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Severe flexible flatfeet with triceps surae complex shortening are prognostically unfavorable in early childhood and may compromise normal foot development.This retrospective, IRB-approved study included 20 children (38 feet) under 6 years with severe flexible flatfeet and triceps surae complex shortening. Treatment included minimally invasive percutaneous achilles tendon lengthening followed by a 4-week cast fixation and corrective orthotic therapy under talo-navicular reposition for at least 6-months. Preoperative weightbearing x-rays and at the last available follow-up included anteroposterior talus-first metatarsal angle and lateral talus pitch, Meary's and talocalcaneal angle and were compared to reference values. ROM, surgeon-rated clinical outcomes and complications/re-interventions were evaluated.Age at surgery was 3.7 years (1.3-5.9 y) and follow-up time was 4.3 years (1.1-8.9 y). No complications occurred. Clinical outcome was good (68 %) to very good (26 %). Ratio of normal angles increased significantly for three angles. Dorsiflexion ROM improved from -5.0 ± 6.8° at baseline to 15.7 ± 7.6°.With significant improvements in clinical and radiographic outcomes, minimal-invasive percutaneous Achilles tendon lengthening followed by orthotic therapy seems to be a valuable treatment option for selected preschool-aged patients with severe, flexible flatfeet with significantly shortened triceps surae.IV.

Aims It is not known whether preservation of the capsule of the hip positively affects patient-reported outcome measures (PROMs) in total hip arthroplasty using the direct anterior approach (DAA-THA). A recent randomized controlled trial found no clinically significant difference at one year postoperatively. This study aimed to determine whether preservation of the anterolateral capsule and anatomical closure improve the outcome and revision rate, when compared with resection of the anterolateral capsule, at two years postoperatively. Methods Two consecutive groups of patients whose operations were performed by the senior author were compared. The anterolateral capsule was resected in the first group of 430 patients between January 2012 and December 2014, and preserved and anatomically closed in the second group of 450 patients between July 2015 and December 2017. There were no other technical changes between the two groups. Patient characteristics, the Charlson Comorbidity Index (CCI), and surgical data were collected from our database. PROM questionnaires, consisting of the Oxford Hip Score (OHS) and Core Outcome Measures Index (COMI-Hip), were collected two years postoperatively. Data were analyzed with generalized multiple regression analysis. Results The characteristics, CCI, operating time, and length of stay were similar in both groups. There was significantly less blood loss in the capsular preservation group (p = 0.037). The revision rate (n = 3, (0.6%) in the resected group, and 1 (0.2%) in the preserved group) did not differ significantly (p = 0.295). Once adjusted for demographic and surgical factors, the preserved group had significantly worse PROMs: + 0.24 COMI-Hip (p < 0.001) and -1.6 OHS points (p = 0.017). However, the effect sizes were much smaller than the minimal clinically important differences (MCIDs) of 0.95 and 5, respectively). The date of surgery (influencing, for instance, the surgeon’s age) was not a significant factor. Conclusion Based on the MCID, the lower PROMs in the capsular preservation group do not seem to have clinical relevance. They do not, however, confirm the expected benefit of capsular preservation reported for the posterolateral approach. Cite this article: Bone Joint J 2022;104-B(7):826–832.

Introduction: The fixation of small intraarticular bone fragments is clinically challenging and an obvious first orthopaedic indication for an effective bone adhesive. In the present study the feasibility of bonding freshly harvested human trabecular bone with OsStic(R), a novel phosphoserine modified cement, was evaluated using a bone cylinder model pull-out test and compared with a commercial fibrin tissue adhesive. Methods: Femoral heads (n=13) were collected from hip fracture patients undergoing arthroplasty and stored refrigerated overnight in saline medium prior to testing. Cylindrical bone cores with a pre-inserted bone screw, were prepared using a coring tool. Each core was removed and glued back in place with either the bone adhesive (alpha-tricalcium phosphate, phosphoserine and 20% trisodium citrate solution) or the fibrin glue. All glued bones were stored in bone medium at 37 degrees C. Tensile loading, using a universal testing machine (5 kN load cell), was applied to each core/head. For the bone adhesive, bone cores were tested at 2 (n=13) and 24 (n=11) hours. For the fibrin tissue adhesive control group (n=9), bone cores were tested exclusively at 2 hours. The femoral bone quality was evaluated with micro-CT. Results: The ultimate pull-out load for the bone adhesive at 2 hours ranged from 36 to 171 N (mean 94 N, SD 42 N). At 24 hours the pull-out strength was similar, 47 to 198 N (mean 123 N, SD 43 N). The adhesive failure usually occurred through the adhesive layer, however in two samples, at 167 N and 198 N the screw pulled out of the bone core. The fibrin tissue adhesive group reached a peak force of 8 N maximally at 2 hours (range 2.8-8 N, mean 5.4 N, SD 1.6 N). The mean BV/TV for femoral heads was 0.15 and indicates poor bone quality. Conclusion: The bone adhesive successfully glued wet and fatty tissue of osteoporotic human bone cores. The mean ultimate pull-out force of 123 N at 24 hours corresponds to similar to 300 kPa shear stress acting on the bone core. These first ex-vivo results in human bone are a promising step toward potential clinical application in osteochondral fragment fixation. (C) 2022 The Authors. Published by Elsevier Ltd.

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for pain management during recovery from orthopaedic surgery. NSAID use is associated with increased risk of bone healing complications but it is currently unknown whether NSAIDs increase the risk of developing an orthopaedic-device-related infection (ODRI) and/or affects its response to antibiotic therapy. The present study aimed to determine if administration of the NSAID carprofen [a preferential cyclooxygenase-2 (COX-2) inhibitor] negatively affected Staphylococcus epidermidis (S. epidermidis) bone infection, or its subsequent treatment with antibiotics, in a rodent ODRI model. Sterile or S. epidermidis-contaminated screws (~ 1.5 x 106 CFU) were implanted into the proximal tibia of skeletally mature female Wistar rats, in the absence or presence of daily carprofen administration. A subset of infected animals received antibiotics (rifampicin plus cefazolin) from day 7 to 21, to determine if carprofen affected antibiotic efficacy. Bone changes were monitored using in vivo µCT scanning and histological analysis. The risk of developing an infection with carprofen administration was assessed in separate animals at day 9 using a screw contaminated with 102 CFU S. epidermidis. Quantitative bacteriological analysis assessed bacterial load at euthanasia. In the 28-day antibiotic treatment study, carprofen reduced osteolysis but markedly diminished reparative bone formation, although total bacterial load was not affected at euthanasia. Antibiotic efficacy was negatively affected by carprofen (carprofen: 8/8 infected; control: 2/9 infected). Finally, carprofen increased bacterial load and diminished bone formation following reduced S. epidermidis inoculum (102 CFU) at day 9. This study suggests that NSAIDs with COX-2 selectivity reduce antibiotic efficacy and diminish reparative responses to S. epidermidis ODRI.

