The effect of constitutive representations and structural constituents of ligaments on knee joint mechanics

Abstract Ligaments provide stability to the human knee joint and play an essential role in restraining motion during daily activities. Compression-tension nonlinearity is a well-known characteristic of ligaments. Moreover, simpler material representations without this feature might give reasonable results because ligaments are primarily in tension during loading. However, the biomechanical role of different constitutive representations and their fibril-reinforced poroelastic properties is unknown. A numerical knee model which considers geometric and material nonlinearities of meniscus and cartilages was applied. Five different constitutive models for the ligaments (spring, elastic, hyperelastic, porohyperelastic, and fibril-reinforced porohyperelastic (FRPHE)) were implemented. Knee joint forces for the models with elastic, hyperelastic and porohyperelastic properties showed similar behavior throughout the stance, while the model with FRPHE properties exhibited lower joint forces during the last 50% of the stance phase. The model with ligaments as springs produced the lowest joint forces at this same stance phase. The results also showed that the fibril network contributed substantially to the knee joint forces, while the nonfibrillar matrix and fluid had small effects. Our results indicate that simpler material models of ligaments with similar properties in compression and tension can be used when the loading is directed primarily along the ligament axis in tension

Simulation of Subject-Specific Progression of Knee Osteoarthritis and Comparison to Experimental Follow-up Data : Data from the Osteoarthritis Initiative

Economic costs of osteoarthritis (OA) are considerable. However, there are no clinical tools to predict the progression of OA or guide patients to a correct treatment for preventing OA. We tested the ability of our cartilage degeneration algorithm to predict the subject-specific development of OA and separate groups with different OA levels. The algorithm was able to predict OA progression similarly with the experimental follow-up data and separate subjects with radiographical OA (Kellgren-Lawrence (KL) grade 2 and 3) from healthy subjects (KL0). Maximum degeneration and degenerated volumes within cartilage were significantly higher (p <0.05) in OA compared to healthy subjects, KL3 group showing the highest degeneration values. Presented algorithm shows a great potential to predict subjectspecific progression of knee OA and has a clinical potential by simulating the effect of interventions on the progression of OA, thus helping decision making in an attempt to delay or prevent further OA symptoms.Peer reviewe

Health-related quality of life in relation to shark symptomatic and radiographic definitions of knee osteoarthritis : data from Osteoarthritis Initiative (OAI) 4-year follow- up study

Background: The purpose was to quantify the decrement in health utility (referred as disutility) associated with knee osteoarthritis (OA) and different symptomatic and radiographic uni- and bilateral definitions of knee OA in a repeated measures design of persons with knee OA or at increased risk of developing knee OA. Methods: Data were obtained from the Osteoarthritis Initiative database. SF-12 health-related quality of life was converted into SF-6D utilities, and were then handled as the health utility loss by subtracting 1.000 from the utility score, yielding a negative value (disutility). Symptomatic OA was defined by radiographic findings (Kellgren-Lawrence, K-L, grade >= 2) and frequent knee pain in the same knee. Radiographic OA was defined by five different definitions (K-L >= 2 unilaterally / bilaterally, or the highest / mean / combination of K-L grades of both knees). Repeated measures generalized estimating equation (GEE) models were used to investigate disutility in relation to these different definitions. Results: Utility decreased with worsening of symptomatic or radiographic status of knee OA. The participants with bilateral and unilateral symptomatic knee OA had 0.03 (p <0.001) and 0.02 (p <0.001) points lower utility scores, respectively, compared with the reference group. The radiographic K-L grade 4 defined as the mean or the highest grade of both knees was related to a decrease of 0.04 (p <0.001) and 0.03 (p <0.001) points in utility scores, respectively, compared to the reference group. Conclusions: Knee OA is associated with diminished health-related quality of life. Health utility can be quantified in relation to both symptomatic and radiographic uni- and bilateral definitions of knee OA, and these definitions are associated with differing disutilities. The performance of symptomatic definition was better, indicating that pain experience is an important factor in knee OA related quality of life.Peer reviewe

