Timothy W. R. Briggs

Identification and Clonal Characterisation of a Progenitor Cell Sub-Population in Normal Human Articular Cartilage

Background Articular cartilage displays a poor repair capacity. The aim of cell-based therapies for cartilage defects is to repair damaged joint surfaces with a functional replacement tissue. Currently, chondrocytes removed from a healthy region of the cartilage are used but they are unable to retain their phenotype in expanded culture. The resulting repair tissue is fibrocartilaginous rather than hyaline, potentially compromising long-term repair. Mesenchymal stem cells, particularly bone marrow stromal cells (BMSC), are of interest for cartilage repair due to their inherent replicative potential. However, chondrocyte differentiated BMSCs display an endochondral phenotype, that is, can terminally differentiate and form a calcified matrix, leading to failure in long-term defect repair. Here, we investigate the isolation and characterisation of a human cartilage progenitor population that is resident within permanent adult articular cartilage. Methods and Findings Human articular cartilage samples were digested and clonal populations isolated using a differential adhesion assay to fibronectin. Clonal cell lines were expanded in growth media to high population doublings and karyotype analysis performed. We present data to show that this cell population demonstrates a restricted differential potential during chondrogenic induction in a 3D pellet culture system. Furthermore, evidence of high telomerase activity and maintenance of telomere length, characteristic of a mesenchymal stem cell population, were observed in this clonal cell population. Lastly, as proof of principle, we carried out a pilot repair study in a goat in vivo model demonstrating the ability of goat cartilage progenitors to form a cartilage-like repair tissue in a chondral defect. Conclusions In conclusion, we propose that we have identified and characterised a novel cartilage progenitor population resident in human articular cartilage which will greatly benefit future cell-based cartilage repair therapies due to its ability to maintain chondrogenicity upon extensive expansion unlike full-depth chondrocytes that lose this ability at only seven population doublings.

Autologous chondrocyte implantation in the knee: mid-term to long-term results.

BACKGROUND From 1998 to 2008, 1000 skeletally mature patients underwent autologous chondrocyte implantation for an osteochondral defect of the knee. We evaluated the functional outcomes in 827 of 869 patients who had undergone autologous chondrocyte implantation with Chondron or periosteum (ACI-C/ACI-P) or matrix-assisted chondrocyte implantation (MACI) and attempted to identify factors that influenced outcome. METHODS The age of the patient, the size and site of the osteochondral lesion, previous surgery, and the presence of early osteoarthritis were assessed for their influence on outcomes. Each factor was evaluated in a separate Cox proportional hazards model with use of hazard ratios (HRs), with 95% confidence intervals (CIs), describing the likelihood of failure for that particular factor. Outcomes were assessed with use of the modified Cincinnati score, visual analog scale pain score, and Stanmore functional score. RESULTS The mean duration of follow-up was 6.2 years (range, two to twelve years). The mean age was thirty-four years (range, fourteen to fifty-six years), with 493 males and 334 females. The average size of the defect was 409 mm2 (range, 64 to 2075 mm2). Four hundred and twenty-one procedures (51%) were performed on the medial femoral condyle; 109 (13%), on the lateral femoral condyle; 200 (24%), on the patella; and fifty (6%), on the trochlea. Kaplan-Meier survival analysis revealed that the unadjusted graft survival rate was 78.2% at five years and 50.7% and ten years for the entire cohort. No difference was found between the survival rates of the ACI-C/ACI-P and MACI techniques (HR = 0.948, 95% CI = 0.738 to 1.219, p = 0.678). There was a significant postoperative improvement in the function and pain scores of all three outcome measures (p < 0.002). Survivorship in the group with a previous cartilage regenerative procedure was inferior to that in patients with a previously untreated lesion, with failure five times more likely in the former group (HR = 4.718, standard error [SE] = 0.742, 95% CI = 3.466 to 6.420, p < 0.001). Degenerative change in any compartment had a significant detrimental effect on survivorship, with survivorship worsening as the osteoarthritis grade increased (Grade 1: HR = 2.077, 95% CI = 1.299 to 3.322, p = 0.002; Grade 2: HR = 3.450, 95% CI = 2.646 to 4.498, p < 0.001; and Grade 3: HR = 3.820, 95% CI = 2.185 to 6.677, p < 0.001). CONCLUSIONS Our study demonstrated an overall graft survival of 78% at five years and 51% beyond ten years following both autologous chondrocyte implantation techniques. Despite study limitations, our results demonstrate that autologous chondrocyte implantation for the treatment of osteochondral defects of the knee can achieve good results. LEVEL OF EVIDENCE Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Current strategies for knee cartilage repair

Defects in knee articular cartilage (AC) can cause pain and disability and present the clinician with an extremely challenging clinical situation. This article describes the most up‐to‐date surgical techniques that aim to repair and/or regenerate symptomatic focal defects in AC, which include arthroscopic debridement, microfracture bone marrow stimulation and autologous osteochondral allografting, with an emphasis on autologous chondrocyte implantation. In the future, refinement of tissue‐engineering approaches promises to further improve outcome for these patients.

