@article{WangStoecklLietal.2022, author = {Wang, Chenglong and St{\"o}ckl, Sabine and Li, Shushan and Herrmann, Marietta and Lukas, Christoph and Reinders, Yvonne and Sickmann, Albert and Gr{\"a}ssel, Susanne}, title = {Effects of extracellular vesicles from osteogenic differentiated human BMSCs on osteogenic and adipogenic differentiation capacity of na{\"i}ve human BMSCs}, series = {Cells}, volume = {11}, journal = {Cells}, number = {16}, issn = {2073-4409}, doi = {10.3390/cells11162491}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-286112}, year = {2022}, abstract = {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 na{\"i}ve (undifferentiated) hBMSCs. We observed that all EV groups increased viability and proliferation capacity and suppressed the apoptosis of na{\"i}ve hBMSCs. In particular, EVs derived from hBMSCs at late-stage osteogenic differentiation promoted the osteogenic potential of na{\"i}ve hBMSCs more effectively than EVs derived from na{\"i}ve hBMSCs (na{\"i}ve EVs), as indicated by the increased gene expression of COL1A1 and OPN. In contrast, the adipogenic differentiation capacity of na{\"i}ve hBMSCs was inhibited by treatment with EVs from osteogenic differentiated hBMSCs. Proteomic analysis revealed that osteogenic EVs and na{\"i}ve 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.}, language = {en} } @article{NedopilHowellHull2022, author = {Nedopil, Alexander J. and Howell, Stephen M. and Hull, Maury L.}, title = {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}, series = {Journal of Personalized Medicine}, volume = {12}, journal = {Journal of Personalized Medicine}, number = {8}, issn = {2075-4426}, doi = {10.3390/jpm12081274}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-286142}, year = {2022}, abstract = {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.}, language = {en} } @article{NedopilHowellHull2022, author = {Nedopil, Alexander J. and Howell, Stephen M. and Hull, Maury L.}, title = {Measurement of tibial orientation helps select the optimal insert thickness to personalize PCL tension in a medial ball-in-socket TKA}, series = {Journal of Personalized Medicine}, volume = {12}, journal = {Journal of Personalized Medicine}, number = {9}, issn = {2075-4426}, doi = {10.3390/jpm12091427}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-286232}, year = {2022}, abstract = {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.}, language = {en} } @article{DhaliwalZamoraNedopiletal.2022, author = {Dhaliwal, Anand and Zamora, Tomas and Nedopil, Alexander J. and Howell, Stephen M. and Hull, Maury L.}, title = {Six commonly used postoperative radiographic alignment parameters do not predict clinical outcome scores after unrestricted caliper-verified kinematically aligned TKA}, series = {Journal of Personalized Medicine}, volume = {12}, journal = {Journal of Personalized Medicine}, number = {9}, issn = {2075-4426}, doi = {10.3390/jpm12091468}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-288186}, year = {2022}, abstract = {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.}, language = {en} } @article{SappeyMarinierHowellNedopiletal.2022, author = {Sappey-Marinier, Elliot and Howell, Stephen M. and Nedopil, Alexander J. and Hull, Maury L.}, title = {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}, series = {Journal of Personalized Medicine}, volume = {12}, journal = {Journal of Personalized Medicine}, number = {10}, issn = {2075-4426}, doi = {10.3390/jpm12101724}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-290482}, year = {2022}, abstract = {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.}, language = {en} } @article{EidmannEisertRudertetal.2022, author = {Eidmann, Annette and Eisert, Marius and Rudert, Maximilian and Stratos, Ioannis}, title = {Influence of Vitamin D and C on bone marrow edema syndrome — A scoping review of the literature}, series = {Journal of Clinical Medicine}, volume = {11}, journal = {Journal of Clinical Medicine}, number = {22}, issn = {2077-0383}, doi = {10.3390/jcm11226820}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-297356}, year = {2022}, abstract = {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.}, language = {en} } @book{Wang2008, author = {Wang, Wen}, title = {Validation of shRNA clones for gene silencing in 293FT cells}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-25955}, publisher = {Universit{\"a}t W{\"u}rzburg}, year = {2008}, abstract = {...}, subject = {shRNA}, language = {en} } @article{RakKlannHeinzetal.2023, author = {Rak, Dominik and Klann, Lukas and Heinz, Tizian and Anderson, Philip and Stratos, Ioannis and Nedopil, Alexander J. and Rudert, Maximilian}, title = {Influence of mechanical alignment on functional knee phenotypes and clinical outcomes in primary TKA: a 1-year prospective analysis}, series = {Journal of Personalized Medicine}, volume = {13}, journal = {Journal of Personalized Medicine}, number = {5}, issn = {2075-4426}, doi = {10.3390/jpm13050778}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-313646}, year = {2023}, abstract = {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.}, language = {en} } @article{WeberBeckKlugetal.2023, author = {Weber, Patrick and Beck, Melina and Klug, Michael and Klug, Andreas and Klug, Alexander and Glowalla, Claudio and Gollwitzer, Hans}, title = {Survival of patient-specific unicondylar knee replacement}, series = {Journal of Personalized Medicine}, volume = {13}, journal = {Journal of Personalized Medicine}, number = {4}, issn = {2075-4426}, doi = {10.3390/jpm13040665}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-313650}, year = {2023}, abstract = {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.}, language = {en} } @article{TrivanovicVolkmannStoeckletal.2023, author = {Trivanovic, Drenka and Volkmann, Noah and Stoeckl, Magdalena and Tertel, Tobias and Rudert, Maximilian and Giebel, Bernd and Herrmann, Marietta}, title = {Enhancement of immunosuppressive activity of mesenchymal stromal cells by platelet-derived factors is accompanied by apoptotic priming}, series = {Stem Cell Reviews and Reports}, volume = {19}, journal = {Stem Cell Reviews and Reports}, number = {3}, doi = {10.1007/s12015-022-10471-4}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-324669}, pages = {713-733}, year = {2023}, abstract = {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.}, language = {en} }