A Finite Element Model to Investigate the Stability of Osteochondral Grafts Within a Human Tibiofemoral Joint.

Osteochondral grafting has demonstrated positive outcomes for treating articular cartilage defects by replacing the damaged region with a cylindrical graft consisting of bone with a layer of cartilage. However, factors that cause graft subsidence are not well understood. The aim of this study was to develop finite element (FE) models of osteochondral grafts within a tibiofemoral joint, suitable for an investigation of parameters affecting graft stability. Cadaveric femurs were used to experimentally calibrate the bone properties and graft-bone frictional forces for use in corresponding image-based FE models, generated from µCT scan data. Effects of cartilage defects and osteochondral graft repair were measured by examining contact pressure changes using further in vitro tests. Here, six defects were created in the femoral condyles, which were subsequently treated with osteochondral autografts or metal pins. Matching image-based FE models were created, and the contact patches were compared. The bone material properties and graft-bone frictional forces were successfully calibrated from the initial tests with good resulting levels of agreement (CCC = 0.87). The tibiofemoral joint experiment provided a range of cases that were accurately described in the resultant pressure maps and were well represented in the FE models. Cartilage defects and repair quality were experimentally measurable with good agreement in the FE model pressure maps. Model confidence was built through extensive validation and sensitivity testing. It was found that specimen-specific properties were required to accurately represent graft behaviour. The final models produced are suitable for a range of parametric testing to investigate immediate graft stability.

Dynamic Acetabular Cup Orientation during Gait: A Study of Fast- and Slow-Walking Total Hip Replacement Patients.

The dynamic orientation of total hip replacement acetabular cups during walking may vary substantially from their assumed position at surgical implantation and may vary between individuals. The scale of this effect is of interest for both pre-clinical device testing and for pre-operative surgical planning. This work aimed to evaluate (1) patient variation in dynamic cup orientation; (2) whether walking speed was a candidate proxy measure for the dynamic cup orientation; and (3) the relationships between dynamic cup orientation angles and planar pelvic angles. Pelvic movement data for patients with fast (20 patients) and slow (19 patients) self-selected walking speeds were used to calculate acetabular cup inclination and version angles through gait. For aim 1, the range and extremes of acetabular cup orientation angles were analysed for all patients. A large patient-to-patient variation was found in the ranges of both inclination angle (1° to 11°) and version angle (4° to 18°). The version angle was typically retroverted in comparison to the implantation position (greatest deviation 27°). This orientation is substantially different to the static, 0° version, simplifying assumptions in pre-clinical 'edge loading' testing. For aim 2, the cup orientation angles were compared between the fast- and slow-walking groups using statistical parametric mapping. The only significant differences observed were for cup version angle, during ~12% of the gait cycle before toe-off (p < 0.05). Therefore, self-selected walking speed, in isolation, is not a sufficient proxy measure for dynamic acetabular orientation. For aim 3, correlations were recorded between the acetabular cup orientation angles and the planar pelvic angles. The cup inclination angle during gait was strongly correlated (Spearman's coefficient -1) with pelvic obliquity alone, indicating that simple planar assessment could be used to anticipate inclination angle range. The cup version angle was correlated with both pelvic rotation and tilt (Spearman's coefficient 0.8-1), indicating that cup version cannot be predicted directly from any single pelvic movement. This complexity, along with the interaction between inclination angle and range of version angle, supports the use of computational tools to aid clinical understanding.

Effect of meniscus modelling assumptions in a static tibiofemoral finite element model: importance of geometry over material.

Finite element studies of the tibiofemoral joint have increased use in research, with attention often placed on the material models. Few studies assess the effect of meniscus modelling assumptions in image-based models on contact mechanics outcomes. This work aimed to assess the effect of modelling assumptions of the meniscus on knee contact mechanics and meniscus kinematics. A sensitivity analysis was performed using three specimen-specific tibiofemoral models and one generic knee model. The assumptions in representing the meniscus attachment on the tibia (shape of the roots and position of the attachment), the material properties of the meniscus, the shape of the meniscus and the alignment of the joint were evaluated, creating 40 model instances. The values of material parameters for the meniscus and the position of the root attachment had a small influence on the total contact area but not on the meniscus displacement or the force balance between condyles. Using 3D shapes to represent the roots instead of springs had a large influence in meniscus displacement but not in knee contact area. Changes in meniscus shape and in knee alignment had a significantly larger influence on all outcomes of interest, with differences two to six times larger than those due to material properties. The sensitivity study demonstrated the importance of meniscus shape and knee alignment on meniscus kinematics and knee contact mechanics, both being more important than the material properties or the position of the roots. It also showed that differences between knees were large, suggesting that clinical interpretations of modelling studies using single geometries should be avoided.

