@article{SteinertKunzPrageretal.2015,
  author    = {Steinert, Andre F. and Kunz, Manuela and Prager, Patrick and G{\"o}bel, Sascha and Klein-Hitpass, Ludger and Ebert, Regina and N{\"o}th, Ulrich and Jakob, Franz and Gohlke, Frank},
  title     = {Characterization of bursa subacromialis-derived mesenchymal stem cells},
  series = {Stem Cell Research \& Therapy},
  volume    = {6},
  journal   = {Stem Cell Research \& Therapy},
  number    = {114},
  doi       = {10.1186/s13287-015-0104-3},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-126446},
  year      = {2015},
  abstract  = {Introduction The bursa subacromialis (BS) provides the gliding mechanism of the shoulder and regenerates itself after surgical removal. Therefore, we explored the presence of mesenchymal stem cells (MSCs) within the human adult BS tissue and characterized the BS cells compared to MSCs from bone marrow (BMSCs) on a molecular level. Methods BS cells were isolated by collagenase digest from BS tissues derived from patients with degenerative rotator cuff tears, and BMSCs were recovered by adherent culture from bone-marrow of patients with osteoarthritis of the hip. BS cells and BMSCs were compared upon their potential to proliferate and differentiate along chondrogenic, osteogenic and adipogenic lineages under specific culture conditions. Expression profiles of markers associated with mesenchymal phenotypes were comparatively evaluated by flow cytometry, immunohistochemistry, and whole genome array analyses. Results BS cells and BMSCs appeared mainly fibroblastic and revealed almost similar surface antigen expression profiles, which was \(CD44^+, CD73^+, CD90^+, CD105^+, CD106^+\),\(STRO-1^+, CD14^-, CD31^-, CD34^- , CD45^-, CD144^-\). Array analyses revealed 1969 genes upregulated and 1184 genes downregulated in BS cells vs. BMSCs, indicating a high level of transcriptome similarity. After 3 weeks of differentiation culture, BS cells and BMSCs showed a similar strong chondrogenic, adipogenic and osteogenic potential, as shown by histological, immunohistochemical and RT-PCR analyses in contrast to the respective negative controls. Conclusions Our in vitro characterizations show that BS cells fulfill all characteristics of mesenchymal stem cells, and therefore merit further attention for the development of improved therapies for various shoulder pathologies.},
  language  = {en}
}
@article{ReichertSchmalzlPrageretal.2013,
  author    = {Reichert, Johannes and Schmalzl, Jonas and Prager, Patrick and Gilbert, Fabian and Quent, Verena M. C. and Steinert, Andre F. and Rudert, Maximilian and N{\"o}th, Ulrich},
  title     = {Synergistic effect of Indian hedgehog and bone morphogenetic protein-2 gene transfer to increase the osteogenic potential of human mesenchymal stem cells},
  series = {Stem Cell Research \& Therapy},
  journal   = {Stem Cell Research \& Therapy},
  doi       = {10.1186/scrt316},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-97010},
  year      = {2013},
  abstract  = {Introduction To stimulate healing of large bone defects research has concentrated on the application of mesenchymal stem cells (MSCs). Methods In the present study, we induced the overexpression of the growth factors bone morphogenetic protein 2 (BMP-2) and/or Indian hedgehog (IHH) in human MSCs by adenoviral transduction to increase their osteogenic potential. GFP and nontransduced MSCs served as controls. The influence of the respective genetic modification on cell metabolic activity, proliferation, alkaline phosphatase (ALP) activity, mineralization in cell culture, and osteogenic marker gene expression was investigated. Results Transduction had no negative influence on cell metabolic activity or proliferation. ALP activity showed a typical rise-and-fall pattern with a maximal activity at day 14 and 21 after osteogenic induction. Enzyme activity was significantly higher in groups cultured with osteogenic media. The overexpression of BMP-2 and especially IHH + BMP-2 resulted in a significantly higher mineralization after 28 days. This was in line with obtained quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) analyses, which showed a significant increase in osteopontin and osteocalcin expression for osteogenically induced BMP-2 and IHH + BMP-2 transduced cells when compared with the other groups. Moreover, an increase in runx2 expression was observed in all osteogenic groups toward day 21. It was again more pronounced for BMP-2 and IHH + BMP-2 transduced cells cultured in osteogenic media. Conclusions In summary, viral transduction did not negatively influence cell metabolic activity and proliferation. The overexpression of BMP-2 in combination with or without IHH resulted in an increased deposition of mineralized extracellular matrix, and expression of osteogenic marker genes. Viral transduction therefore represents a promising means to increase the osteogenic potential of MSCs and the combination of different transgenes may result in synergistic effects.},
