Reduced hypertrophy in vitro after chondrogenic differentiation of adult human mesenchymal stem cells following adenoviral SOX9 gene delivery.

BACKGROUND: Mesenchymal stem cell (MSC) based-treatments of cartilage injury are promising but impaired by high levels of hypertrophy after chondrogenic induction with several bone morphogenetic protein superfamily members (BMPs). As an alternative, this study investigates the chondrogenic induction of MSCs via adenoviral gene-delivery of the transcription factor SOX9 alone or in combination with other inducers, and comparatively explores the levels of hypertrophy and end stage differentiation in a pellet culture system in vitro. METHODS: First generation adenoviral vectors encoding SOX9, TGFB1 or IGF1 were used alone or in combination to transduce human bone marrow-derived MSCs at 5 × 102 infectious particles/cell. Thereafter cells were placed in aggregates and maintained for three weeks in chondrogenic medium. Transgene expression was determined at the protein level (ELISA/Western blot), and aggregates were analysed histologically, immunohistochemically, biochemically and by RT-PCR for chondrogenesis and hypertrophy. RESULTS: SOX9 cDNA was superior to that encoding TGFB1, the typical gold standard, as an inducer of chondrogenesis in primary MSCs as evidenced by improved lacuna formation, proteoglycan and collagen type II staining, increased levels of GAG synthesis, and expression of mRNAs associated with chondrogenesis. Moreover, SOX9 modified aggregates showed a markedly lower tendency to progress towards hypertrophy, as judged by expression of the hypertrophy markers alkaline phosphatase, and collagen type X at the mRNA and protein levels. CONCLUSION: Adenoviral SOX9 gene transfer induces chondrogenic differentiation of human primary MSCs in pellet culture more effectively than TGFB1 gene transfer with lower levels of chondrocyte hypertrophy after 3 weeks of in vitro culture. Such technology might enable the formation of more stable hyaline cartilage repair tissues in vivo.

Customised bi-compartmental knee arthroplasty shows encouraging 3-year results: findings of a prospective, multicenter study.

PURPOSE: The purpose of this study was to assess the clinical and patient-reported outcomes of a customised, individually made (CIM) bi-compartmental knee arthroplasty (BKA). METHODS: A prospectively recruited cohort of 79 patients was implanted with a CIM-BKA (patello-femoral plus either medial or lateral tibio-femoral, iDuo G2 system, Conformis, Billerica MA) at eight centres in the US and Germany. Patients were assessed for the 2011 KSS, KOOS, and ROM pre-operatively and at 2 weeks, 6 weeks, 12 weeks, 1 year, and 2 years post-operatively. RESULTS: The objective KSS score significantly improved from 69 at the pre-operative visit, to 94 at the 2-year post-operative time-point. Similar improvements were observed for the KSS function and satisfaction domains. Significant improvements from pre-operative levels were observed across all five domains of the KOOS. Two patients have undergone surgery to revise their CIM-BKA implant to total knees, resulting in a survivorship rate of 97.5% at an average follow-up of 2.6 years. CONCLUSIONS: CIM-BKA compares favourably to published scores as well as revision rates for previously available monolithic OTS-BKA implants. CIM-BKA implants provide surgeons with a viable and patient-specific monolithic implant solution as an option for patients presenting with bi-compartmental disease, who might, otherwise, be treated by performing uni-condylar + patello-femoral joint or bicruciate sparing TKA surgeries. Longer follow-up and higher numbers have to be awaited for further validation of these encouraging early results. LEVEL OF EVIDENCE: 3b (individual case-controlled study).

The inflamed biceps tendon as a pain generator in the shoulder: A histological and biomolecular analysis.

INTRODUCTION: The long head of the biceps (LHB) is often resected in shoulder surgery. However, its contribution to inflammatory processes in the shoulder remains unclear. In the present study, inflamed and noninflamed human LHBs were comparatively characterized for features of inflammation. MATERIALS AND METHODS: Twenty-two resected LHB tendons were classified into inflamed ( n = 11) and noninflamed ( n = 11) samples. For histological examination, samples were stained with hematoxylin eosin, Azan, van Gieson, and Masson Goldner trichrome. Neuronal tissue was immunohistochemically visualized. In addition, specific inflammatory marker gene expression of primary LHB-derived cell cultures were analyzed. RESULTS: Features of tendinopathy, such as collagen disorganization, infiltration by inflammatory cells, neovascularization, and extensive neuronal innervation were found in the tendinitis group. Compared to noninflamed samples, inflamed LHBs showed a significantly increased inflammatory marker gene expression. CONCLUSION: Structural and biomolecular differences of both groups suggest that the LHB tendon acts as an important pain generator in the shoulder joint. These findings can, on the one hand, contribute to the understanding of the biomolecular genesis of LHB tendinitis and, on the other hand, provide possibilities for new therapeutic approaches.

Bicompartmental individualized knee replacement : Use of patient-specific implants and instruments (iDuo™).

