Vertebral metastases are the most common type of malignant lesions of the spine. Although this tumour is still considered incurable and standard treatments are mainly palliative, the standard approach consists in surgical resection, which results in the formation of bone gaps. Hence, scaffolds, cements and/or implants are needed to fill the bone lacunae. Here, we propose a novel approach to address spinal metastases recurrence, based on the use of anti-tumour metallic-based nanostructured coatings. Moreover, for the first time, a gradient microfluidic approach is proposed for the screening of nanostructured coatings having anti-tumoral effect, to determine the optimal concentration of the metallic compound that permits selective toxicity towards tumoral cells. Coatings are based on Zinc as anti-tumour agent, which had been never explored before for treatment of bone metastases. The customized gradient generating microfluidic chip was designed by Autodesk Inventor and fabricated from a microstructured mould by using replica moulding technique. Microstructured mould were obtained by micro-milling technique. The chip is composed of a system of microfluidic channels generating a gradient of 6 concentrations of drug and a compartment with multiple arrays of cell culture chambers, one for each drug concentration. The device is suitable for dynamic cultures and in-chip biological assays. The formation of a gradient was validated using a methylene blue solution and the cell loading was successful. Preliminary biological data on 3D dynamic cultures of stromal cells (bone-marrow mesenchymal stem cells) and breast carcinoma cells (MDA-MB-231) were performed in a commercial microfluidic device. Results showed that Zn eluates had a selective cytotoxic effect for tumoral cells. Indeed, cell migration and cell replication of treated tumoral cells was inhibited. Moreover, the three-dimensionality of the model strongly affected the efficacy of Zn eluates, as 2D preliminary experiments showed a high cytotoxic effect of Zn also for stromal cells, thus confirming that traditional screening tests on 2D cultured cells usually lead to an overestimation of drug efficacy and toxicity. Based on preliminary data, the customized platform could be considered a major advancement in cancer drug screenings as it also allows the rapid and efficient screening of biomaterials having antitumor effect

Treatment of large bone defects represents a great challenge for orthopedic surgeons. The main causes are congenital abnormalities, traumas, osteomyelitis and bone resection due to cancer. Each surgical method for bone reconstruction leads its own burden of complications. The gold standard is considered the autologous bone graft, either of cancellous or cortical origin, but due to graft resorption and a limitation for large defect, allograft techniques have been identified. In the bone defect, these include the placement of cadaver bone or cement spacer to create the ‘Biological Chamber’ to restore bone regeneration, according to the Masquelet technique. We report eight patients, with large bone defect (for various etiologies and with an average size defect of 13.3 cm) in the lower and upper limbs, who underwent surgery at our Traumatology Department, between January 2019 and October 2020. Three patients were treated with both cortical and cancellous autologous bone grafts, while five received cortical or cement spacer allografts from donors. They underwent pre and postoperative radiographs and complete osseointegration was observed in all patients already undergoing monthly radiographic checks, with a restoration of length and range of motion. In our study, both the two stage-Masquelet and the cortical bone graft from a cadaver donor proved to be valid techniques in patients with very extensive defects to reconstruct the defect, restore the length, minimize implant left in situ and achieve complete functional recovery