Cost-effectiveness of decellularised bone allograft compared with fresh-frozen bone allograft for acetabular impaction bone grafting during a revision hip arthroplasty in the UK.

OBJECTIVES: Fresh-frozen allograft is the gold-standard bone graft material used during revision hip arthroplasty. However, new technology has been developed to manufacture decellularised bone with potentially better graft incorporation. As these grafts cost more to manufacture, the aim of this cost-effectiveness study was to estimate whether the potential health benefit of decellularised bone allograft outweighs their increased cost. STUDY DESIGN: A Markov model was constructed to estimate the costs and the quality-adjusted life years of impaction bone grafting during a revision hip arthroplasty. SETTING: This study took the perspective of the National Health Service in the UK. PARTICIPANTS: The Markov model includes patients undergoing a revision hip arthroplasty in the UK. INTERVENTION: Impaction bone grafting during a revision hip arthroplasty using either decellularised bone allograft or fresh-frozen allograft. MEASURES: Outcome measures included: total costs and quality-adjusted life years of both interventions over the lifetime of the model; and incremental cost-effectiveness ratios for both graft types, using base case parameters, univariate sensitivity analysis and probabilistic analysis. RESULTS: The incremental cost-effectiveness ratio for the base case model was found to be £270 059 per quality-adjusted life year. Univariate sensitivity analysis found that changing the discount rate, the decellularised bone graft cost, age of the patient cohort and the revision rate all had a significant effect on the incremental cost-effectiveness ratio. CONCLUSIONS: As there are no clinical studies of impaction bone grafting using a decellularised bone allograft, there is a high level of uncertainty around the costs of producing a decellularised bone allograft and the potential health benefits. However, if a decellularised bone graft was manufactured for £2887 and lowered the re-revision rate to less than 64 cases per year per 10 000 revision patients, then it would most likely be cost-effective compared with fresh-frozen allograft.

Controlling the Self-Assembly and Material Properties of ß-Sheet Peptide Hydrogels by Modulating Intermolecular Interactions.

Self-assembling peptides are a promising biomaterial with potential applications in medical devices and drug delivery. In the right combination of conditions, self-assembling peptides can form self-supporting hydrogels. Here, we describe how balancing attractive and repulsive intermolecular forces is critical for successful hydrogel formation. Electrostatic repulsion is tuned by altering the peptide's net charge, and intermolecular attractions are controlled through the degree of hydrogen bonding between specific amino acid residues. We find that an overall net peptide charge of +/-2 is optimal to facilitate the assembly of self-supporting hydrogels. If the net peptide charge is too low then dense aggregates form, while a high molecular charge inhibits the formation of larger structures. At a constant charge, altering the terminal amino acids from glutamine to serine decreases the degree of hydrogen bonding within the assembling network. This tunes the viscoelastic properties of the gel, reducing the elastic modulus by two to three orders of magnitude. Finally, hydrogels could be formed from glutamine-rich, highly charged peptides by mixing the peptides in combinations with a resultant net charge of +/-2. These results illustrate how understanding and controlling self-assembly mechanisms through modulating intermolecular interactions can be exploited to derive a range of structures with tuneable properties.

A geometric assessment method for estimating dimensional change of retrieved dual mobility liners for total hip arthroplasty.

Despite their emerging use, the current understanding of the in-vivo functional mechanisms of Dual Mobility (DM) Total Hip Replacements (THRs) is poor, and current characterisation methodologies are not suitable for the unique function and design of these types of devices. Therefore, the aim of this study was to develop a geometric characterisation methodology to estimate dimensional change across the articulating surfaces of retrieved DM polyethylene liners so that their invivo function may be better understood. The method involves the acquisition of three-dimensional coordinate data from the internal and external surfaces of DM liners. The data is processed using a bespoke MATLAB script which approximates the unworn reference geometry of each surface, calculates geometric variance at each point and produces surface deviation heatmaps so that areas of wear and/or deformation may be visualised across the implant. One as-manufactured and five retrieved DM liners were assessed, which demonstrated the efficacy, repeatability and sensitivity of the developed method. This study describes an automated and non-destructive approach for assessing retrieved DM liners of any size and from any manufacturer, which may be used in future research to improve our understanding of their in-vivo function and failure mechanisms.

