TY - JOUR A1 - Wang, Chenglong A1 - Stöckl, Sabine A1 - Li, Shushan A1 - Herrmann, Marietta A1 - Lukas, Christoph A1 - Reinders, Yvonne A1 - Sickmann, Albert A1 - Grässel, Susanne T1 - Effects of extracellular vesicles from osteogenic differentiated human BMSCs on osteogenic and adipogenic differentiation capacity of naïve human BMSCs JF - Cells N2 - Osteoporosis, or steroid-induced osteonecrosis of the hip, is accompanied by increased bone marrow adipogenesis. Such a disorder of adipogenic/osteogenic differentiation, affecting bone-marrow-derived mesenchymal stem cells (BMSCs), contributes to bone loss during aging. Here, we investigated the effects of extracellular vesicles (EVs) isolated from human (h)BMSCs during different stages of osteogenic differentiation on the osteogenic and adipogenic differentiation capacity of naïve (undifferentiated) hBMSCs. We observed that all EV groups increased viability and proliferation capacity and suppressed the apoptosis of naïve hBMSCs. In particular, EVs derived from hBMSCs at late-stage osteogenic differentiation promoted the osteogenic potential of naïve hBMSCs more effectively than EVs derived from naïve hBMSCs (naïve EVs), as indicated by the increased gene expression of COL1A1 and OPN. In contrast, the adipogenic differentiation capacity of naïve hBMSCs was inhibited by treatment with EVs from osteogenic differentiated hBMSCs. Proteomic analysis revealed that osteogenic EVs and naïve EVs contained distinct protein profiles, with pro-osteogenic and anti-adipogenic proteins encapsulated in osteogenic EVs. We speculate that osteogenic EVs could serve as an intercellular communication system between bone- and bone-marrow adipose tissue, for transporting osteogenic factors and thus favoring pro-osteogenic processes. Our data may support the theory of an endocrine circuit with the skeleton functioning as a ductless gland. KW - extracellular vesicles KW - mesenchymal stem cells KW - osteogenic potential KW - osteogenic differentiation KW - adipogenic differentiation KW - ECM remodeling KW - bone regeneration Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286112 SN - 2073-4409 VL - 11 IS - 16 ER - TY - JOUR A1 - Nedopil, Alexander J. A1 - Howell, Stephen M. A1 - Hull, Maury L. T1 - A TKA insert with a lateral flat articular surface maximizes external and internal tibial orientations without anterior lift-off relative to low- and ultracongruent surfaces JF - Journal of Personalized Medicine N2 - Background: In total knee arthroplasty (TKA), inserts can have different levels of medial and lateral congruency determined by the acuteness of the upslopes of the anterior and posterior articular surfaces. The present study evaluated an insert with different levels of lateral congruency and a medial ball-in-socket congruency to test the hypothesis that a lateral flat (F) insert maximizes external tibial orientation at extension and internal orientation at 90° flexion and lowers the incidence of anterior lift-off relative to low-congruent (LC) and ultracongruent (UC) lateral inserts. Methods: Two surgeons treated 23 patients with unrestricted caliper-verified kinematic alignment (KA) and posterior cruciate ligament (PCL) retention. They randomly trialed inserts with a medial radial dial that functioned as a built-in goniometer by measuring the tibial orientation relative to a sagittal line on the femoral trial component. Anterior lift-off of the insert from the baseplate indicated PCL tightness. Results: The F insert’s mean of 9° of external tibial orientation was higher than that of the LC (5°, p < 0.0001) and UC inserts (2°, p < 0.0001). The −13° of internal tibial orientation at 90° flexion was higher than that of the LC (−9°, p < 0.0001) and UC inserts (−7°, p < 0.0001). The 0% incidence of anterior lift-off was less than that of the LC (26%) and UC inserts (57%) (p < 0.0001). Conclusions: Surgeons and implant manufacturers should know that adding congruency to the lateral articular surface limits external tibial orientation in extension and internal tibial orientation at 90° flexion and overtightens the PCL. These rotational limitations and flexion space tightness can adversely affect patellofemoral tracking and knee flexion. KW - total knee arthroplasty KW - kinematic alignment KW - implant design KW - PCL retention KW - congruency Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286142 SN - 2075-4426 VL - 12 IS - 8 ER - TY - JOUR A1 - Nedopil, Alexander J. A1 - Howell, Stephen M. A1 - Hull, Maury L. T1 - Measurement of tibial orientation helps select the optimal insert thickness to personalize PCL tension in a medial