Virtual Clinical Trials - Implications of Computer Simulations and Artificial Intelligence for Musculoskeletal Research.

ABSTRACT: In silico clinical trials, particularly when augmented with artificial intelligence methods, represent an innovative approach with much to offer, particularly in the musculoskeletal field. They are a cost-effective, efficient, and ethical means of evaluating treatments and interventions by supplementing and/or augmenting traditional randomized controlled trials (RCTs). While they are not a panacea and should not replace traditional RCTs, their integration into the research process promises to accelerate medical advancements and improve patient outcomes. To accomplish this, a multidisciplinary approach is needed, and collaboration is instrumental. With advances in computing and analytical prowess, and by adhering to the tenets of team science, realization of such a novel integrative approach toward clinical trials may not be far from providing far-reaching contributions to medical research. As such, by harnessing the power of in silico clinical trials, investigators can potentially unlock new possibilities in treatment and intervention for ultimately improving patient care and outcomes.

Discovery of circulating blood biomarkers in patients with and without Modic changes of the lumbar spine: a preliminary analysis.

PURPOSE: The following study aimed to determine the existence of blood biomarkers in symptomatic patients with or without lumbar Modic changes (MC). METHODS: A cross-sectional sub-analyses of a prospective cohort was performed. Fasting blood samples were collected from patients with and without lumbar MC who had undergone spinal fusion or microdiscectomy. An 80-plex panel and CCL5/RANTES were used to assess preoperative plasma cytokine concentrations. Patient demographics and imaging phenotypes were also assessed. RESULTS: Thirty-one subjects were analysed (n = 18 no MC; n = 13 MC). No significant differences were found in age, sex, body mass index, smoking and alcohol history, and surgical procedure (i.e. fusion, decompression) between the two groups (p > 0.05). Several statistically significant blood biomarkers in MC patients were identified, including elevated levels of C-C Motif Chemokine Ligand 5 (CCL5, p = 0.0006), while Macrophage Migration Inhibitory Factor (MIF) was significantly lower (p = 0.009). Additionally, C-X-C Motif Chemokine Ligand 5 (CXCL5, p = 0.052), Pentraxin 3 (PTX3, p = 0.06) and Galectin-3 (Gal-3, p = 0.07) showed potential relevance. Moreover, MC patients exhibited significantly higher levels of disc degeneration (p = 0.0001) and displacement severity (p = 0.020). Based on multivariate analyses and controlling for disc degeneration/displacement, CCL5 (OR 1.02; 95% CI 1.002-1.033; p = 0.028) and MIF (OR 0.60; 95% CI 0.382-0.951; p = 0.030) were independently associated with MC patients. CONCLUSION: This "proof-of-concept" study is the first to identify specific and significantly circulating blood biomarkers associated with symptomatic patients with lumbar MC, independent of disc alterations of degeneration and/or bulges/herniations. Specifically, differences in CCL5 and MIF protein levels were significantly noted in MC patients compared to those without MC.

Effect of Femoral Head Material, Surgeon Experience, and Assembly Technique on Simulated Head-Neck Total Hip Arthroplasty Impaction Forces.

BACKGROUND: There is no standard method for assembling the femoral head onto the femoral stem during total hip arthroplasty (THA). This study aimed to measure and record dynamic 3-dimensional (3D) THA head-neck assembly loads from residents, fellows, and attending surgeons, for metal and ceramic femoral heads. METHODS: An instrumented apparatus measured dynamic 3D forces applied through the femoral stem taper in vitro for 31 surgeons (11 attendings, 14 residents, 6 fellows) using their preferred technique (ie, number of hits or mallet strikes). Outcome variables included peak axial force, peak resultant force, impulse of the resultant force, loading rate of the resultant force, and off-axis angle. They were compared between femoral head material, surgeon experience level, and the number of hits per trial. RESULTS: Average peak axial force was 6.92 ± 2.11kN for all surgeons. No significant differences were found between femoral head material. Attendings applied forces more "on-axis" as compared to both residents and fellows. Nine surgeons assembled the head with 1 hit, 3 with 2 hits, 14 with 3 hits, 2 with 4 hits, and 3 with ≥5 hits. The first hit of multihit trials was significantly lower than single-hit trials for all outcome measures except the off-axis angle. The last hit of multihit trials had a significantly lower impulse of resultant force than single-hit trials. CONCLUSION: Differences in applied 3D force-time curve dynamic characteristics were found between surgeon experience level and single and multihit trials. No significant differences were found between femoral head material.

Development of a computational-experimental framework for enhanced mechanical characterization and cross-species comparison of the articular cartilage superficial zone.

To provide a better understanding of the contribution of specific constituents (i.e. proteoglycan, collagen, fluid) to the mechanical behavior of the superficial zone of articular cartilage, a complex biological tissue with several time-dependent properties, a finite element model was developed. Optimization was then used to fit the model to microindentation experiments. We used this model to compare superficial zone material properties of mature human vs. immature bovine articular cartilage. Non-linearity and stiffness of the fiber-reinforced component of the model differed between human and bovine tissue. This may be due to the more complex collagen architecture in mature tissue and is of interest to investigate in future work.

Chemokine Regulation in Temporomandibular Joint Disease: A Comprehensive Review.

