TY - JOUR A1 - Ebert, Regina A1 - Weissenberger, Manuel A1 - Braun, Clemens A1 - Wagenbrenner, Mike A1 - Herrmann, Marietta A1 - Müller‐Deubert, Sigrid A1 - Krug, Melanie A1 - Jakob, Franz A1 - Rudert, Maximilian T1 - Impaired regenerative capacity and senescence‐associated secretory phenotype in mesenchymal stromal cells from samples of patients with aseptic joint arthroplasty loosening JF - Journal of Orthopaedic Research N2 - Aseptic loosening of total hip and knee joint replacements is the most common indication for revision surgery after primary hip and knee arthroplasty. Research suggests that exposure and uptake of wear by mesenchymal stromal cells (MSC) and macrophages results in the secretion of proinflammatory cytokines and local osteolysis, but also impaired cell viability and regenerative capacity of MSC. Therefore, this in vitro study compared the regenerative and differentiation capacity of MSC derived from patients undergoing primary total hip arthroplasty (MSCprim) to MSC derived from patients undergoing revision surgery after aseptic loosening of total hip and knee joint implants (MSCrev). Regenerative capacity was examined by measuring the cumulative population doubling (CPD) in addition to the number of passages until cells stopped proliferating. Osteogenesis and adipogenesis in monolayer cultures were assessed using histological stainings. Furthermore, RT‐PCR was performed to evaluate the relative expression of osteogenic and adipogenic marker genes as well as the expression of markers for a senescence‐associated secretory phenotype (SASP). MSCrev possessed a limited regenerative capacity in comparison to MSCprim. Interestingly, MSCrev also showed an impaired osteogenic and adipogenic differentiation capacity compared to MSCprim and displayed a SASP early after isolation. Whether this is the cause or the consequence of the aseptic loosening of total joint implants remains unclear. Future research should focus on the identification of specific cell markers on MSCprim, which may influence complication rates such as aseptic loosening of total joint arthroplasty to further individualize and optimize total joint arthroplasty. KW - aseptic loosening KW - mesenchymal stromal cells KW - regenerative capacity KW - senescence‐associated secretory phenotype Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-238963 VL - 40 IS - 2 SP - 513 EP - 523 ER - TY - JOUR A1 - Jakuscheit, Axel A1 - Schaefer, Nina A1 - Roedig, Johannes A1 - Luedemann, Martin A1 - Hertzberg-Boelch, Sebastian Philipp von A1 - Weissenberger, Manuel A1 - Schmidt, Karsten A1 - Holzapfel, Boris Michael A1 - Rudert, Maximilian T1 - Modifiable individual risks of perioperative blood transfusions and acute postoperative complications in total hip and knee arthroplasty JF - Journal of Personalized Medicine N2 - Background: The primary aim of this study was to identify modifiable patient-related predictors of blood transfusions and perioperative complications in total hip and knee arthroplasty. Individual predictor-adjusted risks can be used to define preoperative treatment thresholds. Methods: We performed this retrospective monocentric study in orthopaedic patients who underwent primary total knee or hip arthroplasty. Multivariate logistic regression models were used to assess the predictive value of patient-related characteristics. Predictor-adjusted individual risks of blood transfusions and the occurrence of any perioperative adverse event were calculated for potentially modifiable risk factors. Results: 3754 patients were included in this study. The overall blood transfusion and complication rates were 4.8% and 6.4%, respectively. Haemoglobin concentration (Hb, p < 0.001), low body mass index (BMI, p < 0.001) and estimated glomerular filtration rate (eGFR, p = 0.004) were the strongest potentially modifiable predictors of a blood transfusion. EGFR (p = 0.001) was the strongest potentially modifiable predictor of a complication. Predictor-adjusted risks of blood transfusions and acute postoperative complications were calculated for Hb and eGFR. Hb = 12.5 g/dL, BMI = 17.6 kg/m\(^2\), and eGFR = 54 min/mL were associated, respectively, with a 10% risk of a blood transfusion, eGFR = 59 mL/min was associated with a 