ball-in-socket TKA JF - Journal of Personalized Medicine N2 - As the conformity of a medial ball-in-socket total knee arthroplasty (TKA) provides intrinsic anterior-posterior (A-P) stability, surgeons cannot rely on the manual examination of sagittal laxity to identify the optimal insert thickness. Instead, the present study determined whether measuring tibial axial orientation in extension and 90° flexion with an insert goniometer could identify the optimal thickness that, when implanted, provides high postoperative function. In twenty-two patients that underwent unrestricted caliper-verified kinematic alignment (KA) with a PCL retaining implant, two surgeons measured tibial orientation in extension and 90° flexion with 10, 11, 12, and 13 mm thick insert goniometers. Each TKA had one insert thickness that restored either the maximum external tibial orientation in extension, the maximum internal tibial orientation at 90° flexion, or both relative to 1 mm thinner and thicker inserts. In addition, the 6-month median [interquartile range] Forgotten Joint Score of 73 (54–87) and Oxford Knee Score of 42 (38–45) indicated high satisfaction and function. In conclusion, surgeons using a medial ball-in-socket TKA design can measure external tibial orientation in extension and internal tibial orientation at 90° flexion with an insert goniometer. Furthermore, implanting an insert with the thickness that provided the maximum orientation values resulted in high postoperative function, thereby personalizing PCL tension. KW - posterior cruciate ligament KW - tibial rotation KW - medial pivot KW - total knee arthroplasty KW - kinematic alignment Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-286232 SN - 2075-4426 VL - 12 IS - 9 ER - TY - JOUR A1 - Dhaliwal, Anand A1 - Zamora, Tomas A1 - Nedopil, Alexander J. A1 - Howell, Stephen M. A1 - Hull, Maury L. T1 - Six commonly used postoperative radiographic alignment parameters do not predict clinical outcome scores after unrestricted caliper-verified kinematically aligned TKA JF - Journal of Personalized Medicine N2 - Background: Unrestricted caliper-verified kinematically aligned (KA) TKA restores patient’s prearthritic coronal and sagittal alignments, which have a wide range containing outliers that concern the surgeon practicing mechanical alignment (MA). Therefore, knowing which radiographic parameters are associated with dissatisfaction could help a surgeon decide whether to rely on them as criteria for revising an unhappy patient with a primary KA TKA using MA principles. Hence, we determined whether the femoral mechanical angle (FMA), hip–knee–ankle angle (HKAA), tibial mechanical angle (TMA), tibial slope angle (TSA), and the indicators of patellofemoral tracking, including patella tilt angle (PTA) and the lateral undercoverage of the trochlear resection (LUCTR), are associated with clinical outcome scores. Methods: Forty-three patients with a CT scan and skyline radiograph after a KA TKA with PCL retention and medial stabilized design were analyzed. Linear regression determined the strength of the association between the FMA, HKA angle, PTS, PTA, and LUCTR and the forgotten joint score (FJS), Oxford knee score (OKS), and KOOS Jr score obtained at a mean of 23 months. Results: There was no correlation between the FMA (range 2° varus to −10° valgus), HKAA (range 10° varus to −9° valgus), TMA (range 10° varus to −0° valgus), TSA (range 14° posterior to −4° anterior), PTA (range, −10° medial to 14° lateral), and the LUCTR resection (range 2 to 9 mm) and the FJS (median 83), the OKS (median 44), and the KOOS Jr (median 85) (r = 0.000 to 0.079). Conclusions: Surgeons should be cautious about using postoperative FMA, HKAA, TMA, TSA, PTA, and LUCTR values within the present study’s reported ranges to explain success and dissatisfaction after KA TKA. KW - total knee arthroplasty KW - kinematic alignment KW - reoperation KW - revision KW - phenotype Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-288186 SN - 2075-4426 VL - 12 IS - 9 ER - TY - JOUR A1 - Sappey-Marinier, Elliot A1 - Howell, Stephen M. A1 - Nedopil, Alexander J. A1 - Hull, Maury L. T1 - The trochlear groove of a femoral component designed for kinematic alignment is lateral to the quadriceps line of force and better laterally covers the anterior femoral resection than a mechanical alignment design JF - Journal of Personalized Medicine N2 - Background: A concern about kinematically aligned (KA) total knee arthroplasty (TKA) is that it relies on femoral components designed for mechanical alignment (MAd-FC) that could affect patellar tracking, in part, because of