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Στην παρούσα διατριβή προσεγγίσθηκε η βιολογική συνιστώσα του φαινομένου της άσηπτης χαλάρωσης των υλικών των ορθοπαιδικών προθέσεων. Κατ’ αρχήν μελετήθηκαν διεξοδικά περιπροθετικοί ιστοί (IFT και PCT) υγρό (PSSF) από πέντε ασθενείς οι οποίοι υποβλήθηκαν σε επέμβαση αναθεώρησης λόγω άσηπτης χαλάρωσης των προθέσεων. Το ενδεχόμενο σηπτικής χαλάρωσης αποκλείσθηκε με μικροβιολογικό και ιστοπαθολογικό έλεγχο. Οι ιστοί αυτοί εκχυλίσθηκαν παρουσία αναστολέων των πρωτεασών ώστε να αποκλεισθεί το ενδεχόμενο in vitro ενεργοποίησης των περιεχομένων στα εκχυλίσματα ενζύμων. Σε όλα τα δείγματα και σε συμφωνία με άλλους ερευνητές, ανιχνεύθηκε ζελατινολυτική και κολλαγονολυτική δραστικότητα. Ο προσδιορισμός της πρώτης έγινε με χρήση ζυμογραφήματος ζελατίνης, αξιολόγηση και επεξεργασία των ζωνών λύσεως, ενώ για την δεύτερη χρησιμοποιήθηκε το συνθετικό πεπτίδιο DNP-S και χρωματογραφία υψηλής επίδοσης ανάστροφης φάσης RP-HPLC. Οι δραστικότητες που ανιχνεύθηκαν οφείλονταν σε εκφραζόμενες στους ιστούς ΜΜPs. Η ζελατινολυτική δραστικότητα οφειλόταν κατά το πλείστον σε ζελατινάσες (MMP-2 και MMP-9), οι οποίες όμως στο μεγαλύτερο ποσοστό τους ανιχνεύθηκαν σε σύμπλοκη με TIMPs μορφές. Η ειδική ζελατινολυτική δραστικότητα μεταξύ δειγμάτων ίδιας κατηγορίας ιστών (IFT ή PCT) δεν παρουσίαζε μεταβολή ανεξάρτητα από το είδος της αρθροπλαστικής ή την παρουσία οστεόλυσης. Ελαττωμένη δραστικότητα εμφάνισαν τα δείγματα των PSSF. Η κολλαγονολυτική δραστικότητα, η οποία ήταν αυξημένη στα δείγματα όπου συνυπήρχε περιπροθετική οστεόλυση, οφειλόταν κυρίως σε κολλαγονάσες του ενδιάμεσου στρώματος. Πιο σημαντική συμβολή φάνηκε ότι είχε η ΜΜΡ-13, η οποία ανιχνεύθηκε στα περισσότερα δείγματα σε ενεργό μορφή, σε σχέση με την ΜΜΡ-1. Η ΜΤ-1-ΜΜΡ μάλλον δεν ανιχνεύθηκε λόγω του τρόπου αρχικής επεξεργασίας των εκχυλισμάτων. Σε πειράματα που ακολούθησαν και δεν περιλαμβάνονται στην παρούσα μελέτη, ανιχνεύθηκε κυρίως σε σύμπλοκη με ΤΙΜΡ-2 μορφή. Συνοψίζοντας τα παραπάνω προέκυψε το συμπέρασμα ότι στους περιπροθετικούς ιστούς εκφράζονται μέλη της οικογένειας των ΜΜPs, που εμπλέκονται, σε διαφορετικό βαθμό το κάθε ένα, στην διαδικασία της οστικής απορρόφησης και της άσηπτης χαλάρωσης. Η ανίχνευση δε δραστικοτήτων στους ιστούς των PCT, αντίστοιχων μάλιστα με αυτών των IFT, στηρίζει την υπόθεση της έναρξης της κυτταρικής αντίδρασης του οργανισμού, στα μικροσωματίδια των υλικών, στον ιστό αυτόν. Η διευκρίνιση του ακριβούς ποσοστού συμμετοχής της κάθε μίας ΜΜΡ αναμένεται να δώσει σημαντική ώθηση στην προσπάθεια επιβράδυνσης των διαδικασιών της χαλάρωσης, μέσω της χρήσης ειδικών και πιθανώς εκλεκτικών φαρμακευτικών αναστολέων των ενζύμων αυτών. Στα πλαίσια της παραπάνω πιθανής θεραπευτικής προσέγγισης μελετήθηκε η επίδραση μερικών γνωστών μη-στεροειδών αντιφλεγμονωδών φαρμάκων (ΜΣΑΦ) στην, επαγόμενη από δέκα IFT, in vitro παραγωγή ΜΜPs και ΤΙΜΡs. Λόγω δε της πολυπλοκότητας των παθογενετικών μηχανισμών της οστικής απορρόφησης, μελετήθηκε η επίδραση των φαρμάκων αυτών και σε άλλους εμπλεκόμενους, στην οστεόλυση και την χαλάρωση, παράγοντες (IL-1β, IL-6, TNF-α και PGE2). Τα ΜΣΑΦ που δοκιμάσθηκαν ήταν η ασεκλοφαινάκη, η πιροξικάμη, η τενοξικάμη και η ινδομεθακίνη, ενώ για τον προσδιορισμό της επίδρασής τους χρησιμοποιήθηκαν ζυμογράφημα ζελατίνης και τεχνικές ELISA. Τα αποτελέσματα έδειξαν στατιστικά μη-σημαντική ανασταλτική επίδραση στα επίπεδα των MMPs και των αναστολέων τους, σημαντικότατη αναστολή της PGE2, αναστολή