@phdthesis{Koschitzki2020,
  author    = {Koschitzki, Kim Christine Cornelia},
  title     = {Evaluation of preclinical animal models in bone tissue engineering and their success in clinical translation},
  doi       = {10.25972/OPUS-20759},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-207593},
  school      = {Universit{\"a}t W{\"u}rzburg},
  year      = {2020},
  abstract  = {Autologous bone still represents today's gold standard for the treatment of critical size bone defects and fracture non-unions despite associated disadvantages regarding limitations in availability, donor site morbidity, costs and efficacy. Bone tissue engineered constructs would present a promising alternative to currently available treatments. However, research on preclinical animal studies still fails to provide clinical applicable results able to allow the replacement of currently applied methods. It seems that the idea of bone tissue engineering, which has now been integral part of academic studies for over 30 years, got somehow stuck at an intermediate level, in between intense preclinical research and striven stages of initial clinical trial phases. A clear discrepancy exists between the number of studies with preclinical animal models for bone tissue engineering and the number of clinically approved bone tissue engineered constructs available to patients. The aim of this thesis was hence to evaluate preclinical animal models for bone tissue engineering as well as the perception of scientists and clinicians towards these models. Moreover, the general role of bone tissue engineering and its clinical need assessed by scientists and surgeons was investigated. A survey was conducted questioning both scientific and clinical opinions on currently available study designs and researchers' satisfaction with preclinical animal models. Additionally, a literature research was conducted, resulting in 167 papers from the last 10 years that report current designs of preclinical orthotopic animal studies in bone tissue engineering. Thereby, the focus lied on the description of the models regarding animal species, strain, age, gender and defect design. The outcome of the literature search was evaluated and compared to the outcome obtained from the survey. The survey data revealed that both scientists and surgeons generally remain positive about the future role of bone tissue engineering and its step to clinical translation, at least in the distant future, where it then might replace the current gold standard, autologous bone. Moreover, most of the participants considered preclinical animal models as relevant and well developed but the results as not yet realizable in the clinics. Surgeons thereby demonstrated a slightly more optimistic perception of currently conducted research with animal models compared to scientists. However, a rather inconsistent description of present preclinical study designs could be discerned when evaluating the reported study designs in the survey and the papers of the literature search. Indeed, defining an appropriate animal species, strain, age, gender, observation time, observation method and surgical design often depends on different indications and research questions and represents a highly challenging task for the establishment of a preclinical animal model. The existing lack of valid guidelines for preclinical testing of bone tissue engineering leads hence to a lack of well standardized preclinical animal models. Moreover, still existing knowledge gaps regarding aspects that affect the process of fracture healing, such as vascularization or immunological aspects, were found to hinder clinical translation of bone tissue engineered constructs. Using literature review and survey, this thesis points out critical issues that need to be addressed to allow clinical translation of bone tissue engineered constructs. It can be concluded that currently existing study designs with preclinical animal models cannot live up to the claim of providing suitable results for clinical implementation. The here presented comprehensive summary of currently used preclinical animal models for bone tissue engineering reveals a missing consensus on the usage of models such as an apparent lack of reporting and standardization regarding the study designs described in both papers from the literature review and the survey. It thereby indicates a crucial need to improve preclinical animal models in order to allow clinical translation. Despite the fact that participants of the survey generally revealed a positive perception towards the use of bone tissue engineered constructs and affirmed the clinical need for such novel designs, the missing standardization constitutes a main weak point for the provision of reliable study outcome and the translational success of the models. The optimization of reproducibility and reliability, as well as the further understanding of ongoing mechanisms in bone healing in order to develop effective tissue engineered constructs, need to form the basis of all study designs. The study outcomes might then fulfill the requirements of maybe today's and hopefully tomorrow's aging population.},