Background: Joint space assessment for rheumatoid arthritis (RA) by ordinal conventional radiographic scales is susceptible to floor and ceiling effects. High-resolution peripheral quantitative computed tomography (HR-pQCT) provides superior resolution, and may detect earlier changes. The goal of this work was to compare existing 3D methods to calculate joint space width (JSW) metrics in human metacarpophalangeal (MCP) joints with HR-pQCT and reach consensus for future studies. Using the consensus method, we established reproducibility with repositioning as well as feasibility for use in second-generation HR-pQCT scanners.Methods: Three published JSW methods were compared using datasets from individuals with RA from three research centers. A SPECTRA consensus method was developed to take advantage of strengths of the individual methods. Using the SPECTRA method, reproducibility after repositioning was tested and agreement between scanner generations was also established.Results: When comparing existing JSW methods, excellent agreement was shown for JSW minimum and mean (ICC 0.987-0.996) but not maximum and volume (ICC 0.000-0.897). Differences were identified as variations in volume definitions and algorithmic differences that generated high sensitivity to boundary conditions. The SPECTRA consensus method reduced this sensitivity, demonstrating good scan-rescan reliability (ICC >0.911) except for minimum JSW (ICC 0.656). There was strong agreement between results from first- and second-generation HR-pQCT (ICC >0.833).Conclusions: The SPECTRA consensus method combines unique strengths of three independently-developed algorithms and leverages underlying software updates to provide a mature analysis to measure 3D JSW. This method is robust with respect to repositioning and scanner generations, suggesting its suitability for detecting change.

Background Cutibacterium species are common pathogens in periprosthetic joint infections (PJI). These infections are often treated with β-lactams or clindamycin as monotherapy, or in combination with rifampin. Clinical evidence supporting the value of adding rifampin for treatment of Cutibacterium PJI is lacking. Methods In this multicenter retrospective study, we evaluated patients with Cutibacterium PJI and a minimal follow-up of 12 months. The primary endpoint was clinical success, defined by the absence of infection relapse or new infection. We used Fisher’s exact tests and Cox proportional hazards models to analyze the effect of rifampin and other factors on clinical success after PJI. Results We included 187 patients (72.2% male, median age 67 years) with a median follow-up of 36 months. The surgical intervention was a 2-stage exchange in 95 (50.8%), 1-stage exchange in 51 (27.3%), debridement and implant retention (DAIR) in 34 (18.2%), and explantation without reimplantation in 7 (3.7%) patients. Rifampin was included in the antibiotic regimen in 81 (43.3%) cases. Infection relapse occurred in 28 (15.0%), and new infection in 13 (7.0%) cases. In the time-to-event analysis, DAIR (adjusted hazard ratio [HR] = 2.15, P = .03) and antibiotic treatment over 6 weeks (adjusted HR = 0.29, P = .0002) significantly influenced treatment failure. We observed a tentative evidence for a beneficial effect of adding rifampin to the antibiotic treatment—though not statistically significant for treatment failure (adjusted HR = 0.5, P = .07) and not for relapses (adjusted HR = 0.5, P = .10). Conclusions We conclude that a rifampin combination is not markedly superior in Cutibacterium PJI, but a dedicated prospective multicenter study is needed.

Objective The objective of this study was to develop a reproducible and semi-automatic method based on micro computed tomography (microCT) to analyze cartilage and bone morphology of human osteoarthritic knee joints in spatially matching regions of interest. Materials and methods Tibial plateaus from randomly selected patients with advanced osteoarthritis (OA) who underwent total knee arthroplasty surgery were microCT scanned once fresh and once after staining with Hexabrix. The articular surface was determined manually in the first scan. Total articular surface, defect surface and cartilage surface were computed by triangulation of the cartilage surface and the spatially corresponding subchondral bone regions were automatically generated and the standard cortical bone and trabecular bone morphometric indices were computed. Results The method to identify cartilage surface and defects was successfully validated against photographic examinations. The microCT measurements of the cartilage defect were also verified by conventional histopathology using safranin O–stained sections. Cartilage thickness and volume was significantly lower for OA condyle compared with healthy condyle. Bone fraction, bone tissue mineral density, cortical density and trabecular thickness differed significantly depending on the level of cartilage damage. Conclusion This new microCT imaging workflow can be used for reproducible quantitative evaluation of articular cartilage damage and the associated changes in subchondral bone morphology in osteoarthritic joints with a relatively high throughput compared to manual contouring. This methodology can be applied to gain better understanding of the OA disease progress in large cohorts.

Introduction While the Patient-Reported Outcomes Measurement Information System (PROMIS) is mainly designed for computer adaptive testing, its static short forms (SF) are used when a paper-pencil format is preferred or item banks are not yet translated into the target language. This study examined the measurement properties of the German PROMIS-SF for pain intensity (PAIN), pain interference (PI) and physical function (PF) in total hip arthroplasty (THA) patients. Methods SF were collected before and 12 months post-surgery. Higher scores indicate more PAIN, higher PI and better PF. Oxford Hip Score (OHS) was the main reference measure. Six months post-surgery, a subsample completed the SF twice within 14 days to test reliability. Results Of 172 eligible patients, 147 consented to participate and received questionnaires; 132 (74 males) returned baseline questionnaires (mean age 65.8 ± 10.2 years) and 116, 12-month questionnaires. Forty-five patients provided test-retest data. Correlations of all SF with OHS were large (│r│ ≥ 0.7; confidence intervals did not include 0.50). Cronbach’s alpha values were: PAIN, 0.86; PI, 0.93; PF, 0.91. Intraclass correlation coefficients were: PAIN, 0.77; PI, 0.81; PF, 0.69. Standard errors of measurement were: PAIN, 3.8; PI, 2.8; PF, 3.6. Smallest detectable change thresholds were: PAIN, 8.8; PI, 6.6; PF, 8.4. Follow-up data showed a ceiling effect (best score) for PAIN (66%), PI (76%), and PF (66%). SF change scores showed large correlations with OHS change scores (│r│ > 0.6). Conclusion Our results provide some evidence of construct validity, and acceptable reliability and responsiveness of PROMIS-SF for pain and function in THA patients. These SF can thus be considered acceptable for use, although patients’ improvement in physical function might be underestimated due to the large follow-up PF score ceiling effects., Plain English summary Measurement qualities of PROMIS instruments are mainly assessed for computer adaptive testing but not for non-adaptive short questionnaires. As these questionnaires are in use, their measurement properties must also be evaluated. Results from computer adaptive testing cannot simply be transferred. We studied the measurement qualities of the German PROMIS short questionnaires for pain intensity, pain interference and physical function in patients undergoing hip replacement. We wanted to see how these questionnaires perform when compared to the Oxford Hip Score, a standard questionnaire commonly used to test hip-related disability in these patients. The three questionnaires can be considered acceptable for use in hip replacement patients, but some limitations do exist. Patient improvement in physical function might be underestimated because many patients reach the highest possible score and further improvements cannot be measured. Also, any small but important improvement in physical function cannot be distinguished from measurement error in individual patients.

