Patrick Strube

Diagnosis of periprosthetic infection following total hip arthroplasty – evaluation of the diagnostic values of pre- and intraoperative parameters and the associated strategy to preoperatively select patients with a high probability of joint infection

BackgroundThe correct diagnosis of a prosthetic joint infection (PJI) is crucial for adequate surgical treatment. The detection may be a challenge since presentation and preoperative tests are not always obvious and precise. This prospective study was performed to evaluate a variety of pre- and intraoperative investigations. Furthermore a detailed evaluation of concordance of each preoperative diagnosis was performed, together with a final diagnosis to assess the accuracy of the pre-operative assumption of PJI.MethodsBetween 01/2005 and 02/2007, a prospective analysis was performed in 50 patients, who had a two stage revision because of assumed PJI. Based on clinical presentation, radiography, haematological screening, or early failure, infection was assumed and a joint aspiration was performed. Depending upon these findings, a two stage revision was performed, with intra-operative samples for culture and histological evaluation obtained. Final diagnosis of infection was based upon the interpretation of the clinical presentation and the pre- and intraoperative findings.ResultsIn 37 patients a positive diagnosis of PJI could be made definitely. The histopathology yielded the highest accuracy (0.94) in identification of PJI and identified 35 of 37 infections (sensitivity 0.94, specificity 0.94, positive-/negative predictive value 0.97/0.86). Intra-operative cultures revealed sensitivities, specificities, positive-/negative predictive values and accuracy of 0.78, 0.92, 0.96, 0.63 and 0.82. These values for blood screening tests were 0.95, 0.62, 0.88, 0.80, and 0.86 respectively for the level of C-reactive protein, and 0.14, 0.92, 0.83, 0.29 and, 0.34 respectively for the white blood-cell count. The results of aspiration were 0.57, 0.5, 0.78, 0.29, and 0.54.ConclusionThe detection of PJI is still a challenge in clinical practice. The histopathological evaluation emerges as a highly practical diagnostic tool in detection of PJI. Furthermore, we found a discrepancy between the pre-operative suspicion of PJI and the final post-operative diagnosis, resulting in a slight uncertainty in whether loosening is due to bacterial infection or not. The variation in accuracy of the single tests may influence the detection of PJI. Level of Evidence: Diagnostic Level I.

Influences of age and mechanical stability on volume, microstructure, and mineralization of the fracture callus during bone healing: Is osteoclast activity the key to age-related impaired healing?

Earlier studies have shown that the influence of fixation stability on bone healing diminishes with advanced age. The goal of this study was to unravel the relationship between mechanical stimulus and age on callus competence at a tissue level. Using 3D in vitro micro-computed tomography derived metrics, 2D in vivo radiography, and histology, we investigated the influences of age and varying fixation stability on callus size, geometry, microstructure, composition, remodeling, and vascularity. Compared were four groups with a 1.5-mm osteotomy gap in the femora of Sprague-Dawley rats: Young rigid (YR), Young semirigid (YSR), Old rigid (OR), Old semirigid (OSR). Hypothesis was that calcified callus microstructure and composition is impaired due to the influence of advanced age, and these individuals would show a reduced response to fixation stabilities. Semirigid fixations resulted in a larger DeltaCSA (Callus cross-sectional area) compared to rigid groups. In vitro microCT analysis at 6 weeks postmortem showed callus bridging scores in younger animals to be superior than their older counterparts (p<0.01). Younger animals showed (i) larger callus strut thickness (p<0.001), (ii) lower perforation in struts (p<0.01), and (iii) higher mineralization of callus struts (p<0.001). Callus mineralization was reduced in young animals with semirigid fracture fixation but remained unaffected in the aged group. While stability had an influence, age showed none on callus size and geometry of callus. With no differences observed in relative osteoid areas in the callus ROI, old as well as semirigid fixated animals showed a higher osteoclast count (p<0.05). Blood vessel density was reduced in animals with semirigid fixation (p<0.05). In conclusion, in vivo monitoring indicated delayed callus maturation in aged individuals. Callus bridging and callus competence (microstructure and mineralization) were impaired in individuals with an advanced age. This matched with increased bone resorption due to higher osteoclast numbers. Varying fixator configurations in older individuals did not alter the dominant effect of advanced age on callus tissue mineralization, unlike in their younger counterparts. Age-associated influences appeared independent from stability. This study illustrates the dominating role of osteoclastic activity in age-related impaired healing, while demonstrating the optimization of fixation parameters such as stiffness appeared to be less effective in influencing healing in aged individuals.