  language  = {en}
}
@article{SteinertRudertSieker2014,
  author    = {Steinert, Andre F. and Rudert, Maximilian and Sieker, Jakob T.},
  title     = {"Symptomatic loosening of a total knee arthroplasty caused by a tibial chondrosarcoma - a case report"},
  doi       = {10.1186/2193-1801-3-308},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-110341},
  year      = {2014},
  abstract  = {Premature implant loosening following total knee arthroplasty (TKA) can have several causes. In this article we report on a rare case of a 74 year old male patient suffering tibial component loosening 14 month after primary TKA. The patient did neither have any malignancies nor joint arthroplasty before. Upon clinical examination the range of motion in the diseased knee was painfully restricted to 80° of knee flexion, with the patient increasingly suffering sleeping and resting pain, and also at weight bearing. In standard radiographs, loosening of the TKA due to a large osteolysis at the tibial component was evident. Local computed tomography (CT) of the right knee revealed loosening of the tibial component due to a presumably malign bone tumor. For determination of the final diagnosis a representative biopsy of the tumor was taken by open surgery prior to the tumor resection. Histopathologic evaluation of the biopsy revealed a periprosthetic myxoid chondrosarcoma of the proximal tibia. Pre-operative staging examination included CT scans of lung and abdomen, as well as a bone scintigraphy which revealed no signs of tumor metastasis in the body. Surgical management comprised wide tumor resection and implantation of a hinged tumor knee arthroplasty with replacements of the distal femur and proximal tibia, as well as a patella tendon replacement using a synthetic ligament. Revision surgery was necessary twice due to impaired wound healing and critical soft tissue coverage, and treatment included a gastrocnemius muscle flap with skin mesh graft covering. Unfortunately long-term follow-up examinations could not be obtained, as the patient deceased due to an alveolitis during rehabilitation. In summary, the specifics of this rare case of aseptic TKA loosening, and the unusual circumstances of chondrosarcoma diagnosis and treatment are informative for those providing surgical treatment of similar cases.},
  language  = {en}
}
@article{SteinertWeissenbergerKunzetal.2012,
  author    = {Steinert, Andre F. and Weissenberger, Manuel and Kunz, Manuela and Gilbert, Fabian and Ghivizzani, Steven C. and Goebel, Sascha and Jakob, Franz and N{\"o}th, Ulrich and Rudert, Maximilian},
  title     = {Indian hedgehog gene transfer is a chondrogenic inducer of human mesenchymal stem cells},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-75425},
  year      = {2012},
  abstract  = {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.},
  subject      = {Medizin},
  language  = {en}
}
@article{WagenbrennerHeinzHorasetal.2020,
  author    = {Wagenbrenner, Mike and Heinz, Tizian and Horas, Konstantin and Jakuscheit, Axel and Arnholdt, J{\"o}rg and Hermann, Marietta and Rudert, Maximilian and Holzapfel, Boris M. and Steinert, Andre F. and Weißenberger, Manuel},
  title     = {The human arthritic hip joint is a source of mesenchymal stromal cells (MSCs) with extensive multipotent differentiation potential},
  series = {BMC Musculoskeletal Disorders},
  volume    = {21},
  journal   = {BMC Musculoskeletal Disorders},
  number    = {1},
  doi       = {10.1186/s12891-020-03340-z},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-229497},
  year      = {2020},