a trochlear groove orientation that is typically 6° from vertical. KA sets the femoral component coincident to the patient’s pre-arthritic distal and posterior femoral joint lines and restores the Q-angle, which varies widely. Relative to KA and the native knee, aligning the femoral component with MA changes most distal joint lines and Q-angles, and rotates the posterior joint line externally laterally covering the anterior femoral resection. Whether switching from a MAd- to a KAd-FC with a wider trochlear groove orientation of 20.5° from vertical results in radiographic measures known to promote patellar tracking is unknown. The primary aim was to determine whether a KAd-FC sets the trochlear groove lateral to the quadriceps line of force (QLF), better laterally covers the anterior femoral resection, and reduces lateral patella tilt relative to a MAd-FC. The secondary objective was to determine at six weeks whether the KAd-FC resulted in a higher complication rate, less knee extension and flexion, and lower clinical outcomes. Methods: Between April 2019 and July 2022, two surgeons performed sequential bilateral unrestricted caliper-verified KA TKA with manual instruments on thirty-six patients with a KAd- and MAd-FC in opposite knees. An observer measured the angle between a line best-fit to the deepest valley of the trochlea and a line representing the QLF that indicated the patient’s Q-angle. When the trochlear groove was lateral or medial relative to the QLF, the angle is denoted + or −, and the femoral component included or excluded the patient’s Q-angle, respectively. Software measured the lateral undercoverage of the anterior femoral resection on a Computed Tomography (CT) scan, and the patella tilt angle (PTA) on a skyline radiograph. Complications, knee extension and flexion measurements, Oxford Knee Score, KOOS Jr, and Forgotten Joint Score were recorded pre- and post-operatively (at 6 weeks). A paired Student’s T-test determined the difference between the KA TKAs with a KAd-FC and MAd-FC with a significance set at p < 0.05. Results: The final analysis included thirty-five patients. The 20.5° trochlear groove of the KAd-FC was lateral to the QLF in 100% (15 ± 3°) of TKAs, which was greater than the 69% (1 ± 3°) lateral to the QLF with the 6° trochlear groove of the MAd-FC (p < 0.001). The KAd-FC’s 2 ± 1.9 mm lateral undercoverage of the anterior femoral resection was less than the 4.4 ± 1.5 mm for the MAd-FC (p < 0.001). The PTA, complication rate, knee extension and flexion, and clinical outcome measures did not differ between component designs. Conclusions: The KA TKA with a KAd-FC resulted in a trochlear groove lateral to the QLF that included the Q-angle in all patients, and negligible lateral undercoverage of the anterior femoral resection. These newly described radiographic parameters could be helpful when investigating femoral components designed for KA with the intent of promoting patellofemoral kinematics. KW - total knee arthroplasty KW - lateral trochlear undercoverage KW - prosthetic design KW - kinematic alignment KW - patellofemoral relationship Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-290482 SN - 2075-4426 VL - 12 IS - 10 ER - TY - JOUR A1 - Eidmann, Annette A1 - Eisert, Marius A1 - Rudert, Maximilian A1 - Stratos, Ioannis T1 - Influence of Vitamin D and C on bone marrow edema syndrome — A scoping review of the literature JF - Journal of Clinical Medicine N2 - Bone marrow edema syndrome (BMES) is a rare disease with a largely unknown etiology. The aim of this scoping review is to systematically evaluate and combine the available evidence about vitamin D and C and BMES. The analysis of the manuscripts was based on country of origin, number of patients, gender, study type, epidemiology, localization, bone mineral density measurements, vitamin status and therapy. Sixty studies were included. The overall number of patients was 823 with a male-to-female ratio of 1.55:1 and a mean age of 40.9 years. Studies were very heterogeneous and of diverging scientific scope with a weak level of evidence. The hip was the most affected joint, followed by the foot and ankle and the knee; 18.3% of patients suffered from multifocal BMES. Sixteen studies reported on vitamin D levels, resulting in a high prevalence of vitamin D deficiency (47%) and insufficiency (17.9%) among BMES patients. Three BME manuscripts were associated with vitamin C deficiency. Current therapeutic interventions include conservative measures (mainly unloading), various osteoactive drugs and iloprost. In summary, data about BMES in association with vitamin status is