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1.  Symptomatic loosening of a total knee arthroplasty caused by a tibial chondrosarcoma – a case report 
SpringerPlus  2014;3:308.
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.
doi:10.1186/2193-1801-3-308
PMCID: PMC4079896  PMID: 24995155
Total knee arthroplasty; Bone tumor; Chondrosarcoma; Aseptic loosening
2.  Synergistic effect of Indian hedgehog and bone morphogenetic protein-2 gene transfer to increase the osteogenic potential of human mesenchymal stem cells 
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.
doi:10.1186/scrt316
PMCID: PMC3854715  PMID: 24004723
3.  Total hip replacement in developmental dysplasia using an oval-shaped cementless press-fit cup 
International Orthopaedics  2012;36(7):1355-1361.
Purpose
Acetabular roof deficiency due to subluxation of the femoral head (Hartofilakidis type II) increases the complexity of total hip arthroplasty. In these cases some form of support is usually required, to reach stable fixation of the acetabular component. Pursuing this aim, the oval-shaped cementless cranial socket could be an alternative to conventional treatment options.
Methods
Between 1998 and 2008, 37 patients (40 hips) underwent primary total hip arthroplasty using the cranial socket (mean follow-up 5.6 years, range 26 to 133 months). In a retrospective study we compared these clinical and radiological results with the results of a matched control group consisting of 35 patients (40 hips) treated with a standard cementless hemispherical cup in combination with bulk femoral autografting (mean follow-up 6.9 years, range 30 to 151 months).
Results
There were no statistically significant differences in the HHS (p = 0.205) or the SF-36 (p = 0.26) between both groups. There was no prosthesis failure due to septic or aseptic loosening. Time of surgery was significantly shorter in the cranial socket group (p < 0.001). The acetabular component could be placed in the ideal rotational hip centre in 24 (60%) hips in the cranial socket group and 32 (80%) hips in the control group, respectively.
Conclusions
Our study indicates, that the cranial socket can be an alternative treatment option for the reconstruction of acetabular deficiency in osteoarthritis secondary to developmental dysplasia.
doi:10.1007/s00264-012-1510-0
PMCID: PMC3385904  PMID: 22382394
4.  Cytotoxic effect and tissue penetration of phenol for adjuvant treatment of giant cell tumours 
Oncology Letters  2013;5(5):1595-1598.
Local adjuvant treatment of giant cell tumours (GCTs) of the bone with phenol has led to a significant reduction in recurrence rates. In the current study, the optimal phenol concentration and duration of intralesional exposure were evaluated. Specimens of GCTs were exposed to various concentrations of phenol solution (6, 60 and 80%) for either 1 or 3 min. Following embedding in glutaraldehyde, the tumour cell layers were examined by transmission electron microscopy. Destroyed cell organelles indicated the penetration depth as a sign of denaturation. Incubation of GCT specimens with 6% phenol solution for 3 min resulted in the most tissue damage and the deepest tissue penetration of ∼200 μm. Incubation with 60 and 80% phenol solution reached a penetration depth of only ∼100 μm. Phenol instillation may be used for the treatment of small scattered cellular debris following intralesional curettage; however, it is not suitable for treatment of remaining solid tumour tissue of GCT. The use of high phenol concentrations has no benefit and increases the risk of local or systemic intoxication.
doi:10.3892/ol.2013.1244
PMCID: PMC3678778  PMID: 23760940
phenol; tissue penetration; giant cell tumour; GCT; cytotoxic; denaturation
5.  Reconstruction of the patella with an autogenous iliac graft: clinical and radiologic results in thirteen patients 
International Orthopaedics  2011;36(3):545-552.
Purpose
Extension lag, quadriceps weakness and subluxation of the extensor apparatus are known complications of patellectomy. In the case of total knee joint replacement with a nonconstrained system an instability may be encountered. Reconstruction of the patella allows restoration of the moment arm to improve quadriceps leverage. The goal of our study was to analyse the clinical and radiological results after reconstruction of the patella with an autogenous iliac graft.
Methods
13 previously patellectomized patients had reconstruction of the patella with an autogenous iliac graft and were retrospectively studied by clinical and radiographic examination. For evaluation we used the scores of Feller and the Knee Society. Also, all complications were recorded.
Results
After an average follow-up of 40.1 months, nine patients had full strength of the quadriceps, while six had an improved function of the extensor apparatus. The mean Feller score was 21.8 and the Knee Society score was 67.3 for knee and 57.5 for function. Six complications occurred including three infections, two problems with the replaced patella and one fracture of the anterior superior iliac spine.