Maximum shear strain-based algorithm can predict proteoglycan loss in damaged articular cartilage

Post-traumatic osteoarthritis (PTOA) is a common disease, where the mechanical integrity of articular cartilage is compromised. PTOA can be a result of chondral defects formed due to injurious loading. One of the first changes around defects is proteoglycan depletion. Since there are no methods to restore injured cartilage fully back to its healthy state, preventing the onset and progression of the disease is advisable. However, this is problematic if the disease progression cannot be predicted. Thus, we developed an algorithm to predict proteoglycan loss of injured cartilage by decreasing the fixed charge density (FCD) concentration. We tested several mechanisms based on the local strains or stresses in the tissue for the FCD loss. By choosing the degeneration threshold suggested for inducing chondrocyte apoptosis and cartilage matrix damage, the algorithm driven by the maximum shear strain showed the most substantial FCD losses around the lesion. This is consistent with experimental findings in the literature. We also observed that by using coordinate system-independent strain measures and selecting the degeneration threshold in an ad hoc manner, all the resulting FCD distributions would appear qualitatively similar, i.e., the greatest FCD losses are found at the tissue adjacent to the lesion. The proposed strain-based FCD degeneration algorithm shows a great potential for predicting the progression of PTOA via biomechanical stimuli. This could allow identification of high-risk defects with an increased risk of PTOA progression.</p

Eight-year trajectories of changes in health-related quality of life in knee osteoarthritis : Data from the Osteoarthritis Initiative (OAI)

Background Knee osteoarthritis (OA) worsens health-related quality of life (HRQoL) but the symptom pathway varies from person to person. We aimed to identify groups of people with knee OA or at its increased risk whose HRQoL changed similarly. Our secondary aim was to evaluate if patient-related characteristics, incidence of knee replacement (KR) and prevalence of pain medication use differed between the identified HRQoL trajectory groups. Methods Eight-year follow-up data of 3053 persons with mild knee OA or at increased risk were obtained from the public Osteoarthritis Initiative (OAI) database. Group-based trajectory modeling was used to identify patterns of experiencing a decrease of >= 10 points (Minimal Important Change, MIC) in the Quality of Life subscale of the Knee injury and Osteoarthritis Outcome Score compared to baseline. Multinomial logistic regression, Cox regression and generalized estimating equation models were used to study secondary aims. Results Four HRQoL trajectory groups were identified. Persons in the 'no change' group (62.9%) experienced no worsening in HRQoL. 'Rapidly' (9.5%) and 'slowly' worsening (17.1%) groups displayed an increasing probability of experiencing the MIC in HRQoL. The fourth group (10.4%) had 'improving' HRQoL. Female gender, higher body mass index, smoking, knee pain, and lower income at baseline were associated with belonging to the 'rapidly worsening' group. People in 'rapidly' (hazard ratio (HR) 6.2, 95% confidence interval (CI) 3.6-10.7) and 'slowly' worsening (HR 3.4, 95% CI 2.0-5.9) groups had an increased risk of requiring knee replacement. Pain medication was more rarely used in the 'no change' than in the other groups. Conclusions HRQoL worsening was associated with several risk factors; surgical and pharmacological interventions were more common in the poorer HRQoL trajectory groups indicating that HRQoL does reflect the need for OA treatment. These findings may have implications for targeting interventions to specific knee OA patient groups.Peer reviewe

An EMG-Assisted Muscle-Force Driven Finite Element Analysis Pipeline to Investigate Joint- and Tissue-Level Mechanical Responses in Functional Activities : Towards a Rapid Assessment Toolbox

