In this study a combination of autologous chondrocyte implantation (ACI) and the osteochondral autograft transfer system (OATS) was used and evaluated as a treatment option for the repair of large areas of degenerative articular cartilage. We present the results at three years post-operatively. Osteochondral cores were used to restore the contour of articular cartilage in 13 patients with large lesions of the lateral femoral condyle (n = 5), medial femoral condyle (n = 7) and patella (n = 1). Autologous cultured chondrocytes were injected underneath a periosteal patch covering the cores. After one year, the patients had a significant improvement in their symptoms and after three years this level of improvement was maintained in ten of the 13 patients. Arthroscopic examination revealed that the osteochondral cores became well integrated with the surrounding cartilage. We conclude that the hybrid ACI/OATS technique provides a promising surgical approach for the treatment of patients with large degenerative osteochondral defects

Treatment with corticosteroids is a risk factor for non-traumatic avascular necrosis of the femoral head, but the pathological mechanism is poorly understood. Short-term treatment with high doses of methylprednisolone is used in severe neurotrauma and after kidney and heart transplantation. We investigated the effect of such treatment on the pattern of perfusion of the femoral head and of bone in general in the pig. We allocated 15 immature pigs to treatment with high-dose methylprednisolone (20 mg/kg per day intramuscularly for three days, followed by 10 mg/kg intramuscularly for a further 11 days) and 15 to a control group. Perfusion of the systematically subdivided femoral head, proximal femur, acetabulum, humerus, and soft tissues was determined by the microsphere technique. Blood flow in bone was severely reduced in the steroid-treated group. The reduction of flow affected all the segments and the entire epiphysis of the femoral head. No changes in flow were found in non-osseous tissue. Short-term treatment with high-dose methylprednisolone causes reduction of osseous blood flow which may be the pathogenetic factor in the early stage of steroid-induced osteonecrosis

Cancer-induced bone diseases are often associated with increased bone resorption and pathological fractures. In recent years, osteoprotective agents such as bisphosphonates have been studied extensively and have been shown to inhibit cancer-related bone resorption in experimental and clinical studies. The third-generation bisphosphonate, ibandronate (BM 21.0955), is a potent compound for controlling tumour osteolysis and hypercalcaemia in rats bearing Walker 256 carcinosarcoma. We have studied the effect of ibandronate given as an interventional treatment on bone strength and bone loss after the onset of tumour growth in bone. Our results suggest that it is capable of preserving bone quality in rats bearing Walker 256 carcinosarcoma cells. Since other bisphosphonates have produced comparable results in man after their success in the Walker 256 animal models our findings suggest that ibandronate may be a powerful treatment for maintaining skeletal integrity in patients with metastatic bone disease

The intermittent administration of parathyroid hormone (PTH) increases the formation of bone by stimulating osteoblastic activity. Our study evaluates the possibility that intermittent treatment with PTH (1-34) may also enhance the implant-bone fixation of stainless-steel screws. Twenty-eight rats received one screw in either one (n = 8) or in both (n = 20) proximal tibiae. We administered either PTH (1-34) in a dosage of 60 μg/kg/day (n = 14) or vehicle (n = 14) over a period of four weeks. At the end of this time, the degree of fixation was assessed by measuring the removal torque on one screw in each rat (n = 28) and the pull-out strength on the contralateral screw (n = 20). PTH increased the mean removal torque from 1.1 to 3.5 Ncm (p = 0.001) and the mean pull-out strength from 66 to 145 N (p = 0.002). No significant differences in body-weight or ash weight of the femora were seen. Histological examination showed that both groups had areas of soft tissue at the implant-bone interface, but these appeared less in the PTH group. These results indicate that intermittent treatment with PTH may enhance the early fixation of orthopaedic implants

