Non-unions treated with bone morphogenic protein 7: introducing the quantitative measurement of human serum cytokine levels as promising tool in evaluation of adjunct non-union therapy.

BACKGROUND: In this study we sought to determine if application of bone morphogenic protein 7 (BMP-7) promotes physiological bone healing of non-unions and to investigate if serum cytokine analysis may serve as a promising tool in the analysis of adjunct non-union therapy. Therefore we analyzed the influence of BMP-7 application on the serum cytokine expression patterns on patients with impaired bone healing compared to patients that showed proper bone healing. METHODS: Our study involved analyzing blood samples from 208 patients with long bone fractures together with patients that subsequently developed non-unions. From this large pool, 15 patients with atrophic non-union were matched to 15 patients with atrophic non-union treated with local application of BMP-7 as well as normal bone healing. Changes in the cytokine expression patterns were monitored during the 1st, 2nd, 4th, 8th, 12th and 52nd week. The patients were followed both clinically and radiologically for the entire duration of the study. Serum cytokine expression levels of transforming growth factor beta (TGF-ß), platelet-derived growth factor (PDGF) and basic fibroblast growth factor (bFGF) were analyzed and compared. RESULTS: Serum expression of TGF-ß were nearly parallel in all three groups, however serum concentrations were significantly higher in patients with proper bone healing and those treated with BMP-7 than in patients with non-unions (p < 0.05). bFGF serum concentrations increased initially in patients with proper bone healing and in those treated with BMP-7. Afterwards, values decreased; bFGF serum concentrations in the BMP-7 group were significantly higher than in the other groups (p < 0.05). PDGF serum concentration levels were nearly parallel in all groups, serum concentrations were significantly higher in patients with proper bone healing and those treated with BMP-7 than in patients with non-unions (p < 0.05). CONCLUSION: Treatment with BMP-7 in patients with former non-unions led to similar cytokine expression patterns after treatment as those found in patients with proper bone healing. Our results suggest that treatment with BMP-7 promote healing of non-unions. Furthermore, quantitative measurement of serum cytokine expression is a promising tool for evaluating the effectiveness of additional non-union therapies such as adjunct application of growth factors.

Mimicry in older patients: tophaceous pseudogout as a tumorlike lesion: a case report.

Pseudogout is frequently seen in painful arthritis of larger joints, especially the knees and shoulders. This case report describes a rare clinical entity of soft-tissue calcium pyrophosphate dihydrate crystal deposition disease surrounding the second metatarsal bone of an 81-year-old man with moderate painful swelling of the right forefoot for 2 years. Diagnostic imaging demonstrated a calcified soft-tissue tumor adjacent to the second metatarsal bone by considering a neoplastic process in the differential diagnosis. Excisional biopsy revealed a chalklike material on the calcified soft tissue that was pathognomonic for chondrocalcinosis or pseudogout. The excisional biopsy findings led to stagnation of the clinical symptoms, and no recurrence of the initial tumor was seen during 12-month follow-up. In the literature, only 28 cases of tophaceous pseudogout tumors in the extremities have been described. In these cases, the lesions were suspected of being chondrosarcomas. For this reason, a correct diagnosis has to be pursued by performing a biopsy to treat the disease correctly.

Intraoperative subcutaneous wound closing culture sample: a predicting factor for periprosthetic infection after hip- and knee-replacement?

INTRODUCTION: It is unknown whether intraoperative subcutaneous wound closing culture samples (WCCS) are useful to predict periprosthetic joint infection (PJI). METHOD: Here we prospectively followed 167 out of a total of 175 consecutive patients with primary total hip (THR) or knee replacement (TKR) between 01/2002 and 12/2002 for a mean follow-up period of 5 years; of those patients, n = 159 (96.8%) underwent WCCS. RESULTS: The results showed a positive WCCS in n = 9 cases (5.8%). Nine patients developed postoperative wound complication and required revision surgery. Two patients developed signs of a deep periprosthetic infection; however, only one out of nine patients had initial positive WCCS. CONCLUSION: Our results thus indicate that WCCS during primary joint replacement is not an appropriate predictive method to identify patients at risk for periprosthetic joint infections.

