Physiologically engineered porous titanium/brushite scaffolds for critical-size bone defects: A design and manufacturing study.

Repairing critical-size bone defects still represents a critical clinical challenge in the field of trauma surgery. This study focuses on a physiological design and manufacturing of porous composite scaffold (titanium Ti with 10 % mole iron doped brushite DCPD-Fe3+) which can mimic the biomechanical properties of natural cortical bone, specifically for the purpose of repairing critical-size defects. To achieve this, the principle of design of experiments (DOE) was applied for investigating the impact of sintering temperature, mineral ratio, and volume fraction of porosity on the mechanical properties of the fabricated scaffolds. The fabricated scaffolds had open porosity up to 60 %, with pore size approximately between 100 µm and 850 µm. The stiffness of the porous composite scaffolds varied between 3.30 GPa and 20.50 GPa, while the compressive strength ranged from approximately 130 MPa-165 MPa at sintering temperatures equal to or exceeding 1000 °C. Scaffolds with higher porosity and mineral content demonstrated lower stiffness values, resembling natural bone. Numerical simulation was employed by Ansys Workbench to investigate the stress and strain distribution of a critical size defect in mid-shaft femur which was designed to be replaced with the fabricated scaffold. The fabricated scaffolds showed flexible biomechanical behaviour at the bone/scaffold interface, generating lower stress levels and indicating a better match with the femoral shaft stiffness. The experimental and numerical findings demonstrated promising applications for manufacturing a patient-specific bone scaffold for critical and potentially large defects for reducing stress shielding and minimizing non-union risk.

Continuous Shoulder Activity Tracking after Open Reduction and Internal Fixation of Proximal Humerus Fractures.

Postoperative shoulder activity after proximal humerus fracture treatment could influence the outcomes of osteosynthesis and may depend on the rehabilitation protocol. This multi-centric prospective study aimed at evaluating the feasibility of continuous shoulder activity monitoring over the first six postoperative weeks, investigating potential differences between two different rehabilitation protocols. Shoulder activity was assessed with pairs of accelerometer-based trackers during the first six postoperative weeks in thirteen elderly patients having a complex proximal humerus fracture treated with a locking plate. Shoulder angles and elevation events were evaluated over time and compared between the two centers utilizing different standard rehabilitation protocols. The overall mean shoulder angle ranged from 11° to 23°, and the number of daily elevation events was between 547 and 5756. Average angles showed longitudinal change <5° over 31 ± 10 days. The number of events increased by 300% on average. Results of the two clinics exhibited no characteristic differences for shoulder angle, but the number of events increased only for the site utilizing immediate mobilization. In addition to considerable inter-patient variation, not the mean shoulder angle but the number of elevations events increased markedly over time. Differences between the two sites in number of daily events may be associated with the different rehabilitation protocols.

Augmented screwdrivers can increase the performance of orthopaedic surgeons compared with use of normal screwdrivers.

Orthopaedic screws insertion can be trivialised as a simple procedure, however it is frequently performed poorly. Limited work exists defining how well surgeons insert screws or whether augmented screwdrivers can aid surgeons to reduce stripping rates and optimise tightness. We aimed to establish the performance of surgeons inserting screws and whether this be improved with screwdriver augmentation. 302 orthopaedic surgeons tightened 10 non-locking screws to what they determined to be optimum tightness into artificial bone sheets. The confidence in the screw purchase was given (1-10). A further 10 screws were tightened, using an augmented screwdriver that indicated when a predetermined optimum tightness was reached. The tightness for unstripped insertions under normal conditions and with the augmented screwdriver were 81% (95% CI 79-82%)(n = 1275) and 70% (95% CI 69-72%)(n = 2577) (p < 0.001). The stripping rates were 58% (95% CI 54-61%) and 15% (95% CI 12-17%) respectively (p < 0.001). The confidences when using the normal and augmented screwdrivers respectively were 7.2 and 7.1 in unstripped insertions and 6.2 and 6.5 in stripped insertions. Performance improved with an augmented screwdriver, both in reduced stripping rates and greater accuracy in detecting stripping. Augmenting screwdrivers to indicate optimum tightness offer potentially enormous clinical benefits by improving screw fixation.

Electrospun and 3D printed polymeric materials for one-stage critical-size long bone defect regeneration inspired by the Masquelet technique: Recent Advances.