The treatment of fractures of the proximal tibia is complex and makes great demands on the implants used. Our study aimed to identify what levels of primary stability could be achieved with various forms of osteosynthesis in the treatment of diaphyseal fractures of the proximal tibia. Pairs of human tibiae were investigated. An unstable fracture was simulated by creating a defect at the metaphyseal-diaphyseal junction. Six implants were tested in a uniaxial testing device (Instron) using the quasi-static and displacement-controlled modes and the force-displacement curve was recorded. The movements of each fragment and of the implant were recorded video-optically (MacReflex, Qualysis). Axial deviations were evaluated at 300 N. The results show that the nailing systems tolerated the highest forces. The lowest axial deviations in varus and valgus were also found for the nailing systems; the highest axial deviations were recorded for the buttress plate and the less invasive stabilising system (LISS). In terms of rotational displacement the LISS was better than the buttress plate. In summary, it was found that higher loads were better tolerated by centrally placed load carriers than by eccentrically placed ones. In the case of the latter, it appears advantageous to use additive procedures for medial buttressing in the early phase

We have developed a new drug-delivery system using reconstituted bone xenograft to treat chronic osteomyelitis. This material, which has the capabilities of osteoinduction and osteoconduction, was supplemented with up to 2000 times the minimum inhibitory concentration of gentamicin against Staphylococcus aureus to prepare a gentamicin-reconstituted bone xenograft-composite (G-RBX-C). In a rabbit model, we evaluated the release of gentamicin from this composite in vivo, its capability for induction of ectopic bone and the repair of segmental defects of the radius. There was a high level of concentration of antibiotics, which was sustained for at least ten days. In the study of induction of ectopic bone, there was abundant woven bone in the G-RBX-C group two weeks after operation. At 16 weeks after implantation of G-RBX-C the radial defects had been repaired, with the formation of lamellar bone and recanalisation of the marrow cavity. Our findings suggest that G-RBX-C may be useful in the treatment of chronic osteomyelitis

Immobilisation causes denervation-like changes in the motor endplates, decreases the content of IGF-I, and increases the number of IGF-I receptors in the spinal cord. In the rat we investigated whether similar changes occur after a fracture of the midshaft of the femur which had been treated by intramedullary fixation with adequate or undersized pins. A more pronounced reduction in muscle wet weight was seen after fixation by undersized pins as well as decreased ash density of the ipsilateral tibia which did not completely return to normal within the 12-week experimental period. The nicotinic cholinergic receptors in the motor endplates of tibialis anterior were increased (p < 0.01) and there was a significant increase (p < 0.02) in IGF-I receptors in the lumbar spinal cord ipsilateral to the fracture after treatment by undersized nails. These changes may be associated with the impaired proprioception, co-ordination and motor activity which are sometimes seen after fractures

In a series of 12 patients with inoperable gastric carcinoma who had treatment with a synthetic matrix metalloproteinase inhibitor (Marimastat) for more than one month, six developed a frozen shoulder or a condition resembling Dupuytren’s disease. This suggests that the matrix metalloproteinases, a family of naturally occurring proteinases, may be involved in the pathogenesis of these two conditions. Our observation opens avenues for further research which could lead to local or systemic therapeutic interventions for frozen shoulder and Dupuytren’s disease

The use of a composite osteochondral device for simulating partial hemiarthroplasty was examined. The device was composed of a polyvinyl alcohol hydrogel and a titanium fibre mesh, acting as artificial cartilage and as porous artificial bone, respectively. The titanium fibre mesh was designed to act as an interface material, allowing firm attachment to both the polyvinyl alcohol gel (through injection moulding) and the femoral joint surface (through bony ingrowth). We implanted 22 of these devices into canine femoral heads. Histological findings from the acetabular cartilage and synovial membrane, as well as the attachment of the prosthesis to bone, were examined up until one year after operation.

No marked pathological changes were found and firm attachment of the device to the underlying bone was confirmed. The main potential application for this device is for partial surface replacement of the femoral head after osteonecrosis. Other applications could include articular resurfacing and the replacement of intervertebral discs.

The efficacy of β-tricalcium phosphate (β-TCP) loaded with bone morphogenetic protein-2 (BMP-2)-gene-modified bone-marrow mesenchymal stem cells (BMSCs) was evaluated for the repair of experimentally-induced osteonecrosis of the femoral head in goats.