Introduction. 20 cases of bone defect have been treated by the induced membrane technique avoiding allograft, microsurgery and amputation. Material and Methods. 9 cases of long bone defect (humerus and 2 bones arm) and 11 cases of bone defct at the hand have been included in this multicentric prospective study (3 centers). 11 cases were traumatic, 7 cases were septic non union and 2 cases were tumor. At hand level's bone reached at least one phalanx, and for long bone the mean defect was 5cm (3–11). All cases were treated by the induced membrane technique which consists in stable fixation, flap if necessary and in filling the void created by the bone defect by a cement spacer (PMMA). This technique needs a second stage procedure at the 2. nd. month where the cement is removed and the void is filled by cancellous bone. The key point of this induced membrane technique is to respect the foreign body membane which appeared around the cement spacer and which create a biologic chamber after the second time. Bone union was evaluated prospectively in each case by an surgeon not involved in the treatment by Xray and CT scan. Failure was defined as a non union at 1 year, or an uncontrolled sepsis at 1 month. Results. 3 cases failed to achieve bone union, 2 at hand level and 1 for long bone. No septic complications occured and all septic cases werre stopped. In 14 cases bone union was achieved with a delay of 5 months (1, 5–12). 2 biopsies allowed to proove us that osteoid tissue was created by the technic. At hand level all fingers have included. At shoulder and elbow level, function reached 75% of motion than controlateral side. Discussion. Masquelet first reported 35 cases of large bone defect of tibia non union treated by the induced membrane technic which allow to fill bone defect with cancellous bone alone. The cement spacer allows to induce a foreign body membrane which constitute a biological chamber. Works on animal model reported by Pellissier and Viatteau showed the properties of the membrane: secretion of growths factors (VEGF, TGFbéta1, BMP2) and osteoinductive activitie of the cells. The induced membrane seem to play the role of a neo periosteum. Using this technic is possible in emergency or in septic condition where bone defect can not been solved by shortening. This technic avoids to use microsurgical technic and the limit is the quantity of avalaible cancellous bone

Although cemented fixation provides excellent results in primary total hip replacement (THR), particularly in patients older than 75 years, uncemented implants are most commonly used nowadays. We compare the rate of complications, clinical and radiological results of three different designs over 75-years-old patients. 433 hips implanted in patients over 75 years old were identified from our Local Joint Registry. Group A consisted of 139 tapered cemented hips, group B of 140 tapered grit-blasted uncemented hips and group C of 154 tapered porous-coated uncemented hips. A 28 mm femoral head size on polyethylene was used in all cases. The mean age was greater in group A and the physical activity level according to Devane was lower in this group (p<0.001 for both variables). Primary osteoarthritis was the most frequent diagnoses in all groups. The radiological acetabular shape was similar according to Dorr, however, an osteopenic-cylindrical femur was most frequently observed in group A (p<0.001). The pre- and post-operative clinical results were evaluated according to the Merle-D'Aubigne and Postel scale. Radiological cup position was assessed, including hip rotation centre distance according to Ranawat and cup anteversion according to Widmer. We also evaluated the lever arm and height of the greater trochanter distances and the stem position. Kaplan-Meier analysis was done for revision for any cause and loosening. The hip rotation centre distance was greater and the height of the greater trochanter was lower in group B (p=0.003, p<0.001, respectively). The lever arm distance was lower in group C (p<0.001). A varus stem position was more frequently observed in group B (p<0.001). There were no intra- or post-operative fractures in group A, although there were five intra-operative fractures in the other groups plus two post-operative fractures in group B and four in group C. The rate of dislocation was similar among groups and was the most frequent cause for revision surgery (8 hips for the whole series). The mean post-operative clinical score improved in all groups. The overall survival rate for revision for any cause at 120 months was 88.4% (95% CI 78.8–98), being 97.8% (95% CI 95.2–100) for group A, 81.8% (95% CI 64.8–98.8) for group B and 95.3% (95% CI 91.1–99.6) for group C (log Rank: 0.416). Five hips were revised for loosening. The overall survival rate for loosening at 120 months was 91.9% (95% CI 81.7–100), being 99.2%(95% CI 97.6–100) for group A, 85.5 (95% CI 69.9 −100) for group B and 100% for group C (Log Rank 0.093). Despite a more osteopenic bone in the cemented group, the rate of peri-prosthetic fractures was higher after uncemented THR in patients older than 75 years. Although the overall outcome is good with both types of fixation, the post-operative reconstruction of the hip, which might be more reliable after cemented fixation, may affect the rate of complications in this population