Nonbacterial osteitis: a clinical, histopathological, and imaging study with a proposal for protocol-based management of patients with this diagnosis

BackgroundNonbacterial osteitis (NBO), a term referring to sterile bone lesions with nonspecific histopathological features of inflammation, may be either unifocal or multifocal, acute (≤6 months) or chronic, and recurrent. Only when the condition is chronic, recurrent, and multifocal is it appropriate to use the term chronic recurrent multifocal osteomyelitis (CRMO). We present our clinical experience as the largest reported series of children with NBO to date.MethodsWe report a retrospective clinical, histopathological, and radiological study of 41 children with nonbacterial osteitis.ResultsOf 41 children (2–16 years of age) diagnosed with NBO in our institution over the last 6 years, 21 (51%) had recurrent disease and 18 (44%) had multifocal disease. The most common bones affected were the clavicle, femur, and tibia (in order of decreasing prevalence) accounting for 44 (63%) of a total of 70 lesions. Only one individual had SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis, osteitis) and no other patients had evidence of bowel or skin disease. In the absence of evidence for an infective etiology, we recommend nonsteroidal anti-inflammatory agents as the firstline therapy and bisphosphonates only in cases of resistant disease.ConclusionsOn the basis of our findings, we propose using a patient questionnaire and protocol for investigating and managing patients who present with NBO to orthopedic surgeons. We predict that this will benefit patients with this disorder by improving our knowledge of the presenting signs and symptoms and related disorders, rationalizing the therapeutic approach, and allowing us to learn about the natural history of the disease.

Earlier diagnosis of bone and soft-tissue tumours

Although bone and soft-tissue sarcomas are rare, early diagnosis and prompt referral to a specialised unit offers the best chance of a successful outcome both in terms of survival and surgical resection. This paper highlights the clinical and radiological features that might suggest the possibility of a bone or soft-tissue sarcoma and suggests a succinct management pathway for establishing whether a suspicious bone or soft-tissue lesion could be malignant.

Hazard of ionizing radiation to trauma surgeons: reducing the risk

A study aimed to establish the level of radiation exposure to orthopaedic surgeons involved in the care of injured patients; parts of the body most at risk, and to establishing whether surgeon control of X-ray image intensification reduced the risk. This was conducted on five orthopaedic surgeons regularly involved in musculoskeletal care. Radiation dosage (in millisieverts (mSv) to the body, neck, eyes and hands, was measured by means of dosimeters applied to these areas, before and after surgeon-controlled use of X-ray image intensification. Although all doses measured were within current safety guidelines (1.25 mSv total body dose/month, 3.75 mSv eye dose/month and 12.5 mSv extremity dose/month), the hands were most at risk (maximum recorded dosage 3.95 mSv/month). Control by the surgeons of X-ray image intensification significantly reduced exposure of the hands (P < 0.05).

Stanmore custom-made extendible distal femoral replacements: Clinical experience in children with primary malignant bone tumours

The use of extendible distal femoral replacements is a relatively new treatment alternative for malignant bone tumours in growing individuals. Although their appearance was widely appreciated, questions about functional practicality and longevity remain unclear. With longer follow-up, advantages of immediate functional restoration and beneficial psychological aspects seem to be overshadowed by an increase in complications such as aseptic loosening, infection or prosthetic failure. We have reviewed 18 children with such tumours who were treated between 1983 and 1990 by custom-made Stanmore extendible distal femoral replacements. Four died from metastatic disease within 2.5 years of operation and two required amputation for local recurrence or chronic infection. The remaining 12 patients were followed for a mean of 8.7 years (6 to 13.2). A mean total lengthening of 5.2 cm was achieved, requiring, on average, 4.3 operations. Using the Musculoskeletal Tumor Society rating score the functional result at review was, on average, 77% of the expected normal function, with seven patients achieving > or = 80%. Revision of the prosthesis was required in ten patients, in six for aseptic loosening, at a mean of 6.2 years after the initial procedure.