10% risk of a complication. Conclusion: The individual risks for blood transfusions and acute postoperative complications are strongly increased in patients with a low preoperative Hb, low BMI or low eGFR. We recommend aiming at a preoperative Hb ≥ 13g/dL, an eGFR ≥ 60 mL/min and to avoid a low BMI. Future studies must show if a preoperative increase of eGFR and BMI is feasible and truly beneficial. KW - patient blood management KW - total joint arthroplasty KW - haemoglobin KW - perioperative management Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-250290 SN - 2075-4426 VL - 11 IS - 11 ER - TY - JOUR A1 - Wagenbrenner, Mike A1 - Mayer-Wagner, Susanne A1 - Rudert, Maximilian A1 - Holzapfel, Boris Michael A1 - Weissenberger, Manuel T1 - Combinations of hydrogels and mesenchymal stromal cells (MSCs) for cartilage tissue engineering — a review of the literature JF - Gels N2 - Cartilage offers limited regenerative capacity. Cell-based approaches have emerged as a promising alternative in the treatment of cartilage defects and osteoarthritis. Due to their easy accessibility, abundancy, and chondrogenic potential mesenchymal stromal cells (MSCs) offer an attractive cell source. MSCs are often combined with natural or synthetic hydrogels providing tunable biocompatibility, biodegradability, and enhanced cell functionality. In this review, we focused on the different advantages and disadvantages of various natural, synthetic, and modified hydrogels. We examined the different combinations of MSC-subpopulations and hydrogels used for cartilage engineering in preclinical and clinical studies and reviewed the effects of added growth factors or gene transfer on chondrogenesis in MSC-laden hydrogels. The aim of this review is to add to the understanding of the disadvantages and advantages of various combinations of MSC-subpopulations, growth factors, gene transfers, and hydrogels in cartilage engineering. KW - hydrogels KW - osteoarthritis KW - cartilage defects KW - MSCs KW - cartilage regeneration KW - tissue engineering Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-250177 SN - 2310-2861 VL - 7 IS - 4 ER - TY - JOUR A1 - Weissenberger, Manuel A1 - Weissenberger, Manuela H. A1 - Wagenbrenner, Mike A1 - Heinz, Tizian A1 - Reboredo, Jenny A1 - Holzapfel, Boris M. A1 - Rudert, Maximilian A1 - Groll, Jürgen A1 - Evans, Christopher H. A1 - Steinert, Andre F. T1 - Different types of cartilage neotissue fabricated from collagen hydrogels and mesenchymal stromal cells via SOX9, TGFB1 or BMP2 gene transfer JF - PLoS One N2 - Objective As native cartilage consists of different phenotypical zones, this study aims to fabricate different types of neocartilage constructs from collagen hydrogels and human mesenchymal stromal cells (MSCs) genetically modified to express different chondrogenic factors. Design Human MSCs derived from bone-marrow of osteoarthritis (OA) hips were genetically modified using adenoviral vectors encoding sex-determining region Y-type high-mobility-group-box (SOX)9,transforming growth factor beta (TGFB) 1or bone morphogenetic protein (BMP) 2cDNA, placed in type I collagen hydrogels and maintained in serum-free chondrogenic media for three weeks. Control constructs contained unmodified MSCs or MSCs expressing GFP. The respective constructs were analyzed histologically, immunohistochemically, biochemically, and by qRT-PCR for chondrogenesis and hypertrophy. Results Chondrogenesis in MSCs was consistently and strongly induced in collagen I hydrogels by the transgenesSOX9,TGFB1andBMP2as evidenced by positive staining for proteoglycans, chondroitin-4-sulfate (CS4) and collagen (COL) type II, increased levels of glycosaminoglycan (GAG) synthesis, and expression of mRNAs associated with chondrogenesis. The control groups were entirely non-chondrogenic. The levels of hypertrophy, as judged by expression of alkaline phosphatase (ALP) and COL X on both the protein and mRNA levels revealed different stages of hypertrophy within the chondrogenic groups (BMP2>TGFB1>SOX9). Conclusions Different types of neocartilage with varying levels of hypertrophy could be generated from human MSCs in collagen hydrogels by transfer of genes encoding the chondrogenic factorsSOX9,TGFB1andBMP2. This technology