Introduction. Glenoid loosening, still a main complication for shoulder arthroplasty, was suggested to be related implant design, surgical aspects, and also bone quality. However, typical studies of fixation do not account for heterogeneity in bone morphology and density which were suggested to affect fixation failure. In this study, a combination of cyclic rocking horse tests on cadaver specimens and microCT-based finite element (microFE) analysis of specimens of a wide range of bone density were used to evaluate the effects of periprosthetic bone quality on the risks of loosening of anatomical keeled or pegged glenoid implants. Methods. Six pairs of cadaveric scapulae, scanned with a quantitative computer tomography (QCT) scanner to calculate bone mineral density (BMD), were implanted with either cemented anatomical pegged or keeled glenoid components and tested under constant glenohumeral load while a humeral head component was moved cyclically in the inferior and superior directions. Edge displacements were measured after 1000, 4000 and 23000 test cycles, and tested for statistical differences with regards to changes or implant design. Relationships were established between edge displacements and QCT-based BMD below the implant. Four other specimens were scanned with high-resolution peripheral QCT (82µm) and implanted with the same 2 implants to generate virtual models. These were loaded with constant glenohumeral force, varying glenohumeral conformity and superior or inferior load shifts while internal stresses at the cement-bone and implant-cement interfaces were calculated and related to apparent bone density in the periprosthetic zone. Results. Mean displacements at the inferior and superior edges showed no statistical difference between keeled and pegged designs (p>0.05). Compression and distraction were however statistically different from the initial reference measurement at even 1000 and 4000 cycles for both implant designs (p<0.05). For both implant designs, superior and inferior distractions were generally highest at each measurement time in specimens where BMD below the lifting edge was lower, showing a trend of increased distraction with decreased BMD. Moreover, the microFE models predicted higher bone and cement stresses for specimens of lower apparent bone density. Finally, highest peak stresses were located at the cement-bone interface, which seemed the weaker part of the fixation. Discussion. With this combined experimental and numerical study, it was shown that implant distraction and stresses in the cement layer are greater in glenoids of lower bone density for both implant designs. This indicates that fixation failure will most likely occur in bone of lower density, and that fixation design itself may play a secondary role. These results have important impact for understanding the mechanisms of glenoid component failure, a common complication of total shoulder arthroplasty

We have developed a bioactive bone cement (BA cement) consisting of Bis-GMA resin and bioactive glass powder. It has high compressive and tensile strengths, a low curing temperature and its bioactivity allows it to bond directly with bone. We operated on the 18 femora of nine mongrel dogs for intercalary replacement of part of the bone by a metal prosthesis using either PMMA cement or BA cement for fixation. Three dogs were killed at each of 4, 12 and 26 weeks after surgery for the evaluation of fixation strength by a push-out test and for histological examination by Giemsa surface staining and SEM. Fixation strengths with PMMA cement at 4, 12 and 26 weeks after surgery were 46.8 ± 18.9, 50.0 ± 24.7, and 58.2 ± 28.9 kgf (mean ±SD), respectively. Those with BA cement were 56.8 ± 26.1, 67.2 ± 19.2, and 72.8 ± 22.2 kgf, respectively. Fibrous tissue intervened between bone and PMMA cement but BA cement had bonded directly to bone at 12 and 26 weeks. This suggests that BA cement will be useful in providing long-lasting fixation of implants to bone under weight-bearing conditions

Summary Statement. To test regenerative therapies for the intervertebral disc it is necessary to create a cavity in the nucleus polposus mantaining the annulus fibrosus intact. The transpedicular mechanical nucleotomy represents the best method for this purpose. Introduction. 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 doesn't allow the injection of a significant volume into intact IVD. The objective of the study was to compare different methods to create a cavity into ovine nucleus pulposus (NP) by enzymatic digestion (E), mechanical discectomy (M) and a combination of both (E+M), as a model to study IVD regeneration strategies with intact anulus fibrosus (AF). Methods. Ovine lumbar functional spinal units (FSU) were used. The transpedicular approach via the endplate route (2mm tunnel) was performed to access the NP with AF intact. FSUs were treated through M (Arthroscopic shaver), E (Trypsin/Collagenase) and E+M. The cavity was macro- and micro-scopically evaluated. The degradation of GAG (gel chromatography) around the cavity (inner AF) was assessed. The cavity volume was quantified through µCT after injection of Agarose gel/Contrast agent. Results. The cavity has been successfully created using all methods. The M group showed high reproducibility, low GAG degradation and no endplate thinning compared to other groups. The histology analysis demonstrated NP matrix degradation in E groups while the proteoglycan content was still homogenous in the M. The percentage of the cavity volume normalised to the total IVD volume was 5.2% ± 1.6 in E, 5% ±1.4 in E+M and 4, 2% ± 0.1in M. Discussion. M represents the best method to create a reproducible and less destructive cavity in the NP. Indeed, E-based methods perform better in terms of cavity volume but the GAG of the surrounding tissue may be affected. While a lesion of the end-plate might lead to further IVD degeneration, this approach is minimal invasive (2mm) and can be easily sealed using bone cylinder, cements or scaffolds. The biomechanical characterization and in vivo evaluation are on going