Femoral diaphyseal endoprosthetic reconstruction after segmental resection of primary bone tumours

Segmental resection of malignant bone disease in the femoral diaphysis with subsequent limb reconstruction is a major undertaking. This is a retrospective review of 23 patients who had undergone limb salvage by endoprosthetic replacement of the femoral diaphysis for a primary bone tumour between 1989 and 2005. There were 16 males and seven females, with a mean age of 41.3 years (10 to 68). The mean overall follow-up was for 97 months (3 to 240), and 120 months (42 to 240) for the living patients. The cumulative patient survival was 77% (95% confidence interval 63% to 95%) at ten years. Survival of the implant, with failure of the endoprosthesis as an endpoint, was 85% at five years and 68% (95% confidence interval 42% to 92%) at ten years. The revision rate was 22% and the overall rate of re-operation was 26%. Complications included deep infection (4%), breakage of the prosthesis (8%), periprosthetic fracture (4%), aseptic loosening (4%), local recurrence (4%) and metastases (17%). The 16 patients who retained their diaphyseal endoprosthesis had a mean Musculoskeletal Tumour Society score of 87% (67% to 93%). They were all able to comfortably perform most activities of daily living. Femoral diaphyseal endoprosthetic replacement is a viable option for reconstruction following segmental resection of malignant bone disease. It allows immediate weight-bearing, is associated with a good long-term functional outcome, has an acceptable complication and revision rate and, most importantly, does not appear to compromise patient survival.

Diagnosing an extra-axial chordoma of the proximal tibia with the help of brachyury, a molecule required for notochordal differentiation

Chordomas are rare malignant bone tumours considered to arise from notochordal remnants that persist in the axial skeleton. Although their morphology can resemble that of a carcinoma, chondrosarcoma or malignant melanoma, the axial location and their well-defined immunophenotype, including expression of cytokeratins (CK7/20/8/18/19) and S100, generally allow the diagnosis to be made with confidence once the possibility is considered. In contrast, making a robust diagnosis of an extra-axial chordoma has been difficult in the absence of specific markers for chordomas. We have recently shown in gene expression microarray and immunohistochemistry studies that brachyury, a transcription factor crucial for notochordal development, is a specific and sensitive maker for chordomas. We now present a case of an intracortical tibial tumour, with detailed report of the imaging, and morphological features consistent with a chordoma, where notochordal differentiation was demonstrated with an antibody to brachyury. The tumour cells were also positive for cytokeratins, including CK19, and S100, CEA, EMA and HMBE1, findings which support the diagnosis of chordoma. Brachyury can be employed as a marker of notochordal differentiation and help identify confidently, for the first time, extra-axial bone and soft tissue chordomas, and tumours which may show focal notochordal differentiation.

Evaluation and Management of Periprosthetic Joint Infection–an International, Multicenter Study

BackgroundControversies still exist regarding the optimal diagnostic and therapeutic strategies in patients with prosthetic joint infections (PJI).Questions/PurposesHow effective are preoperative and intraoperative cultures in isolating organisms and how do these culture results compare to one another? What are the results of surgical treatment of PJI in the hip and knee in an international, tertiary referral center cohort?Patients and MethodsOne hundred sixteen patients (N = 59 hip PJI, N = 57 knee PJI) were recruited prospectively to registries at three international, tertiary referral centers between December 2008 to November 2011. Retrospective review of prospective registry data including demographics, microbiology results, and operative reports was performed.ResultsPreoperative synovial fluid aspiration yielded an organism in only 45.2% and 44.4% of cases, respectively, for knee and hip PJI. False-negative rates of preoperative aspiration relative to intraoperative culture were 56% and 46% in hip and knee PJI, respectively, with discordance rates of 25% and 21.4%, respectively. Rates of negative intraoperative cultures were 15% in hip PJI and 20.7% in knee PJI. Open debridement with prosthetic retention was the most common initial revision procedure performed (48.3% of hip PJI and 63.8% of knee PJI). This method of revision was successful in 41.3% of hip PJI and 59.4% of knee PJI. Initial failure rates for prosthetic revision was lower than debridement with prosthetic retention but remained substantial in both hip PJI (initial success of one-stage exchange 60% and two-stage exchange 70%) and knee PJI (initial success of one-stage exchange 80% and two-stage exchange 75%).ConclusionDiagnosis and treatment of PJI remains challenging with difficulty in isolating the offending organism and with high rates of prosthetic revision and initial treatment failures. Future advances in organism isolation and international standardization of treatment protocols may improve patient outcomes.