Patient-specific resurfacing implant knee surgery in subjects with early osteoarthritis results in medial pivot and lateral femoral rollback during flexion: a retrospective pilot study

Purpose: Metallic resurfacing implants have been developed for the treatment of early, small, condylar and trochlear osteoarthritis (OA) lesions. They represent an option for patients who do not fulfill the criteria for unicompartmental knee arthroplasty (UKA) or total knee arthroplasty (TKA) or are too old for biological treatment. Although clinical evidence has been collected for different resurfacing types, the in vivo post-operative knee kinematics remain unknown. The present study aims to analyze the knee kinematics in subjects with patient-specific episealer implants. This study hypothesized that patient-specific resurfacing implants would lead to knee kinematics close to healthy knees, resulting in medial pivot and a high degree of femoral rollback during flexion. Methods: Retrospective study design. Fluoroscopic analysis during unloaded flexion-extension and loaded lunge was conducted at > 12 months post-surgery in ten episealer knees, and compared to ten healthy knees. Pre- and post-operative clinical data of the episealer knees were collected using a visual analog scale (VAS), the EQ 5d Health, and the Knee Injury and Osteoarthritis Outcome Score (KOOS) questionnaires. Results: A consistent medial pivot was observed in both episealer and healthy knees. Non-significant differences were found in the unloaded (p = 0.15) and loaded (p = 0.51) activities. Although lateral rollback was observed in both groups, it was significantly higher for the episealer knees in both the unloaded (p = 0.02) and loaded (p = 0.01) activities. Coupled axial rotation was significantly higher in the unloaded (p = 0.001) but not in the loaded (p = 0.06) activity in the episealer knees. Improved scores were observed at 1-year post-surgery in the episealer subjects for the VAS (p = 0.001), KOOS (p = 0.001) and EQ Health (p = 0.004). Conclusion: At 12 month follow-up, a clear physiological knee kinematics pattern of medial pivot, lateral femoral rollback and coupled axial external femoral rotation during flexion was observed in patients treated with an episealer resurfacing procedure. However, higher femoral rollback and axial external rotation in comparison to healthy knees was observed, suggesting possible post-operative muscle weakness and consequent insufficient stabilization at high flexion

Short locked nucleic acid antisense oligonucleotides potently reduce apolipoprotein B mRNA and serum cholesterol in mice and non-human primates

The potency and specificity of locked nucleic acid (LNA) antisense oligonucleotides was investigated as a function of length and affinity. The oligonucleotides were designed to target apolipoprotein B (apoB) and were investigated both in vitro and in vivo. The high affinity of LNA enabled the design of short antisense oligonucleotides (12- to 13-mers) that possessed high affinity and increased potency both in vitro and in vivo compared to longer oligonucleotides. The short LNA oligonucleotides were more target specific, and they exhibited the same biodistribution and tissue half-life as longer oligonucleotides. Pharmacology studies in both mice and non-human primates were conducted with a 13-mer LNA oligonucleotide against apoB, and the data showed that repeated dosing of the 13-mer at 1–2 mg/kg/week was sufficient to provide a significant and long lasting lowering of non-high-density lipoprotein (non-HDL) cholesterol without increasing serum liver toxicity markers. The data presented here show that oligonucleotide length as a parameter needs to be considered in the design of antisense oligonucleotide and that potent short oligonucleotides with sufficient target affinity can be generated using the LNA chemistry. Conclusively, we present a 13-mer LNA oligonucleotide with therapeutic potential that produce beneficial cholesterol lowering effect in non-human primates