Influence of age and mechanical stability on bone defect healing: Age reverses mechanical effects

Non-unions and delayed healing are still prevalent complications in fracture and bone defect healing. Both mechanical stability and age are known to influence this process. However, it remains unclear which factor dominates and how they interact. Within this study, we sought a link between both factors. In 36 female Sprague-Dawley rats, the left femur was osteotomized, distracted to an osteotomy gap of 1.5 mm and externally fixated. Variation of age (12 vs. 52 weeks - biologically challenging) and fixator stiffness (mechanically challenging) resulted in 4 groups (each 9 animals): YS: young semi-rigid, OS: old semi-rigid, YR: young rigid and OR: old rigid. Qualitative and quantitative radiographical analyses were performed at weeks 2, 4 and 6 after surgery. Six weeks post-op, rats were sacrificed and femora were harvested for biomechanical testing (torsional stiffness (TS) and maximum torque at failure (MTF)). Six weeks after surgery, TS showed a significant interaction between age and fixation stiffness (p<0.0001). TS in YR was significantly higher than that in the other groups (YS: p<0.001; OR: p<0.001; OS: p<0.001). Additionally, YS showed a significantly higher TS compared to the OS (p=0.006) and OR (p=0.046). Testing of MTF showed a significant interaction of both variables (p=0.0002) and led to significant differences between OR and YS (p<0.001), OS (p=0.046) and YR (p<0.001). The YR showed a higher MTF compared to YS (p=0.012) and OS (p=0.001), whereas ORs MTF was inferior compared to OS. At 2-week follow-up, YR (p=0.006), and at 6-week follow-up, YS and YR (p=0.032) showed significantly higher radiographic scores. At 2-week follow-up, YSs callus was larger than that of the old groups (OS: p=0.025; OR: p=0.003). In YR a significantly smaller callus was observed compared to YS at time points 4 and 6 weeks (p=0.002 for both) and compared to OS at 6-week follow-up (p=0.03). The effect of age seems to invert the effect of mechanical properties of the callus, which was not correlated to callus size. Optimization of mechanics alone seems to be not sufficient. The underlying mechanisms and causes of the age-related influences and their clinical counterparts need to be further investigated.

Designing biomimetic scaffolds for bone regeneration: why aim for a copy of mature tissue properties if nature uses a different approach?

This review aims to address the current limitations in biomaterial scaffold-based treatment strategies for bone defect healing and suggests new, alternative approaches that merit further investigation. The question of whether the biomaterial scaffold properties should mimic the natural extracellular matrix of mature tissue or some phase of the dynamic range of tissues observed during the healing process is discussed. Additionally, the authors advocate for a biomimetic approach, which uses the endogenous secondary fracture healing processes to inform the design of scaffold constructs. In particular, the mechanical environment is emphasized as an important factor influencing the clinical success of these constructs. The authors stress the need for a scaffolds design that provides an optimal mechanical environment for cell fate, supplies necessary signals and nutrition to the cells and, thus, more closely mimics the natural healing cascade.

Intra-operatively customized implant coating strategies for local and controlled drug delivery to bone.