limited. A causal relationship between vitamin D or vitamin C status, osteopenia, and BMES cannot be determined from the existing literature. KW - lower extremity KW - regional transient osteoporosis KW - bone marrow edema KW - vitamin D KW - vitamin C KW - scoping review Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-297356 SN - 2077-0383 VL - 11 IS - 22 ER - TY - BOOK A1 - Wang, Wen T1 - Validation of shRNA clones for gene silencing in 293FT cells N2 - ... N2 - The goal of the project was to establish knock down of mRNA in human mesenchymal stem cells. Since these cells are difficult to transfect, a viral approach is needed to achieve sufficient expression of e. g. shRNA in a high percentage of cells to allow for an efficient silencing of corresponding mRNAs. For this purpose for every gene product of interest, a number of shRNA clones have to be tested to detect an individual shRNA with sufficient efficacy. Lentiviral systems for shRNA approaches have recently become available. The principal advantage of the lentiviral system is that it allows gene silencing in nondividing cells and therefore expands the usefulness of the RNAi-based gene silencing system. Lentivirus-delivered shRNAs are capable of specific, highly stable and functional silencing of gene expression in a variety of cell types. Since the viral transfection of MSCs is a time consuming process that involves transfection of 293 FT cells plus transduction of target cells, for this thesis the following approach was chosen: genes of interest were checked for expression in 293FT cells by RT-PCR. These gene products can be silenced in 293FT cells simply by transfection of shRNA clones and efficacy was subsequently tested by RT-PCR. Beyond this thesis then the project can proceed with effective clones to transduce primary MSCs with individual shRNA clones identified as effective silencing tool in this thesis. KW - shRNA KW - RNAi KW - .................................................................... KW - shRNA KW - RNAi Y1 - 2008 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-25955 N1 - Aus rechtlichen Gründen wurde der Zugriff auf den Volltext zu diesem Dokument gesperrt. ER - TY - JOUR A1 - Rak, Dominik A1 - Klann, Lukas A1 - Heinz, Tizian A1 - Anderson, Philip A1 - Stratos, Ioannis A1 - Nedopil, Alexander J. A1 - Rudert, Maximilian T1 - Influence of mechanical alignment on functional knee phenotypes and clinical outcomes in primary TKA: a 1-year prospective analysis JF - Journal of Personalized Medicine N2 - In total knee arthroplasty (TKA), functional knee phenotypes are of interest regarding surgical alignment strategies. Functional knee phenotypes were introduced in 2019 and consist of limb, femoral, and tibial phenotypes. The hypothesis of this study was that mechanically aligned (MA) TKA changes preoperative functional phenotypes, which decreases the 1-year Forgotten Joint (FJS) and Oxford Knee Score (OKS) and increases the 1-year WOMAC. All patients included in this study had end-stage osteoarthritis and were treated with a primary MA TKA, which was supervised by four academic knee arthroplasty specialists. To determine the limb, femoral, and tibial phenotype, a long-leg radiograph (LLR) was imaged preoperatively and two to three days after TKA. FJS, OKS, and WOMAC were obtained 1 year after TKA. Patients were categorized using the change in functional limb, femoral, and tibial phenotype measured on LLR, and the scores were compared between the different categories. A complete dataset of preoperative and postoperative scores and radiographic images could be obtained for 59 patients. 42% of these patients had a change of limb phenotype, 41% a change of femoral phenotype, and 24% a change of tibial phenotype of more than ±1 relative to the preoperative phenotype. Patients with more than ±1 change of limb phenotype had significantly lower median FJS (27 points) and OKS (31 points) and higher WOMAC scores (30 points) relative to the 59-, 41-, and 4-point scores of those with a 0 ± 1 change (p < 0.0001 to 0.0048). Patients with a more than ±1 change of femoral phenotype had significantly lower median FJS (28 points) and OKS (32 points) and higher WOMAC scores (24 points) relative to the 69-, 40-, and 8-point scores of those with a 0 ± 1 change (p < 0.0001). A change in tibial phenotype had no effect on the FJS, OKS, and WOMAC scores. Surgeons performing MA TKA could consider limiting coronal alignment corrections of the limb and femoral joint line to within one phenotype to reduce the risk of low patient-reported satisfaction and function at 1-year. KW - knee arthroplasty KW - mechanical