Dynamic finite element analysis of hip replacement edge loading: Balancing precision and run time in a challenging model.

An important aspect in evaluating the resilience of hip replacement designs is testing their performance under adverse conditions that cause edge loading of the acetabular liner. The representation of edge loading conditions in finite element models is computationally challenging due to the changing contact locations, need for fine meshes, and dynamic nature of the system. In this study, a combined mesh and mass-scaling sensitivity study was performed to identify an appropriate compromise between convergence and solution time of explicit finite element analysis in investigating edge loading in hip replacement devices. The optimised model was then used to conduct a sensitivity test investigating the effect of different hip simulator features (the mass of the translating fixture and mediolateral spring damping) on the plastic strain in the acetabular liner. Finally, the effect of multiple loading cycles on the progressive accumulation of plastic strain was then also examined using the optimised model. A modelling approach was developed which provides an effective compromise between mass-scaling effects and mesh refinement for a solution time per cycle of less than 1 h. This 'Recommended Mesh' model underestimated the plastic strains by less than 10%, compared to a 'Best Estimate' model with a run time of ∼190 h. Starting with this model setup would therefore significantly reduce any new model development time while also allowing the flexibility to incorporate additional complexities as required. The polyethylene liner plastic strain was found to be sensitive to the simulator mass and damping (doubling the mass or damping had a similar magnitude effect to doubling the swing phase load) and these should ideally be described in future experimental studies. The majority of the plastic strain (99%) accumulated within the first three load cycles.

Contribution of Shape Features to Intradiscal Pressure and Facets Contact Pressure in L4/L5 FSUs: An In-Silico Study.

Finite element models (FEMs) of the spine commonly use a limited number of simplified geometries. Nevertheless, the geometric features of the spine are important in determining its FEM outcomes. The link between a spinal segment's shape and its biomechanical response has been studied, but the co-variances of the shape features have been omitted. We used a principal component (PCA)-based statistical shape modelling (SSM) approach to investigate the contribution of shape features to the intradiscal pressure (IDP) and the facets contact pressure (FCP) in a cohort of synthetic L4/L5 functional spinal units under axial compression. We quantified the uncertainty in the FEM results, and the contribution of individual shape modes to these results. This parameterisation approach is able to capture the variability in the correlated anatomical features in a real population and sample plausible synthetic geometries. The first shape mode ([Formula: see text]) explained 22.6% of the shape variation in the subject-specific cohort used to train the SSM, and had the largest correlation with, and contribution to IDP (17%) and FCP (11%). The largest geometric variation in ([Formula: see text]) was in the annulus-nucleus ratio.

Research priorities to reduce the impact of musculoskeletal disorders: a priority setting exercise with the child health and nutrition research initiative method.

Involving research users in setting priorities for research is essential to ensure the outcomes are patient-centred and maximise its value and impact. The Musculoskeletal Disorders Research Advisory Group Versus Arthritis led a research priority setting exercise across musculoskeletal disorders. The Child Health and Nutrition Research Initiative (CHNRI) method of setting research priorities with a range of stakeholders was used, involving four stages and two surveys, to: (1) gather research uncertainties, (2) consolidate these, (3) score uncertainties against importance and impact, and (4) analyse scoring for prioritisation. 213 people responded to the first survey and 285 people to the second, representing clinicians, researchers, and people with musculoskeletal disorders. Key priorities included developing and testing new treatments, better treatment targeting, early diagnosis, prevention, and better understanding and management of pain, with an emphasis on understanding underpinning mechanisms. We present a call to action to researchers and funders to target these priorities.

Development of robust finite element models to investigate the stability of osteochondral grafts within porcine femoral condyles.