Bone is one of the few tissues in the human body with high endogenous healing capacity. However, failure of the healing process presents a significant clinical challenge; it is a tremendous burden for the individual and has related health and economic consequences. To overcome such healing deficits, various concepts for a local drug delivery to bone have been developed during the last decades. However, in many cases these concepts do not meet the specific requirements of either surgeons who must use these strategies or individual patients who might benefit from them. We describe currently available methods for local drug delivery and their limitations in therapy. Various solutions for drug delivery to bone focusing on clinical applications and intra-operative constraints are discussed and drug delivery by implant coating is highlighted. Finally, a new set of design and performance requirements for intra-operatively customized implant coatings for controlled drug delivery is proposed. In the future, these requirements may improve approaches for local and intra-operative treatment of patients.

Time course of skeletal muscle regeneration after severe trauma

Background and purpose Animal models of skeletal muscle injury should be thoroughly described and should mimic the clinical situation. We established a model of a critical size crush injury of the soleus muscle in rats. The aim was to describe the time course of skeletal muscle regeneration using mechanical, histological, and magnetic resonance (MR) tomographic methods. Methods Left soleus muscles of 36 Sprague-Dawley rats were crushed in situ in a standardized manner. We scanned the lower legs of 6 animals by 7-tesla MR one week, 4 weeks, and 8 weeks after trauma. Regeneration was evaluated at these times by in vivo measurement of muscle contraction forces after fast-twitch and tetanic stimulation (groups 1W, 4W, 8W; 6 per group). Histological and immunohistological analysis was performed and the amount of fibrosis within the injured muscles was determined histomorphologically. Results MR signals of the traumatized soleus muscles showed a clear time course concerning microstructure and T1 and T2 signal intensity. Newly developed neural endplates and myotendinous junctions could be seen in the injured zones of the soleus. Tetanic force increased continuously, starting at 23% (SD 4) of the control side (p < 0.001) 1 week after trauma and recovering to 55% (SD 23) after 8 weeks. Fibrotic tissue occupied 40% (SD 4) of the traumatized muscles after the first week, decreased to approximately 25% after 4 weeks, and remained at this value until 8 weeks. Interpretation At both the functional level and the morphological level, skeletal muscle regeneration follows a distinct time course. Our trauma model allows investigation of muscle regeneration after a standardized injury to muscle fibers.

A new device to control mechanical environment in bone defect healing in rats

Mechanical conditions have a significant influence on the biological processes of bone healing. Small animal models that allow controlling the mechanical environment of fracture and bone defect healing are needed. The aim of this study was to develop a new animal model that allows to reliably control the mechanical environment in fracture and bone defect healing in rats using different implant materials. An external fixator was designed and mounted in vitro to rat femurs using four Kirschner-wires (titanium (T) or steel (S)) of 1.2 mm diameter. The specimens were distracted to a gap of 1.5mm. Axial and torsional stiffness of the device was tested increasing the offset (distance between bone and fixator crossbar) from 5 to 15 mm. In vivo performance (well-being, infection, breaking of wires and bone healing) was evaluated in four groups of 24 Sprague-Dawley rats varying in offset (7.5 and 15 mm) and implant material (S/T) over 6 weeks. Torsional and axial stiffness were higher in steel compared to titanium setups. A decrease in all configurations was observed by increasing the offset. The offset 7.5 mm showed a significantly higher torsional (S: p<0.01, T: p<0.001) and axial in vitro stiffness (S: p<0.001, T: p<0.001) compared to 15 mm offset of the fixator. Although in vitro designed to be different in mechanical stiffness, no difference was found between the groups regarding complication rate. The overall-complication rate was 5.2%. In conclusion, we were able to establish a small animal model for bone defect healing which allows modeling the mechanical conditions at the defect site in a defined manner.

In serum veritas-in serum sanitas? Cell non-autonomous aging compromises differentiation and survival of mesenchymal stromal cells via the oxidative stress pathway.