Conclusions
Reconstruction of the patella with an autogenous iliac graft enables the strength of the extensor apparatus with restoration of the knee joint.
doi:10.1007/s00264-011-1281-z
PMCID: PMC3291753  PMID: 21626390
6.  Reduced postoperative pain in total hip arthroplasty after minimal-invasive anterior approach 
International Orthopaedics  2011;36(3):491-498.
Purpose
The development of minimal-incision techniques for total hip replacement with preservation of soft tissue is generally associated with faster rehabilitation, reduction of postoperative pain and increased patient comfort. The aim of this study was to compare a minimal-incision anterior approach with a transgluteal lateral technique for hip replacement surgery with respect to postoperative pain, consumption of rescue medication, length of hospital stay and time to reach a defined range of motion.
Methods
In this retrospective cohort study we investigated 100 patients with a minimal-incision anterior approach (group I) and 100 patients with a transgluteal lateral approach (group II) retrospectively undergoing unilateral hip replacement. The study variables were pain at rest and during physiotherapy, amount of rescue medication, the time to reach a defined flexion and time in hospital.
Results
The patients of group I consumed less rescue medication (19.6 ± 6.9 mg vs. 23.6 ± 11.3 mg;  p = 0.005) and experienced less pain on the day of surgery (1.3 ± 1 vs. 2.3 ± 1.3, p = 0.0001) and the first postoperative day (0.41 ± 0.8 vs. 0.66 ± 1.1, p = 0.036). The time to reach the defined range of motion (6.4 ± 2 days vs. 7.4 ± 2.1 days; p = 0.001) and the length of hospital stay were shorter (10.2 ± 1.9 days vs. 13.4 ± 1.6 days; p = 0.0001) for group I. However, pain during physiotherapy was higher on the third and sixth through ninth days after surgery in comparison to group II (p = 0.001–0.013).
Conclusion
The implantation of a hip prosthesis through a minimal-incision anterior approach is successful in reducing postoperative pain and consumption of pain medication. Time to recovery and length of hospital stay are also influenced positively. Pain increases during physiotherapy, and may be mitigated by adopting limited weight bearing during the early postoperative period.
doi:10.1007/s00264-011-1280-0
PMCID: PMC3291765  PMID: 21611823
7.  Stem cell- and growth factor-based regenerative therapies for avascular necrosis of the femoral head 
Avascular necrosis (AVN) of the femoral head is a debilitating disease of multifactorial genesis, predominately affects young patients, and often leads to the development of secondary osteoarthritis. The evolving field of regenerative medicine offers promising treatment strategies using cells, biomaterial scaffolds, and bioactive factors, which might improve clinical outcome. Early stages of AVN with preserved structural integrity of the subchondral plate are accessible to retrograde surgical procedures, such as core decompression to reduce the intraosseous pressure and to induce bone remodeling. The additive application of concentrated bone marrow aspirates, ex vivo expanded mesenchymal stem cells, and osteogenic or angiogenic growth factors (or both) holds great potential to improve bone regeneration. In contrast, advanced stages of AVN with collapsed subchondral bone require an osteochondral reconstruction to preserve the physiological joint function. Analogously to strategies for osteochondral reconstruction in the knee, anterograde surgical techniques, such as osteochondral transplantation (mosaicplasty), matrix-based autologous chondrocyte implantation, or the use of acellular scaffolds alone, might preserve joint function and reduce the need for hip replacement. This review summarizes recent experimental accomplishments and initial clinical findings in the field of regenerative medicine which apply cells, growth factors, and matrices to address the clinical problem of AVN.
doi:10.1186/scrt98
PMCID: PMC3340551  PMID: 22356811
8.  Can Bone Tissue Engineering Contribute to Therapy Concepts after Resection of Musculoskeletal Sarcoma? 
Sarcoma  2013;2013:153640.
Resection of musculoskeletal sarcoma can result in large bone defects where regeneration is needed in a quantity far beyond the normal potential of self-healing. In many cases, these defects exhibit a limited intrinsic regenerative potential due to an adjuvant therapeutic regimen, seroma, or infection. Therefore, reconstruction of these defects is still one of the most demanding procedures in orthopaedic surgery. The constraints of common treatment strategies have triggered a need for new therapeutic concepts to design and engineer unparalleled structural and functioning bone grafts. To satisfy the need for long-term repair and good clinical outcome, a paradigm shift is needed from methods to replace tissues with inert medical devices to more biological approaches that focus on the repair and reconstruction of tissue structure and function. It is within this context that the field of bone tissue engineering can offer solutions to be implemented into surgical therapy concepts after resection of bone and soft tissue sarcoma. In this paper we will discuss the implementation of tissue engineering concepts into the clinical field of orthopaedic oncology.
doi:10.1155/2013/153640
PMCID: PMC3556880  PMID: 23509421
9.  Biphasic bone substitute and fibrin sealant for treatment of benign bone tumours and tumour-like lesions 
International Orthopaedics  2011;36(1):139-148.
