicalement suivant une intervention au niveau des genoux de souris. Nous avons confirmé les niveaux d’expression de L-PGDS histologiquement et par immunohistochimie. In vitro, dans les chondrocytes humains qui ont été traités avec différents médiateurs de l'inflammation, nous avons observé une augmentation de l’expression de la L-PGDS dose et temps dépendante. Nous avons montré, in vivo et in vitro que l’inflammation induit une sécrétion chondrocytaire de la L-PGDS dans le milieu extracellulaire. Enfin, nous avons observé la production de différentes isoformes de la L-PGDS en réponse à l'inflammation.Osteoarthritis is a complex multifactorial disease; many factors are involved in its pathogenesis, among those factors prostaglandins. Some prostaglandins have inflammatory role and some have anti-inflammatory role. Prostaglandin D2 (PGD2) is a well-established anti-inflammatory PG which is synthesized by the Lipocalin prostaglandin-D synthase (L-PGDS) enzyme. Upon the initiation of the inflammatory process in osteoarthritis, chondrocytes try to save themselves by activating salvage pathways, among these pathways is the induction of L-PGDS gene. In this study we are addressing the signaling pathways involved in the regulation of (L-PGDS) gene expression, in chondrocytes treated with different inflammatory mediator. Rationale: understanding the regulation of L-PGDS will allow us to design therapeutic targets that can switch on the intrinsic anti-inflammatory pathway. Method and findings: In vivo, osteoarthritis was induced in mice knees surgically or naturally following aging, the development of osteoarthritis was then confirmed histologically. The expression levels of L-PGDS were detected by Immunohistochemistry. In vitro, human chondrocytes were treated with different inflammatory mediators (interleukin-1 beta, interleukin-17, hydrogen peroxide and tert-Butyl hydroperoxide). Interestingly, in most cases chondrocytes increased expression of L-PGDS in a dose and time dependent manner. We discovered that chondrocytes release L-PGDS into the extracellular space in response to inflammation, in vivo and in vitro. Lastly we observed different isoforms of L-PGDS generated in response to inflammation

3D modelling and tissue-level morphology of trapeziometacarpal joint

The ligaments of the trapeziometacarpal joint (TMC) are complex and highly varied. Several studies have reported different patterns of ligament arrangement. Which ligaments are responsible for governing the stability of the TMC is still a source of controversy; the very naming of some of the ligaments is also in dispute. The overall aim of the experiments in this thesis is to explore the stabilization of the TMC ligaments during a specific positions (the neutral and full abduction positions), the mechanics of the attachment, the relaxing and stretching of the TMC ligaments, and the responsibilities of the TMC ligaments to prevent the TMC joint subluxations such as dorsal subluxation, palmar subluxation, and lateral subluxation. An additional aim is to describe the orientation of the TMC ligaments (origin, insertion) and the ligament fibres’ directions. The study used development devices to render the TMC ligaments into 2D reconstruction and 3D modelling in the 3D virtual environment such as Rhinoceros V5, 3D Landmark software, and 3D Amira software. Length, width, area, volume, thickness, and cross-sectional measurements were assessed in the neutral and full abduction positions. The ligament stretcher was designed to stretch the TMC ligaments after the ligaments were cut away from the joint. Also used in the thesis is a new technique to develop staining procedures by combining two different stains with accurate timing and re-timing the procedures of the Miller’s Elastin Staining protocol. Also, the entheses investigations have been applied on the attachments of the TMC ligaments with trapezuim and first metacarpal bones (proximal and distal). Moreover, the technique of the high resolution episcopic microscopy (HREM) was used to identify the relation of the TMC ligaments fibres to the flexor retinaculum, especially at dorso-ulnar trapeziometacarpal ligament (DUTML). The layers of the palmar trapeziometacarpal ligament (PTML) were also investigated to identify the nature of this ligament. The osteological descriptions were noted for the first metacarpal and trapezium bones, the geometrical measurement experiments on the articular surface of both bones allowed for a description of the effects of the degenerative disease, especially osteioarthritis disease (OA), and comparisons between both genders, the right and left specimens, embalmed and fresh cadavers were investigated to achieve the most accurate and precise results. The index procedures against the third metacarpal assisted in describing the relation between the actual reading and index reading. Seven ligaments were shown in the 3D virtual environment: radial trapeziometacarpal ligament (RTML), superficial palmar trapeziometacarpal ligament (sPTML), deep palmar trapeziometacarpal ligament (dPTML), palmo-ulnar trapeziometacarpal ligament (PUTML), dorso-ulnar trapeziometacarpal ligament (DUTML), palmar intermetacarpal ligament (PIML), and dorsal intermetacarpal ligament (DIML). Also, the results revealed that the PIML and DIML were the main stabilizers through the experiments, and the DUTML and PUTML served as associated ligaments to prevent TMC joint dislocation. The RTML prevented radial subluxation, while the superficial and deep layers of the PTML acted as a pivot for the movement of the TMC joint and assisted in preventing a palmar subluxation. In addition, there were no significant differences (p>0.05) between embalmed and fresh cadavers, but there were significant differences (p<0.05) between male and female cadavers as well as between the right and left hands, especially in the measurement investigations. Moreover, the TMC ligament attachments were found to be of the fibrocartilagenous type; this was found at both attachments, proximal and distal. The combination beginning with Miller Elastin stain (ME) was better than that starting with Modified Masson Trichrome stain (MME) and the colours were nearer to those of the MMT results; however, the MMT alone was clearest. Also, a re-timing of the ME stain revealed that the experiment involving 2.5 hours of Miller’s Elastin and 15 seconds of Van Gieson Solution was the best of all experiments. The HREM technique revealed no connection between the collagen fibres of both the DUTML and the flexor retinaculum. The single coordination points of each of the first metacarpal (1st MC) and trapezium (TM) bones revealed varieties of prominences and declines in the bones’ surfaces, especially the articular surface. New names of the TMC ligaments as following: Old Name New Name Ulnar collateral ligament (UCL). Radial trapeziometacarpal ligament (RTML). Superficial anterior oblique ligament (sAOL). Superficial palmar trapeziometacarpal ligament (sPTML). Deep anterior oblique ligament (dAOL). Deep palmar trapeziometacarpal ligament (dPTML). Posterior oblique ligament (POL). Palmo-ulnar trapeziometacarpal ligament (PUTML). Dorso-radial ligament (DRL). Dorso-ulnar trapeziometacarpal ligament (DUTML). New osteological definitions were noted, such as the distal border of the 1st MC facet, the distal and proximal ridge of the palmar surface of the1st MC, and eminences of the trapezial ridge of TM. Overall, the results of my studies suggested that the importance of the PIML, DIML, and RTML should be considered when planning surgeries involving ligament reconstruction of the TMC joint