Summary Statement. There are no standardised methods for assessing the cement flow behaviour in vertebroplasty. We propose a novel methodology to help understand the interaction of cement properties on the underlying displacement of bone marrow by bone cement in porous media. Introduction. Concerns related to cement extravasation in vertebroplasty provide the motivation for the development of methodologies for assessing cements (novel and commercially available) and delivery systems. Reproducible and pathologically representative three-dimensional bone surrogates are used to understand the complex rheology underlying the two-phase flow in porous media. Patients & Methods. The bone surrogates were achieved by first developing CAD models then manufacturing the physical models through a suitable rapid prototyping technique. MicroCT 100 (Scanco Medical, Switzerland) was used to assess the variability in the model morphology (n=8). Contact angle measurements were performed on the material to compare the surface wettability to that of bone. The surrogates were filled with bone marrow substitute (Carboxymethyl cellulose 2.5 % in water, 0.4 Pa.s) then 5 ml of silicone oil (Dow Corning Corp. 200® Fluid, 60 Pa.s) was injected at a constant flow rate (3mL/min) using a syringe pump. The injection was radiographically monitored and the video sequences were captured. Experiments were repeated three times. The displacement of the syringe plunger and the force applied on the plunger were recorded. Image processing was performed on the video sequences to quantitatively describe the resulting flow patterns and calculate parameters including the time of leakage and the mean spreading distance. Results. The variability in the model morphology was very low with a strut thickness of 0.253 ± 0.010 mm and a pore spacing of 0.83 + 0.01 mm. The surface wettability was very similar between all materials with a contact angle around 65°. The measured displacement of the syringe plunger confirmed the flow rate to be constant at 3 ml/min. The peak injection pressure was 0.443 ± 0.013 MPa which is well below the reported clinical measurement of injection pressure during vertebroplasty. 1. Anterior oil leakage occurred at 34.6 ± 4.71 seconds. The oil never reached the posterior wall and the mean spreading distance at the end of the injection was 23.39 ± 1.11 mm. Discussion/Conclusion. These complex three-dimensional bone surrogates provide a clinically relevant representation of the in vivo situation in terms of geometry, porosity and permeability. They overcome limitations of previous models by being constant in terms of both porosity and geometry which is crucial to reduce the variability, render the experiments reproducible and shift the focus onto understanding the cement flow behaviour. The proposed methodology will help study cement-fluid interaction to get better representation of in vivo cement flow patterns and provide a tool for validating computational simulations. Funding was provided by the EU under the FP7 Marie Curie Action (PITN-GA-2009-238690-SPINEFX)