Even tissues capable of complete regeneration, such as bone, show an age-related reduction in their healing capacity. Here, we hypothesized that this decline is primarily due to cell non-autonomous (extrinsic) aging mediated by the systemic environment. We demonstrate that culture of mesenchymal stromal cells (MSCs) in serum from aged Sprague–Dawley rats negatively affects their survival and differentiation ability. Proteome analysis and further cellular investigations strongly suggest that serum from aged animals not only changes expression of proteins related to mitochondria, unfolded protein binding or involved in stress responses, it also significantly enhances intracellular reactive oxygen species production and leads to the accumulation of oxidatively damaged proteins. Conversely, reduction of oxidative stress levels in vitro markedly improved MSC function. These results were validated in an in vivo model of compromised bone healing, which demonstrated significant increase regeneration in aged animals following oral antioxidant administration. These observations indicate the high impact of extrinsic aging on cellular functions and the process of endogenous (bone) regeneration. Thus, addressing the cell environment by, for example, systemic antioxidant treatment is a promising approach to enhance tissue regeneration and to regain cellular function especially in elderly patients.

Age-related loss of lumbar spinal lordosis and mobility--a study of 323 asymptomatic volunteers.

Background The understanding of the individual shape and mobility of the lumbar spine are key factors for the prevention and treatment of low back pain. The influence of age and sex on the total lumbar lordosis and the range of motion as well as on different lumbar sub-regions (lower, middle and upper lordosis) in asymptomatic subjects still merits discussion, since it is essential for patient-specific treatment and evidence-based distinction between painful degenerative pathologies and asymptomatic aging. Methods and Findings A novel non-invasive measuring system was used to assess the total and local lumbar shape and its mobility of 323 asymptomatic volunteers (age: 20–75 yrs; BMI <26.0 kg/m2; males/females: 139/184). The lumbar lordosis for standing and the range of motion for maximal upper body flexion (RoF) and extension (RoE) were determined. The total lordosis was significantly reduced by approximately 20%, the RoF by 12% and the RoE by 31% in the oldest (>50 yrs) compared to the youngest age cohort (20–29 yrs). Locally, these decreases mostly occurred in the middle part of the lordosis and less towards the lumbo-sacral and thoraco-lumbar transitions. The sex only affected the RoE. Conclusions During aging, the lower lumbar spine retains its lordosis and mobility, whereas the middle part flattens and becomes less mobile. These findings lay the ground for a better understanding of the incidence of level- and age-dependent spinal disorders, and may have important implications for the clinical long-term success of different surgical interventions.

Interaction of Age and Mechanical Stability on Bone Defect Healing: An Early Transcriptional Analysis of Fracture Hematoma in Rat

Among other stressors, age and mechanical constraints significantly influence regeneration cascades in bone healing. Here, our aim was to identify genes and, through their functional annotation, related biological processes that are influenced by an interaction between the effects of mechanical fixation stability and age. Therefore, at day three post-osteotomy, chip-based whole-genome gene expression analyses of fracture hematoma tissue were performed for four groups of Sprague-Dawley rats with a 1.5-mm osteotomy gap in the femora with varying age (12 vs. 52 weeks - biologically challenging) and external fixator stiffness (mechanically challenging). From 31099 analysed genes, 1103 genes were differentially expressed between the six possible combinations of the four groups and from those 144 genes were identified as statistically significantly influenced by the interaction between age and fixation stability. Functional annotation of these differentially expressed genes revealed an association with extracellular space, cell migration or vasculature development. The chip-based whole-genome gene expression data was validated by q-RT-PCR at days three and seven post-osteotomy for MMP-9 and MMP-13, members of the mechanosensitive matrix metalloproteinase family and key players in cell migration and angiogenesis. Furthermore, we observed an interaction of age and mechanical stimuli in vitro on cell migration of mesenchymal stromal cells. These cells are a subpopulation of the fracture hematoma and are known to be key players in bone regeneration. In summary, these data correspond to and might explain our previously described biomechanical healing outcome after six weeks in response to fixation stiffness variation. In conclusion, our data highlight the importance of analysing the influence of risk factors of fracture healing (e.g. advanced age, suboptimal fixator stability) in combination rather than alone.