may be harnessed for regeneration of specific zones of native cartilage upon damage. KW - stem cells KW - in vitro KW - chondrogenic differentiation KW - repair KW - chondrocytes KW - transplantation KW - stimulation KW - scaffolds KW - defects KW - therapy Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230494 VL - 15 IS - 8 ER - TY - JOUR A1 - Horas, Konstantin A1 - van Herck, Ulrike A1 - Maier, Gerrit S. A1 - Maus, Uwe A1 - Harrasser, Norbert A1 - Jakob, Franz A1 - Weissenberger, Manuel A1 - Arnholdt, Jörg A1 - Holzapfel, Boris M. A1 - Rudert, Maximilian T1 - Does vitamin D deficiency predict tumour malignancy in patients with bone tumours? Data from a multi-center cohort analysis JF - Journal of Bone Oncology N2 - Vitamin D deficiency is a global health concern that is estimated to afflict over one billion people globally. The major role of vitamin D is that of a regulator of calcium and phosphate metabolism, thus, being essential for proper bone mineralisation. Concomitantly, vitamin D is known to exert numerous extra-skeletal actions. For example, it has become evident that vitamin D has direct anti-proliferative, pro-differentiation and pro-apoptotic actions on cancer cells. Hence, vitamin D deficiency has been associated with increased cancer risk and worse prognosis in several malignancies. We have recently demonstrated that vitamin D deficiency promotes secondary cancer growth in bone. These findings were partly attributable to an increase in bone remodelling but also through direct effects of vitamin D on cancer cells. To date, very little is known about vitamin D status of patients with bone tumours in general. Thus, the objective of this study was to assess vitamin D status of patients with diverse bone tumours. Moreover, the aim was to elucidate whether or not there is an association between pre-diagnostic vitamin D status and tumour malignancy in patients with bone tumours. In a multi-center analysis, 25(OH)D, PTH and calcium levels of 225 patients that presented with various bone tumours between 2017 and 2018 were assessed. Collectively, 76% of all patients had insufficient vitamin D levels with a total mean 25(OH)D level of 21.43 ng/ml (53.58 nmol/L). In particular, 52% (117/225) of patients were identified as vitamin D deficient and further 24% of patients (55/225) were vitamin D insufficient. Notably, patients diagnosed with malignant bone tumours had significantly lower 25(OH)D levels than patients diagnosed with benign bone tumours [19.3 vs. 22.75 ng/ml (48.25 vs. 56.86 nmol/L); p = 0.04). In conclusion, we found a widespread and distressing rate of vitamin D deficiency and insufficiency in patients with bone tumours. However, especially for patients with bone tumours sufficient vitamin D levels seem to be of great importance. Thus, we believe that 25(OH)D status should routinely be monitored in these patients. Collectively, there should be an increased awareness for physicians to assess and if necessary correct vitamin D status of patients with bone tumours in general or of those at great risk of developing bone tumours. KW - bone tumour KW - vitamin D KW - hypovitaminosis D KW - vitamin D deficiency KW - malignancy KW - tumour malignancy Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-230314 VL - 25 ER - TY - JOUR A1 - Weissenberger, Manuel A1 - Heinz, Tizian A1 - Rueckl, Kilian A1 - Rudert, Maximilian A1 - Klug, Alexander A1 - Hoffmann, Reinhard A1 - Schmidt-Horlohé, Kay T1 - No functional differences in anatomic reconstruction with one vs. two suture anchors after non-simultaneous bilateral distal biceps brachii tendon rupture: a case report and review of the literature JF - BMC Musculoskeletal Disorders N2 - Background Surgical reattachment of the tendon is still the gold standard for ruptures of the distal biceps brachii tendon. Several fixation techniques have been described in the literature, with suture anchors being one of the most common fixation techniques. Currently, there is no data available on how many anchors are required for a safe and stable refixation. In this case report clinical data of a patient with non-simultaneous bilateral distal biceps tendon ruptures treated with a different number of suture anchors for each side (one vs. two) are