Osteoarthritis (OA) is the most prevalent chronic rheumatic disease worldwide with knee OA having an estimated lifetime risk of approximately 14%. Autologous osteochondral grafting has demonstrated positive outcomes in some patients, however, understanding of the biomechanical function and how treatments can be optimised remains limited. Increased short-term stability of the grafts allows cartilage surfaces to remain congruent prior to graft integration. In this study methods for generating specimen specific finite element (FE) models of osteochondral grafts were developed, using parallel experimental data for calibration and validation. Experimental testing of the force required to displace osteochondral grafts by 2 mm was conducted on three porcine knees, each with four grafts. Specimen specific FE models of the hosts and grafts were created from registered µCT scans captured from each knee (pre- and post-test). Material properties were based on the µCT background with a conversion between µCT voxel brightness and Young's modulus. This conversion was based on the results of the separate testing of eight porcine condyles and optimization of specimen specific FE models. The comparison between the experimental and computational push-in forces gave a strong agreement with a concordance correlation coefficient (CCC) = 0.75, validating the modelling approach. The modelling process showed that homogenous material properties based on whole bone BV/TV calculations are insufficient for accurate modelling and that an intricate description of the density distribution is required. The robust methodology can provide a method of testing different treatment options and can be used to investigate graft stability in full tibiofemoral joints.

Impingement in total hip arthroplasty: A geometric model.

Total Hip Arthroplasty (THA) is one of the most common and successful surgical interventions. The survivorship at 10 years for the most commonly used systems is over 95%. However, the incidence of revision is usually much higher in the 0-1 year time period following the intervention. The most common reason for revision in this early time period is dislocation and subluxation, which may be defined as complete or permanent, and partial or temporary loss of contact between the bearing surfaces respectively. This study comprises the development of a geometric model of bone and an in situ total hip replacement, to predict the occurrence and location of bone and component impingement for a wide range of acetabular cup positions and for a series of frequently practiced activities of daily living. The model developed predicts that anterior-superior component impingement is associated with activities that result in posterior dislocation. The incidence may be reduced by increased cup anteversion and inclination. Posterior-inferior component impingement is associated with anterior dislocation activities. Its incidence may be reduced by decreased cup anteversion and inclination. A component impingement-free range was identified, running from when the cup was positioned with 45° inclination and 25° anteversion to 70° inclination and 15°-20° anteversion.

Evaluation of injectable nucleus augmentation materials for the treatment of intervertebral disc degeneration.

Back pain affects a person's health and mobility as well as being associated with large health and social costs. Lower back pain is frequently caused by degeneration of the intervertebral disc. Current operative and non-operative treatments are often ineffective and expensive. Nucleus augmentation is designed to be a minimally invasive method of restoring the disc to its native healthy state by restoring the disc height, and mechanical and/or biological properties. The majority of the candidate materials for nucleus augmentation are injectable hydrogels. In this review, we examine the materials that are currently under investigation for nucleus augmentation, and compare their ability to meet the design requirements for this application. Specifically, the delivery of the material into the disc, the mechanical properties of the material and the biological compatibility are examined. Recommendations for future testing are also made.

Importance of dynamics in the finite element prediction of plastic damage of polyethylene acetabular liners under edge loading conditions.

After hip replacement, in cases where there is instability at the joint, contact between the femoral head and the acetabular liner can move from the bearing surface to the liner rim, generating edge loading conditions. This has been linked to polyethylene liner fracture and led to the development of a regulatory testing standard (ISO 14242:4) to replicate these conditions. Performing computational modelling alongside simulator testing can provide insight into the complex damage mechanisms present in hard-on-soft bearings under edge loading. The aim of this work was to evaluate the need for inertia and elastoplastic material properties to predict kinematics (likelihood of edge loading) and plastic strain accumulation (as a damage indicator). While a static, rigid model was sufficient to predict kinematics for experimental test planning, the inclusion of inertia, alongside elastoplastic material, was required for prediction of plastic strain behaviour. The delay in device realignment during heel strike, caused by inertia, substantially increased the force experienced during rim loading (e.g. 600 N static rigid, ∼1800 N dynamic elastoplastic, in one case). The accumulation of plastic strain is influenced by factors including cup orientation, swing phase force balance, the moving mass, and the design of the device itself. Evaluation of future liner designs could employ dynamic elastoplastic models to investigate the effect of design feature changes on bearing resilience under edge loading.

Experimental and Computational Comparison of Intervertebral Disc Bulge for Specimen-Specific Model Evaluation Based on Imaging.