της IL-6 και του TNF-α ιδιαίτερα από ασεκλοφαινάκη και τενοξικάμη και αύξηση των επιπέδων IL-1β (ιδιαίτερα από την ασεκλοφαινάκη). Για να υποστηριχθεί βέβαια η θέση της χορήγησης των ΜΣΑΦ αυτών με σκοπό τουλάχιστον την επιβράδυνση των διαδικασιών της χαλάρωσης απαιτούνται μετρήσεις σε μεγαλύτερο αριθμό δειγμάτων ή in vivo μετρήσεις. / In this study the biological mechanisms, which contribute to aseptic loosening process, were evaluated. Periprosthetic tissues (IFT and PCT) and liquids (PSSF) from five patients, who subjected to hip revision due to aseptic loosening, were collected. The possibility of septic loosening was, by histopathological and culture examinations, excluded. Extraction of tissues and dialysis were, in the presence of proteinases inhibitors, performed in order to exclude the in vitro activation of the sample-enzymes. Collagenolytic and gelatinolytic activity were, in all samples, detected. In order to examine the gelatinolytic activity, all samples were subjected in gelatin zymography and the lysis bands were evaluated. The collagenolytic activity was examined by using the DNP-S peptide and reverse phase high performance liquid chromatography (RP-HPLC). The activities, mentioned above, were the outcome of, expressed in periprosthetic tissues, MMPs. The gelatinolytic activity was the result of gelatinases (MMP-2 and MMP-9), which were mainly in complex with TIMPs forms detected. The specific gelatinolytic activities of the samples were almost equal, independently the type of arthroplasty and the presence or absence of osteolysis. In PSSF samples low activity was detected. Collagenolytic activity, which was higher in samples collected from osteolytic lesions, was the result of presence and action of interstitial callagenases. MMP-13 seems to have the major contribution, compared to MMP-1 in collagenolytic activity. MT1-MMP was not detected, possibly due to the extraction methods. In more recent and unpublished results, MT1-MMP was detected in complex to TIMP-2. In brief, different members of the MMP family are expressed in periprosthetic tissues and fluids. These MMPs contribute in different way in loosening and osteolysis processes. The fact that in PCTs high activities were measured can support the hypothesis that all the biological events that lead to loosening start to take place in the PCT tissue. The contribution of each MMP in these processes has to be elucidated in order to try to decelerate them by using selective MMPs-inhibitors. In order to evaluate the possible usage of several well-known non-steroidal anti-inflammatory drugs for retarding the loosening process, the in vitro effect of these drugs in the IFT- induced production of MMPs and TIMPs was studied. Because of the complexity of the involved in pathogenesis factors, the effect of the drugs in other soluble cytokines (such as IL-6, IL-1β, TNF-a) and PGE2 was also measured. For all these experiments cultures of IFT of ten patients were used. Aceclofenac, Piroxicam, Tenoxicam and Indomethacin were used. The drugs didn’t have a statistically significant effect in the MMPs or TIMPs production. In all cases the inhibitory effect on PGE2 was potent. Aceclofnac and tenoxicam reduced strongly the IL-6 and TNF-α levels. Finally the drugs seemed to induce the ΙL-1β levels (especially aceclofenac). More experimental studies are necessary for supporting the usage of the tested drugs, for retarding the aseptic loosening phenomenon. In vivo studies will also be useful.