  abstract  = {Background While multiple in vitro studies examined mesenchymal stromal cells (MSCs) derived from bone marrow or hyaline cartilage, there is little to no data about the presence of MSCs in the joint capsule or the ligamentum capitis femoris (LCF) of the hip joint. Therefore, this in vitro study examined the presence and differentiation potential of MSCs isolated from the bone marrow, arthritic hyaline cartilage, the LCF and full-thickness samples of the anterior joint capsule of the hip joint. Methods MSCs were isolated and multiplied in adherent monolayer cell cultures. Osteogenesis and adipogenesis were induced in monolayer cell cultures for 21 days using a differentiation medium containing specific growth factors, while chondrogenesis in the presence of TGF-ss1 was performed using pellet-culture for 27 days. Control cultures were maintained for comparison over the same duration of time. The differentiation process was analyzed using histological and immunohistochemical stainings as well as semiquantitative RT-PCR for measuring the mean expression levels of tissue-specific genes. Results This in vitro research showed that the isolated cells from all four donor tissues grew plastic-adherent and showed similar adipogenic and osteogenic differentiation capacity as proven by the histological detection of lipid droplets or deposits of extracellular calcium and collagen type I. After 27 days of chondrogenesis proteoglycans accumulated in the differentiated MSC-pellets from all donor tissues. Immunohistochemical staining revealed vast amounts of collagen type II in all differentiated MSC-pellets, except for those from the LCF. Interestingly, all differentiated MSCs still showed a clear increase in mean expression of adipogenic, osteogenic and chondrogenic marker genes. In addition, the examination of an exemplary selected donor sample revealed that cells from all four donor tissues were clearly positive for the surface markers CD44, CD73, CD90 and CD105 by flow cytometric analysis. Conclusions This study proved the presence of MSC-like cells in all four examined donor tissues of the hip joint. No significant differences were observed during osteogenic or adipogenic differentiation depending on the source of MSCs used. Further research is necessary to fully determine the tripotent differentiation potential of cells isolated from the LCF and capsule tissue of the hip joint.},
  language  = {en}
}
@article{SchmalzlPlumhoffGilbertetal.2019,
  author    = {Schmalzl, Jonas and Plumhoff, Piet and Gilbert, Fabian and Gohlke, Frank and Konrads, Christian and Brunner, Ulrich and Jakob, Franz and Ebert, Regina and Steinert, Andre F.},
  title     = {Tendon-derived stem cells from the long head of the biceps tendon},
  series = {Bone \& Joint Research},
  volume    = {8},
  journal   = {Bone \& Joint Research},
  number    = {9},
  doi       = {10.1302/2046-3758.89.BJR-2018-0214.R2},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-200370},
  pages     = {414-424},
  year      = {2019},
  abstract  = {Objectives The long head of the biceps (LHB) is often resected in shoulder surgery and could therefore serve as a cell source for tissue engineering approaches in the shoulder. However, whether it represents a suitable cell source for regenerative approaches, both in the inflamed and non-inflamed states, remains unclear. In the present study, inflamed and native human LHBs were comparatively characterized for features of regeneration. Methods In total, 22 resected LHB tendons were classified into inflamed samples (n = 11) and non-inflamed samples (n = 11). Proliferation potential and specific marker gene expression of primary LHB-derived cell cultures were analyzed. Multipotentiality, including osteogenic, adipogenic, chondrogenic, and tenogenic differentiation potential of both groups were compared under respective lineage-specific culture conditions. Results Inflammation does not seem to affect the proliferation rate of the isolated tendon-derived stem cells (TDSCs) and the tenogenic marker gene expression. Cells from both groups showed an equivalent osteogenic, adipogenic, chondrogenic and tenogenic differentiation potential in histology and real-time polymerase chain reaction (RT-PCR) analysis. Conclusion These results suggest that the LHB tendon might be a suitable cell source for regenerative approaches, both in inflamed and non-inflamed states. The LHB with and without tendinitis has been characterized as a novel source of TDSCs, which might facilitate treatment of degeneration and induction of regeneration in shoulder surgery.},
  language  = {en}
}
@article{ArnholdtKamawalHorasetal.2020,
  author    = {Arnholdt, J{\"o}rg and Kamawal, Yama and Horas, Konstantin and Holzapfel, Boris M. and Gilbert, Fabian and Ripp, Axel and Rudert, Maximilian and Steinert, Andre F.},
  title     = {Accurate implant fit and leg alignment after cruciate-retaining patient-specific total knee arthroplasty},
  series = {BMC Musculoskeletal Disorders},