Bilateral early-stage osteonecrosis was induced in adult goats three weeks after ligation of the lateral and medial circumflex arteries and delivery of liquid nitrogen into the femoral head. After core decompression, porous β-TCP loaded with BMP-2 gene- or β-galactosidase (gal)-gene-transduced BMSCs was implanted into the left and right femoral heads, respectively. At 16 weeks after implantation, there was collapse of the femoral head in the untreated group but not in the BMP-2 or β-gal groups. The femoral heads in the BMP-2 group had a normal density and surface, while those in the β-gal group presented with a low density and an irregular surface. Histologically, new bone and fibrous tissue were formed in the macropores of the β-TCP. Sixteen weeks after implantation, lamellar bone had formed in the BMP-2 group, but there were some empty cavities and residual fibrous tissue in the β-gal group. The new bone volume in the BMP-2 group was significantly higher than that in the β-gal group. The maximum compressive strength and Young’s modulus of the repaired tissue in the BMP-2 group were similar to those of normal bone and significantly higher than those in the β-gal group.

Our findings indicate that porous β-TCP loaded with BMP-2-gene-transduced BMSCs are capable of repairing early-stage, experimentally-induced osteonecrosis of the femoral head and of restoring its mechanical function.

We have developed a new drug delivery system using porous apatite-wollastonite glass ceramic (A-W GC) to treat osteomyelitis. A-W GC (porosity, 70% and 20% to 30%), or porous hydroxyapatite (HA) blocks (porosity 35% to 48%) used as controls, were soaked in mixtures of two antibiotics, isepamicin sulphate (ISP) and cefmetazole (CMZ) under high vacuum.

We evaluated the release concentrations of the antibiotics from the blocks. The bactericidal concentration of ISP from A-W GC was maintained for more than 42 days, but that from HA decreased to below the detection limit after 28 days. The concentrations of CMZ from both materials were lower than those of ISP. An in vivo study using rabbit femora showed that an osseous concentration of ISP was maintained at eight weeks after implantation. Osteoconduction of the A-W GC block was good.

Four patients with infected hip arthroplasties and one with osteomyelitis of the tibia have been treated with the new delivery system with excellent results.

We have investigated the anatomy of the proximal part of the ulna to assess its influence on the use of plates in the management of fractures at this site. We examined 54 specimens from cadavers. The mean varus angulation in the proximal third was 17.5° (11° to 23°) and the mean anterior deviation 4.5° (1° to 14°). These variations must be considered when applying plates to the dorsal surface of the ulna for Monteggia-type fractures. A pre-operative radiograph of the contralateral elbow may also be of value.

Various chemicals are commonly used as adjuvant treatment to surgery for giant-cell tumour (GCT) of bone. The comparative effect of these solutions on the cells of GCT is not known. In this study we evaluated the cytotoxic effect of sterile water, 95% ethanol, 5% phenol, 3% hydrogen peroxide (H. 2. O. 2. ) and 50% zinc chloride (ZnCI. 2. ) on GCT monolayer tumour cultures which were established from six patients. The DNA content, the metabolic activity and the viability of the cultured samples of tumour cells were assessed at various times up to 120 hours after their exposure to these solutions. Equal cytotoxicity to the GCT monolayer culture was observed for 95% ethanol, 5% phenol, 3% H. 2. O. 2. and 50% ZnCI. 2. The treated samples showed significant reductions in DNA content and metabolic activity 24 hours after treatment and this was sustained for up to 120 hours. The samples treated with sterile water showed an initial decline in DNA content and viability 24 hours after treatment, but the surviving cells were viable and had proliferated. No multinucleated cell formation was seen in these cultures. These results suggest that the use of chemical adjuvants other than water could help improve local control in the treatment of GCT of bone

We studied 51 patients with osteo-articular tuberculosis who were divided into two groups. Group I comprised 31 newly-diagnosed patients who were given first-line antituberculous treatment consisting of isoniazid, rifampicin, ethambutol and pyrazinamide. Group II (non-responders) consisted of 20 patients with a history of clinical non-responsiveness to supervised uninterrupted antituberculous treatment for a minimum of three months or a recurrence of a previous lesion which on clinical observation had healed. No patient in either group was HIV-positive. Group II were treated with an immunomodulation regime of intradermal BCG, oral levamisole and intramuscular diphtheria and tetanus vaccines as an adjunct for eight weeks in addition to antituberculous treatment. We gave antituberculous treatment for a total of 12 to 18 months in both groups and they were followed up for a mean of 30.2 months (24 to 49). A series of 20 healthy blood donors served as a control group. Twenty-nine (93.6%) of the 31 patients in group I and 14 of the 20 (70%) in group II had a clinicoradiological healing response to treatment by five months. The CD4 cell count in both groups was depressed at the time of enrolment, with a greater degree of depression in the group-II patients (686 cells/mm. 3. (. sd. 261) and 545 cells/mm. 3. (. sd. 137), respectively; p < 0.05). After treatment for three months both groups showed significant elevation of the CD4 cell count, reaching a level comparable with the control group. However, the mean CD4 cell count of group II (945 cells/mm. 3. (. sd. 343)) still remained lower than that of group I (1071 cells/mm. 3. (. sd. 290)), but the difference was not significant. Our study has shown encouraging results after immunomodulation and antituberculous treatment in non-responsive patients. The pattern of change in the CD4 cell count in response to treatment may be a reliable clinical indicator