Finite element modelling of the spinal unit is a promising preclinical tool to assess the biomechanical outcome of emerging interventions. Currently, most models are calibrated and validated against range of motion and rarely directly against soft-tissue deformation. The aim of this contribution was to develop an in vitro methodology to measure disc bulge and assess the ability of different specimen-specific modelling approaches to predict disc bulge. Bovine bone-disc-bone sections (N = 6) were prepared with 40 glass markers on the intervertebral disc surface. These were initially magnetic resonance (MR)-imaged and then sequentially imaged using peripheral-qCT under axial compression of 1 mm increments. Specimen-specific finite-element models were developed from the CT data, using three different methods to represent the nucleus pulposus geometry with and without complementary use of the MR images. Both calibrated specimen-specific and averaged compressive material properties for the disc tissues were investigated. A successful methodology was developed to quantify the disc bulge in vitro, enabling observation of surface displacement on qCT. From the finite element model results, no clear advantage was found in using geometrical information from the MR images in terms of the models' ability to predict stiffness or disc bulge for bovine intervertebral disc.

Hydrodynamic Mixing Tunes the Stiffness of Proteoglycan-Mimicking Physical Hydrogels.

Self-assembling hydrogels are promising materials for regenerative medicine and tissue engineering. However, designing hydrogels that replicate the 3-4 order of magnitude variation in soft tissue mechanics remains a major challenge. Here hybrid hydrogels are investigated formed from short self-assembling ß-fibril peptides, and the glycosaminoglycan chondroitin sulfate (CS), chosen to replicate physical aspects of proteoglycans, specifically natural aggrecan, which provides structural mechanics to soft tissues. Varying the peptide:CS compositional ratio (1:2, 1:10, or 1:20) can tune the mechanics of the gel by one to two orders of magnitude. In addition, it is demonstrated that at any fixed composition, the gel shear modulus can be tuned over approximately two orders of magnitude through varying the initial vortex mixing time. This tuneability arises due to changes in the mesoscale structure of the gel network (fibril width, length, and connectivity), giving rise to both shear-thickening and shear-thinning behavior. The resulting hydrogels range in shear elastic moduli from 0.14 to 220 kPa, mimicking the mechanical variability in a range of soft tissues. The high degree of discrete tuneability of composition and mechanics in these hydrogels makes them particularly promising for matching the chemical and mechanical requirements of different applications in tissue engineering and regenerative medicine.

Decellularized Intervertebral Discs: A Potential Replacement for Degenerate Human Discs.

Intervertebral disc (IVD) degeneration is a major cause of back pain. Current surgical interventions have limitations. An alternative approach is to replace degenerated IVDs with a natural biological scaffold. The removal of cellular components from human IVDs should render them nonimmunogenic upon implantation. The aim of this initial proof of technical feasibility study was to develop a decellularization protocol on bovine IVDs with endplates (EPs) and assess protocol performance before application of the protocol to human IVDs with attached EP and vertebral bone (VB). A decellularization protocol based on hypotonic low concentration sodium dodecyl sulfate (0.1% w/v) with proteinase inhibitors, freeze/thaw cycles, and nuclease and sonication treatments was applied to IVDs. Histological, biochemical, and biomechanical comparisons were made between cellular and decellularized tissue. Cell removal from bovine IVDs was demonstrated and total DNA levels of the decellularized inner annulus fibrosus (iAF), outer annulus fibrosus (oAF), and EP were 40.7 (±11.4), 25.9 (±3.8), and 29.3 (±3.1) ng.mg-1 dry tissue weight, respectively (n = 6, ±95% confidence level [CL]). These values were significantly lower than in cellular tissue. No significant difference in DNA levels between bovine cellular and decellularized nucleus pulposus (NP) was found. Glycosaminoglycans (GAGs) were largely retained in the NP, iAF, and oAF. Cyclic compression testing showed sufficient sensitivity to detect an increase in stiffness of bovine IVD postdecellularization (2957.2 ± 340.8 N.mm-1) (predecellularization: 2685.4 ± 263.1 N.mm-1; n = 5, 95% CL), but the difference was within natural tissue variation. Total DNA levels for all decellularized tissue regions of human IVDs (NP, iAF, oAF, EP, and VB) were below 50 ng.mg-1 dry tissue weight (range: 2 ng.mg-1, iAF to 29 ng.mg-1, VB) and the tissue retained high levels of GAGs. Further studies to assess the biocompatibility and regenerative potential of decellularized human IVDs in vitro and in vivo are now required; however, proof of technical feasibility has been demonstrated and the retention of bone in the IVD samples would allow incorporation of the tissue into the recipient spine. Impact statement Intervertebral disc (IVD) degeneration is a major cause of back pain. Current surgical treatments have limitations and relatively poor outcomes. An implantable cell-free biological scaffold, which will not invoke adverse immune responses, has the potential to preserve the natural mobility of the patient's spine and be regenerated with endogenous cells, preventing further degeneration and improving surgical outcomes. This study demonstrates, for the first time, that it is possible to create a cell-free human IVD biological scaffold with attached bone using decellularization technology, the first step toward the development of an implantable regenerative device for IVD replacement.