  language  = {en}
}
@article{DotterweichSchlegelmilchKelleretal.2016,
  author    = {Dotterweich, Julia and Schlegelmilch, Katrin and Keller, Alexander and Geyer, Beate and Schneider, Doris and Zeck, Sabine and Tower, Robert J. J. and Ebert, Regina and Jakob, Franz and Sch{\"u}tze, Norbert},
  title     = {Contact of myeloma cells induces a characteristic transcriptome signature in skeletal precursor cells-implications for myeloma bone disease},
  series = {Bone},
  volume    = {93},
  journal   = {Bone},
  doi       = {10.1016/j.bone.2016.08.006},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-186688},
  pages     = {155-166},
  year      = {2016},
  abstract  = {Physical interaction of skeletal precursors with multiple myeloma cells has been shown to suppress their osteogenic potential while favoring their tumor-promoting features. Although several transcriptome analyses of myeloma patient-derived mesenchymal stem cells have displayed differences compared to their healthy counterparts, these analyses insufficiently reflect the signatures mediated by tumor cell contact, vary due to different methodologies, and lack results in lineage-committed precursors. To determine tumor cell contact-mediated changes on skeletal precursors, we performed transcriptome analyses of mesenchymal stem cells and osteogenic precursor cells cultured in contact with the myeloma cell line INA-6. Comparative analyses confirmed dysregulation of genes which code for known disease-relevant factors and additionally revealed upregulation of genes that are associated with plasma cell homing, adhesion, osteoclastogenesis, and angiogenesis. Osteoclast-derived coupling factors, a dysregulated adipogenic potential, and an imbalance in favor of anti-anabolic factors may play a role in the hampered osteoblast differentiation potential of mesenchymal stem cells. Angiopoietin-Like 4 (ANGPTL4) was selected from a list of differentially expressed genes as a myeloma cell contact-dependent target in skeletal precursor cells which warranted further functional analyses. Adhesion assays with full-length ANGPTL4-coated plates revealed a potential role of this protein in INA6 cell attachment. This study expands knowledge of the myeloma cell contact-induced signature in the stromal compartment of myelomatous bones and thus offers potential targets that may allow detection and treatment of myeloma bone disease at an early stage.},
  language  = {en}
}
@article{ArnholdtKamawalHolzapfeletal.2018,
  author    = {Arnholdt, J{\"o}rg and Kamawal, Yama and Holzapfel, Boris Michael and Ripp, Axel and Rudert, Maximilian and Steinert, Andre Friedrich},
  title     = {Evaluation of implant fit and frontal plane alignment after bi-compartmental knee arthroplasty using patient-specific instruments and implants},
  series = {Archives of Medical Science},
  volume    = {14},
  journal   = {Archives of Medical Science},
  number    = {6},
  doi       = {10.5114/aoms.2018.79007},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-159668},
  pages     = {1424-1431},
  year      = {2018},
  abstract  = {Introduction The goals of successful bi-compartmental knee arthroplasty are to achieve correct fit and positioning of the implant, while appropriately correcting the mechanical alignment of the leg after surgery. As these requirements are not always reliably fulfilled using off-the-shelf implant systems, newer approaches for bi-compartmental resurfacing have been explored. Material and methods In this article we report the radiographic results of 30 patients with anteromedial osteoarthritis (OA) who were treated with a novel patient-specific fixed-bearing bi-compartmental knee resurfacing system using custom-made implants and instruments. Utilizing standardized pre- and postoperative radiographic analyses (based on anterior-posterior and lateral, anterior-posterior weight-bearing full-length radiographs, patella skyline views and preoperative computed tomography (CT) scanning) implant fit and positioning as well as correction of the mechanical axis (hip-knee-ankle angle, HKA) were determined. Results On average, HKA was corrected from 173.4 ±3.47° preoperatively to 179.4 ±2.85° postoperatively. The coronal femoro-tibial angle was corrected on average 5.61°. The preoperative tibial slope measured on lateral views was 6.38 ±2.4°, while the average slope in the CT-based planning protocol (iView) was 6.14 ±2.40°. Postoperative lateral tibial slope was determined to be 5.77 ±1.97°. The thickness of the posterior femoral cuts was measured intraoperatively and, in all cases, corresponded well to the targeted thickness of the cuts provided by the iView. The joint line was preserved in all cases and the average Insall-Salvati index was 1.078 ±0.11 pre- and 1.072 ±0.11 postoperatively. The fit of the implant components measured by over- or underhang was excellent throughout (< 1.01 mm). Conclusions Custom-made bicompartmental knee arthroplasty can ensure optimized fitting and positioning of the implant with restoration of the leg axis. These implants could be considered as an alternative primary solution for knee surgeons treating bi-compartmental disease.},
  language  = {en}
}
@article{WittmannSiebervonStengeletal.2016,
  author    = {Wittmann, Katharina and Sieber, Cornel and von Stengel, Simon and Kohl, Matthias and Freiberger, Ellen and Jakob, Franz and Lell, Michael and Engelke, Klaus and Kemmler, Wolfgang},
  title     = {Impact of whole body electromyostimulation on cardiometabolic risk factors in older women with sarcopenic obesity: the randomized controlled FORMOsA-sarcopenic obesity study},
  series = {Clinical Interventions in Aging},
  volume    = {11},
  journal   = {Clinical Interventions in Aging},
  doi       = {10.2147/CIA.S116430},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-164930},
  pages     = {1697—1706},
  year      = {2016},
  abstract  = {Background: Sarcopenic obesity (SO) is characterized by a combination of low muscle and high fat mass with an additive negative effect of both conditions on cardiometabolic risk. The aim of the study was to determine the effect of whole-body electromyostimulation (WB-EMS) on the metabolic syndrome (MetS) in community-dwelling women aged ≥70 years with SO. Methods: The study was conducted in an ambulatory university setting. Seventy-five community-dwelling women aged ≥70 years with SO living in Northern Bavaria, Germany, were randomly allocated to either 6 months of WB-EMS application with (WB-EMS\&P) or without (WB-EMS) dietary supplementation (150 kcal/day, 56\% protein) or a non-training control group (CG). WB-EMS included one session of 20 min (85 Hz, 350 µs, 4 s of strain-4 s of rest) per week with moderate-to-high intensity. The primary study endpoint was the MetS Z-score with the components waist circumference (WC), mean arterial pressure (MAP), triglycerides, fasting plasma glucose, and high-density lipoprotein cholesterol (HDL-C); secondary study endpoints were changes in these determining variables. Results: MetS Z-score decreased in both groups; however, changes compared with the CG were significant (P=0.001) in the WB-EMS\&P group only. On analyzing the components of the MetS, significant positive effects for both WB-EMS groups (P≤0.038) were identified for MAP, while the WB-EMS group significantly differed for WC (P=0.036), and the WB-EMS\&P group significantly differed for HDL-C (P=0.006) from the CG. No significant differences were observed between the WB-EMS groups. Conclusion: The study clearly confirms the favorable effect of WB-EMS application on the MetS in community-dwelling women aged ≥70 years with SO. However, protein-enriched supplements did not increase effects of WB-EMS alone. In summary, we considered this novel technology an effective and safe method to prevent cardiometabolic risk factors and diseases in older women unable or unwilling to exercise conventionally.},
  language  = {en}
}
@article{DotterweichTowerBrandletal.2016,
  author    = {Dotterweich, Julia and Tower, Robert J. and Brandl, Andreas and M{\"u}ller, Marc and Hofbauer, Lorenz C. and Beilhack, Andreas and Ebert, Regina and Gl{\"u}er, Claus C. and Tiwari, Sanjay and Sch{\"u}tze, Norbert and Jakob, Franz},
  title     = {The KISS1 Receptor as an In Vivo Microenvironment Imaging Biomarker of Multiple Myeloma Bone Disease},
  series = {PLoS One},
  volume    = {11},
  journal   = {PLoS One},
  number    = {5},
  doi       = {10.1371/journal.pone.0155087},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146960},
  pages     = {e0155087},
  year      = {2016},