Untersuchung der rotatorischen Laxizität im menschlichen Kniegelenk

Als Arthrose wird eine degenerative Erkrankung der Gelenke bezeichnet, die sich durch einen Gelenkverschleiß auszeichnet. Sie ist eine der häufigsten Ursachen für Behinderungen weltweit und kann verschiedenste Gelenke betreffen. Vermehrt tritt die Erkrankung im Kniegelenk auf und wird dort als Gonarthorse bezeichnet. Obwohl als Krankheit multifaktoriellen Ursprungs bekannt, besteht ein deutlicher Zusammenhang der Arthrose mit früheren Gelenkverletzungen, insbesondere Schäden am Bandapparat des Knies. Obwohl in der Literatur ausführlich sowohl über erhöhte anterior-posteriore Instabilität als auch die Genesung nach Bandrekonstruktionen berichtet wird, besteht kein Konsens hinsichtlich der Veränderungen der rotatorischen Laxizität sowie deren Einfluss auf die Entwicklung posttraumatischer Arthrose. Ursächlich dafür sind möglicherweise fehlende Objektivität und Genauigkeit bestehender Messverfahren. Um eine frühere und differenziertere Diagnose stellen zu können, bedarf es der Entwicklung eines zuverlässigen und genauen Messverfahrens. Im Zuge dieser Dissertation wurde daher eine Reihe von Studien durchgeführt, um ein klares Verständnis der passiven axialen rotatorischen Laxizität bei Patienten mit erhöhtem Gonarthroserisiko zu gewinnen. Zur Untersuchung der Eignung der Single Plane Fluoroskopie zur Bestimmung dieses Parameters wurde eingangs eine erste in-vitro-Studie durchgeführt. Die Ergebnisse zeigten eine hinreichende Genauigkeit, um klinisch-relevante Unterschiede feststellen zu können. Dies konnte in einer weiteren in-vitro-Studie bestätigt werden. Dabei wurden Kniepräparate vor und nach dem Durchtrennen des vorderen Kreuzbandes mit einem externen Moment belastet und die Laxizität untersucht. Es zeigte sich eine erhöhte axiale rotatorische Laxizität nach dem Durchtrennen des Ligaments. Zur objektiven und reproduzierbaren Untersuchung der tiobiofemoralen Rotation wurde ein Gerät, das die Einleitung von standardisierten Momenten ermöglicht, entwickelt, zertifiziert und mit der Single Plane Flouroskopie kombiniert. In einer in-vivo-Studie wurden invasive (fluoroskopie) und nicht-invasive (externe reflektive Positionsmarker) Messmethoden verglichen. Dabei wurde die tibiofemorale Rotation unter 0, 30, 60 und 90 Grad Knieflexion verglichen. Mit steigendem Beugewinkel konnte eine Zunahme der rotatorischen Laxizität gezeigt werden. Zwar wurde eine hohe Korrelation beider Messmethoden gefunden, durch den hohen RMS-Fehler der nicht-invasive Methode mussten jedoch Korrekturgleichungen eingeführt werden, um eine klinisch relevante Genauigkeit zu erreichen. Dabei konnte auch eine hohe Reliabilität des Gerätes (Knee Rotometer) gezeigt werden. Mit dem Ziel, ein Verständnis der intern wirkenden Kräfte bei passiver Belastung zu erlangen, wurde ein Proband mit einem telemetrischen Knieimplantat im Rotometer untersucht. Obwohl nur die Wechselwirkung zwischen den externen passiven Strukturen, der femoralen Komponente und den Inlays als auch nur ein einziger Proband untersucht wurde, zeigte sich ein deutlicher Einfluss des Beugewinkels auf die Lastverteilung und die rotatorische Laxizität. Ursächlich dafür sind unterschiedliche Bandspannungen und die geometrische Kongruenz des Implantats. Die Ergebnisse können als Beleg für das Zusammenspiel interner und externer passiver Strukturen bei der Stabilisierung des Kniegelenks interpretiert werden. An 13 Patienten mit bestätigter Ruptur des vorderen Kreuzbandes wurden im Anschluss Veränderungen der axialen rotatorischen Laxizität vor und nach der Rekonstruktion des Kreuzbandes untersucht. Signifikante Unterschiede in der rotatorischen Laxizität zwischen dem verletzten und dem gesunden Kontroll-Knie konnten bei 30 und 90 Grad Beugewinkel beobachtet werden. Drei Monate nach der Rekonstruktion wurde eine Minderung der internen rotatorischen Laxizität beobachtet, allerdings veränderte sich die Gesamtlaxizität nur gering. Der signifikante Unterschied im Vergleich zum gesunden Knie blieb bestehen. 12 Monate postoperativ konnte indes eine nahezu vollständige Wiederherstellung der Stabilität beobachtet werden. Die signifikant höhere Laxizität bei beiden Beugewinkeln 3 Monate postoperativ deutet auf anfänglich mangelnde postoperative Stabilität hin, möglicherweise verursacht durch verringerte mechanische Eigenschaften oder ungenügende Fixierung des Transplantates. Die deutliche Abnahme sowohl interner als auch externer Laxizität nach 12 Monaten weist auf eine zeitlich progressive Stabilisierung hin. Diese Verbesserung der Stabilität konnte auch bei der Untersuchung weiterer Parameter, wie der internen rotatorischen Steifigkeit und der dissipierten Energie, beobachtet werden. Die beobachteten Veränderungen der passiven rotatorischen Laxizität zeigen, dass die Single Bundle Rekonstruktion des vorderen Kreuzbandes erfolgreich die Stabiliät des Kniegelenks wiederherstellen kann. Diese Annahme konnte zusätzlich mithilfe der KT-1000 Arthrometer Analyse und der darin gezeigten Reduktion der anterior-posterioren Translation bestätigt werden. Die drei Monate postoperativ beobachtete Instabilität unterstreicht die Bedeutung der Reha, da bei einer frühen Rückkehr zu sportlichen Aktivitäten das Risiko einer erneuten Ruptur erhöht ist. Die routinemäßige postoperative klinische Untersuchung sollte um eine Analyse der rotatorischen Stabilität ergänzt werden, um neue Perspektiven bezüglich Ursachenfindung von Patientenunzufriedenheit als auch Evaluierung der Lernkurve junger Ärzte und Effektivitätssteigerung der klinischen Rehabilitation zu haben.As a degenerative disorder, osteoarthritis (OA) is one of the most common causes of disability in the world, affecting several joints in the human body, albeit with a higher rate in the knee