Subchondral bone circulation in osteoarthritis of the human knee.

OBJECTIVE: The hypothesis of this study is that human subchondral bone exhibits abnormal patterns of perfusion in osteoarthritis (OA) that can be characterized by kinetic parameters of blood flow using dynamic contrast enhanced (DCE) MRI. DESIGN: Fifteen subjects with advanced OA of the knee and seven control subjects without OA were studied at 1.5 T with DCE-MRI. Region of interest (ROIs) analysis of pharmacokinetic perfusion parameters were used to examine initial uptake and washout of the contrast agent in the lateral tibial plateau. RESULTS: Arterial and venous perfusion kinetics were abnormal in subchondral OA bone compared to those of normal controls. Time-intensity curves (TIC) exhibited delayed contrast clearance in OA knees compared to normal. Quantitatively, changes were observed in the kinetic parameters, kep, Akep, and kel. The mean kep and Akep were reduced in OA, compared to normal bone, indicating a reduction of arterial inflow and delayed signal enhancement. The kel in OA bone was lower than in normal bone, the negative kel indicating a reduction in venous outflow. The area under the TIC (AUC60) indicated greater residual contrast in OA bone. CONCLUSIONS: DCE-MRI can quantitatively assess subchondral bone perfusion kinetics in human OA and identify heterogeneous regions of perfusion deficits. The results are consistent with venous stasis in OA, reflecting venous outflow obstruction, and can affect intraosseous pressure, reduce arterial inflow, reduce oxygen content, and may contribute to altered cell signaling in, and the pathophysiology of, OA.

Passage-dependent relationship between mesenchymal stem cell mobilization and chondrogenic potential.

OBJECTIVE: Galvanotaxis, the migratory response of cells in response to electrical stimulation, has been implicated in development and wound healing. The use of mesenchymal stem cells (MSCs) from the synovium (synovium-derived stem cells, SDSCs) has been investigated for repair strategies. Expansion of SDSCs is necessary to achieve clinically relevant cell numbers; however, the effects of culture passage on their subsequent cartilaginous extracellular matrix production are not well understood. METHODS: Over four passages of SDSCs, we measured the expression of cell surface markers (CD31, CD34, CD49c, CD73) and assessed their migratory potential in response to applied direct current (DC) electric field. Cells from each passage were also used to form micropellets to assess the degree of cartilage-like tissue formation. RESULTS: Expression of CD31, CD34, and CD49c remained constant throughout cell expansion; CD73 showed a transient increase through the first two passages. Correspondingly, we observed that early passage SDSCs exhibit anodal migration when subjected to applied DC electric field strength of 6 V/cm. By passage 3, CD73 expression significantly decreased; these cells exhibited cell migration toward the cathode, as previously observed for terminally differentiated chondrocytes. Only late passage cells (P4) were capable of developing cartilage-like tissue in micropellet culture. CONCLUSIONS: Our results show cell priming protocols carried out for four passages selectively differentiate stem cells to behave like chondrocytes, both in their motility response to applied electric field and their production of cartilaginous tissue.

Noninvasive methods of measuring bone blood perfusion.

Measurement of bone blood flow and perfusion characteristics in a noninvasive and serial manner would be advantageous in assessing revascularization after trauma and the possible risk of avascular necrosis. Many disease states, including osteoporosis, osteoarthritis, and bone neoplasms, result in disturbed bone perfusion. A causal link between bone perfusion and remodeling has shown its importance in sustained healing and regrowth following injury. Measurement of perfusion and permeability within the bone was performed with small and macromolecular contrast media, using dynamic contrast-enhanced magnetic resonance imaging in models of osteoarthritis and the femoral head. Bone blood flow and remodeling was estimated using (18)F-Fluoride positron emission tomography in fracture healing and osteoarthritis. Multimodality assessment of bone blood flow, permeability, and remodeling by using noninvasive imaging techniques may provide information essential in monitoring subsequent rates of healing and response to treatment as well as identifying candidates for additional therapeutic or surgical interventions.