Corticosteroids are prescribed for the treatment of many medical conditions and their adverse effects on bone, including steroid-associated osteoporosis and osteonecrosis, are well documented. Core decompression is performed to treat osteonecrosis, but the results are variable. As steroids may affect bone turnover, this study was designed to investigate bone healing within a bone tunnel after core decompression in an experimental model of steroid-associated osteonecrosis. A total of five 28-week-old New Zealand rabbits were used to establish a model of steroid-induced osteonecrosis and another five rabbits served as controls. Two weeks after the induction of osteonecrosis, core decompression was performed by creating a bone tunnel 3 mm in diameter in both distal femora of each rabbit in both the experimental osteonecrosis and control groups. An in vivo micro-CT scanner was used to monitor healing within the bone tunnel at four, eight and 12 weeks postoperatively. At week 12, the animals were killed for histological and biomechanical analysis. In the osteonecrosis group all measurements of bone healing and maturation were lower compared with the control group. Impaired osteogenesis and remodelling within the bone tunnel was demonstrated in the steroid-induced osteonecrosis, accompanied by inferior mechanical properties of the bone. We have confirmed impaired bone healing in a model of bone defects in rabbits with pulsed administration of corticosteroids. This finding may be important in the development of strategies for treatment to improve the prognosis of fracture healing or the repair of bone defects in patients receiving steroid treatment

The discrepancy between successful experimental studies of cartilage repair and the clinical results is unexplained. We have evaluated the effect of metabolic alterations in joint homeostasis owing to an articular defect on the outcome of cartilage repair using tissue engineering methods. We used 21 adolescent Dutch goats divided into three groups. The control knees were left untreated while the contralateral knee was randomised to receive either no treatment (N), early treatment (E) or late treatment (L). The metabolism of proteoglycans in the surrounding joint surface was determined and correlated with the O’Driscoll score used to quantify the histological aspect of the repair of the defect. Synthesis of proteoglycan (PG) was increased in all groups. The release of glucosaminoglycan (GAG) was significantly higher in the untreated but not after early transplantation (1.3 v 1.8 NS). The cartilage repair scores in the early treatment group were not as good as those of the normal control group, but were significantly better when compared with both the untreated defects and the late treated defects. Defects which had been treated late showed a significantly decreased score when compared with those which had had early treatment or the normal control group and did not differ (p = 0.12) from those with no treatment. The histological and biochemical scores closely resembled the macroscopic and functional parameters which showed a significant deterioration for the late treated group and those without treatment compared with animals treated early. Thus, tissue-engineered cartilage repair is negatively influenced by altered matrix metabolism. Early treatment showed significantly better results for repair of cartilage than late or no treatment, with a concurrent decrease in the detrimental disturbance of cartilage metabolism which constituted a protective effect on the articulation

We evaluated the possible induction of a systemic immune response to increase anti-tumour activity by the re-implantation of destructive tumour tissue treated by liquid nitrogen in a murine osteosarcoma (LM8) model. The tumours were randomised to treatment by excision alone or by cryotreatment after excision. Tissue from the tumour was frozen in liquid nitrogen, thawed in distilled water and then re-implanted in the same animal. In addition, some mice received an immunological response modifier of OK-432 after treatment. We measured the levels of interferon-gamma and interleukin-12 cytokines and the cytotoxicity activity of splenocytes against murine LM8 osteosarcoma cells. The number of lung and the size of abdominal metastases were also measured. Re-implantation of tumour tissue after cryotreatment activated immune responses and inhibited metastatic tumour growth. OK-432 synergistically enhanced the anti-tumour effect. Our results suggest that the treatment of malignant bone tumours by reconstruction using autografts containing tumours which have been treated by liquid nitrogen may be of clinical value