demonstrated. Case presentation A 47-year-old factory worker suffered a rupture of the distal biceps tendon on both arms following two different occasions. The left side was fixed using a single suture anchor, while refixation on the right side was performed with two anchors. The patient was prospectively followed for one year. Functional outcome was assessed using the Andrews Carson Score (ACS), the Oxford Elbow Score (OES), and the Disabilities of Arm, Shoulder and Hand (DASH) Score after six, twelve, 24 and 48 weeks. Furthermore, an isokinetic strength measurement for flexion strength was performed after 24 and 48 weeks. After 48 weeks the patient presented with excellent functional outcome scores and no follow-up complications. During the follow-up period, no differences in the functional scores nor in the isokinetic flexion strength measurement could be detected. Furthermore, no radiological complications (like heterotopic ossifications) could be detected in the postoperative radiographs after one year. Conclusions Anatomic reattachment of the distal biceps tendon is a successful operative treatment option for distal biceps tendon ruptures. Suture anchor fixation remains one of the most common techniques, as it allows fast surgery and provides good results with respect to range of motion (ROM) and functional scoring according to the current literature. However, the number of anchors required for a stable fixation remains unclear. As indicated by our presented case, we hypothesize, that there are no significant differences between a one-point or a two-point fixation. In the presented case report, no intraindividual differences between the usage of one versus two suture anchors were evident in the short-term follow-up. KW - Non-simultaneous bilateral distal biceps tendon rupture KW - Distal biceps tendon repair KW - Anatomic reattachment KW - Suture anchor KW - Case report Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-229266 VL - 21 ER - TY - JOUR A1 - Prodinger, Peter Michael A1 - Lazic, Igor A1 - Horas, Konstantin A1 - Burgkart, Rainer A1 - von Eisenhart-Rothe, Rüdiger A1 - Weissenberger, Manuel A1 - Rudert, Maximilian A1 - Holzapfel, Boris Michael T1 - Revision Arthroplasty Through the Direct Anterior Approach Using an Asymmetric Acetabular Component JF - Journal of Clinical Medicine N2 - Despite increasing numbers of primary hip arthroplasties performed through the direct anterior approach (DAA), there is a lack of literature on DAA revision arthroplasty. The present study was performed in order to evaluate outcomes and revision rates after revision through the DAA using an asymmetric acetabular component with optional intra- and extramedullary fixation. In a retrospective cohort study, we analyzed prospectively collected data of 57 patients (61 hips, 43 female, 18 male) who underwent aseptic acetabular component revision through the DAA with the abovementioned implant system between January 2015 and December 2017. The mean follow-up was 40 months (12–56). Survival rates were estimated using the Kaplan–Meier method. All complications were documented and functional outcomes were assessed pre- and postoperatively. Kaplan–Meier analysis revealed an estimated five-year implant survival of 97% (confidence interval CI 87–99%). The estimated five-year survival with revision for any cause was 93% (CI 83–98%). The overall revision rate was 6.6% (n = 4). Two patients had to undergo revision due to periprosthetic infection (3.3%). In one patient, the acetabular component was revised due to aseptic loosening four months postoperatively. Another patient suffered from postoperative iliopsoas impingement and was treated successfully by arthroscopic iliopsoas tenotomy. Two (3.3%) of the revised hips dislocated postoperatively. The mean Harris Hip Score improved from 35 (2–66) preoperatively to 86 (38–100) postoperatively (p < 0.001). The hip joint’s anatomical center of rotation was restored at a high degree of accuracy. Our findings demonstrate that acetabular revision arthroplasty through the DAA using an asymmetric acetabular component with optional intra- and extramedullary fixation is safe and practicable, resulting in good radiographic and clinical midterm results. KW - anterior