The surgical treatment of unstable distal radius fractures by angle stable implants: a multicenter prospective study.

OBJECTIVES: The goal of this study is to document the 2-year outcome after surgical treatment of distal radius fractures using an angle stable implant. DESIGN: Prospective case-series. SETTING: Multicenter study in nine trauma units with recruitment between December 2001 and May 2003. PATIENTS: One hundred eight patients with the same number of distal radius fractures. INTERVENTION: Open reduction and internal fixation with the LCP DR 3.5 mm (Synthes GmbH, Oberdorf, Switzerland). MAIN OUTCOME MEASUREMENTS: Disabilities of the Arm, Shoulder and Hand, Gartland and Werley, SF-36 scores, radiologic assessment, and return to work status at 2 years. RESULTS: At 2 years, the mean range of motion (relative to the contralateral wrist) was 83% for palmar flexion, 91% for extension, 94% for radial deviation, 92% for ulnar deviation, and 98%/94% for pronation/supination angles. Grip strength was 90% of the mean uninjured side. The average radiographic measurements were 23.6° for radial inclination angle, 6.1° for palmar (volar) tilt angle, and 0 mm for ulnar variance. The proportion of fractures for which the Gartland and Werley score was categorized as either good or excellent was 89%. Minor complications occurred in 14 patients, although none of these events were considered to be directly related to the implant. CONCLUSION: After a 2-year follow-up period, the use of an angle stable implant for unstable distal radius fractures provides adequate fixation with minimal loss of reduction. This device is associated with good functional and radiologic outcome for the patient and is indicated for distal radius fractures classified as Orthopaedic Trauma Association (OTA) Type 23-A2/A3, OTA Type 23-B2/B3, and OTA Type 23-C.

Clinical application of BMP 7 in long bone non-unions.

BACKGROUND: Non-unions of long bone fractures are a therapeutic and economic problem of increasing frequency. Aside from conservative treatment options such as ultrasound, impulse waves, and casts, the basic surgical options are autogenous cancellous bone grafting, rod dynamization, reamed nailing, plate fixation, and bone transport techniques. If these methods fail to work, there is a need for alternative treatment options. METHODS: Since May 2001, treatment with recombinant human bone morphogenic protein 7 (BMP 7 or osteogenic protein 1) in combination with a type-one collagen carrier has been the subject of increasing interest. BMP 7 induces the formation of new bone by stem cell differentiation, thereby initiating the reaction cascade of osteogenesis. Non-unions over 9 months and unsuccessful bone grafting constitute the indication for this treatment. RESULTS: We report our experience with 54 patients who had atrophic non-union of long bone fractures. Between May 2002 and May 2006, 57 units of BMP 7 were used. The localization of the non-unions included 21 in the femur, 26 in the tibia, 3 in the humerus and 7 in the forearm. In 36 cases, BMP 7 was used in combination with osteosynthesis revision and bone grafting; in 9 additional patients, BMP 7 was used with bone grafting alone. In 12 patients, BMP 7 was applied as a single procedure without any bone grafting or any change in osteosynthesis. CONCLUSIONS: There were no perioperative or postoperative complications. Follow-up was obtained for a minimum of 6 months. 47 of the 57 (82%) implantations were successful, with bony healing confirmed by clinical and radiological evaluation. In summary, our results support BMP 7 as an additional innovative therapy for long bone non-unions.

T lymphocytes in acute bacterial infection: increased prevalence of CD11b(+) cells in the peripheral blood and recruitment to the infected site.