Subchondral fluid dynamics in a model of osteoarthritis: use of dynamic contrast-enhanced magnetic resonance imaging.

OBJECTIVE: The hypothesis of this study is that changes in fluid dynamics in subchondral bone bear a functional relationship to bone remodeling and cartilage breakdown in osteoarthritis (OA). We have utilized dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) to extract kinetic parameters of bone perfusion at various stages in the development of OA in the Dunkin-Hartley guinea pig. DESIGN: Animals of four different ages (6, 9, 12 and 15 months), representing various stages in the development of OA, were studied. All animals underwent DCE MRI and perfusion data were analyzed based on the Brix two-compartment pharmacokinetic model. Regions of interest were studied at the medial and lateral tibial plateaus and compared to histological-histochemical scores of articular cartilage and subchondral bone plate thickness. RESULTS: A decrease in perfusion as well as outflow obstruction was observed in animals between 6 and 9 months of age, only in the medial tibial plateau subchondral bone. The eventual cartilage and bone lesions of OA occurred also in the medial tibia. Changes in perfusion occurred in the lateral tibia but not until OA lesions were established. Kinetic parameters of inflow were unchanged in both the medial and lateral plateaus. CONCLUSIONS: DCE MRI can be used to extract kinetic information on bone perfusion in an animal model of OA. The signal enhancement in subchondral bone temporally precedes and spatially localizes at the same site of the eventual bone and cartilage lesions. Time-intensity curves suggest outflow obstruction as an underlying mechanism.

Modification of osteoarthritis by pulsed electromagnetic field--a morphological study.

OBJECTIVE: Hartley guinea pigs spontaneously develop arthritis that bears morphological, biochemical, and immunohistochemical similarities to human osteoarthritis. It is characterized by the appearance of superficial fibrillation by 12 months of age and severe cartilage lesions and eburnation by 18 months of age. This study examines the effect of treatment with a pulsed electromagnetic field (PEMF) upon the morphological progression of osteoarthritis in this animal model. DESIGN: Hartley guinea pigs were exposed to a specific PEMF for 1h/day for 6 months, beginning at 12 months of age. Control animals were treated identically, but without PEMF exposure. Tibial articular cartilage was examined with histological/histochemical grading of the severity of arthritis, by immunohistochemistry for cartilage neoepitopes, 3B3(-) and BC-13, reflecting enzymatic cleavage of aggrecan, and by immunoreactivity to collagenase (MMP-13) and stromelysin (MMP-3). Immunoreactivity to TGFbeta, interleukin (IL)-1beta, and IL receptor antagonist protein (IRAP) antibodies was examined to suggest possible mechanisms of PEMF activity. RESULTS: PEMF treatment preserves the morphology of articular cartilage and retards the development of osteoarthritic lesions. This observation is supported by a reduction in the cartilage neoepitopes, 3B3(-) and BC-13, and suppression of the matrix-degrading enzymes, collagenase and stromelysin. Cells immunopositive to IL-1 are decreased in number, while IRAP-positive cells are increased in response to treatment. PEMF treatment markedly increases the number of cells immunopositive to TGFbeta. CONCLUSIONS: Treatment with PEMF appears to be disease-modifying in this model of osteoarthritis. Since TGFbeta is believed to upregulate gene expression for aggrecan, downregulate matrix metalloprotease and IL-1 activity, and upregulate inhibitors of matrix metalloprotease, the stimulation of TGFbeta may be a mechanism through which PEMF favorably affects cartilage homeostasis.

Power frequency fields promote cell differentiation coincident with an increase in transforming growth factor-beta(1) expression.