Platelet-leucocyte gel (PLG), a new biotechnological blood product, has hitherto been used primarily to treat chronic ulcers and to promote soft-tissue and bone regeneration in a wide range of medical fields. In this study, the antimicrobial efficacy of PLG against Staphylococcus aureus (ATCC 25923) was investigated in a rabbit model of osteomyelitis. Autologous PLG was injected into the tibial canal after inoculation with Staph. aureus. The prophylactic efficacy of PLG was evaluated by microbiological, radiological and histological examination. Animal groups included a treatment group that received systemic cefazolin and a control group that received no treatment. Treatment with PLG or cefazolin significantly reduced radiological and histological severity scores compared to the control group. This result was confirmed by a significant reduction in the infection rate and the number of viable bacteria. Although not comparable to cefazolin, PLG exhibited antimicrobial efficacy in vivo and therefore represents a novel strategy to prevent bone infection in humans

Extracorporeal shock-wave (ESW) treatment hasbeen shown to be effective in promoting the healing of fractures. We aimed to determine whether ESW could enhance the growth of bone-marrow osteoprogenitor cells. We applied ESW to the left femur of rats 10 mm above the knee at 0.16 mJ/mm. 2. in a range of between 250 and 2000 impulses. Bone-marrow cells were harvested after ESW for one day and subjected to assessment of colony-forming unit (CFU) granulocytes, monocytes, erythocytes, megakaryocytes (CFU-Mix), CFU-stromal cells (CFU-S) and CFU-osteoprogenitors (CFU-O). We found that the mean value for the CFU-O colonies after treatment with 500 impulses of ESW was 168.2 CFU-O/well (. sem. 11.3) compared with 88.2 CFU-O/well (. sem. 7.2) in the control group. By contrast, ESW treatment did not affect haematopoiesis as shown by the CFU-Mix (p = 0.557). Treatment with 250 and 500 impulses promoted CFU-O, but not CFU-Mix formations whereas treatment with more than 750 impulses had an inhibiting effect. Treatment with 500 impulses also enhanced the activity of bone alkaline phosphatase in the subculture of CFU-O (p< 0.01), indicating a selective promotion of growth of osteoprogenitor cells. Similarly, formation of bone nodules in the long-term culture of bone-marrow osteoprogenitor cells was also significantly enhanced by ESW treatment with 500 impulses. The mean production of TGF-β1 was 610 pg/ml (. sem. 84.6) in culture supernatants from ESW-treated rats compared with 283 pg/ml (. sem. 36.8) in the control group. Our findings suggest that optimal treatment with ESW could enhance rat bone-marrow stromal growth and differentiation towards osteoprogenitors presumably by induction of TGF-β1

Thrombin has many biological properties similar to those of growth factors. In a previous study, we showed that thrombin improves healing of the rat tendo Achillis. Low molecular weight heparin (LMWH) inhibits the activity and the generation of thrombin. We therefore considered that LMWH at a thromboprophylactic dose might inhibit tendon repair. Transection of the tendo Achillis was carried out in 86 rats and the healing tested mechanically. Low molecular weight heparin (dalateparin) was either injected a few minutes before the operation and then given continuously with an osmotic mini pump for seven days, or given as one injection before the operation. In another experiment ,we gave LMWH or a placebo by injection twice daily. The anti-factor Xa activity was analysed. Continuous treatment with LMWH impaired tendon healing. After seven days, this treatment caused a 33% reduction in force at failure, a 20% reduction in stiffness and a 67% reduction in energy uptake. However, if injected twice daily, LMWH had no effect on tendon healing. Anti-factor Xa activity was increased by LMWH treatment, but was normal between intermittent injections. Low molecular weight heparin delays tendon repair if given continuously, but not if injected intermittently, probably because the anti-factor Xa activity between injections returns to normal, allowing sufficient thrombin stimulation for repair. These findings indicate the need for caution in the assessment of long-acting thrombin and factor Xa inhibitors