joint. Considered as a disease of multifactorial etiology, osteoarthritis is also related with a history of previous joint injury, and particularly knee ligament damage. Among such ligament damages, the rupture of the anterior cruciate ligament (ACL) is one of the most frequent. Increased anterior-posterior instability after ACL rupture as well as recovery in anterior-posterior translation after ligament reconstruction has been reported in existing literature. However, changes in axial rotational laxity as well as its influence on post-traumatic degenerative OA remain unclear, possibly due to the lack of objectivity and accuracy concerning the measurement techniques used. Accordingly, the development of reliable and accurate measurement approaches is necessary to achieve an early diagnosis of pathological axial rotation. A series of studies have been conducted within this thesis to gain an understanding of passive axial rotational laxity in patients with higher risk of OA development. In order to achieve a proper quantification of this parameter, a detailed in-vitro study was firstly conducted to determine the accuracy and suitability of single plane fluoroscopy, which resulted in adequate accuracy of this technique to detect clinically relevant differences between groups. This was supported by a second in-vitro study in which intact and ACL resected knees were fluoroscopically assessed while external axial torques were applied, resulting in higher axial rotational laxity values in the knees without ACL. A device to achieve a controlled and objective application of external axial torques to the knee joint was designed, constructed and certified according to the german Medical Product Law. The controlled application of an external torque achieved with this device was subsequently combined with single plane fluoroscopy to gain an accurate and objective measurement of tibio-femoral axial rotation. The device (knee rotometer) was found to be highly reliable, as determined in an in-vivo study in which invasive (fluoroscopy) and non-invasive (external reflective markers) assessments of tibio-femoral axial rotation at 0, 30, 60 and 90 degrees of knee joint flexion were compared. Additionally, the measured internal and external axial laxity values proportionally increased with higher flexion angles in the fluoroscopic assessment, which is consistent with increasing laxity at higher flexion angles as expected. Although a strong correlation was found when comparing the two measurement techniques, the high root mean square (RMS) errors values found in the non-invasive technique required the determination of correction equations to reach a clinically relevant accuracy. In a further analysis, a subject with a telemetric knee joint implant was measured in the knee rotometer to gain an overview of the changes on the internal loading conditions during passive rotation. Although only the interaction between the external structures, the femoral component and the tibial insert geometry would play a role in this case and that the analysis is limited to only one subject, the observed changes in the internal loading conditions measured in the telemetric implant as well as the increase in axial rotational laxity measured with the fluoroscope showed evidence of the interaction of the internal and external passive structures in the stabilisation of the knee joint as well as its dependence on knee joint flexion. An investigation into the changes in axial rotational laxity after ligament injury and reconstruction was conducted in 13 subjects with confirmed ACL injury. Significant differences in rotational laxity were found between the injured and the healthy contralateral knees at 30 and 90° of knee flexion angles. After three months, a reduction of internal rotational laxity was observed, although the range of total laxity remained similar and significantly different from the healthy knees. However, after 12 months, a considerable restoration of rotational stability was observed towards the levels of the contralateral healthy controls. The significantly greater laxity observed at both knee flexion angles after three months (but not at 12 months) suggests an initial lack of post-operative stability, possibly due to the reduced mechanical properties or fixation stability of the graft tissue. After 12 months, remaining but reduced rotational laxity - both internally and externally - suggests a progressive stabilisation over time. Such changes were also observed in the progressive increase of the internal rotational stiffness, as well as the reduction in the energy dissipation. Although the efficacy of single bundle ACL reconstruction is still discussed controversially, the results in this thesis show evidence that this clinical procedure seems to be able to achieve an almost complete recovery in axial rotational stability in the longer term. A general stabilization was also confirmed by the reduction in anterior-posterior translation showed in the additional KT-1000 arthrometer analysis conducted. The instability observed at three months after reconstruction highlights the importance of properly undertaken rehabilitation programmes due to the high risk of re-rupture after early returning to sporting activities. As an addition to the routine postoperative clinical analysis, the objective and controlled analysis of axial rotational stability should then be included in these clinical routines in order to be able to identify possible negative changes in stability that could not be detected by the usual methods conducted. With this, new perspectives can be opened to properly identify post-operative patient´s dissatisfaction, to evaluate the learning process of young clinicians and to assess the effectiveness of clinical rehabilitation