T-cell activation, particularly of CD8(+) cells, is invariably associated with viral infections. We now provide evidence for the activation of T cells in patients with localized bacterial soft tissue infections. During acute disease we detected in the peripheral blood of these patients, small though conspicuous populations of CD4(+) CD28(+) CD11b(+) and CD8(+) CD28(+) CD11b(+) cells, indicative of an expansion of effector T cells. Moreover, we identified CD4(+) and CD8(+) cells at the infected site, in addition to highly activated polymorphonuclear neutrophils (PMN). In keeping with their role as first-line defence, PMN were preponderant, but T cells amounted to 20% of the infiltrated cells. The majority of the infiltrated T cells expressed CXCR6, a homing receptor for non-lymphoid tissue. The infiltrated T cells produced interferon-gamma (IFN-gamma), while the peripheral blood cells obtained at the same time did not. In conclusion, in response to localized bacterial infections, T cells are activated and recruited to the infected site. We propose that these T cells, e.g. by producing IFN-gamma, enhance the efficiency of the infiltrated phagocytic cells, particularly of the PMN, thereby supporting the local host defence.

The dynamic vacuum orthosis: a functional and economical benefit?

In a prospective, randomised study, 27 patients with internally fixed ankle fractures were treated post-operatively for a period of six weeks by application of either a new dynamic vacuum orthosis with permitted mobilisation to 10 degrees -0 degrees -10 degrees at the ankle joint or a synthetic cast. Full weight bearing was allowed in both groups after two weeks. The cast group was prescribed four weeks of physiotherapy following six weeks of immobilisation. After ten weeks, the Olerud and Molander score showed a significant difference in favour of the orthosis. Early functional outcomes were significantly better for this group after six weeks and ten weeks. Patients in the orthosis group who were in formal employment returned to work 24 days earlier than those in the control group. Treatment of the orthosis patients took up three to four times less working time for the medical personnel. A saving of 38 euros on directly ascertainable costs could be evaluated. Rehabilitation of ankle fractures with a dynamic vacuum orthosis leads to better early functional results and greater patient satisfaction. The orthosis fulfils the conditions for early return to work. Treatment with an orthosis not only reduces working time for medical personnel but economises on expenditure for treatment and rehabilitation.

T lymphocytes in implant-associated posttraumatic osteomyelitis: Identification of cytotoxic T effector cells at the site of infection.

In implant-associated posttraumatic osteomyelitis, a massive infiltration of leukocytes into the infected site is seen. As described previously, the most infiltrated cells were highly activated polymorphonuclear neutrophils. In addition, a considerable T-cell infiltrate was noted. Whereas our previous work was mainly concerned with the phenotypical and functional characterization of the polymorphonuclear neutrophils, we now analyzed T lymphocytes of 32 patients with implant-associated posttraumatic osteomyelitis. We found evidence for an expansion of CD8 T cells in the peripheral blood of the patients and for an infiltration of these cells into the infected site. Further analysis of the surface-receptor pattern by three-color cytofluorometry revealed that the majority of these cells belonged to the cytotoxic-effector phenotype. Of note is that cytotoxic T cells are generally associated with virus infection. Thus, the detection of those cells in patients with bacterial infection was rather unexpected and points to a novel, not yet appreciated, role of CD8 T cells also in the defense of bacterial infections.

Computer-assisted LISS plate osteosynthesis of proximal tibia fractures: feasibility study and first clinical results.

Fluoroscopy is the most common tool for the intraoperative control of long-bone fracture reduction. Limitations of this technology include high radiation exposure for the patient and the surgical team, limited visual field, distorted images, and cumbersome verification of image updating. Fluoroscopy-based navigation systems partially address these limitations by allowing fluoroscopic images to be used for real-time surgical localization and instrument tracking. Existing fluoroscopy-based navigation systems are still limited as far as the virtual representation of true surgical reality is concerned. This article, for the first time, presents a reality-enhanced virtual fluoroscopy with radiation-free updates of in situ surgical fluoroscopic images to control metaphyseal fracture reduction. A virtual fluoroscopy is created using the projection properties of the fluoroscope; it allows the display of detailed three-dimensional (3D) geometric models of surgical tools and implants superimposed on the X-ray images. Starting from multiple registered fluoroscopy images, a virtual 3D cylinder model for each principal bone fragment is constructed. This spatial cylinder model not only supplies a 3D image of the fracture, but also allows effective fragment projection recovery from the fluoroscopic images and enables radiation-free updates of in situ surgical fluoroscopic images by non-linear interpolation and warping algorithms. Initial clinical experience was gained during four tibia fracture fixations that were treated by LISS (Less Invasive Stabilization System) osteosynthesis. In the cases operated on, after primary image acquisition, the image intensifier was replaced by the virtual reality system. In all cases, the procedure including fracture reduction and LISS osteosynthesis was performed entirely in virtual reality. A significant disadvantage was the unfamiliar operation of this prototype software and the need for an additional operator for the navigation system.