Purpose
Bone defects resulting from tumour resection or curettage are most commonly reconstructed with autologous bone graft which is associated with limited availability and donor site morbidity. Recent research has focussed on synthetic biomaterials as bone graft substitutes. The aim of this study was to assess the safety and efficiency of a bone substitute as an alternative for autologous bone in the treatment of benign bone tumours and tumour-like lesions.
Methods
In the present study, a biphasic ceramic (60% HA and 40% β-TCP) combined with a fibrin sealant was used to reconstruct defects in 51 patients after curettage of benign bone tumours or tumour-like lesions. Patient age ranged from eight to 68 years (mean 29.7), defect size from 2 cm3 to 35 cm3 (mean 12.1), and time of follow-up from one to 56 months (mean 22.7).
Results
Radiologic analysis showed complete bony defect consolidation in 50 of 51 patients after up to 56 months. No postoperative fractures were observed. Revision surgery had to be performed in one case. Histological analysis showed new bone formation and good biocompatibility and osseointegration of the implanted material.
Conclusion
In summary, the biphasic ceramic in combination with fibrin sealant was proven an effective alternative to autologous bone grafts eliminating the risk of donor site morbidity for the patient.
doi:10.1007/s00264-011-1282-y
PMCID: PMC3251681  PMID: 21626113
10.  Desmoplastic Fibroma: A Case Report with Three Years of Clinical and Radiographic Observation and Review of the Literature 
Background:
Desmoplastic fibroma (DF) is an extremely rare locally aggressive bone tumor with an incidence of 0.11% of all primary bone tumors. The typical clinical presentation is pain and swelling above the affected area. The most common sites of involvement are the mandible and the metaphysis of long bones. Histologically and biologically, desmoplastic fibroma mimics extra-abdominal desmoid tumor of soft tissue.
Case Presentation and Literature Review:
A case of a 27-year old man with DF in the ilium, including the clinical, radiological and histological findings over a 4-year period is presented here. CT scans performed in 3-year intervals prior to surgical intervention were compared with respect to tumor extension and cortical breakthrough. The patient was treated with curettage and grafting based on anatomical considerations. Follow-up CT scans over 18-months are also documented here. Additionally, a review and analysis of 271 cases including the presented case with particular emphasis on imaging patterns in MRI and CT as well as treatment modalities and outcomes are presented.
Conclusion:
In patients with desmoplastic fibroma, CT is the preferred imaging technique for both the diagnosis of intraosseus tumor extension and assessment of cortical involvement, whereas MRI is favored for the assessment of extraosseus tumor growth and preoperative planning. While tumor resection remains the preferred treatment for DF, curettage and grafting prove to be an acceptable alternative treatment modality with close follow-up when resection is not possible. Curettage and grafting have been shown to provide good clinical results and are associated with long recurrence free intervals.
doi:10.2174/1874325001307010040
PMCID: PMC3583030  PMID: 23459513
Desmoplastic fibroma; rare bone tumor; benign bone tumor; curettage; autograft; review.
11.  Indian hedgehog gene transfer is a chondrogenic inducer of human mesenchymal stem cells 
Arthritis Research & Therapy  2012;14(4):R168.
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-β1) 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 serum-free 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-β1 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.
doi:10.1186/ar3921
PMCID: PMC3580562  PMID: 22817660
12.  In situ guided tissue regeneration in musculoskeletal diseases and aging 
Cell and Tissue Research  2011;347(3):725-735.
In situ guided tissue regeneration, also addressed as in situ tissue engineering or endogenous regeneration, has a great potential for population-wide “minimal invasive” applications. During the last two decades, tissue engineering has been developed with remarkable in vitro and preclinical success but still the number of applications in clinical routine is extremely small. Moreover, the vision of population-wide applications of ex vivo tissue engineered constructs based on cells, growth and differentiation factors and scaffolds, must probably be deemed unrealistic for economic and regulation-related issues. Hence, the progress made in this respect will be mostly applicable to a fraction of post-traumatic or post-surgery situations such as big tissue defects due to tumor manifestation. Minimally invasive procedures would probably qualify for a broader application and ideally would only require off the shelf standardized products without cells. Such products should mimic the microenvironment of regenerating tissues and make use of the endogenous tissue regeneration capacities. Functionally, the chemotaxis of regenerative cells, their amplification as a transient amplifying pool and their concerted differentiation and remodeling should be addressed. This is especially important because the main target populations for such applications are the elderly and diseased. The quality of regenerative cells is impaired in such organisms and high levels of inhibitors also interfere with regeneration and healing. In metabolic bone diseases like osteoporosis, it is already known that antagonists for inhibitors such as activin and sclerostin enhance bone formation. Implementing such strategies into applications for in situ guided tissue regeneration should greatly enhance the efficacy of tailored procedures in the future.