Critical-size long bone defects represent one of the major causes of fracture non-union and remain a significant challenge in orthopaedic surgery. Two-stage procedures such as a Masquelet technique demonstrate high level of success however their main disadvantage is the need for a second surgery, which is required to remove the non-resorbable cement spacer and to place the bone graft into the biological chamber formed by the 'induced membrane'. Recent research efforts have therefore been dedicated towards the design, fabrication and testing of resorbable implants that could mimic the biological functions of the cement spacer and the induced membrane. Amongst the various manufacturing techniques used to fabricate these implants, three-dimensional (3D) printing and electrospinning methods have gained a significant momentum due their high-level controllability, scalable processing and relatively low cost. This review aims to present recent advances in the evaluation of electrospun and 3D printed polymeric materials for critical-size, long bone defect reconstruction, emphasizing both their beneficial properties and current limitations. Furthermore, we present and discuss current state-of-the art techniques required for characterisation of the materials' physical, mechanical and biological characteristics. These represent the essential first steps towards the development of personalised implants for single-surgery, large defect reconstruction in weight-bearing bones.

Adhesives for treatment of bone fractures: A review of the state-of-the art.

Treatment of fractures remains challenging and carries a high economical burden to both patients and society. In order to prevent some of the complications, the use of bone adhesives has been proposed, but up to date, bone adhesives are not part of the current clinical practice. Early results of use of bone cements and bone glues are promising, focusing in the areas of highly fragmented fractures, fixation of long bone fractures, filling bone voids and defects, promoting osseointegration, preventing non-union while maintaining the reduction of fracture fixation. This review aims to describe the state-of-the-art of the development, properties and use of adhesives in fracture treatment.

Experimental and numerical investigation of secondary screw perforation in the human proximal humerus.

Surgical treatment of proximal humerus fractures remains challenging, with a reported failure rate ranging from 15% to 35%. The dominant failure mode is secondary, i.e. post-operative screw perforation through the glenohumeral joint. A better understanding and the ability to predict this complication could lead to improved fracture fixation and decreased failure rate. The aims of this study were (1) to develop an experimental model for single screw perforation in the human humeral head and (2) to evaluate the ability of densitometric measures and micro finite element (microFE) analyses to predict the experimental failure event. Screw perforation was investigated experimentally in twenty cuboidal specimens cut from four pairs of fresh-frozen human cadaveric proximal humeral heads. A centrally inserted 3.5 mm screw was pushed quasi-statically at a constant displacement rate until perforation of the articular cartilage in each specimen. Force and displacement were recorded and evaluated at both initial screw loosening and perforation events. Bone volume was calculated around and in front of the screw and tip-to-joint distance was measured on the combined pre- and post-instrumentation micro computed tomography (microCT) scans. Implicit linear and explicit non-linear microFE models were created based on the microCT scans. The strength of these densitometric, geometrical and microFE methods to predict the experimental results was evaluated via correlation analysis. The bone volume measures were optimized in a parametric analysis to maximize correlation coefficients. The strongest and quantitatively correct predictions of perforation force (R2 = 0.93) and displacement (R2 = 0.77) were achieved using the explicit, non-linear microFE models. Linear microFE simulations provided the strongest predictions of loosening force (R2 = 0.90). Correlation strengths reached by optimized bone volume measures for predicting experimental force and by tip-to-joint distance for predicting displacement were only slightly inferior compared to the results of microFE models. The strong correlations achieved with densitometric and geometric measures indicate that monotonic perforation of single screws through the articular surface of the humeral head can be well predicted with these easily accessible measures. However, non-linear microFE models delivered even stronger correlations and quantitatively correct predictions of perforation force and displacement. This indicates that if computational resources are available, non-linear simulations may have a high potential to investigate more complex fixations and loading scenarios.

Late screw-related complications in locking plating of proximal humerus fractures: A systematic review.

Locking plating is a common surgical treatment of proximal humeral fractures with satisfactory clinical results. Implant-related complications, especially screw-related, have been reported, however, the lack of information regarding their onset, used surgical technique, complexity of the fracture, bone quality etc., prevents from understanding the causes for them. The aim of this systematic review is to identify the potential risk factors for late screw complications by gathering information about the patient characteristics, comorbidities, fracture types, surgical approaches and implant types. A PubMed search was performed using humerus, fractures, bone and locking as keywords in clinical papers written in English. All abstracts and manuscripts on distal or humerus shaft fractures, and those on proximal humerus fractures without any or with only iatrogenic complications were excluded. One hundred studies met the inclusion criteria, resulting in 33% of the reported cases having at least one complication, with 11% of all complications being screw-related. Most of the latter were secondary screw perforations and screw cut-outs, being predominantly linked to poor bone quality, while screw loosening and retraction were found less frequently as a result of locking mechanism failure. Overall, the amount of information for complications was limited and screw perforation was the most frequent screw-related complication, mostly reported in female patients older than 50 years, following four-part or AO/OTA type C fractures and detected four weeks postoperatively. The sparse information in the literature could be an indicator that the late screw complications might have been under-reported and under-described, making the understanding of the screw-related complications even more challenging.