Introduction. Hip resurfacing has become a popular procedure for young active patients with osteonecrosis of the femoral head. However, it is not yet clear exactly how much osteonecrosis would permit this procedure and how much would be a contraindication. The aim of the present study was to analyze the resurfaced femoral head using finite element models and, in particular, to examine the influence of the extent of osteonecrosis and metaphysical stem shaft angles within the femoral head. Methods. We evaluated biomechanical changes at various extents of necrosis and implant alignments, using the finite element analysis method. We established three patterns of necrosis by depth from the surface of femoral head and five stem angles. Extension of necrosis as a quarter of femoral head diameter is type A, from a half is type B, and three-fourths is type C. We set five types of different stem angles from 125 to 145 degrees for the axis of femoral shaft. For these models, we evaluated biomechanical changes associated with the extent of necrosis and the stem alignment. Results. Stress distribution near the bone-cement interface increased with expansion of the necrosis. The stress concentration was particularly evident in the Type C model which had wide cement mantle replacement on the resurfaced femoral head. The maximum stress on the prosthesis was decreased with stem angles ranging from 130 to 140 degrees. Stress concentration at the stem shaft was observed when implanted varus or valgus alignment. Stress concentration of cement was observed at the anterior and inferior edges in each model. Regardless of the extent of necrosis replaced by cement, the stress values at the inferior edge increased as the stem shaft angle became varus. Conclusion. This study suggests that hip resurfacing for patients in whom osteonecrosis extends widely should be considered carefully; increased stress concentration near the bone-cement interface may occur when all the necrotic bone is replaced by cement. Furthermore, excessive varus or valgus implantation of the prosthesis has potentially adverse biomechanical effects for implants and the cement mantle

Vertebroplasty is a minimal invasive surgical procedure for treatment of vertebral compressive fractures, whereby cement is injected percutaneously into a vertebral body. Cement viscosity is believed to influence injectability, cement wash-out and leakage. Altering the liquid to powder ratio can affect the viscosity, level of cohesion and extent cement fill within the vertebral body and the ultimately strength and stiffness of the cement-vertebra composite. The association of these combined factors remains unclear. The aim of this study was to determine the relationship between cement viscosity and the potential augmentation of strength and stiffness in a model simulating in-vitro prophylactic vertebroplasty of osteoporotic vertebral bodies. Samples of synthetic bone (Sawbone) representing osteoporotic bone were manually injected with 1mL of calcium phosphate cement using a 11G cannulated needle. Calcium phosphate cement was produced by mixing alpha-tricalcium phosphate, calcium carbonate and hydroxyapatite with an aqueous solution of 5 wt% disodium hydrogen phosphate. Three liquid to powder ratio (LPR) representing different viscosity levels were used; i.e. 0.5mL/g (low viscosity), 0.45mL/g (medium viscosity) and 0.35mL/g (high viscosity). Cement filled samples were then placed in an oven (37oC) for 20 min and then immersed in Ringer's solution (37oC) for 3 days. Samples of synthetic bone without cement injection were used as controls. Potential for leakage and wash-out was determined using gravimetric analysis. Extent of cement fill was determined using computer tomography (CT). Samples were tested under axial compression at a rate of 1 mm/min and the strength and stiffness determined. Statistical significance against controls was determined using a one-way analysis of variance (p<0.05). Low viscosity cement showed more cement leakage (p=0.512) and increased cement wash-out after 3 days in Ringer's solution (p=0.476). Qualitative assessment of cement fill within the vertebral body using CT imaging supported the wash-out results. The strength (p<0.05-0.01) and stiffness (p<0.01) of samples significantly increased by cement injection in comparison to control, the extent of this increase was greater with increasing cement viscosity. Linear correlation analysis showed a definite association between the mechanical properties and viscosity of injected cement and was dependent on the amount of cement retained within the synthetic bone post-setting

The aim of this study was to determine whether subchondral bone influences in situ chondrocyte survival. Bovine explants were cultured in serum-free media over seven days with subchondral bone excised from articular cartilage (group A), subchondral bone left attached to articular cartilage (group B), and subchondral bone excised but co-cultured with articular cartilage (group C). Using confocal laser scanning microscopy, fluorescent probes and biochemical assays, in situ chondrocyte viability and relevant biophysical parameters (cartilage thickness, cell density, culture medium composition) were quantified over time (2.5 hours vs seven days). There was a significant increase in chondrocyte death over seven days, primarily within the superficial zone, for group A, but not for groups B or C (p < 0.05). There was no significant difference in cartilage thickness or cell density between groups A, B and C (p > 0.05). Increases in the protein content of the culture media for groups B and C, but not for group A, suggested that the release of soluble factors from subchondral bone may have influenced chondrocyte survival. In conclusion, subchondral bone significantly influenced chondrocyte survival in articular cartilage during explant culture.