Introduction: Aseptic loosening is the most common indication for revision surgery of hipimplants. However, sometimes diagnosis from planar radiography is uncertain, makingdecision regarding revision surgery problematic. Implant Movement Analysis (IMA) is anewly introduced method of analysing uncertain aseptic loosening of hip prostheses. It usescomputer tomography with rotational provocation to expose movement of the implantrelatively to the surrounding bone. Aim: To evaluate the role of IMA as a complementary method to planar radiography indiagnosing aseptic loosening of total hip artroplasty (THA) at Lindesberg Hospital. 1) HasIMA improved diagnosing of uncertain cases of aseptic loosening? 2) Has IMA reduced thenumber of unnecessary THA revision surgeries? Methods: Retrospective cohort study analysing 43 cases of uncertain aseptic looseningexamined with IMA at Lindesberg Hospital. Paired results from planar radiography and IMAwere statistically compared with McNemar’s test, IMA held as the reference. Additional datawas also collected (i.e. age and symptoms). Results: Planar radiography had 70 % sensitivity and 65 % specificity compared to certainresults from IMA. IMA provided diagnoses in 84 % of the cases and changed the diagnosisfor 33 % compared to planar radiography. Eight cases got their diagnosis changed from looseto not loose. Conclusions: IMA has improved diagnosing cases of uncertain aseptic loosening and cantherefore be seen as a good complementary method to planar radiography in these cases.However, as it is a new method further evaluation is needed.

Wear particles and ions from cobalt-chromium-molybdenum (CoCrMo)-based implants have been shown to cause adverse immune responses, including periprosthetic osteolysis leading to aseptic loosening, the main cause of implant failure. Previous studies have shown that these wear and corrosion products can lead to the release of inflammatory cytokines, including interleukin-1β (IL-1β), suggesting the involvement of the NLRP3 inflammasome. However, the mechanisms leading to IL-1β release have not been fully elucidated. The primary objectives of this thesis were to determine if, in murine macrophages, IL-1β release induced by micrometre-size CoCrMo particles and nanometre-size chromium oxide (Cr2O3) particles is: 1. Caspase-1-dependent; 2. Reduction-oxidation (redox)-dependent; and 3. NLRP3 inflammasome-dependent. Additionally, the effects of metal ions (Co2+, Cr3+, and Ni2+) on NLRP3 inflammasome activation and the effects of matrix metalloproteinase (MMP) inhibition on IL-1β release induced by CoCrMo particles were analyzed. Results showed that IL-1β release induced by CoCrMo particles was partly caspase-1-, redox-, and MMP-dependent, but NLRP3 inflammasome-independent. On the other hand, IL-1β release induced by Cr2O3 particles appeared to be NLRP3 inflammasome-dependent. Finally, IL-1β release induced by Cr3+, but not Co2+, appeared to be NLRP3 inflammasome-dependent, while Ni2+-induced IL-1β release appeared to be only partially NLRP3 inflammasome-dependent, suggesting that other pathways may also be involved. These findings, which provide additional insights into the mechanisms leading to IL-1β release induced by wear particles and ions from CoCrMo-based implants, may help the future development of therapeutic treatments to modulate wear product-induced inflammation and increase implant longevity.