Expression of elastase on polymorphonuclear neutrophils in vitro and in vivo: identification of CD11b as ligand for the surface-bound elastase.

Elastase is a major serine protease of polymorphonuclear neutrophils (PMN). On activation of PMN, the preformed protein is mobilized from intracellular stores and, depending on the activating conditions, is either released into the supernatant or is bound to the cell surface. By a variety of methods, including uptake and crosslink studies, as well as confocal laser scan microscopy, we now provide evidence that elastase binds to the beta(2)-integrin CD11b and induces a conformational alteration of CD11b, apparent as expression of a neodeterminant. Similarly to the in vitro data, elastase surface expression and conformational alterations of CD11b were seen on PMN of patients with Staphylococcus aureus-induced localized infection, particularly on PMNs recovered from the infected site. The presence of elastase at the site of inflammation is in keeping with its presumed role in leukocyte trafficking and host defense. On the other hand, because of its potential for degrading extracellular matrix proteins, elastase could participate in localized tissue damage as it occurs in severe S. aureus infection.

Polymorphonuclear neutrophils in posttraumatic osteomyelitis: cells recovered from the inflamed site lack chemotactic activity but generate superoxides.

The pathogenesis of posttraumatic osteomyelitis, one of the major complications after orthopedic surgery, is not yet understood. Formation of bacterial biofilms on the implant is presumed, conferring resistance to antibiotic therapy and probably also to the host defense mechanisms. In that context, the polymorphonuclear neutrophils (PMN) having infiltrated the infected site were recovered and characterized phenotypically and functionally. Loss of CD62L and upregulation of CD14 were seen, as was expression of CD83. Expression of the latter is dependent on de novo protein synthesis and thus is indicative of an extended life span and a transdifferentiation of the PMN at the infected site. The infiltrated PMN had lost their chemotactic activity, whereas the capacity to produce superoxides was preserved and in some patients even enhanced. In vitro experiments done in parallel showed that long-term culture with interferon-gamma resulted in similar alterations of PMN: loss of chemotactic activity, whereas other functions of PMN, such generation of superoxides and phagocytosis of opsonized bacteria, were preserved or even enhanced. The loss of the migratory capacity of PMN having already emigrated from the blood vessel to the infected site is not expected to affect the host defense negatively. Assuming, however, that bacteria are organized as a biofilm and that infiltration into this biofilm is required for phagocytosis of the bacteria, our data could to some extent explain why despite being activated, the PMN are not able to control the infection. By releasing their cytotoxic, proteolytic, and collagenolytic potential, PMN might instead contribute to tissue destruction and eventually to osteolysis.

C-arm based navigation in total hip arthroplasty-background and clinical experience.

After experimental and preclinical evaluation of a CT-free image guided surgical navigation system for acetabular cup placement, the system was introduced into clinical routine. The computation of the angular orientation of the cup is based on reference coordinates from the anterior pelvic plane concept. A hybrid strategy for pelvic landmark acquisition has been introduced, involving percutaneous pointer-based digitization with the noninvasive bi-planar landmark reconstruction using multiple registered fluoroscopy images. From January 2001 to October 2003, a total of 236 consecutive patients (mean age 66 years, 144 male, 92 female, 124 left and 112 right hip joints) were operated on with the hybrid CT-free navigation system. During each operation, the angular orientation of the inserted implant was recorded. To determine the placement accuracy of the acetabular components, the first 50 consecutive patients underwent a CT scan 7-10 days postoperatively to analyze the cup position relative to the anterior pelvic plane. This procedure was done blinded and with commercial planning software. There was no significant learning curve observed for the use of the system. Mean values for postoperative inclination read 42 degrees (SD 3.6, range (37-49)) and anteversion 21 degrees (SD 3.9, range (10-28)). The resulting system accuracy, ie, the difference between intraoperatively calculated cup orientation and postoperatively measured implant position shows a maximum error of 5 degrees for the inclination (mean 1.5 degrees, SD 1.1) and 6 degrees for the anteversion (mean 2.4 degrees, SD 1.3). An accuracy of better than 5 degrees inclination and 6 degrees anteversion was achieved under clinical conditions, which implies that there is no significant difference in performance from the established CT-based navigation methods. Image-guided CT-free cup navigation provides a reliable solution for future total hip arthroplasty (THA).