  abstract  = {Multiple myeloma is one of the most common hematological diseases and is characterized by an aberrant proliferation of plasma cells within the bone marrow. As a result of crosstalk between cancer cells and the bone microenvironment, bone homeostasis is disrupted leading to osteolytic lesions and poor prognosis. Current diagnostic strategies for myeloma typically rely on detection of excess monoclonal immunoglobulins or light chains in the urine or serum. However, these strategies fail to localize the sites of malignancies. In this study we sought to identify novel biomarkers of myeloma bone disease which could target the malignant cells and/or the surrounding cells of the tumor microenvironment. From these studies, the KISS1 receptor (KISS1R), a G-protein-coupled receptor known to play a role in the regulation of endocrine functions, was identified as a target gene that was upregulated on mesenchymal stem cells (MSCs) and osteoprogenitor cells (OPCs) when co-cultured with myeloma cells. To determine the potential of this receptor as a biomarker, in vitro and in vivo studies were performed with the KISS1R ligand, kisspeptin, conjugated with a fluorescent dye. In vitro microscopy showed binding of fluorescently-labeled kisspeptin to both myeloma cells as well as MSCs under direct co-culture conditions. Next, conjugated kisspeptin was injected into immune-competent mice containing myeloma bone lesions. Tumor-burdened limbs showed increased peak fluorescence compared to contralateral controls. These data suggest the utility of the KISS1R as a novel biomarker for multiple myeloma, capable of targeting both tumor cells and host cells of the tumor microenvironment.},
  language  = {en}
}
@article{KamawalSteinertHolzapfeletal.2016,
  author    = {Kamawal, Yama and Steinert, Andre F and Holzapfel, Boris M and Rudert, Maximilian and Barthel, Thomas},
  title     = {Case report - calcification of the medial collateral ligament of the knee with simultaneous calcifying tendinitis of the rotator cuff},
  series = {BMC Muscoskeletal Disorders},
  volume    = {17},
  journal   = {BMC Muscoskeletal Disorders},
  number    = {283},
  doi       = {10.1186/s12891-016-1147-z},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-147669},
  year      = {2016},
  abstract  = {Calcification of the medial collateral ligament (MCL) of the knee is a very rare disease. We report on a case of a patient with a calcifying lesion within the MCL and simultaneous calcifying tendinitis of the rotator cuff in both shoulders. Case presentation: Calcification of the MCL was diagnosed both via x-ray and magnetic resonance imaging (MRI) and was successfully treated surgically. Calcifying tendinitis of the rotator cuff was successfully treated applying conservative methods. Conclusion: This is the first case report of a patient suffering from both a calcifying lesion within the medial collateral ligament and calcifying tendinitis of the rotator cuff in both shoulders. Clinical symptoms, radio-morphological characteristics and macroscopic features were very similar and therefore it can be postulated that the underlying pathophysiology is the same in both diseases. Our experience suggests that magnetic resonance imaging and x-ray are invaluable tools for the diagnosis of this inflammatory calcifying disease of the ligament, and that surgical repair provides a good outcome if conservative treatment fails. It seems that calcification of the MCL is more likely to require surgery than calcifying tendinitis of the rotator cuff. However, the exact reason for this remains unclear to date.},
  language  = {en}
}
@article{WehrleLiedertHeilmannetal.2015,
  author    = {Wehrle, Esther and Liedert, Astrid and Heilmann, Aline and Wehner, Tim and Bindl, Ronny and Fischer, Lena and Haffner-Luntzer, Melanie and Jakob, Franz and Schinke, Thorsten and Amling, Michael and Ignatius, Anita},
  title     = {The impact of low-magnitude high-frequency vibration on fracture healing is profoundly influenced by the oestrogen status in mice},
  series = {Disease Models \& Mechanisms},
  volume    = {8},
  journal   = {Disease Models \& Mechanisms},
  doi       = {10.1242/dmm.018622},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-144700},
  pages     = {93-104},
  year      = {2015},