Temporomandibular joint disorders (TMDs) are conditions that affect the muscles of mastication and joints that connect the mandible to the base of the skull. Although TMJ disorders are associated with symptoms, the causes are not well proven. Chemokines play an important role in the pathogenesis of TMJ disease by promoting chemotaxis inflammatory cells to destroy the joint synovium, cartilage, subchondral bone, and other structures. Therefore, enhancing our understanding of chemokines is critical for developing appropriate treatment of TMJ. In this review, we discuss chemokines including MCP-1, MIP-1α, MIP-3a, RANTES, IL-8, SDF-1, and fractalkine that are known to be involved in TMJ diseases. In addition, we present novel findings that CCL2 is involved in ß-catenin-mediated TMJ osteoarthritis (OA) and potential molecular targets for the development of effective therapies. The effects of common inflammatory factors, IL-1ß and TNF-α, on chemotaxis are also described. In conclusion, this review aims to provide a theoretical basis for future chemokine-targeted therapies for TMJ OA.

Transient stiffening of cartilage during joint articulation: A microindentation study.

As a mechanoactive tissue, articular cartilage undergoes compression and shear on a daily basis. With the advent of high resolution and sensitive mechanical testing methods, such as micro- and nanoindentation, it has become possible to assess changes in small-scale mechanical properties due to compression and shear of the tissue. However, investigations on the changes of these properties before and after joint articulation have been limited. To simulate articular loading of cartilage in the context of human gait, a previously developed bioreactor system was used. Immediately after bioreactor testing, the stiffness was measured using microindentation. Specifically, we investigated whether the mechanical response of the tissue was transient or permanent, dependent on counterface material, and an effect limited to the superficial zone of cartilage. We found that cartilage surface stiffness increases immediately after articular loading and returns to baseline values within 3 hr. Cartilage-on-cartilage stiffening was found to be higher compared to both alumina- and cobalt chromium-on-cartilage stiffening, which were not significantly different from each other. This stiffening response was found to be unique to the superficial zone, as articular loading on cartilage with the superficial zone removed showed no changes in stiffness. The findings of this study suggest that the cartilage superficial zone may adapt its stiffness as a response to articular loading. As the superficial zone is often compromised during the course of osteoarthritic disease, this finding is of clinical relevance, suggesting that the load-bearing function deteriorates over time.

Correction: Nanoscale insight into the degradation mechanisms of the cartilage articulating surface preceding OA.

Correction for 'Nanoscale insight into the degradation mechanisms of the cartilage articulating surface preceding OA' by Tooba Shoaib, et al., Biomater. Sci., 2020, 8, 3944-3955, DOI: 10.1039/D0BM00496K.

Nanoscale insight into the degradation mechanisms of the cartilage articulating surface preceding OA.

Osteoarthritis (OA) is a degenerative joint disease and a leading cause of disability globally. In OA, the articulating surface of cartilage is compromised by fissures and cracks, and sometimes even worn away completely. Due to its avascular nature, articular cartilage has a poor self-healing ability, and therefore, understanding the mechanisms underlying degradation is key for OA prevention and for optimal design of replacements. In this work, the articulating surface of bovine cartilage was investigated in an environment with enhanced calcium concentration -as often found in cartilage in relation to OA- by combining atomic force microscopy, spectroscopy and an extended surface forces apparatus for the first time. The experimental results reveal that increased calcium concentration irreversibly weakens the cartilage's surface layer, and promotes stiction and high friction. The synergistic effect of calcium on altering the cartilage surface's structural, mechanical and frictional properties is proposed to compromise cartilage integrity at the onset of OA. Furthermore, two mechanisms at the molecular level based on the influence of calcium on lubricin and on the aggregation of the cartilage's matrix, respectively, are identified. The results of this work might not only help prevent OA but also help design better cartilage replacements.

Articulation of an alumina-zirconia composite ceramic against living cartilage - An in vitro wear test.

BACKGROUND: There is interest in minimally invasive solutions that reduce osteoarthritic symptoms and restore joint mobility in the early stages of cartilage degeneration. The aim of the present study was to evaluate an alumina-zirconia composite (AZC) as a counterface for articulation against live cartilage explants in comparison to the clinically relevant cobalt-chromium (CoCrMo) alloy. METHODS: A four-station bioreactor designed to articulate against living tissue in an incubator was used for testing. Twelve 32 mm AZC and twelve 32 mm CoCrMo femoral heads with equal surface roughness made up both test groups. Each head articulated against a cartilage disk harvested from stifle joints of 24-week old steers. Test samples and free-swelling control cartilage samples were cultured in Mini ITS medium. Testing was conducted 3 h daily over 10 days applying a contact load of approximately 2 MPa. PG/GAG and hydroxyproline were analyzed using biochemical assays. Additionally, chondrocyte survival and Mankin score analyses were performed on histological slides. RESULTS: Cells stayed alive during the course of the experiment, with cell survival values close to 80% at test completion in the superficial zone. There was no significant difference between AZC and free-swelling control tissue. However, cell count values were inferior for CoCrMo (p = 0.003). Tested tissue suffered mostly structural abnormalities. The PG/GAG content in medium was not different between CoCrMo and AZC (p = 0.315); however, the hydroxyproline release into medium was nearly 30% higher for CoCrMo (p = 0.024). CONCLUSION: Based on average values, AZC induces less cell and tissue damage than CoCrMo. However, only the hydroxyproline measurements reached statistical significance, partially due to substantial scatter within both groups.