Background Inaccurate projection on standard pelvic radiographs leads to the underestimation of femoral offset—a critical determinant of postoperative hip function—during total hip arthroplasty (THA) templating. We noted that the posteromedial facet of the greater trochanter and piriformis fossa form a double contour on radiographs, which may be valuable in determining the risk of underestimating femoral offset. We evaluate whether projection errors can be predicted based on the double contour width. Methods Plain anteroposterior (AP) pelvic radiographs and magnetic resonance images (MRIs) of 64 adult hips were evaluated retrospectively. Apparent femoral offset, apparent femoral head diameter and double contour widths were evaluated from the radiographs. X-ray projection errors were estimated by comparison to the true neck length measured on MRIs after calibration to the femoral heads. Multivariate analysis with backward elimination was used to detect associations between the double contour width and radiographic projection errors. Femoral offset underestimation below 10% was considered acceptable for templating. Results The narrowest width of the double line between the femoral neck and piriformis fossa is significantly associated with projection error. When double line widths exceed 5 mm, the risk of projection error greater than 10% is significantly increased compared to narrower double lines, and the acceptability rate for templating drops below 80% (p = 0.02). Conclusion The double contour width is a potential landmark for excluding pelvic AP radiographs unsuitable for THA templating due to inaccurate femoral rotation.

Background A new locking screw technology, named variable fixation, has been developed aiming at promoting bone callus formation providing initial rigid fixation followed by progressive fracture gap dynamisation. In this study, we compared bone callus formation in osteotomies stabilized with standard locking fixation against that of osteotomies stabilized with variable fixation in an established tibia ovine model. Methods A 3 mm tibial transverse osteotomy gap was stabilized in three groups of six female sheep each with a locking plate and either 1) standard fixation in both segments (group LS) or 2) variable fixation in the proximal and standard fixation in the distal bone segment (group VFLS3) or 3) variable fixation in both segments (group VFLS6). The implantation site and fracture healing were compared between groups by means of radiologic, micro tomographic, biomechanical, and histological investigations. Results Compared to LS callus, VFLS3 callus was 40% larger and about 3% denser, while VFLS6 callus was 93% larger and its density about 7.2% lower. VFLS3 showed 65% and VFLS6 163% larger amount of callus at the cis-cortex. There wasn’t a significant difference in the amount of callus at the cis and trans-cortex in groups featuring variable fixation only. Investigated biomechanical variables were not significantly different among groups and histology showed comparable good healing in all groups. Tissues adjacent to the implants did not show any alteration of the normal structure in all groups. Conclusions Variable fixation promoted the formation of a larger amount of bone callus, equally distributed at the cis and trans cortices. The histological and biomechanical properties of the variable fixation callus were equivalent to those of the standard fixation callus. The magnitude of variable fixation had a biological effect on the formation of bone callus. At the implantation site, the usage of variable fixation did not raise additional concerns with respect to standard fixation. The formation of a larger amount of mature callus suggests that fractures treated with variable fixation might have a higher probability to bridge the fracture gap. The conditions where its usage can be most beneficial for patients needs to be clinically defined., BMC Musculoskeletal Disorders, 21 (1), ISSN:1471-2474

A significant proportion of orthopedic devices are implanted in osteoporotic patients, but it is currently unclear how estrogen deficiency and/or exposure to antiresorptive bisphosphonates (BPs) influence orthopedic device-related infection (ODRI), or response to therapy. The aim of this study is to characterize the bone changes resulting from Staphylococcus epidermidis infection in a rodent ODRI model and to determine if ovariectomy (OVX) or BP treatment influences the infection or the success of antibiotic therapy. A sterile or S. epidermidis-contaminated screw was implanted into the proximal tibia of skeletally mature female Wistar rats (n = 6-9 per group). Bone changes were monitored over 28 days using in vivo micro-computed tomography scanning. OVX was performed 12 weeks before screw implantation. The BP zoledronic acid (ZOL) was administered 4 days before screw insertion. A combination antibiotic regimen (rifampin plus cefazolin) was administered from Days 7-21. In skeletally healthy animals, S. epidermidis induced marked changes in bone, with peak osteolysis occurring at Day 9 and woven bone deposition and periosteal mineralization from Day 14 onwards. Antibiotic therapy cleared the infection in the majority of animals (2/9 infected) but did not affect bone responses. OVX did not affect the pattern of infection-induced changes in bone, nor bacterial load, but reduced antibiotic efficacy (5/9 infected). ZOL treatment did not protect from osteolysis in OVX animals, or further affect antibiotic efficacy (5/9 infected) but did significantly increase the bacterial load. This study suggests that both BPs and OVX can influence host responses to bone infections involving S. epidermidis.

Background Heterotopic ossification (HO) is a known finding after total hip arthroplasty (THA) that potentially affects clinical outcomes. The incidence of HO is related to various factors, including soft-tissue trauma, postoperative medication, surgical approach, and the surgeon's experience. Because use of the direct anterior approach (DAA) is gaining popularity, we aimed (1) to determine the incidence of HO after DAA-THA and (2) to evaluate the impact of HO on patient-reported outcomes (PROs). Methods We retrospectively reviewed 401 THAs (67 ± 10 years old, 210 men). The incidence and grade of HO were evaluated using the Brooker classification with anteroposterior and lateral radiographs. PROs were collected with use of the Oxford Hip Score (OHS) and the Core Outcome Measures Index (COMI)-Hip and were correlated with HO grades using generalized multiple regression models. Results The incidence of HO was 29.9% on the anteroposterior radiographic views (Brooker grade 1, 14.5%; grade 2, 11.1%; grade 3, 2.7%; and grade 4, 0.57%); the lateral radiographic views detected 9% additional HO when compared with the anteroposterior radiographs alone (Brooker grade 1, 8%, and grade 2, 1%). HO was more frequent in men. The American Society of Anesthesiologists (ASA) grade, age in women, and higher body mass index (BMI) in men were associated with higher HO grades. A transverse "bikini" incision was associated with a lower rate (4%) of Brooker grades 3 and 4 HO when compared with a longitudinal incision (12%). A Brooker grade of 0 to 3 HO did not impact outcomes. Only Brooker grade-4 HO was associated with significantly worse PROs; however, pain was not affected. Conclusions Low-grade HO after DAA-THA is not uncommon, and its rate is underestimated when anteroposterior radiographic views are evaluated without lateral views. The risk factors for developing HO in our cohort were an ASA grade of >3, male sex (especially with a high BMI), older age in women, and use of longitudinal incisions. With use of the bikini incision, patients had lower rates of severe HO, but mostly senior surgeons with more experience performed their surgery. Age, ASA grade, experience level of the surgeon, and Brooker grade-4 HO all had a significant influence on PROs. Clinically important HO (Brooker grade 4) remains rare after DAA-THR. Level of evidence Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Total joint arthroplasty (TJA) surgeries are common orthopedic procedures, but bacterial infection remains a concern. The aim of this study was to assess interactions between wear particles (WPs) and immune cells in vitro and to investigate if WPs affect the severity, or response to antibiotic therapy, of a Staphylococcus epidermidis orthopedic device-related infection (ODRI) in a rodent model. Biofilms grown on WPs were challenged with rifampin and cefazolin (100 µg/mL) to determine antibiotic efficacy. Neutrophils or peripheral blood mononuclear cells (PBMCs) were incubated with or without S. epidermidis and WPs, and myeloperoxidase (MPO) and cytokine release were analyzed, respectively. In the ODRI rodent model, rats (n = 36) had a sterile or S. epidermidis-inoculated screw implanted in the presence or absence of WPs, and a subgroup was treated with antibiotics. Bone changes were monitored using microCT scanning. The presence of WPs decreased antibiotic efficacy against biofilm-resident bacteria and promoted MPO and pro-inflammatory cytokine production in vitro. WPs exacerbated osteolytic responses to S. epidermidis infection and markedly reduced antibiotic efficacy in vivo. Overall, this work shows that the presence of titanium WPs reduces antibiotic efficacy in vitro and in vivo, induces proinflammatory cytokine release, and exacerbates S. epidermidis-induced osteolysis.