Physiological joint line total knee arthroplasty designs are especially sensitive to rotational placement - A finite element analysis.

Mechanical and kinematical aligning techniques are the usual positioning methods during total knee arthroplasty. However, alteration of the physiological joint line and unbalanced medio-lateral load distribution are considered disadvantages in the mechanical and kinematical techniques, respectively. The aim of this study was to analyse the influence of the joint line on the strain and stress distributions in an implanted knee and their sensitivity to rotational mal-alignment. Finite element calculations were conducted to analyse the stresses in the PE-Inlay and the mechanical strains at the bone side of the tibia component-tibia bone interface during normal positioning of the components and internal and external mal-rotation of the tibial component. Two designs were included, a horizontal and a physiological implant. The loading conditions are based on internal knee joint loads during walking. A medialization of the stresses on the PE-Inlay was observed in the physiological implant in a normal position, accompanied by higher stresses in the mal-rotated positions. Within the tibia component-tibia bone interface, similar strain distributions were observed in both implant geometries in the normal position. However, a medialization of the strains was observed in the physiological implant in both mal-rotated conditions with greater bone volume affected by higher strains. Although evident changes due to mal-rotation were observed, the stresses do not suggest a local plastic deformation of the PE-Inlay. The strains values within most of the tibia component-tibia bone interface were in the physiological strain zone and no significant bone changes would be expected. The physiological cut on the articular aspect showed no detrimental effect compared to the horizontal implant