  volume    = {21},
  journal   = {BMC Musculoskeletal Disorders},
  doi       = {10.1186/s12891-020-03707-2},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230012},
  year      = {2020},
  abstract  = {Background For improved outcomes in total knee arthroplasty (TKA) correct implant fitting and positioning are crucial. In order to facilitate a best possible implant fitting and positioning patient-specific systems have been developed. However, whether or not these systems allow for better implant fitting and positioning has yet to be elucidated. For this reason, the aim was to analyse the novel patient-specific cruciate retaining knee replacement system iTotal (TM) CR G2 that utilizes custom-made implants and instruments for its ability to facilitate accurate implant fitting and positioning including correction of the hip-knee-ankle angle (HKA). Methods We assessed radiographic results of 106 patients who were treated with the second generation of a patient-specific cruciate retaining knee arthroplasty using iTotal\(^{TM}\) CR G2 (ConforMIS Inc.) for tricompartmental knee osteoarthritis (OA) using custom-made implants and instruments. The implant fit and positioning as well as the correction of the mechanical axis (hip-knee-ankle angle, HKA) and restoration of the joint line were determined using pre- and postoperative radiographic analyses. Results On average, HKA was corrected from 174.4 degrees +/- 4.6 degrees preoperatively to 178.8 degrees +/- 2.2 degrees postoperatively and the coronal femoro-tibial angle was adjusted on average 4.4 degrees. The measured preoperative tibial slope was 5.3 degrees +/- 2.2 degrees (mean +/- SD) and the average postoperative tibial slope was 4.7 degrees +/- 1.1 degrees on lateral views. The joint line was well preserved with an average modified Insall-Salvati index of 1.66 +/- 0.16 pre- and 1.67 +/- 0.16 postoperatively. The overall accuracy of fit of implant components was decent with a measured medial overhang of more than 1 mm (1.33 mm +/- 0.32 mm) in 4 cases only. Further, a lateral overhang of more than 1 mm (1.8 mm +/- 0.63) (measured in the anterior-posterior radiographs) was observed in 11 cases, with none of the 106 patients showing femoral notching. Conclusion The patient-specific iTotal\(^{TM}\) CR G2 total knee replacement system facilitated a proper fitting and positioning of the implant components. Moreover, a good restoration of the leg axis towards neutral alignment was achieved as planned. Nonetheless, further clinical follow-up studies are necessary to validate our findings and to determine the long-term impact of using this patient- specific system.},
  language  = {en}
}
@article{ArnholdtGilbertBlanketal.2017,
  author    = {Arnholdt, J{\"o}rg and Gilbert, Fabian and Blank, Marc and Papazoglou, Jannis and Rudert, Maximilian and N{\"o}th, Ulrich and Steinert, Andre F.},
  title     = {The Mayo conservative hip: complication analysis and management of the first 41 cases performed at a University level 1 department},
  series = {BMC Muskoskeletal Disorders},
  volume    = {18},
  journal   = {BMC Muskoskeletal Disorders},
  number    = {250},
  doi       = {10.1186/s12891-017-1613-2},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-157812},
  year      = {2017},
  abstract  = {Background: To prevent bone loss in hip arthroplasty, several short stem systems have been developed, including the Mayo conservative hip system. While there is a plethora of data confirming inherent advantages of these systems, only little is known about potential complications, especially when surgeons start to use these systems. Methods: In this study, we present a retrospective analysis of the patients' outcome, complications and the complication management of the first 41 Mayo conservative hips performed in 37 patients. For this reason, functional scores, radiographic analyses, peri- and postoperative complications were assessed at an average follow-up of 35 months. Results: The overall HHS improved from 61.2 pre-operatively to 85.6 post-operatively. The German Extra Short Musculoskeletal Function Assessment Questionnaire (XSFMA-D) improved from 30.3 pre-operatively to 12.2 post-operatively. The most common complication was an intraoperative non-displaced fracture of the proximal femur observed in 5 cases (12.1\%). Diabetes, higher BMI and older ages were shown to be risk factors for these intra-operative periprosthetic fractures (p < 0.01). Radiographic analysis revealed a good offset reconstruction in all cases. Conclusion: In our series, a high complication rate with 12.1\% of non-displaced proximal femoral fractures was observed using the Mayo conservative hip. This may be attributed to the flat learning curve of the system or the inherent patient characteristics of the presented cohort."},