Recent information from several laboratories suggest that power frequency fields may stimulate cell differentiation in a number of model systems. In this way, they may be similar to pulsed electromagnetic fields, which have been used therapeutically. However, the effects of power frequency fields on phenotypic or genotypic expression have not been explained. This study describes the ability of power frequency fields to accelerate cell differentiation in vivo and describes dose relationships in terms of both amplitude and exposure duration. No change in proliferation or cell content were observed. A clear dose relationship, in terms of both amplitude and duration of exposure, was determined with the maximal biological response occurring at 0.1 mT and 7-9 h/day. Because this study was designed to explore biological activity at environmental exposure levels, this exposure range does not necessarily define optimal dosing conditions from the therapeutic point of view. This study reports the stimulation by power frequency fields of transforming growth factor-beta, an important signalling cytokine known to regulate cell differentiation. The hypothesis is raised that the stimulation of regulatory cytokines by electromagnetic fields may be an intermediary mechanism by which these fields have their biological activity.

Survival analysis of hips treated with core decompression or vascularized fibular grafting because of avascular necrosis.

Avascular necrosis of the femoral head is a multifaceted process that leads to articular incongruity and subsequent osteoarthrosis of the joint. Clinicians concur that primary treatment should focus on preservation of the natural surface of the joint; however, there has not been a consensus on how best to accomplish this. While a number of therapeutic interventions have been reported, the efficacy has varied markedly and there have been few statistical comparisons. The purpose of the current study was to use statistical analysis to compare the results of two widely used procedures, vascularized fibular grafting (614 hips; 480 patients) and core decompression (ninety-eight hips; seventy-two patients), for the treatment of avascular necrosis. The patients were stratified according to age and the stage of disease, and a survival analysis was performed with total hip arthroplasty as the end point for failure. None of the eleven hips that had Ficat stage-I disease needed a total joint replacement after being treated with either regimen. Analysis of the hips that had stage-II disease revealed rates of survival, at fifty months, of 65 per cent (twenty-eight of forty-three hips) after core decompression and 89 per cent (ninety-nine of 111 hips) after vascularized fibular grafting. For the hips that had Ficat stage-III disease, the rates of survival at fifty months were 21 per cent (ten of forty-seven hips) after core decompression and 81 per cent (405 of 500 hips) after vascularized fibular grafting. Among the hips that had Ficat stage-II or III disease, the rate of eventual total joint arthroplasty after vascularized fibular grafting was significantly lower than that after core decompression (p < 0.0001). The results indicate that the increased morbidity associated with vascularized fibular grafting is justified by the associated delay in or prevention of articular collapse in hips that have stage-II or III disease.

Acceleration of experimental endochondral ossification by biophysical stimulation of the progenitor cell pool.

Endochondral ossification can be modulated by a number of biochemical and biophysical stimuli. This study uses the experimental model of decalcified bone matrix-induced endochondral ossification to examine the effect of one biophysical stimulus, an electromagnetic field, on chondrogenesis, calcification, and osteogenesis. A temporal acceleration and quantitative increase in sulfate incorporation, glycosaminoglycan content, and calcification suggests that the stimulation of endochondral ossification is due to an increase in extracellular matrix synthesis. The locus of that stimulation is identified in the mesenchymal stage of endochondral bone development, and stimulation at this stage is essential for accelerated bone formation. The data suggest that enhanced differentiation of mesenchymal stem cells present at this stage is most likely responsible for the increase in extracellular matrix synthesis and bone maturation.

Therapeutic effects of electromagnetic fields in the stimulation of connective tissue repair.

The therapeutic effects of electric and magnetic fields have been studied largely for their promotion of connective tissue repair. The most widely studied application concerns bone repair and deals with acceleration of the healing of fresh fractures, delayed and non-unions, incorporation of bone grafts, osteoporosis, and osteonecrosis. More recently the effects of these fields upon the repair of cartilage and soft fibrous tissues have been described. In all these experimental systems and clinical applications an acceleration of extracellular matrix synthesis and tissue healing has been observed. A degree of specificity, in terms of the parameters of applied energy and biological response, is hypothesized.

Influence of electromagnetic fields on endochondral bone formation.