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Η αναθεώρηση μιας ολικής αρθροπλαστικής ισχίου λόγω χαλάρωσης του μηριαίου τμήματος της αποτελεί μια πρόκληση ακόμα και για πεπειραμένους χειρουργούς. Η άσηπτη χαλάρωση συνήθως σχετίζεται με κάποιο βαθμό οστικής απώλειας. Διερευνήσαμε εάν η πρόθεση Zweymüller SLR-Plus ®, μαζί με την βιολογική αναδόμηση με αλλομοσχεύματα του ελλειμματικού οστικού περιβάλλοντος του μηριαίου, θα επιτύγχανε επιβίωση, οστεοενσωμάτωση και σταθερότητα παρόμοια ή και καλύτερη από άλλες προθέσεις που χρησιμοποιούνται στη βιβλιογραφία για αναθεώρηση του μηριαίου τμήματος ΟΑΙ. Εξετάσαμε αναδρομικά 69 επιλεγμένους ασθενείς (70 ισχία) οι οποίοι υποβλήθηκαν σε αναθεώρηση του μηριαίου τμήματος με χρήση του SLR-Plus ® στειλεού σε μια περίοδο 10 ετών. Οι ενδείξεις για την αναθεώρηση περιελάμβαναν άσηπτη και σηπτική αποτυχία της βιολογικής στερέωσης, εσφαλμένη εμφύτευση, και περιπροθετικό κάταγμα. Επτά ασθενείς πέθαναν και τέσσερις χάθηκαν κατά το διάστημα παρακολούθησης. Πενήντα οκτώ από τους 69 ασθενείς (59 ισχία) ήταν διαθέσιμοι σε μέσο χρονικό διάστημα 8,3 ± 2,7 χρόνια (εύρος, 4-14 ετών) μετά τη χειρουργική επέμβαση αναθεώρησης. Υπήρχαν 14 άνδρες και 44 γυναίκες (μέση ηλικία, 69 έτη, εύρος, 42-89 ετών). Τέσσερις μηριαίες προθέσεις (7%) αναθεωρήθηκαν ξανά. Η 10ετής επιβίωση της πρόθεσης λαμβάνοντας ως αιτία αναθεώρησης την άσηπτη χαλάρωση ήταν 95% (95% C.I.: 86% -98%). Δεν παρατηρήθηκε περιπροθετική οστεόλυση του μηριαίου γύρω από την πρόθεση και 91% των SLR-Plus στειλεών εμφανίστηκε ακτινολογικά σταθερό είτε μέσω οστεοενσωμάτωσης είτε μέσω ινώδους στερέωσης. Με βάση τα στοιχεία επιβίωσης, πιστεύουμε ότι η χρήση του SLR-Plus® στειλεόυ είναι μια αξιόπιστη λύση για τους ασθενείς που υποβάλλονται σε χειρουργική επέμβαση αναθεώρησης ΟΑΙ, με απώλεια οστικής μάζας στο κεντρικό τμήμα του μηριαίου. / Revision after failed THA resulting from loosening of the femoral component can be challenging even for experienced surgeons. Aseptic loosening usually is associated with some degree of bone loss. We asked whether the Zweymüller SLR-Plus®, along with allograft reconstruction of the deficient femoral bone stock, would provide survivorship, osseointegration, and stability similar to or better than previously reported implants for femoral revision. We retrospectively reviewed 69 selected patients (70 hips) who underwent revision of the femoral component using the SLR-Plus® stem during a 10-year period. The indications for revision included aseptic and septic failure of biologic fixation, incorrect implantation, and periprosthetic fracture. Seven patients died and four were lost to followup. Fifty-eight of the 69 patients (59 hips) were available at a mean 8.3 ± 2.7 years (range, 4–14 years) after revision surgery. There were 14 men and 44 women (mean age, 69 years; range, 42–89 years). Four stems (7%) were rerevised. With rerevision for aseptic reasons, the survival at 10 years was 95% (95% confidence interval, 86%–98%). No femoral periprosthetic osteolysis occurred around the stem and 91% of stems appeared stable radiographically (osseointegration, fibrous). Based on the survival data, we believe the SLR-Plus® stems are reliable for patients undergoing hip revision surgery with central bone loss.