The extrapolation of bone-cartilage interactions in vitro to the clinical situation must be made with caution, but the findings from these experiments suggest that future investigation into in vivo mechanisms of articular cartilage survival and degradation must consider the interactions of cartilage with subchondral bone.

Interfacial defects between the cement mantle and a hip implant may arise from constrained shrinkage of the cement or from air introduced during insertion of the stem. Shrinkage-induced interfacial porosity consists of small pores randomly located around the stem, whereas introduced interfacial gaps are large, individual and less uniformly distributed areas of stem-cement separation. Using a validated CT-based technique, we investigated the extent, morphology and distribution of interfacial gaps for two types of stem, the Charnley-Kerboul and the Lubinus SPII, and for two techniques of implantation, line-to-line and undersized.

The interfacial gaps were variable and involved a mean of 6.43% (sd 8.99) of the surface of the stem. Neither the type of implant nor the technique of implantation had a significant effect on the regions of the gaps, which occurred more often over the flat areas of the implant than along the corners of the stems, and were more common proximally than distally for Charnley-Kerboul stems cemented line-to-line. Interfacial defects could have a major effect on the stability and survival of the implant.

Finite element analysis was used to examine the initial stability after hip resurfacing and the effect of the procedure on the contact mechanics at the articulating surfaces. Models were created with the components positioned anatomically and loaded physiologically through major muscle forces. Total micromovement of less than 10 μm was predicted for the press-fit acetabular components models, much below the 50 μm limit required to encourage osseointegration. Relatively high compressive acetabular and contact stresses were observed in these models. The press-fit procedure showed a moderate influence on the contact mechanics at the bearing surfaces, but produced marked deformation of the acetabular components. No edge contact was predicted for the acetabular components studied.

It is concluded that the frictional compressive stresses generated by the 1 mm to 2 mm interference-fit acetabular components, together with the minimal micromovement, would provide adequate stability for the implant, at least in the immediate post-operative situation.

The effects of the method of fixation and interface conditions on the biomechanics of the femoral component of the Birmingham hip resurfacing arthroplasty were examined using a highly detailed three-dimensional computer model of the hip. Stresses and strains in the proximal femur were compared for the natural femur and for the femur resurfaced with the Birmingham hip resurfacing. A comparison of cemented versus uncemented fixation showed no advantage of either with regard to bone loading. When the Birmingham hip resurfacing femoral component was fixed to bone, proximal femoral stresses and strains were non-physiological. Bone resorption was predicted in the inferomedial and superolateral bone within the Birmingham hip resurfacing shell. Resorption was limited to the superolateral region when the stem was not fixed. The increased bone strain observed adjacent to the distal stem should stimulate an increase in bone density at that location. The remodelling of bone seen during revision of failed Birmingham hip resurfacing implants appears to be consistent with the predictions of our finite element analysis.

The use of impaction bone grafting during revision arthroplasty of the hip in the presence of cortical defects has a high risk of post-operative fracture. Our laboratory study addressed the effect of extramedullary augmentation and length of femoral stem on the initial stability of the prosthesis and the risk of fracture.

Cortical defects in plastic femora were repaired using either surgical mesh without extramedullary augmentation, mesh with a strut graft or mesh with a plate. After bone impaction, standard or long-stem Exeter prostheses were inserted, which were tested by cyclical loading while measuring defect strain and migration of the stem.

Compared with standard stems without extramedullary augmentation, defect strains were 31% lower with longer stems, 43% lower with a plate and 50% lower with a strut graft. Combining extramedullary augmentation with a long stem showed little additional benefit (p = 0.67). The type of repair did not affect the initial stability. Our results support the use of impaction bone grafting and extramedullary augmentation of diaphyseal defects after mesh containment.