Endochondral ossification is a basic physiological process in limb development and is central to bone repair and linear growth. Factors which regulate endochondral ossification include several biophysical and biochemical agents and are of interest from clinical and biological perspectives. One of these agents, electric stimulation, has been shown to result in enhanced synthesis of extracellular matrix, calcification, and bone formation in a number of experimental systems and is the subject of this review. The effects of electric stimulation have been studied in embryonic limb rudiments, growth plates, and experimental endochondral ossification induced with decalcified bone matrix and, in all these models, endochondral ossification has been enhanced. It is not known definitively whether electric fields stimulate cell differentiation or modulate an increased number of molecules synthesized by committed cell population and this is a fertile area of current study.

Electrical stimulation of osteonecrosis of the femoral head.

Osteonecrosis of the femoral head in the adult is a progressive condition that, if untreated, usually results in femoral head collapse and secondary osteoarthritis. The experimental application of electrical and electromagnetic fields has been shown to favorably affect a number of biological processes pertinent to osteonecrosis of the femoral head and has led to several clinical trials. The condition has been treated by the application of electrical fields invasively by the surgical implantation of electrodes within the femoral head and noninvasively by capacitative or inductive coupling. This review describes results in osteonecrosis of the femoral head with these therapeutic techniques. Stimulation by means of inductive coupling with pulsed magnetic fields seems to be the most promising technique studied so far, but the optimal signal characteristics and device design are not yet known.

Seronegative symmetric polyarthritis in Sezary syndrome.

We describe a patient with Sezary syndrome and seronegative symmetric polyarthritis. Detailed analysis of the synovial membrane, including T lymphocyte subset delineation, demonstrated that malignant synovial infiltration was the direct cause of arthritis in this patient.

The conservative treatment of osteonecrosis of the femoral head. A comparison of core decompression and pulsing electromagnetic fields.

Once roentgenographic changes are apparent, osteonecrosis of the femoral head in the adult generally progresses to osteoarthritis within two to three years. A variety of conservative surgical procedures have been devised to conserve the femoral head with varying success. This study examines the effectiveness of pulsing electromagnetic fields and core decompression in the treatment of osteonecrosis of the femoral head. Both techniques reduce the incidence of clinical and roentgenographic progression. Exposure to pulsing electromagnetic fields appears to be more effective in hips with Ficat II lesions than in hips with more advanced lesions.

Stimulation of experimental endochondral ossification by low-energy pulsing electromagnetic fields.

Pulsed electromagnetic fields (PEMFs) of certain configuration have been shown to be effective clinically in promoting the healing of fracture nonunions and are believed to enhance calcification of extracellular matrix. In vitro studies have suggested that PEMFs may also have the effect of modifying the extracellular matrix by promoting the synthesis of matrix molecules. This study examines the effect of one PEMF upon the extracellular matrix and calcification of endochondral ossification in vivo. The synthesis of cartilage molecules is enhanced by PEMF, and subsequent endochondral calcification is stimulated. Histomorphometric studies indicate that the maturation of bone trabeculae is also promoted by PEMF stimulation. These results indicate that a specific PEMF can change the composition of cartilage extracellular matrix in vivo and raises the possibility that the effects on other processes of endochondral ossification (e.g., fracture healing and growth plates) may occur through a similar mechanism.

Compression ultrasonography for the detection of deep venous thrombosis in patients who have a fracture of the hip. A prospective study.

The effectiveness of compression ultrasonography in the detection of femoral and popliteal venous thrombosis was determined in a prospective trial over a period of seven months. Forty-two patients who had an isolated intertrochanteric or femoral neck fracture participated, and forty of these patients completed the study. The average age of the patients was 81.6 years. Venography was the standard with which all ultrasonic studies were compared. A total of 112 ultrasonic studies were performed. The incidence of major venous thrombosis, as detected by venography, was 12.5 per cent. All patients were clinically asymptomatic. The compression ultrasonic technique had an accuracy of 97 per cent, a sensitivity of 100 per cent, and a specificity of 97 per cent. Compression ultrasonography appears to be a very effective technique for diagnosing venous thrombosis in patients who have a fracture of the hip. It is safe, well accepted by both patients and staff, and simply and quickly performed, and it carries no inherent risks. It also can be readily repeated, making it ideal for monitoring high-risk patients.