We report the novel use of a tuneable, non-integrating viral gene delivery system to bone that can be combined with clinically approved biomaterials in an 'off-the shelf' manner. Specifically, a doxycycline inducible Tet-on adenoviral vector (AdTetBMP-2) in combination with mesenchymal stromal cells (MSCs), fibrin and a biphasic calcium phosphate ceramic (MBCP®) was used to repair large bone defects in nude rats. BMP-2 transgene expression could be effectively tuned by modification of doxycycline concentration. The effect of adenoviral BMP-2 gene delivery upon bone healing was investigated in vivo in 4 mm critically sized, internally fixated, femoral defects. MSCs were transduced either by direct application of AdTetBMP-2 or by pre-coating MBCP® granules with the virus. Radiological assessment scores post-mortem, were significantly improved upon delivery of AdTetBMP-2. In AdTetBMP-2 groups, histological analysis revealed significantly more newly formed bone at the defect site compared to controls. Newly formed bone was vascularised and fully integrated with nascent tissue and implanted biomaterial. Improvement in healing outcome was achieved using both methods of vector delivery (direct application vs. pre-coating MCBP®). Adenoviral delivery of BMP-2 enhanced bone regeneration achieved by the transplantation of MSCs, fibrin and MBCP® in vivo. Importantly, our in vitro and in vivo data suggests that this can be achieved with relatively low (ng/ml) levels of the growth factor. Our model and novel gene delivery system may provide a powerful standardised tool for the optimisation of growth factor delivery and release for the healing of large bone defects. This article is protected by copyright. All rights reserved.

Fabrication of composite scaffolds using stereolithography (SLA) for bone tissue engineering has shown great promises. However, in order to trigger effective bone formation and implant integration, exogenous growth factors are commonly combined to scaffold materials. In this study, we fabricated biodegradable composite scaffolds using SLA and endowed them with osteopromotive properties in the absence of biologics. First we prepared photo-crosslinkable poly(trimethylene carbonate) (PTMC) resins containing 20 and 40 wt% of hydroxyapatite (HA) nanoparticles and fabricated scaffolds with controlled macro-architecture. Then, we conducted experiments to investigate how the incorporation of HA in photo-crosslinked PTMC matrices improved human bone marrow stem cells osteogenic differentiation in vitro and kinetic of bone healing in vivo. We observed that bone regeneration was significantly improved using composite scaffolds containing as low as 20 wt% of HA, along with difference in terms of osteogenesis and degree of implant osseointegration. Further investigations revealed that SLA process was responsible for the formation of a rich microscale layer of HA corralling scaffolds. To summarize, this work is of substantial importance as it shows how the fabrication of hierarchical biomaterials via surface-enrichment of functional HA nanoparticles in composite polymer stereolithographic structures could impact in vitro and in vivo osteogenesis. Statement of Significance This study reports for the first time the enhance osteopromotion of composite biomaterials, with controlled macro-architecture and microscale distribution of hydroxyapatite particles, manufactured by stereolithography. In this process, the hydroxyapatite particles are not only embedded into an erodible polymer matrix, as reported so far in the literature, but concentrated at the surface of the structures. This leads to robust in vivo bone formation at low concentration of hydroxyapatite. The reported 3D self-corralling composite architecture provides significant opportunities to develop functional biomaterials for bone repair and tissue engineering.

The orbital floor (OF) is an anatomical location in the craniomaxillofacial (CMF) region known to be highly variable in shape and size. When fractured, implants commonly consisting of titanium meshes are customized by plying and crude hand-shaping. Nevertheless, more precise customized synthetic grafts are needed to meticulously reconstruct the patients’ OF anatomy with better fidelity. As alternative to titanium mesh implants dedicated to OF repair, we propose a flexible patient-specific implant (PSI) made by stereolithography (SLA), offering a high degree of control over its geometry and architecture. The PSI is made of biodegradable poly(trimethylene carbonate) (PTMC) loaded with 40 wt % of hydroxyapatite (called Osteo-PTMC). In this work, we developed a complete work-flow for the additive manufacturing of PSIs to be used to repair the fractured OF, which is clinically relevant for individualized medicine. This work-flow consists of (i) the surgical planning, (ii) the design of virtual PSIs and (iii) their fabrication by SLA, (iv) the monitoring and (v) the biological evaluation in a preclinical large-animal model. We have found that once implanted, titanium meshes resulted in fibrous tissue encapsulation, whereas Osteo-PMTC resulted in rapid neovascularization and bone morphogenesis, both ectopically and in the OF region, and without the need of additional biotherapeutics such as bone morphogenic proteins. Our study supports the hypothesis that the composite osteoinductive Osteo-PTMC brings advantages compared to standard titanium mesh, by stimulating bone neoformation in the OF defects. PSIs made of Osteo-PTMC represent a significant advancement for patients whereby the anatomical characteristics of the OF defect restrict the utilization of traditional hand-shaped titanium mesh.

Objectives To devise a macroscopic, radiological, and histological scale for assessing pathological changes associated with medication-related osteonecrosis of the jaw in a minipig model. Materials and methods Medication-related osteonecrosis of the jaw was induced in Gottingen minipigs by weekly intravenous administration of bisphosphonate (zoledronic acid) combined with a tooth extraction procedure. Controls either did not receive zoledronic acid or did not undergo tooth extraction. After 20 weeks, minipigs were euthanized and underwent computed tomography and micro-computed tomography scanning. The mandible underwent additional histological examination. Results The most consistent macroscopic findings in animals that had developed bisphosphonate-related osteonecrosis of the jaw (BRONJ) were necrotic, denuded bone, and formation of fistula and pus. Under radiological examination, impaired extraction socket healing, decrease in attenuation of bone beneath the extraction site, and periosteal reaction were observed. Under histological examination, demineralization of the extracellular bone matrix, denuding of bone, and osteonecrosis were recorded. Conclusion These parameters were used to develop a scoring system for grading BRONJ.