Assessment of material loss of retrieved magnetically controlled implants for limb lengthening.

PURPOSE: We aimed to understand wear from the telescopic component of PRECICE nails, which are used for distraction osteogenesis of the femur or tibia. We also aimed to identify any correlation between implant performance and patient factors. METHODS: This retrieval study involved 11 magnetically controlled intramedullary nails from nine patients who had achieved the targeted leg length. All the nails were assessed macroscopically and microscopically for wear. All implants were radiographed to assess the internal mechanism. A Talyrond 365 (Taylor Hobson, Leicester, UK) roundness measuring machine was used to generate three-dimensional surface maps of the telescopic components to allow for measurement of wear. RESULTS: Visual assessment of all the nails showed evidence of wear from the telescopic component. The radiographs revealed that all the nails had intact internal mechanism and no evidence of fractured pins. The roundness measuring machine showed that the quantity of wear was lowest in the latest design of the PRECICE nail. There was no significant correlation between wear and the two patient factors (duration of the lengthening phase, the time of implantation) included in this study. CONCLUSION: This study is the first to investigate the performance of the three different designs of the PRECICE system with a focus on wear. We found that the latest design had the best implant performance. We are confident of the continued success of the PRECICE system and reassure surgeons and patients that they are unlikely to encounter problems with the implant related to wear.

The Chemical Form of Metal Species Released from Corroded Taper Junctions of Hip Implants: Synchrotron Analysis of Patient Tissue.

The mechanisms of metal release from the articulation at the head cup bearing and the tapered junctions of orthopaedic hip implants are known to differ and the debris generated varies in size, shape and volume. Significantly less metal is lost from the taper junction between Cobalt-Chromium-Molybdenum (CoCrMo) and Titanium (Ti) components (fretting-corrosion dominant mechanism), when compared to the CoCrMo bearing surfaces (wear-corrosion dominant mechanism). Corrosion particles from the taper junction can lead to Adverse Reactions to Metal Debris (ARMD) similar to those seen with CoCrMo bearings. We used synchrotron methods to understand the modes underlying clinically significant tissue reactions to Co, Cr and Ti by analysing viable peri-prosthetic tissue. Cr was present as Cr2O3 in the corroded group in addition to CrPO4 found in the metal-on-metal (MoM) group. Interestingly, Ti was present as TiO2 in an amorphous rather than rutile or anatase physical form. The metal species were co-localized in the same micron-scale particles as result of corrosion processes and in one cell type, the phagocytes. This work gives new insights into the degradation products from metal devices as well as guidance for toxicological studies in humans.

Analysing a mechanism of failure in retrieved magnetically controlled spinal rods.

PURPOSE: We aim to describe a mechanism of failure in magnetically controlled growth rods which are used for the correction of the early onset scoliosis. METHODS: This retrieval study involved nine magnetically controlled growth rods, of a single design, revised from five patients for metal staining, progression of scoliosis, swelling, fractured actuator pin, and final fusion. All the retrieved rods were radiographed and assessed macroscopically and microscopically for material loss. Two implants were further analysed using micro-CT scanning and then sectioned to allow examination of the internal mechanism. No funding was obtained to analyse these implants. There were no potential conflicts interests. RESULTS: Plain radiographs revealed that three out of nine retrieved rods had a fractured pin. All had evidence of surface degradation on the extendable telescopic rod. There was considerable corrosion along the internal mechanism. CONCLUSIONS: We found that a third of the retrieved magnetically controlled growth rods had failed due to pin fracture secondary to corrosion of the internal mechanism. We recommend that surgeons consider that any inability of magnetically controlled growth rods to distract may be due to corrosive debris building up inside the mechanism, thereby preventing normal function.

On the stability of a spherical tumour.

The mathematical analysis of the tumour growth attracted a lot of interest in the last two decades. However, as of today no generally accepted model for tumour growth exists. This is due partially to the incomplete understanding of the related pathology as well as the extremely complicated procedure that guides the evolution of a tumour. In the present work, we analyse the stability of a spherical tumour for four continuous models of an avascular tumour. Conditions for the stability are stated and the results are implemented numerically. It is observed that the steady-state radii that secure the stability of the tumour are different for each of the four models, although the differences are not very pronounced.