approach KW - revision arthroplasty KW - hip joint KW - acetabular bone defect KW - asymmetric implant KW - anatomic center of rotation Y1 - 2020 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-213184 SN - 2077-0383 VL - 9 IS - 9 ER - TY - JOUR A1 - Boelch, Sebastian Philipp A1 - Weissenberger, Manuel A1 - Spohn, Frederik A1 - Rudert, Maximilian A1 - Luedemann, Martin T1 - Insufficient sensitivity of joint aspiration during the two-stage exchange of the hip with spacers JF - Journal of Orthopedic Surgery and Research N2 - Background: Evaluation of infection persistence during the two-stage exchange of the hip is challenging. Joint aspiration before reconstruction is supposed to rule out infection persistence. Sensitivity and specificity of synovial fluid culture and synovial leucocyte count for detecting infection persistence during the two-stage exchange of the hip were evaluated. Methods: Ninety-two aspirations before planned joint reconstruction during the two-stage exchange with spacers of the hip were retrospectively analyzed. Results: The sensitivity and specificity of synovial fluid culture was 4.6 and 94.3%. The sensitivity and specificity of synovial leucocyte count at a cut-off value of 2000 cells/μl was 25.0 and 96.9%. C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) values were significantly higher before prosthesis removal and reconstruction or spacer exchange (p = 0.00; p = 0.013 and p = 0.039; p = 0.002) in the infection persistence group. Receiver operating characteristic area under the curve values before prosthesis removal and reconstruction or spacer exchange for ESR were lower (0.516 and 0.635) than for CRP (0.720 and 0.671). Conclusions: Synovial fluid culture and leucocyte count cannot rule out infection persistence during the two-stage exchange of the hip. KW - two-stage exchange KW - hip KW - periprosthetic infection KW - joint aspiration KW - spacer Y1 - 2018 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-175576 VL - 13 IS - 7 ER - TY - JOUR A1 - Steinert, Andre F. A1 - Weissenberger, Manuel A1 - Kunz, Manuela A1 - Gilbert, Fabian A1 - Ghivizzani, Steven C. A1 - Goebel, Sascha A1 - Jakob, Franz A1 - Nöth, Ulrich A1 - Rudert, Maximilian T1 - Indian hedgehog gene transfer is a chondrogenic inducer of human mesenchymal stem cells N2 - Introduction: To date, no single most-appropriate factor or delivery method has been identified for the purpose of mesenchymal stem cell (MSC)-based treatment of cartilage injury. Therefore, in this study we tested whether gene delivery of the growth factor Indian hedgehog (IHH) was able to induce chondrogenesis in human primary MSCs, and whether it was possible by such an approach to modulate the appearance of chondrogenic hypertrophy in pellet cultures in vitro. Methods: First-generation adenoviral vectors encoding the cDNA of the human IHH gene were created by cre-lox recombination and used alone or in combination with adenoviral vectors, bone morphogenetic protein-2 (Ad.BMP- 2), or transforming growth factor beta-1 (Ad.TGF-b1) to transduce human bone-marrow derived MSCs at 5 × 102 infectious particles/cell. Thereafter, 3 × 105 cells were seeded into aggregates and cultured for 3 weeks in serumfree medium, with untransduced or marker gene transduced cultures as controls. Transgene expressions were determined by ELISA, and aggregates were analysed histologically, immunohistochemically, biochemically and by RT-PCR for chondrogenesis and hypertrophy. Results: IHH, TGF-b1 and BMP-2 genes were equipotent inducers of chondrogenesis in primary MSCs, as evidenced by strong staining for proteoglycans, collagen type II, increased levels of glycosaminoglycan synthesis, and expression of mRNAs associated with chondrogenesis. IHH-modified aggregates, alone or in combination, also showed a tendency to progress towards hypertrophy, as judged by the expression of alkaline phosphatase and stainings for collagen type X and Annexin 5. Conclusion: As this study provides evidence for chondrogenic induction of MSC aggregates in vitro via IHH gene delivery, this technology may be efficiently employed for generating cartilaginous repair tissues in vivo. KW - Medizin Y1 - 2012 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-75425 ER -