The effect of age on implant fixation in bone is not always considered during the design of preclinical models. The decision on animal's age is often related to practical or historical reasons, which ultimately may affect the reproducibility of results. This study aimed to quantify the effect of age by monitoring the fixation of contrast-enhanced PEEK screws in rats, hypothesizing that the kinetics of fixation is impaired in older animals but that age effects are less severe than osteoporotic effects. The time course of implant fixation was investigated in healthy rats at 24, 40, and 60 weeks of age; and in ovariectomized rats. Implant fixation was monitored using in-vivo microCT and dynamic histomorphometry during 1 month. The rats were euthanized 28 days post screw insertion. The data was analyzed both in absolute value and after normalization to baseline bone mass. In absolute terms, greater age had a detrimental effect on bone implant contact, bone fraction, implant stiffness, and bone remodeling but less than ovariectomy. Interestingly, once data was normalized to baseline bone mass this effect disappeared, suggesting that the physiologic response to implant placement was not affected by age. In conclusion, implant fixation kinetics is less affected by age than by baseline bone mass in this rat model. Animals of different ages can therefore be compared but data must be construed relatively to baseline bone mass and not in absolute terms. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 9999:1-12, 2018.

Bone is an organ with high natural regenerative capacity and most fractures heal spontaneously when appropriate fracture fixation is provided. However, additional treatment is required for patients with large segmental defects exceeding the endogenous healing potential and for patients suffering from fracture non-unions. These cases are often associated with insufficient vascularization. Transplantation of CD34+ endothelial progenitor cells (EPCs) has been successfully applied to promote neovascularization of bone defects, however including extensive ex vivo manipulation of cells. Here we hypothesized, that treatment with Granulocyte colony-stimulating factor (G-CSF) may improve bone healing by mobilization of CD34+ progenitor cells into the circulation, which in turn may facilitate vascularization at the defect site. In this pilot study, we aimed to characterize the different cell populations mobilized by G-CSF and investigate the influence of cell mobilization on the healing of a critical size femoral defect in rats. Cell mobilization was investigated by flow cytometry at different time points after five consecutive daily G-CSF injections. In a pilot study, bone healing of a 4.5 mm critically-sized femoral defect in F344 rats was compared between a saline-treated control group and a G-CSF treatment group. In vivo micro computed tomography and histology were applied to compare bone formation in both treatment groups. Our data revealed that leukocyte counts show a peak increase at the first day after the last G-CSF injection. In addition, we found that CD34+ progenitor cells, including EPCs, were significantly enriched at day 1, and further increased at day 5 and day 11. Upregulation of monocytes, granulocytes and macrophages peaked at day 1. G-CSF treatment significantly increased bone volume and bone density in the defect, which was confirmed by histology. Our data show that different cell populations are mobilized by G-CSF treatment in cell specific patterns. Although in this pilot study no bridging of the critically-sized defect was observed, significantly improved bone formation by G-CSF treatment was clearly shown.

Infection associated with orthopedic implants often results in bone loss and requires surgical removal of the implant. The aim of this study was to evaluate morphological changes of bone adjacent to a bacteria-colonized implant, with the aim of identifying temporal patterns that are characteristic of infection. In anin vivostudy with rats, bone changes were assessed usingin vivomicroCT at 7 time points during a one-month postoperative period. The rats received either a sterile orStaphylococcus aureus-colonized polyetheretherketone screw in the tibia. Bone-implant contact, bone fraction, and bone changes (quiescent, resorbed, and new bone) were calculated from consecutive scans and validated against histomorphometry. The screw pullout strength was estimated from FE models and the results were validated against mechanical testing. In the sterile group, bone-implant contact, bone fraction, and mechanical fixation increased steadily until day 14 and then plateaued. In the infected group, they decreased rapidly. Bone formation was reduced while resorption was increased, with maximum effects observed within 6 days. In summary, the model presented is capable of evaluating the patterns of bone changes due to implant-related infections. The combined use of longitudinalin vivomicroCT imaging and image-based finite element analysis provides characteristic signs of infection within 6 days.

© 2018 The Author(s). The prevention of fragility fractures in bone-pathologic fractures resulting from daily activity and mostly occurring in the elderly population-has been a long-Term clinical quest. Recent research indicating that falls in the elderly might be the consequence of fracture rather than its cause has raised fundamental questions about the origin of fragility fractures. Is day-To-day cyclic loading, instead of a single-load event such as a fall, the main cause of progressively growing fractures? Are fragility fractures predominantly affected by bone quality rather than bone mass, which is the clinical indicator of fracture risk? Do osteocytes actively participate in the bone repair process? In this Perspective, we discuss the central role of cyclic fatigue in bone fragility fracture.

Objectives X-ray-based planning and post-implantation assessment of titanium implants is the commonly accepted standard to date. However, new implant materials such as zirconia (ZrO2) have become available, and magnetic resonance imaging may be a valuable alternative with these implants. The present in vitro study investigated artifacts produced by titanium and zirconia implants in magnetic resonance imaging (MRI) and assessed the accuracy of pre-implant planning and post-implantation assessment comparing MRI to standard X-ray-based imaging modalities: Orthopantomogram (OPT), cone beam (CBCT), and computed tomography (CT). Materials and methods Twelve porcine mandibles were prepared and scanned (MRI, OPT, CBCT, μCT), and bone height above the nerve canal was measured. Specimens were implanted with either two titanium or zirconia implants and rescanned to investigate the influence of implant materials on post-implantation assessment. MRI and μCT artifacts were quantified with implants embedded in gelatin phantoms and porcine specimens. Results Compared with CBCT set as standard, μCT, OPT, and MRI showed similar accuracy in pre-op bone height measurements. Post-implantation, while titanium implants induced a strong B0-field distortion resulting in extensive signal voids, zirconia implants were clearly depictable with only minor distortions. Conclusions Excellent contrast, limited artifacts, radiation-free and accurate implant assessment may indicate that MRI is a valuable imaging alternative for zirconia-based implant dentistry.

Immediately after implantation, a dynamic process of bone formation and resorption takes place around an orthopaedic implant, influencing its mechanical fixation. The delay until complete fixation depends on local bone architecture and metabolism. Despite its importance, the temporal pattern of implant fixation is still unknown. The optimal duration of post-operative care is therefore difficult to establish for an individual situation, and a method to evaluate non-invasively the evolution of the mechanical stability would be a significant asset in a clinical environment. The aim of this study was to evaluate the potential of micro-finite element modelling based on in vivo micro-computed tomography to monitor longitudinally the contact between bone and implant and the implant strength in vivo. The model was first validated for screw pull-out in synthetic bone surrogate. Correlation coefficients of R(2) = 0.94 and 0.85 (p 0.01) were measured between experimental and numerical results for stiffness and failure loads, respectively. Then, the mechanical integration of screws in the proximal tibia of 12 rats was monitored at seven time points over a period of 1 month. We observed significant increases (p 0.05) of bone-screw contact (+28%), stiffness (+93%) and failure load (+71%) over the course of the experiment, and more than 75% of these changes occurred during the first 2 weeks. Limitations, such as image artefacts and radiation, still compromise the immediate clinical application of this method, but it has a promising potential in preclinical animal studies, as it provides very valuable data about the dynamic aspect of implant integration with considerably reduced animal resources.