  abstract  = {Fracture healing is impaired in aged and osteoporotic individuals. Because adequate mechanical stimuli are able to increase bone formation, one therapeutical approach to treat poorly healing fractures could be the application of whole-body vibration, including low-magnitude high-frequency vibration (LMHFV). We investigated the effects of LMHFV on fracture healing in aged osteoporotic mice. Female C57BL/6NCrl mice (n=96) were either ovariectomised (OVX) or sham operated (non-OVX) at age 41 weeks. When aged to 49 weeks, all mice received a femur osteotomy that was stabilised using an external fixator. The mice received whole-body vibrations (20 minutes/day) with 0.3 g peak-to-peak acceleration and a frequency of 45 Hz. After 10 and 21 days, the osteotomised femurs and intact bones (contra-lateral femurs, lumbar spine) were evaluated using bending-testing, micro-computed tomography (mu CT), histology and gene expression analyses. LMHFV disturbed fracture healing in aged non-OVX mice, with significantly reduced flexural rigidity (-81\%) and bone formation (-80\%) in the callus. Gene expression analyses demonstrated increased oestrogen receptor β (ERβ, encoded by Esr2) and Sost expression in the callus of the vibrated animals, but decreased β-catenin, suggesting that ERβ might mediate these negative effects through inhibition of osteoanabolic Wnt/β-catenin signalling. In contrast, in OVX mice, LMHFV significantly improved callus properties, with increased flexural rigidity (+ 1398\%) and bone formation (+637\%), which could be abolished by subcutaneous oestrogen application (0.025 mg oestrogen administered in a 90-day-release pellet). On a molecular level, we found an upregulation of ER alpha in the callus of the vibrated OVX mice, whereas ERβ was unaffected, indicating that ERa might mediate the osteoanabolic response. Our results indicate a major role for oestrogen in the mechanostimulation of fracture healing and imply that LMHFV might only be safe and effective in confined target populations.},
  language  = {en}
}
@article{RudertHorasHobergetal.2016,
  author    = {Rudert, Maximilian and Horas, Konstantin and Hoberg, Maik and Steinert, Andre and Holzapfel, Dominik Emanuel and H{\"u}bner, Stefan and Holzapfel, Boris Michael},
  title     = {The Wuerzburg procedure: the tensor fasciae latae perforator is a reliable anatomical landmark to clearly identify the Hueter interval when using the minimally-invasive direct anterior approach to the hip joint},
  series = {BMC Musculoskeletal Disorders},
  volume    = {17},
  journal   = {BMC Musculoskeletal Disorders},
  number    = {57},
  doi       = {10.1186/s12891-016-0908-z},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146031},
  year      = {2016},
  abstract  = {Background The key for successful delivery in minimally-invasive hip replacement lies in the exact knowledge about the surgical anatomy. The minimally-invasive direct anterior approach to the hip joint makes it necessary to clearly identify the tensor fasciae latae muscle in order to enter the Hueter interval without damaging the lateral femoral cutaneous nerve. However, due to the inherently restricted overview in minimally-invasive surgery, this can be difficult even for experienced surgeons. Methods and Surgical Technique In this technical note, we demonstrate for the first time how to use the tensor fasciae latae perforator as anatomical landmark to reliably identify the tensor fasciae latae muscle in orthopaedic surgery. Such perforators are used for flaps in plastic surgery as they are constant and can be found at the lateral third of the tensor fasciae latae muscle in a direct line from the anterior superior iliac spine. Conclusion As demonstrated in this article, a simple knowledge transfer between surgical disciplines can minimize the complication rate associated with minimally-invasive hip replacement.},
  language  = {en}
}
@article{KonradsHobergRudert2015,
  author    = {Konrads, C. and Hoberg, M. and Rudert, M.},
  title     = {New Mechanism of Hip Endoprosthesis Damage Caused by High-frequency Electrocautery},
  series = {Journal of Medical Implants \& Surgery},
  volume    = {1},
  journal   = {Journal of Medical Implants \& Surgery},
  number    = {1},
  doi       = {10.4172/jmis.1000102},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146528},
  pages     = {103},
  year      = {2015},
  abstract  = {No abstract available.},
  language  = {en}
}
@article{KonradsBarthel2015,
  author    = {Konrads, Christian and Barthel, Thomas},
  title     = {Children and Adolescents with Knee Pain Need Diagnostics for Osteochondritis Dissecans},
  series = {Journal of Pain Management \& Medicine},
  volume    = {2},
  journal   = {Journal of Pain Management \& Medicine},
  number    = {1},
  doi       = {10.4172/jpmme.1000107},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-146531},
  pages     = {107},
  year      = {2015},
  abstract  = {No abstract available.},
  language  = {en}
}