doi:10.1007/s00441-011-1237-z
PMCID: PMC3306563  PMID: 22011785
In situ guided tissue regeneration; Stem cells; Scaffolds; Regenerative medicine; Mesenchymal tissues
13.  Attachment to laminin‐111 facilitates transforming growth factor β‐induced expression of matrix metalloproteinase‐3 in synovial fibroblasts 
Annals of the Rheumatic Diseases  2006;66(4):446-451.
Background
In the synovial membrane of patients with rheumatoid arthritis (RA), a strong expression of laminins and matrix degrading proteases was reported.
Aim
To investigate the regulation of matrix metalloproteinases (MMPs) in synovial fibroblasts (SFs) of patients with osteoarthritis (OA) and RA by attachment to laminin‐1 (LM‐111) and in the presence or absence of costimulatory signals provided by transforming growth factor β (TGFβ).
Methods
SFs were seeded in laminin‐coated flasks and activated by addition of TGFβ. The expression of genes was investigated by quantitative reverse transcriptase‐polymerase chain reaction (qRT‐PCR), immunocytochemistry and ELISA, and intracellular signalling pathways by immunoblotting, and by poisoning p38MAPK by SB203580, MEK‐ERK by PD98059 and SMAD2 by A‐83‐01.
Results
Attachment of SF to LM‐111 did not activate the expression of MMPs, but addition of TGFβ induced a fivefold higher expression of MMP‐3. Incubation of SF on LM‐111 in the presence of TGFβ induced a significant 12‐fold higher expression of MMP‐3 mRNA, and secretion of MMP‐3 was elevated 20‐fold above controls. Functional blocking of LM‐111–integrin interaction reduced the laminin‐activated MMP‐3 expression significantly. Stimulation of SF by LM‐111 and TGFβ activated the p38MAPK, ERK and SMAD2 pathways, and inhibition of these pathways by using SB203580, PD98059 or A‐83‐01 confirmed the involvement of these pathways in the regulation of MMP‐3.
Conclusion
Attachment of SF to LM‐111 by itself has only minor effects on the expression of MMP‐1 or MMP‐3, but it facilitates the TGFβ‐induced expression of MMP‐3 significantly. This mode of MMP‐3 induction may therefore contribute to inflammatory joint destruction in RA independent of the proinflammatory cytokines interleukin (IL)1β or tumour necrosis factor (TNF)α.
doi:10.1136/ard.2006.060228
PMCID: PMC1856036  PMID: 17124250
14.  Comparison of marker gene expression in chondrocytes from patients receiving autologous chondrocyte transplantation versus osteoarthritis patients 
Currently, autologous chondrocyte transplantation (ACT) is used to treat traumatic cartilage damage or osteochondrosis dissecans, but not degenerative arthritis. Since substantial refinements in the isolation, expansion and transplantation of chondrocytes have been made in recent years, the treatment of early stage osteoarthritic lesions using ACT might now be feasible. In this study, we determined the gene expression patterns of osteoarthritic (OA) chondrocytes ex vivo after primary culture and subculture and compared these with healthy chondrocytes ex vivo and with articular chondrocytes expanded for treatment of patients by ACT. Gene expression profiles were determined using quantitative RT-PCR for type I, II and X collagen, aggrecan, IL-1β and activin-like kinase-1. Furthermore, we tested the capability of osteoarthritic chondrocytes to generate hyaline-like cartilage by implanting chondrocyte-seeded collagen scaffolds into immunodeficient (SCID) mice. OA chondrocytes ex vivo showed highly elevated levels of IL-1β mRNA, but type I and II collagen levels were comparable to those of healthy chondrocytes. After primary culture, IL-1β levels decreased to baseline levels, while the type II and type I collagen mRNA levels matched those found in chondrocytes used for ACT. OA chondrocytes generated type II collagen and proteoglycan-rich cartilage transplants in SCID mice. We conclude that after expansion under suitable conditions, the cartilage of OA patients contains cells that are not significantly different from those from healthy donors prepared for ACT. OA chondrocytes are also capable of producing a cartilage-like tissue in the in vivo SCID mouse model. Thus, such chondrocytes seem to fulfil the prerequisites for use in ACT treatment.
doi:10.1186/ar2218
PMCID: PMC2206334  PMID: 17596264

Results 1-14 (14)