We report the novel use of a tuneable, non-integrating viral gene delivery system to bone that can be combined with clinically approved biomaterials in an 'off-the-shelf' manner. Specifically, a doxycycline inducible Tet-on adenoviral vector (AdTetBMP-2) in combination with mesenchymal stromal cells (MSCs), fibrin and a biphasic calcium phosphate ceramic (MBCP®) was used to repair large bone defects in nude rats. Bone morphogenetic protein-2 (BMP-2) transgene expression could be effectively tuned by modification of the doxycycline concentration. The effect of adenoviral BMP-2 gene delivery upon bone healing was investigated in vivo in 4 mm critically sized, internally fixated, femoral defects. MSCs were transduced either by direct application of AdTetBMP-2 or by pre-coating MBCP granules with the virus. Radiological assessment scores post-mortem were significantly improved upon delivery of AdTetBMP-2. In AdTetBMP-2 groups, histological analysis revealed significantly more newly formed bone at the defect site compared with controls. Newly formed bone was vascularized and fully integrated with nascent tissue and implanted biomaterial. Improvement in healing outcome was achieved using both methods of vector delivery (direct application vs. pre-coating MCBP). Adenoviral delivery of BMP-2 enhanced bone regeneration achieved by the transplantation of MSCs, fibrin and MBCP in vivo. Importantly, our in vitro and in vivo data suggest that this can be achieved with relatively low (ng/ml) levels of the growth factor. Our model and novel gene delivery system may provide a powerful standardized tool for the optimization of growth factor delivery and release for the healing of large bone defects. Copyright © 2016 John WileySons, Ltd.

Bisphosphonate-associated osteonecrosis of the jaw (BP-ONJ) is a side effect of antiresorptive treatment that is increasingly prescribed for patients with osteoporosis or malignant diseases with bone metastases. Surgical treatment of BP-ONJ requires adequate pre-operative imaging. To date, CT is the imaging standard in clinical routine; however, defining the extent of the pathological area is difficult and soft tissues are poorly displayed. MRI with zero echo time (ZTE-MRI) to display hard tissues enables a precise display of calcified structures and soft tissues for the delineation of bone necrosis and soft-tissue reactions.BP-ONJ was induced in eight sheep by extraction of two premolars in the left mandible and zoledronate (ZOL) administration. Eight sheep without ZOL administration served as the control group. Four sheep of each main group underwent osteopenia induction via ovariectomy, glucocorticoid administration and a calcium-free diet. After sacrifice, the area of tooth extraction was harvested and scanned with micro-CT (µCT) and ZTE-MRI. Two trained dentists analyzed digital imaging and communications in medicine data sets using three-dimensional imaging software. The periosteal reaction and the remaining extraction sockets were measured.BP-ONJ was evident, and the remaining extraction sockets were observed in all animals treated with ZOL. Periosteal reactions were more pronounced in animals treated with ZOL, and they appeared broader in ZTE-MRI.BP-ONJ lesions in the sheep mandible can be detected using µCT and ZTE-MRI. Although illustration of sequester was more consistent using the µCT, ZTE-MRI was advantageous in evaluation of periosteal reaction.

In lower cancellous apparent bone density, it can be difficult to achieve adequate screw fixation and hence stable fracture fixation. Different strategies have been proposed, one of them is through augmentation using calcium phosphate cement in the region at or close to the screw thread itself. To support the hypothesis of an improved screw fixation technique by augmentation of the bone surrounding the implanted screw, in vivo biomechanical and densitometric studies are performed on rabbit specimen where normal and simulated weak bone quality are considered. In particular, the evolution of screw stability till 12 weeks following the implantation is quantified. A statistical significance in the pull out force for augmented versus non-augmented screws was found for the shorter time periods tested of ≤ 5 days whilst the pull out force was found to increase with time for both augmented and non-augmented screws during the 12 week course of the study. The results of the study demonstrate that the use of an injectable calcium phosphate cement which sets in vivo can significantly improve screw pull out strength at and after implantation for normal and simulated weak bone quality.

Background: Local bisphosphonate delivery may be a solution to prevent periprosthetic bone loss and improve orthopedic implants fixation. In load-bearing implants, periprosthetic bone is exposed to high mechanical demands, which in normal conditions induce an adaptation of bone. In this specific mechanical situation, the modulation of the bone response by bisphosphonate remains uncertain. Methods: We assessed the combined effects of zoledronate and mechanical loading on bone adaptation using an in-vivo axial compression model of the mouse tibia and injections of zoledronate. Bone structure was quantified with in-vivo µCT before and after the period of stimulation and the biomechanical properties of the tibias were evaluated with 3 point-bending tests after sacrifice. Findings: Axial loading induced a localized increase of cortical thickness and bone area. Zoledronate increased cortical thickness, bone perimeter, and bone area. At the most loaded site of the tibia, the combined effect of zoledronate and mechanical stimulation was significantly smaller than the effect of zoledronate plus the effect of mechanical loading. Interpretations: The results of this study suggested that a negative interaction between zoledronate and mechanical loading might exist at high level of strain.

An obvious means to improve the fixation of a cancellous bone screw is to augment the surrounding bone with cement. Previous studies have shown that bone augmentation with Calcium Phosphate (CaP) cement significantly improves screw fixation. Nevertheless, quantitative data about the optimal distribution of CaP cement is not available. The present study aims to show the effect of cement distribution on the screw fixation strength for various cortical thicknesses and to determine the conditions at which cement augmentation can compensate for the absence of cortical fixation in osteoporotic bone. In this study, artificial bone materials were used to mimic osteoporotic cancellous bone and cortical bone of varying thickness. These bone constructs were used to test the fixation strength of cancellous bone screws in different cortical thicknesses and different cement augmentation depths. The cement distribution was measured with microCT. The maximum pullout force was measured experimentally. The microCT analysis revealed a pseudo-conic shape distribution of the cement around the screws. While the maximum pullout strength of the screws in the artificial bone only was 30±7N, it could increase up to approximately 1000N under optimal conditions. Cement augmentation significantly increased pullout force in all cases. The effect of cortical thickness on pullout force was reduced with increased cement augmentation depth. Indeed, cement augmentation without cortical fixation increased pullout forces over that of screws without cement augmentation but with cortical fixation. Since cement augmentation significantly increased pullout force in all cases, we conclude that the loss of cortical fixation can be compensated by cement augmentation.

The fixation of an orthopedic implant depends strongly upon its initial stability. Peri-implant bone may resorb shortly after the surgery. This resorption is directly followed by new bone formation and implants fixation strengthening, the so-called secondary fixation. If the initial stability is not reached, the resorption continues and the implant fixation weakens, which leads to implant loosening. Studies with rats and dogs have shown that a solution to prevent peri-implant resorption is to deliver bisphosphonate from the implant surface. The aims of the study were, first, to develop a model of bone remodeling around an implant delivering bisphosphonate, second, to predict the bisphosphonate dose that would induce the maximal peri-implant bone density, and third to verify in vivo that peri-implant bone density is maximal with the calculated dose. The model consists of a bone remodeling equation and a drug diffusion equation. The change in bone density is driven by a mechanical stimulus and a drug stimulus. The drug stimulus function and the other numerical parameters were identified from experimental data. The model predicted that a dose of 0.3 microg of zoledronate on the implant would induce a maximal bone density. Implants with 0.3 microg of zoledronate were then implanted in rat femurs for 3, 6 and 9 weeks. We measured that peri-implant bone density was 4% greater with the calculated dose compared to the dose empirically described as best. The approach presented in this paper could be used in the design and analysis processes of experiments in local delivery of drug such as bisphosphonate.