alignment KW - clinical outcome KW - phenotype KW - level of evidence III KW - prospective study Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-313646 SN - 2075-4426 VL - 13 IS - 5 ER - TY - JOUR A1 - Weber, Patrick A1 - Beck, Melina A1 - Klug, Michael A1 - Klug, Andreas A1 - Klug, Alexander A1 - Glowalla, Claudio A1 - Gollwitzer, Hans T1 - Survival of patient-specific unicondylar knee replacement JF - Journal of Personalized Medicine N2 - Unicompartmental knee arthroplasty (UKA) in isolated medial or lateral osteoarthritis leads to good clinical results. However, revision rates are higher in comparison to total knee arthroplasty (TKA). One reason is suboptimal fitting of conventional off-the-shelf prostheses, and major overhang of the tibial component over the bone has been reported in up to 20% of cases. In this retrospective study, a total of 537 patient-specific UKAs (507 medial prostheses and 30 lateral prostheses) that had been implanted in 3 centers over a period of 10 years were analyzed for survival, with a minimal follow-up of 1 year (range 12 to 129 months). Furthermore, fitting of the UKAs was analyzed on postoperative X-rays, and tibial overhang was quantified. A total of 512 prostheses were available for follow-up (95.3%). Overall survival rate (medial and lateral) of the prostheses after 5 years was 96%. The 30 lateral UKAs showed a survival rate of 100% at 5 years. The tibial overhang of the prosthesis was smaller than 1 mm in 99% of cases. In comparison to the reported results in the literature, our data suggest that the patient-specific implant design used in this study is associated with an excellent midterm survival rate, particularly in the lateral knee compartment, and confirms excellent fitting. KW - unicompartmental knee arthroplasty KW - osteoarthritis KW - patient-specific implant KW - partial knee arthroplasty KW - patient-specific instruments Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-313650 SN - 2075-4426 VL - 13 IS - 4 ER - TY - JOUR A1 - Trivanovic, Drenka A1 - Volkmann, Noah A1 - Stoeckl, Magdalena A1 - Tertel, Tobias A1 - Rudert, Maximilian A1 - Giebel, Bernd A1 - Herrmann, Marietta T1 - Enhancement of immunosuppressive activity of mesenchymal stromal cells by platelet-derived factors is accompanied by apoptotic priming JF - Stem Cell Reviews and Reports N2 - The pro-inflammatory phase of bone healing, initiated by platelet activation and eventually hematoma formation, impacts bone marrow mesenchymal stromal cells (MSCs) in unknown ways. Here, we created platelet-rich plasma (PRP) hydrogels to study how platelet-derived factors modulate functional properties of encapsulated MSCs in comparison to a non-inflammatory fibrin (FBR) hydrogel environment. MSCs were isolated from human bone marrow, while PRP was collected from pooled apheresis thrombocyte concentrates and used for hydrogel preparation. After their encapsulation in hydrogels for 72 h, retrieved MSCs were analyzed for immunomodulatory activities, apoptosis, stem cell properties, senescence, CD9\(^+\), CD63\(^+\) and CD81\(^+\) extracellular vesicle (EV) release, and metabolism-related changes. PRP-hydrogels stimulated immunosuppressive functions of MSCs, along with their upregulated susceptibility to cell death in communication with PBMCs and augmented caspase 3/7 activity. We found impaired clonal growth and cell cycle progression, and more pronounced β-galactosidase activity as well as accumulation of LC3-II-positive vacuoles in PRP-MSCs. Stimuli derived from PRP-hydrogels upregulated AKT and reduced mTOR phosphorylation in MSCs, which suggests an initiation of survival-related processes. Our results showed that PRP-hydrogels might represent a metabolically stressful environment, inducing acidification of MSCs, reducing polarization of the mitochondrial membrane and increasing lipid accumulation. These features were not detected in FBR-MSCs, which showed reduced CD63\(^+\) and CD81\(^+\) EV production and maintained clonogenicity. Our data revealed that PRP-derived hematoma components cause metabolic adaptation of MSCs followed by increased immune regulatory functions. For the first time, we showed that PRP stimuli represent a survival challenge and “apoptotic priming” that are detrimental for stem cell-like growth of MSCs and important for their therapeutic consideration. KW - hematoma KW - platelet-rich plasma KW - fibrin KW - mesenchymal stromal cells KW - immunomodulation KW - apoptosis KW - autophagy KW - senescence KW - extracellular vesicles KW - metabolism Y1 - 2023 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-324669 VL - 19 IS - 3 ER -