OBJECTIVE: Bicompartmental knee replacement in patients with combined osteoarthritis (OA) of the medial or lateral and patellofemoral compartment. Patient-specific instruments and implants (ConforMIS iDuo™) with a planning protocol for optimal implant fit. INDICATIONS: Bicompartmental OA of the knee (Kellgren & Lawrence stage IV) affecting both the medial or lateral and patellofemoral compartment after unsuccessful conservative or joint-preserving surgery. CONTRAINDICATIONS: Tricompartmental OA, knee ligament instabilities, knee deformities >15° (varus, valgus, extension deficit). Relative contraindication: body mass index >40; prior unicompartmental knee replacement or osteotomies. SURGICAL TECHNIQUE: Midline or parapatellar medial skin incision, medial arthrotomy; identify mechanical contact zone of the intact femoral condyle (linea terminalis); remove remaining cartilage and all osteophytes that may interfere with the correct placement of the individually designed instruments. Balance knee in extension with patient-specific balancing chips. Resection of proximal tibia with an individual cutting block; confirm axial alignment using an extramedullary alignment guide, balance flexion gap using spacer blocks in 90° flexion. Final femur preparation with resection of the anterior trochlea. After balancing and identification of insert heights, final tibial preparation is performed. Implant is cemented in 45° of knee flexion. Remove excess cement and final irrigation, followed by closure. POSTOPERATIVE MANAGEMENT: Sterile wound dressing; compressive bandage. No limitation of active/passive range of motion (ROM). Partial weight bearing the first 2 weeks, then transition to full weight bearing. Follow-up directly after surgery, at 12 and 52 weeks, then every 1-2 years. RESULTS: In all, 44 patients with bicompartmental OA of the medial and patellofemoral compartment were treated. Mean age 59 years. Minimum follow-up 12 months. Implant converted to TKA due to tibial loosening (1 patient); patella resurfacing (3 patients). No further revisions or complications. Radiographic analyses demonstrated ideal fit of the implant with less than 2 mm subsidence or overhang. KSS pain scores improved from preoperatively 5.7 to 1.7 postoperatively with level walking, and from 7.3 preoperatively to 2.8 postoperatively with climbing stairs or inclines. The WOMAC score improved from preoperatively 43 to 79 postoperatively.

[Individualized unicondylar knee replacement : Use of patient-specific implants and instruments]. / Individualisierte unikondyläre Kniegelenkendoprothetik : Einsatz patientenspezifischer Implantate und Instrumente.

OBJECTIVE: Unicompartmental knee replacement in patients with osteoarthritis (OA) of the medial compartment. Individualized instruments and implants with a planning protocol for optimal fit. The individualized instruments and implants (ConforMIS Inc.; Burlington, MA, USA) are manufactured based on a computed tomography scan of the affected lower extremity and are provided together with a planning protocol (iView®) of the surgery. INDICATIONS: Unicompartmental OA of the knee (Kellgren & Lawrence stage IV) or Morbus Ahlbäck after unsuccessful conservative or joint preserving surgery. CONTRAINDICATIONS: Bi- or tricompartmental OA, knee ligament instabilities, knee deformities >15° (varus, valgus, extension deficit). Relative contraindication: body mass index >40. SURGICAL TECHNIQUE: Limited medial arthrotomy, identification of mechanical contact zone of the femoral condyle (linea terminalis); removal of remaining cartilage and all osteophytes that may interfere with the correct placement of the individually designed instruments. Balancing of knee in extension using patient-specific balancing chips of incremental heights. Resection of tibia with a fitted individualized tibial cutting block; confirmation of axial alignment with an extramedullary alignment tower; balancing flexion gap using spacer blocks in 90° flexion. Final femur preparation with the individual cutting instruments. Final tibial preparation with an individual drill jig for the placement of cavities fitting the cement pegs of the prosthesis. Lavage, cementing of implants in 45° of knee flexion, removal of excess cement, and wound closure. POSTOPERATIVE MANAGEMENT: Sterile wound dressing, compressive bandage. Unlimited active/passive range of motion. Functional rehabilitation with partial weight bearing first 2 weeks, then transition to full weight bearing. Clinical/radiographic follow-up directly after surgery, at 12 and 52 weeks, then every 1-2 years. RESULTS: In all, 31 patients with medial OA (27 medial knee osteoarthritis, 4 osteonecrosis) were treated. Mean age 60 years. Minimum follow-up 17 months. One aseptic loosening needed exchange; one acute late-onset infection with consecutive implant removal. No further revisions/reoperations or complications. X-rays showed an ideal fit of the implant with less than 2 mm subsidence or overhang in all cases. Clinically the VAS changed from 6.51 preoperatively to 1.11 postoperatively. The mean KSS (Knee Society Score) improved from 111.23 preoperatively to 180.61 postoperatively; the functional part of KSS improved from mean 60.39 to 94.51.

Acetabular defect classification in times of 3D imaging and patient-specific treatment protocols.