Aseptic loosening due to polyethylene wear presents one of the most frequently occurring joint replacement complications requiring a revision surgery. Numerous scientific works and publications deal with the issue of morphology, determination and distribution of wear particles. Few studies, however, determine reliably amounts of particles in individual periprosthetic zones. The objective of this work was to evaluate the correlation between amounts of wear particles and periprosthetic osteolysis findings. Description of distribution of these particles in the surroundings of joint replacement presented further objectives of the work. Wear particles were isolated from granuloma obtained during revisions of total hip replacements. Amounts of wear particles were determined using IRc. These findings were correlated with X-ray examinations and intraoperative findings. Method of progressive enzymatic degradation of tissue was used in order to describe wear particles distribution in polyethylene granuloma and surrounding periprosthetic tissues. Results showed uneven incidence of wear particles in the surroundings of the total joint replacement. The incidence correlated with X-ray examinations and intraoperative findings. Distribution of particles was described as well as new determination methods and further...

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Today is the implantation of joint replacements, although a radical, but very functional restoration frequent way ill joint. The implants are placed high demands on their biocompatible and long-term function, which is directly related to wear of joint replacements in the human body. Therefore, analysis of the complex behavior of the implant in the human body is a fundamental problem of biomechanics of implants. This issue is dedicated, this dissertation thesis. Dissertation thesis deals with the solution design and development of experimental device for testing the TEP acetabula and wear identification using optical method. The proposed device allows the joint burden hole TEP physiological manner, but by working with the acetabulum burdened by Power resultant joint axis passes through the hole. The physiological loading of articular wells and evaluating the size of the loss of polyethylene is currently intensively addressed. The results of this study may in the near future, serving as information for assessing the conduct of wear prosthetic hip joint in vivo. The work is devoted to solving the problem of the size required to detect the loss of polyethylene for joint replacement arthroplasty: Design and development of experimental equipment for testing the acetabulum of the hip joint arthroplasty. Identify wear using optical methods. Design and development of experimental equipment was made in the system Inventor Professional 2010 at the level of 3D modeling. Great attention was paid to the design fit into the acetabulum TEP testing machines and gripping the acetabulum into an optical device. Management options were tested with combinations of experimental equipment engines. Suggestions were made and then tests for fixing the acetabulum into an optical device. Has the possibility of depth analysis and identification of wear joined with innovative solutions to evaluate the loss of polyethylene acetabulum arthroplasty. Identification of abrasion (loss of polyethylene) joint arthroplasty holes were carried out experimental measurements using an optical holographic interferometry. The comprehensive analysis of the results of experimental measurement of the loss of polyethylene shows that this method can identify both the size but also an area where there is even to small changes in the surface, which depend on the abrasion. One can also say that using this method we are able to affect the will or displacements that affect the size of the loss of polyethylene in joint arthroplasty hole. Despite the number of known and lessons learned arising from the results of solving the problem of design and development of experimental equipment for testing the acetabulum and hip arthroplasty wear identification using optical methods, this work is that the initial study to identify problematics wear of joint replacements. Complete resolution of this issue is beyond the scope of one doctoral thesis.