Post-traumatic osteomyelitis: analysis of inflammatory cells recruited into the site of infection.

Device-associated infections after implants or endoprostheses inflict local inflammation and ultimately osteolysis, a clinical entity referred to as posttraumatic osteomyelitis. The underlying molecular mechanisms are not yet known; formation of bacterial biofilms on the implant is presumed, conferring resistance to antibiotics and to host defense mechanisms as well. To gain insight into the pathogenesis of post-traumatic osteomyelitis, the infected site was analyzed for the presence of immunocompetent cells. In 18 patients, the infected site was rinsed intraoperatively. This so-called lavage contained 1-2 x 107 leukocytes, predominantly highly activated polymorphonuclear neutrophils (PMNs), as characterized by low expression of CD62L (selectin), and high expression of the adhesion protein CD18, of the high-affinity immunoglobulin (IgG) receptor CD64, and of the LPS-receptor CD14. CD16, the low-affinity IgG receptor, was affected in some patients only. Because the majority of infections were caused by staphylococci species, the effect of bacteria-derived lipoteichoic acid on PMN of healthy donors was tested in vitro. A similar activation pattern was found: rapid down-regulation of CD62L, a slower loss of CD16, and upregulation of CD18, CD64, and CD14. Lipoteichoic acid signaling required p38 mitogen-activated protein kinase and resulted in induction of CD14-specific mRNA and de novo protein synthesis. We conclude that PMNs infiltrate the infected site, but despite local activation they are unable to clear the bacteria, presumably because of biofilm formation. Our data are consistent with the hypothesis that during the ineffective "frustrated" attempt to phagocytose, PMNs release cytotoxic and proteolytic entities that in turn contribute to the progression of tissue injury and ultimately to osteolysis.

Image-based hip navigation.

After experimental and preclinical evaluation (HAP Paul Award 2001) of a CT-free image-guided surgical navigation system for acetabular cup placement, the system was introduced into clinical routine. The computation of the angular orientation of the cup is based on reference coordinates from the anterior pelvic plane (APP) concept. A hybrid strategy for pelvic landmark acquisition has been introduced involving percutaneous pointer-based digitization with the noninvasive biplanar landmark reconstruction using multiple registered fluoroscopy images. From January 2001 to May 2002, 118 consecutive patients (mean age 68 years, 82 male, 36 female, and 62 left and 56 right hip joints) were operated on with the hybrid CT-free navigation system. During each operation, the angular orientation of the inserted implant was recorded. To determine the placement accuracy of the acetabular components, the first 50 consecutive patients underwent a CT scan 7-10 days postoperatively to analyze the cup position relative to the APP. This was done blinded with commercial planning software. There was no significant learning curve observed for the use of the system. Mean values for postoperative inclination read 43 degrees (SD 3.0, range 37-49) and anteversion 19 degrees (SD 3.9, range 10-28). The resulting system accuracy, i.e., the difference between intraoperatively calculated cup orientation and postoperatively measured implant position, shows a maximum error of 5 degrees for the inclination (mean 1.5 degrees, SD 1.1) and 6 degrees for the anteversion (mean 2.4 degrees, SD 1.3). An accuracy of better than 5 degrees inclination and 6 degrees anteversion was achieved under clinical conditions, which implies that there is no significant difference in performance from the established CT-based navigation methods. Image-guided CT-free cup navigation provides a reliable solution for future total hip arthroplasty (THA).