  language  = {en}
}
@article{WagenbrennerPokerHeinzetal.2022,
  author    = {Wagenbrenner, Mike and Poker, Konrad and Heinz, Tizian and Herrmann, Marietta and Horas, Konstantin and Ebert, Regina and Mayer-Wagner, Susanne and Holzapfel, Boris M. and Rudert, Maximilian and Steinert, Andre F. and Weißenberger, Manuel},
  title     = {Mesenchymal stromal cells (MSCs) isolated from various tissues of the human arthritic knee joint possess similar multipotent differentiation potential},
  series = {Applied Sciences},
  volume    = {12},
  journal   = {Applied Sciences},
  number    = {4},
  issn      = {2076-3417},
  doi       = {10.3390/app12042239},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-262334},
  year      = {2022},
  abstract  = {(1) Background: The mesenchymal stromal cells (MSCs) of different tissue origins are applied in cell-based chondrogenic regeneration. However, there is a lack of comparability determining the most suitable cell source for the tissue engineering (TE) of cartilage. The purpose of this study was to compare the in vitro chondrogenic potential of MSC-like cells from different tissue sources (bone marrow, meniscus, anterior cruciate ligament, synovial membrane, and the infrapatellar fat pad removed during total knee arthroplasty (TKA)) and define which cell source is best suited for cartilage regeneration. (2) Methods: MSC-like cells were isolated from five donors and expanded using adherent monolayer cultures. Differentiation was induced by culture media containing specific growth factors. Transforming growth factor (TGF)-ß1 was used as the growth factor for chondrogenic differentiation. Osteogenesis and adipogenesis were induced in monolayer cultures for 27 days, while pellet cell cultures were used for chondrogenesis for 21 days. Control cultures were maintained under the same conditions. After, the differentiation period samples were analyzed, using histological and immunohistochemical staining, as well as molecularbiological analysis by RT-PCR, to assess the expression of specific marker genes. (3) Results: Plastic-adherent growth and in vitro trilineage differentiation capacity of all isolated cells were proven. Flow cytometry revealed the clear co-expression of surface markers CD44, CD73, CD90, and CD105 on all isolated cells. Adipogenesis was validated through the formation of lipid droplets, while osteogenesis was proven by the formation of calcium deposits within differentiated cell cultures. The formation of proteoglycans was observed during chondrogenesis in pellet cultures, with immunohistochemical staining revealing an increased relative gene expression of collagen type II. RT-PCR proved an elevated expression of specific marker genes after successful differentiation, with no significant differences regarding different cell source of native tissue. (4) Conclusions: Irrespective of the cell source of native tissue, all MSC-like cells showed multipotent differentiation potential in vitro. The multipotent differentiation capacity did not differ significantly, and chondrogenic differentiation was proven in all pellet cultures. Therefore, cell suitability for cell-based cartilage therapies and tissue engineering is given for various tissue origins that are routinely removed during total knee arthroplasty (TKA). This study might provide essential information for the clinical tool of cell harvesting, leading to more flexibility in cell availability.},
  language  = {en}
}
@article{WeissenbergerWeissenbergerWagenbrenneretal.2020,
  author    = {Weissenberger, Manuel and Weissenberger, Manuela H. and Wagenbrenner, Mike and Heinz, Tizian and Reboredo, Jenny and Holzapfel, Boris M. and Rudert, Maximilian and Groll, J{\"u}rgen and Evans, Christopher H. and Steinert, Andre F.},
  title     = {Different types of cartilage neotissue fabricated from collagen hydrogels and mesenchymal stromal cells via SOX9, TGFB1 or BMP2 gene transfer},
  series = {PLoS One},
  volume    = {15},
  journal   = {PLoS One},
  number    = {8},
  doi       = {10.1371/journal.pone.0237479},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-230494},
  year      = {2020},
  abstract  = {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.},
  language  = {en}
}