Biokompatibilita a potenciálna cytotoxicita materiálov na výrobu a pokrývanie totálnych endoprotéz

Currently used prostheses for total joint replacement still have numerous disadvantages: extreme stiffness or elastic modulus of the bulk metallic material; insufficient integration of the implant into the host bone; and a high wear and corrosion rate, which causes an accumulation of mostly metallic or polymeric wear debris. Because of these reasons, many patients experience increasing local pain, swelling, allergic reactions, and inflammation resulting in bone loss and the aseptic loosening of the implant leading to the need for painful and expensive revision surgery. To address the mechanical issues of commonly used orthopaedic alloys, this thesis presents the development of the new β-type titanium alloy Ti-35Nb-7Zr-6Ta-2Fe-0.5Si with a relatively low elastic modulus (up to 85 GPa), increased tensile strength (880 MPa), and enhanced biocompatibility and osteoconductivity. Considering the generally low osteoinductivity of metallic implants, various surface modifications and coatings have been developed to improve the cell-material interaction, e.g. carbon-based coatings. Among these coatings, C60 fullerene layers have emerged as a great candidate for coating orthopaedic implants due to their therapeutic potential in arthritis. The potential cytotoxicity and DNA damage response of fullerenes have...V súčasnosti používané totálne endoprotézy kĺbov majú niekoľko nedostatkov vrátane príliš veľkej tuhosti kovového materiálu, nedostatočnej integrácie implantátu do kosti a vysokej miery opotrebovania či korózie. To má za následok úbytok kostnej hmoty a následné aseptické uvoľnenie protézy s nutnosťou ďalšieho chirurgického zákroku. Nepostačujúce mechanické vlastnosti súčasných ortopedických zliatin rieši táto práca vývojom novej beta-titánovej zliatiny s konečným zložením Ti-35Nb-7Zr-6Ta-2Fe-0,5Si, ktorá má relatívne nízky modul pružnosti (do 85 GPa), vysokú pevnosť v ťahu (850 MPa) a vylepšenú biokompatibilitu, ako aj osteokonduktivitu. Vzhľadom k všeobecne nízkej osteoinduktivite kovových implantátov sa vyvíjajú rôzne povrchové úpravy a vrstvy pre zlepšenie interakcie buniek s materiálmi, ako napríklad vrstvy na báze uhlíka. Fullerénové vrstvy sa zdajú byť sľubným kandidátom na pokrývanie ortopedických implantátov vzhľadom k ich ochranným anti-oxidačným vlastnostiam. Hoci čerstvé C60 vrstvy tlmili adhéziu a rast buniek, žiadne známky bunkovej toxicity ani poškodenia DNA neboli nájdené. Sledovaná biokompatibilita fullerénových C60 filmov sa výrazne zlepšila s pribúdajúcim vekom vrstiev alebo s ko-depozíciou fullerénových molekúl s atómami titánu. Vysvetlenie spočíva v chemicko-fyzikálnych zmenách...Department of Genetics and MicrobiologyKatedra genetiky a mikrobiologieFaculty of SciencePřírodovědecká fakult