The angiogenic response to PLL-g-PEG-mediated HIF-1α plasmid DNA delivery in healthy and diabetic rats.

Impaired angiogenesis is a major clinical problem and affects wound healing especially in diabetic patients. Improving angiogenesis is a reasonable strategy to increase diabetes-impaired wound healing. Recently, our lab described a system of transient gene expression due to pegylated poly-l-lysine (PLL-g-PEG) polymer-mediated plasmid DNA delivery in vitro. Here we synthesized peptide-modified PLL-g-PEG polymers with two functionalities, characterized them in vitro and utilized them in vivo via a fibrin-based delivery matrix to induce dermal wound angiogenesis in diabetic rats. The two peptides were 1) a TG-peptide to covalently bind these nanocondensates to the fibrin matrix (TG-peptide) for a sustained release and 2) a polyR peptide to improve cellular uptake of these nanocondensates. In order to induce angiogenesis in vivo we condensed modified and non-modified polymers with plasmid DNA encoding a truncated form of the therapeutic candidate gene hypoxia-inducible transcription factor 1α (HIF-1α). HIF-1α is the primarily oxygen-dependent regulated subunit of the heterodimeric transcription factor HIF-1, which controls angiogenesis among other physiological pathways. The truncated form of HIF-1α lacks the oxygen-dependent degradation domain (ODD) and therefore escapes degradation under normoxic conditions. PLL-g-PEG polymer-mediated HIF-1α-ΔODD plasmid DNA delivery was found to lead to a transiently induced gene expression of angiogenesis-related genes Acta2 and Pecam1 as well as the HIF-1α target gene Vegf in vivo. Furthermore, HIF-1α gene delivery was shown to enhance the number endothelial cells and smooth muscle cells - precursors for mature blood vessels - during wound healing. We show that - depending on the selection of the therapeutic target gene - PLL-g-PEG nanocondensates are a promising alternative to viral DNA delivery approaches, which might pose a risk to health.

On a biophysical and mathematical model of Pgp-mediated multidrug resistance: understanding the "space-time" dimension of MDR.

Multidrug resistance (MDR) is explained by drug transporters with a drug-handling activity. Despite much work, MDR remains multifaceted, and several conditions are required to generate drug resistance. The drug pumping was conceptually described using a kinetic, i.e., temporal, approach. The re-emergence of physical biology has allowed us to take into account new parameters focusing on the notion of space. This, in turn, has given us important clues regarding the process whereby drug and transporter interact. We will demonstrate that the likelihood of drug-transporter meeting (i.e., the affinity) and thus interaction are also driven by the mechanical interaction between drug molecular weight (MW) and the membrane mechanical properties. This should allow us to mechanically control drug delivery.

Determination of patulin in fruit juices using HPLC-DAD and GC-MSD techniques.

A high performance liquid chromatography with a diode-array detector (HPLC-DAD) and a gas chromatography with a mass spectrometer (GC-MSD) are described for the determination of patulin (PAT) in apple juice. The limits of detection (DL) and quantification (QL) for the HPLC-DAD and GC-MSD method were found to be (DL=0.23µgkg(-1) QL=1.2µgkg(-1)) and (DL=5.8µgkg(-1) and QL=13.8µgkg(-1)), respectively. The recovery factors for HPLC-DAD and GC-MSD were found to be 99.5% (RSD%=0.73) and 41% (RSD%=10.03), respectively. The HPLC-DAD method was used to determine the occurrence of PAT in 90 samples of fruit juices. Results revealed the presence of PAT in 100% of the samples examined. The mean values of PAT in concentrated fruit juices and in the commercial fruit juices collected from the Greek market were found to be 10.54µg PAT kg(-1) and 5.57µg PAT kg(-1) juice, respectively. The most contaminated samples were four concentrated juices ranging from 18.10µg PAT kg(-1) to 36.8µg PAT kg(-1) juice. The daily exposure to patulin for the consumers of all ages in Greece, is ranging from 0.008µg PAT kg(-1) bw to 0.1µg PAT kg(-1) bw if the daily intake of fruit juices is from 0.1 to 0.5kg. With the exception to the most contaminated sample, the daily exposure due to the samples examined, is below the provisional maximum tolerable daily intake for PAT (0.4µg PAT kg(-1) bw).