Parallel to the rising number of revision hip procedures, an increasing number of complex periprosthetic osseous defects can be expected. Stable long-term fixation of the revision implant remains the ultimate goal of the surgical protocol. Within this context, an elaborate preoperative planning process including anticipation of the periacetabular defect form and size and analysis of the remaining supporting osseous elements are essential. However, detection and evaluation of periacetabular bone defects using an unsystematic analysis of plain anteroposterior radiographs of the pelvis is in many cases difficult. Therefore, periacetabular bone defect classification schemes such as the Paprosky system have been introduced that use standardized radiographic criteria to better anticipate the intraoperative reality. Recent studies were able to demonstrate that larger defects are often underestimated when using the Paprosky classification and that the intra- and interobserver reliability of the system is low. This makes it hard to compare results in terms of defects being studied. Novel software tools that are based on the analysis of CT data may provide an opportunity to overcome the limitations of native radiographic defect analysis. In the following article we discuss potential benefits of these novel instruments against the background of the obvious limitations of the currently used native radiographic defect analysis.

[Treatment of acetabular bone defects in revision hip arthroplasty using the Revisio-System]. / Defektadaptierte Versorgung azetabulärer Knochendefekte mit dem Revisio-System.

BACKGROUND: Many different systems for the management of primary and secondary acetabular defects are available, each with its inherent advantages and disadvantages. The Revisio-System is a press-fit oval mono-block implant that makes a defect-oriented reconstruction and restoration of the center of rotation possible. MATERIAL AND METHODS: In this study, we retrospectively reviewed the outcome of 92 consecutive patients treated with this oval press-fit cup due to periacetabular bone loss. The average follow-up was 58.2 months. Defects were classified according to D'Antonio. There were 39 type II, 38 Type III, and 15 type IV defects. After an average of 4.9 years, the implant survival rate was 94.6% with cup revision as the end point and 89.1% with revision for any reason as the end point. The Harris Hip Score increased from 41.1 preoperatively to 62.3 postoperatively. The mean level of pain measured with the Visual Analogue Scale (VSA) was reduced from 6.9 preoperatively to 3.8 postoperatively. RESULTS: The Revisio-System represents a promising toolbox for defect-orientated reconstruction of acetabular bone loss in revision hip arthroplasty. Our results demonstrate that the implantation of the Revisio-System can result in a good mid-term clinical outcome.

[Individualized total knee arthroplasty]. / Individualendoprothetik am Kniegelenk.

This article describes the rationale and the surgical technique of patient-specific uni-, bi-, or three-compartmental knee arthroplasty using the second generation (G2) of ConforMIS™ technology. The patient-individual implants and instruments are designed and fabricated based on data from a preoperative computed tomography of the lower limb. The disposable patient-specific drill guides and cutting-jigs are manufactured under consideration of the anatomical and biomechanical axes of the knee joint and mediate efficient pre-navigation of the saw-cuts on the femoral and tibial bone without the need for an additional navigation or balancing device. The surgical technique for all types of knee resurfacement comprises the steps of cartilage removal, knee balancing in extension and flexion, sparing bony cuts, final preparation of femur and tibia, trialling, cementing of components and final choice of tibial insert. The use of individualized three-dimensional image-derived resurfacing implants, as well as personalized single-use instrumentation, facilitates the surgeon to perform an almost anatomical knee resurfacement that has the potential to restore almost normal knee kinematics. The limited data on this novel technology is promising, however long-term clinical data is needed for final evaluation of this technology.

Direct bone morphogenetic protein 2 and Indian hedgehog gene transfer for articular cartilage repair using bone marrow coagulates.

OBJECTIVE: Bone morphogenetic protein 2 (BMP-2, encoded by BMP2) and Indian hedgehog protein (IHH, encoded by IHH) are well known regulators of chondrogenesis and chondrogenic hypertrophy. Despite being a potent chondrogenic factor BMP-2 was observed to induce chondrocyte hypertrophy in osteoarthritis (OA), growth plate cartilage and adult mesenchymal stem cells (MSCs). IHH might induce chondrogenic differentiation through different intracellular signalling pathways without inducing subsequent chondrocyte hypertrophy. The primary objective of this study is to test the efficacy of direct BMP2 and IHH gene delivery via bone marrow coagulates to influence histological repair cartilage quality in vivo. METHOD: Vector-laden autologous bone marrow coagulates with 10(11) adenoviral vector particles encoding BMP2, IHH or the Green fluorescent protein (GFP) were delivered to 3.2 mm osteochondral defects in the trochlea of rabbit knees. After 13 weeks the histological repair cartilage quality was assessed using the ICRS II scoring system and the type II collagen positive area. RESULTS: IHH treatment resulted in superior histological repair cartilage quality than GFP controls in all of the assessed parameters (with P < 0.05 in five of 14 assessed parameters). Results of BMP2 treatment varied substantially, including severe intralesional bone formation in two of six joints after 13 weeks. CONCLUSION: IHH gene transfer is effective to improve repair cartilage quality in vivo, whereas BMP2 treatment, carried the risk intralesional bone formation. Therefore IHH protein can be considered as an attractive alternative candidate growth factor for further preclinical research and development towards improved treatments for articular cartilage defects.