Development of robust finite element models of porcine tibiofemoral joints loaded under varied flexion angles and tibial freedoms.

The successful development of cartilage repair treatments for the knee requires understanding of the biomechanical environment within the joint. Computational finite element models play an important role in non-invasively understanding knee mechanics, but it is important to compare model findings to experimental data. The purpose of this study was to develop a methodology for generating subject-specific finite element models of porcine tibiofemoral joints that was robust and valid over multiple different constraint scenarios. Computational model predictions of two knees were compared to experimental studies on corresponding specimens loaded under several different constraint scenarios using a custom designed experimental rig, with variations made to the femoral flexion angle and level of tibial freedom. For both in vitro specimens, changing the femoral flexion angle had a marked effect on the contact distribution observed experimentally. With the tibia fixed, the majority of the contact region shifted to the medial plateau as flexion was increased. This did not occur when the tibia was free to displace and rotate in response to applied load. These trends in contact distribution across the medial and lateral plateaus were replicated in the computational models. In an additional model with the meniscus removed, contact pressures were elevated by a similar magnitude to the increase seen when the meniscus was removed experimentally. Overall, the models were able to capture specimen-specific trends in contact distribution under a variety of different loads, providing the potential to investigate subject-specific outcomes for knee interventions.

Optimizing computational methods of modeling vertebroplasty in experimentally augmented human lumbar vertebrae.

Vertebroplasty has been widely used for the treatment of osteoporotic compression fractures but the efficacy of the technique has been questioned by the outcomes of randomized clinical trials. Finite-element (FE) models allow an investigation into the structural and geometric variation that affect the response to augmentation. However, current specimen-specific FE models are limited due to their poor reproduction of cement augmentation behavior. The aims of this study were to develop new methods of modeling the vertebral body in both a nonaugmented and augmented state. Experimental tests were conducted using human lumbar spine vertebral specimens. These tests included micro-computed tomography imaging, mechanical testing, augmentation with cement, reimaging, and retesting. Specimen-specific FE models of the vertebrae were made comparing different approaches to capturing the bone material properties and to modeling the cement augmentation region. These methods significantly improved the modeling accuracy of nonaugmented vertebrae. Methods that used the registration of multiple images (pre- and post-augmentation) of a vertebra achieved good agreement between augmented models and their experimental counterparts in terms of predictions of stiffness. Such models allow for further investigation into how vertebral variation influences the mechanical outcomes of vertebroplasty.

Initiating factors for the onset of OA: A systematic review of animal bone and cartilage pathology in OA.

There is controversy over whether bone or cartilage is primarily involved in osteoarthritis (OA) pathogenesis; this is important for targeting early interventions. We explored evidence from animal models of knee OA by preforming a systematic review of PubMed, Scopus, and Web of Science for original articles reporting subchondral bone and cartilage pathology in animal models with epiphyseal closure. Extracted data included: method of induction; animal model; cartilage and bone assessment and method; meniscal assessment; skeletal maturity; controls; and time points assessed. Quality scoring was performed. The best evidence was synthesized from high-quality skeletally mature models, without direct trauma to tissues of interest and with multiple time points. Altogether, 2849 abstracts were reviewed. Forty-seven papers were included reporting eight different methods of inducing OA, six different species, six different methods of assessing cartilage, five different bone structural parameters, and four assessed meniscus as a potential initiator. Overall, the simultaneous onset of OA in cartilage and bone was reported in 82% of datasets, 16% reported bone onset, and 2% reported cartilage onset. No dataset containing meniscal data reported meniscal onset. However, using the best evidence synthesis (n = 8), five reported simultaneous onset when OA was induced, while three reported bone onset when OA occurred spontaneously; none reported cartilage onset. In summary, there is a paucity of well-designed studies in this area which makes the conclusions drawn conjectures rather than proven certainties. However, within the limitation of data quality, this review suggests that in animal models, the structural onset of knee OA occurs either in bone prior to cartilage pathology or simultaneously.