The transcription factor Sox4 is vital for fetal development, as Sox4–/– homozygotes die in utero. Sox4 mRNA is expressed in the early embryonic growth plate and is regulated by parathyroid hormone, but its function in bone modeling/remodeling is unknown. We report that Sox4+/– mice exhibit significantly lower bone mass (by dual-energy X-ray absorptiometry) from an early age, and fail to obtain the peak bone mass of wild-type (WT) animals. Microcomputed tomography (μCT), histomorphometry and biomechanical testing of Sox4+/– bones show reduced trabecular and cortical thickness, growth plate width, ultimate force and stiffness compared with WT. Bone formation rate (BFR) in 3-month-old Sox4+/– mice is 64% lower than in WT. Primary calvarial osteoblasts from Sox4+/– mice demonstrate markedly inhibited proliferation, differentiation and mineralization. In these cultures, osterix (Osx) and osteocalcin (OCN) mRNA expression was reduced, whereas Runx2 mRNA was unaffected. No functional defects were found in osteoclasts. Silencing of Sox4 by siRNA in WT osteoblasts replicated the defects observed in Sox4+/– cells. We demonstrate inhibited formation and altered microarchitecture of bone in Sox4+/– mice versus WT, without apparent defects in bone resorption. Our results implicate the transcription factor Sox4 in regulation of bone formation, by acting upstream of Osx and independent of Runx2.

New cells/hydrogel-based treatments for intervertebral disc (IVD) regeneration need to be tested on animal models before clinical translation. Ovine IVD represents a good model but does not allow the injection of a significant volume into intact IVD. The aim of this study was to compare different methods to create a cavity into ovine nucleus pulposus (NP) by enzymatic digestion (E), mechanical nucleotomy (N), or a combining technique (E+N), as a model to study IVD regeneration strategies with intact annulus fibrosus (AF) in functional spinal units (FSUs) in vitro.The transpedicular approach via the endplate route (2 mm tunnel) was performed on ovine FSU (IVD and superior and inferior endplate) to access the NP. FSUs were treated by N (Arthroscopic shaver), E (Trypsin/Collagenase), or E+N. Treatments were evaluated macro- and microscopically. The degradation of proteoglycan (PG) around the cavity was assessed by gel electrophoresis. Cell viability was evaluated using the lactate dehydrogenase (LDH) assay. Cavity volume was quantified through computerized tomography after injection of agarose gel/contrast agent.A cavity with intact AF was successfully created with all three methods. The N group showed high reproducibility, low PG degradation, and no endplate thinning. Histological analysis demonstrated NP matrix degradation in enzyme-treated groups, while the PG content was homogenous using mechanical discectomy. Cell viability was affected only in the E group. The cavity volume normalized to the total IVD volume was 5.2% ± 1.6% in E, 5.0% ± 1.4% in E+N, and 4.2% ± 0.1% in N.Mechanical nucleotomy leads to a more reproducible and less destructive cavity in the NP. Enzymatic methods perform better in terms of cavity volume; however, the cells and PG of the surrounding tissue may be affected. The mechanical nucleotomy enables the creation of a cavity into the IVD while keeping the AF intact, allowing the injection of reproducible volumes of hydrogel and tissue engineering construct for preclinical tests.

Vertebroplasty has been shown to reinforce weak vertebral bodies and reduce fracture risks, yet cement leakage is a major problem that can cause severe complications. Since cement flow is nearly impossible to control during surgery, small volumes of cement are injected, but then mechanical benefits might be limited. A better understanding of cement flows within bone structure is required to further optimize vertebroplasty and bone augmentation in general. We developed a novel imaging method, composite time-lapse CT, to characterize cement flow during injection. In brief, composite-resolution time-lapse CT exploits the qualities of microCT and clinical CT. The method consists in overlaying low-resolution time-lapse CT scans acquired during injection onto pre-operative high-resolution microCT scans, generating composite-resolution time-lapse CT series of cement flow within bone. In this in vitro study, composite-resolution time-lapse CT was applied to eight intact and five artificially fractured cadaveric vertebrae during vertebroplasty. The time-lapse scans were acquired at one-milliliter cement injection steps until a total of 10 ml cement was injected. The composite-resolution series were then converted into micro finite element models to compute strains distribution under virtual axial loading. Relocation of strain energy density within bone structure was observed throughout the progression of the procedure. Interestingly, the normalized effect of cement injection on the overall stiffness of the vertebrae was similar between intact and fractured specimens, although at different orders of magnitude. In conclusion, composite time-lapse CT can picture cement flows during bone augmentation. The composite images can also be easily converted into finite element models to compute virtual strain distributions under loading at every step of an injection, providing deeper understanding on the biomechanics of vertebroplasty.

Summary Percutaneous vertebroplasty represents a current procedure to effectively reinforce osteoporotic bone via the injection of bone cement. This contribution considers a continuum-mechanically based modelling approach and simulation techniques to predict the cement distributions within a vertebra during injection. To do so, experimental investigations, imaging data and image processing techniques are combined and exploited to extract necessary data from high-resolution μCT image data. The multiphasic model is based on the Theory of Porous Media, providing the theoretical basis to describe within one set of coupled equations the interaction of an elastically deformable solid skeleton, of liquid bone cement and the displacement of liquid bone marrow. The simulation results are validated against an experiment, in which bone cement was injected into a human vertebra under realistic conditions. The major advantage of this comprehensive modelling approach is the fact that one can not only predict the complex cement flow within an entire vertebra but is also capable of taking into account solid deformations in a fully coupled manner. The presented work is the first step towards the ultimate and future goal of extending this framework to a clinical tool allowing for pre-operative cement distribution predictions by means of numerical simulations. Copyright © 2015 John Wiley & Sons, Ltd.

The aim of this laboratory method is to describe two approaches for the investigation of bone responses to mechanical loading in mice in vivo. The first is running exercise, because it is easily translatable clinically, and the second is axial compression of the tibia, because it is precisely controllable. The effects of running exercise, and in general physical activity, on bone tissue have been shown to be both direct through mechanical loading (ground impact and muscle tension) and indirect through metabolic changes. Therefore, running exercise has been considered the most convenient preclinical model for demonstrating the general idea that exercise is good for bone health, either early in age for increasing peak bone mass or later in age by slowing down bone loss. However, numerous combinations of protocols have been reported, which makes it difficult to formulate a simple take-home message. This laboratory method also provides a detailed description of in vivo direct mechanical axial compression of the mouse tibia. The effects of mechanical loading depend on the force (strain), frequency, waveform and duration of application, and they range from bone anabolism with low bone remodeling, inducing lamellar bone accumulation, to bone catabolism with high bone remodeling, leading to microdamage, woven bone formation and bone loss. Direct in vivo loading models are extensively used to study mechanotransduction pathways, and contribute by this way to the development of new bone anabolism treatments. Although it is particularly difficult to assemble an internationally adopted protocol description, which would give reproducible bone responses, here we have attempted to provide a comprehensive guide for best practice in performing running exercise and direct in vivo mechanical loading in the laboratory.

Bisphosphonate-related osteonecrosis of the jaw (BP-ONJ) occurs in 1 % of patients with medication-induced osteoporosis treated with bisphosphonates. Sheep are an established large animal model for investigating osteoporotic skeletal changes. Zoledronate significantly reduces tissue mineral variability in ovariectomized sheep. The aim of this study was to analyze bone healing after tooth extraction in sheep with induced osteopenia and zoledronate administration.Eight adult ewes were randomly divided into two groups of four animals. All sheep underwent ovariectomy and a low-calcium diet. Dexamethasone was administered weekly for 16 weeks. Zoledronate was then given every third week for a further 16 weeks in four sheep; these infusions were repeated after extraction of two lower premolars. Four sheep without zoledronate administrations served as controls.Due to general health conditions, two sheep of the zoledronate group had to be excluded before surgery. The remaining two sheep of this group developed BP-ONJ lesions at the extraction site and various other sites in both jaws. Control group animals showed uneventful wound healing. Histology of the alveolar processes as well as lumbar spine revealed larger portions of old bone and smaller portions of new bone in the zoledronate group.This animal study showed uneventful wound healing after tooth extraction in osteopenic sheep whereas zoledronate treatment leads to development of BP-ONJ-like lesions.As bisphosphonate administration is a standard treatment for glucocorticoid-induced osteoporosis, this model can be used for further research in pathogenesis and management of bisphosphonate-related adverse events.

Percutaneous vertebroplasty represents a current procedure to effectively reinforce osteoporotic bone via the injection of bone cement. This contribution considers a continuum-mechanically based modelling approach and simulation techniques to predict the cement distributions within a vertebra during injection. To do so, experimental investigations, imaging data and image processing techniques are combined and exploited to extract necessary data from high-resolution μCT image data. The multiphasic model is based on the Theory of Porous Media, providing the theoretical basis to describe within one set of coupled equations the interaction of an elastically deformable solid skeleton, of liquid bone cement and the displacement of liquid bone marrow. The simulation results are validated against an experiment, in which bone cement was injected into a human vertebra under realistic conditions. The major advantage of this comprehensive modelling approach is the fact that one can not only predict the complex cement flow within an entire vertebra but is also capable of taking into account solid deformations in a fully coupled manner. The presented work is the first step towards the ultimate and future goal of extending this framework to a clinical tool allowing for pre-operative cement distribution predictions by means of numerical simulations.

BackgroundAreal bone mineral density is predictive for fracture risk. Microstructural bone parameters evaluated at the appendicular skeleton by high-resolution peripheral quantitative computed tomography (HR-pQCT) display differences between healthy patients and fracture patients. With the simple geometry of the cortex at the distal tibial diaphysis, a cortical index of the tibia combining material and mechanical properties correlated highly with bone strength ex vivo. The trabecular bone score derived from the scan of the lumbar spine by dual-energy X-ray absorptiometry (DXA) correlated ex vivo with the micro architectural parameters. It is unknown if these microstructural correlations could be made in healthy premenopausal women.MethodsRandomly selected women between 20-40 years of age were examined by DXA and HR-pQCT at the standard regions of interest and at customized sub regions to focus on cortical and trabecular parameters of strength separately. For cortical strength, at the distal tibia the volumetric cortical index was calculated directly from HR-pQCT and the areal cortical index was derived from the DXA scan using a Canny threshold-based tool. For trabecular strength, the trabecular bone score was calculated based on the DXA scan of the lumbar spine and was compared with the corresponding parameters derived from the HR-pQCT measurements at radius and tibia.ResultsSeventy-two healthy women were included (average age 33.8 years, average BMI 23.2 kg/m(2)). The areal cortical index correlated highly with the volumetric cortical index at the distal tibia (R = 0.798). The trabecular bone score correlated moderately with the microstructural parameters of the trabecular bone.ConclusionThis study in randomly selected premenopausal women demonstrated that microstructural parameters of the bone evaluated by HR-pQCT correlated with the DXA derived parameters of skeletal regions containing predominantly cortical or cancellous bone. Whether these indexes are suitable for better predictions of the fracture risk deserves further investigation.

The stability of the human spine is highly dependent on the cancellous bone structure of the vertebra. In the case of osteoporosis and accompanied weaking of the vertebral structure, compression fractures and other lesions of the affected patient may occur. The reinforcement of the porous cancellous bone by the injection of bone-cement is a common procedure in order to overcome this issues. The modelling and computational simulation of vertebroplasty, i.e., bone-cement-injection into the vertebra, is of major interest to obtain valid and reliable predicitions for this surgery. A detailed micromechanical (and locally single-phasic) model exhibits the drawback that all geometrical and physical transition conditions of the individual parts and their complex microstructure have to be known. Therefore, this study considers a macro-scopic (and multi-constituent) continuum-mechanical model based on the Theory of Porous Media, where the homogenisation of the underlying micro-structure results in a model of three constituents. In particular, these are the solid bone skeleton, which is saturated by bone marrow, where the latter may be displaced by the injected liquid bone cement. The micro-architecture is regarded by heterogeneous and anisotropic permeability tensors and the preferred directions of the trabecular bone structure. The presented strongly coupled macroscopic model offers the opportunity to not only simulate the flow of the pore fluids but also predicts the arising stresses and strains of the solid bone skeleton due to the numerical investigation of the injection process. (© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim)

The reinforcement of porous vertebral cancellous bone by the injection of bone cement is a practical procedure for the stabilisation of osteoporotic compression fractures and other weakening lesions. This contribution concerns the reproduction and prediction of the resulting bone-cement distribution during the injection procedure by means of numerical simulation. A detailed micromechanical (locally single-phasic) model exhibits the drawback that all geometrical and physical transition conditions of the individual parts of the complex aggregate have to be known. Therefore, we rather proceed from a macroscopic (and multi-constituent) continuum-mechanical model based on the Theory of Porous Media. In this regard, the homogenisation of the underlying micro-structure results in a model of three constituents: these are the solid bone skeleton, which is saturated by the liquid bone marrow that may be displaced by the injected liquid bone cement. The influence of the micro-architecture of the pore space on the spreading of the bone cement is considered by a spatial diversification of the anisotropic permeability tensors, obtained through image processing techniques applied to medical imaging data (µCT). The numerical investigation of the strongly coupled problem enables the study of vertebroplasty and allows for the comparison between the simulation results and the experimentally determined bone-cement distribution that were imaged during injections. (© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim)

A partial review is proposed on the existing literature for the research performed in orthopedic implant used as drug delivery system. In the first part, an evaluation is given on the clinical need to deliver a drug in the surrounding of an implant. Secondly, a review of the clinical situation is developed for implants already used as drug delivery system. Experimental works performed for local delivery are reported. In particular, a description is given on the in vitro and in vivo studies where the implant is coated with different proteins or drugs. Finally, a conclusion is proposed on the next step in the development of orthopedic implant as drug delivery system mentioning also the industrial situation.