Publisher Copyright: © 1964-2012 IEEE.Joint tissue mechanics (e.g., stress and strain) are believed to have a major involvement in the onset and progression of musculoskeletal disorders, e.g., knee osteoarthritis (KOA). Accordingly, considerable efforts have been made to develop musculoskeletal finite element (MS-FE) models to estimate highly detailed tissue mechanics that predict cartilage degeneration. However, creating such models is time-consuming and requires advanced expertise. This limits these complex, yet promising, MS-FE models to research applications with few participants and makes the models impractical for clinical assessments. Also, these previously developed MS-FE models have not been used to assess activities other than gait. This study introduces and verifies a semi-automated rapid state-of-the-art MS-FE modeling and simulation toolbox incorporating an electromyography- (EMG) assisted MS model and a muscle-force driven FE model of the knee with fibril-reinforced poro(visco)elastic cartilages and menisci. To showcase the usability of the pipeline, we estimated joint- and tissue-level knee mechanics in 15 KOA individuals performing different daily activities. The pipeline was verified by comparing the estimated muscle activations and joint mechanics to existing experimental data. To determine the importance of the EMG-assisted MS analysis approach, results were compared to those from the same FE models but driven by static-optimization-based MS models. The EMG-assisted MS-FE pipeline bore a closer resemblance to experiments compared to the static-optimization-based MS-FE pipeline. Importantly, the developed pipeline showed great potential as a rapid MS-FE analysis toolbox to investigate multiscale knee mechanics during different activities of individuals with KOA.Peer reviewe

Mitochondrial genome-wide analysis of nuclear DNA methylation quantitative trait loci

Mitochondria have a complex communication network with the surrounding cell and can alter nuclear DNA methylation (DNAm). Variation in the mitochondrial DNA (mtDNA) has also been linked to differential DNAm. Genome-wide association studies have identified numerous DNAm quantitative trait loci, but these studies have not examined the mitochondrial genome. Herein, we quantified nuclear DNAm from blood and conducted a mitochondrial genome-wide association study of DNAm, with an additional emphasis on sex- and prediabetes-specific heterogeneity. We used the Young Finns Study (n = 926) with sequenced mtDNA genotypes as a discovery sample and sought replication in the Ludwigshafen Risk and Cardiovascular Health study (n = 2317). We identified numerous significant associations in the discovery phase (P < 10(-9)), but they were not replicated when accounting for multiple testing. In total, 27 associations were nominally replicated with a P < 0.05. The replication analysis presented no evidence of sex- or prediabetes-specific heterogeneity. The 27 associations were included in a joint meta-analysis of the two cohorts, and 19 DNAm sites associated with mtDNA variants, while four other sites showed haplogroup associations. An expression quantitative trait methylation analysis was performed for the identified DNAm sites, pinpointing two statistically significant associations. This study provides evidence of a mitochondrial genetic control of nuclear DNAm with little evidence found for sex- and prediabetes-specific effects. The lack of a comparable mtDNA data set for replication is a limitation in our study and further studies are needed to validate our results.Peer reviewe

Visible and Near-Infrared Spectroscopy Enables Differentiation of Normal and Early Osteoarthritic Human Knee Joint Articular Cartilage

Osteoarthritis degenerates cartilage and impairs joint function. Early intervention opportunities are missed as current diagnostic methods are insensitive to early tissue degeneration. We investigated the capability of visible light-near-infrared spectroscopy (Vis-NIRS) to differentiate normal human cartilage from early osteoarthritic one. Vis-NIRS spectra, biomechanical properties and the state of osteoarthritis (OARSI grade) were quantified from osteochondral samples harvested from different anatomical sites of human cadaver knees. Two support vector machines (SVM) classifiers were developed based on the Vis-NIRS spectra and OARSI scores. The first classifier was designed to distinguish normal (OARSI: 0–1) from general osteoarthritic cartilage (OARSI: 2–5) to check the general suitability of the approach yielding an average accuracy of 75% (AUC = 0.77). Then, the second classifier was designed to distinguish normal from early osteoarthritic cartilage (OARSI: 2–3) yielding an average accuracy of 71% (AUC = 0.73). Important wavelength regions for differentiating normal from early osteoarthritic cartilage were related to collagen organization (wavelength region: 400–600 nm), collagen content (1000–1300 nm) and proteoglycan content (1600–1850 nm). The findings suggest that Vis-NIRS allows objective differentiation of normal and early osteoarthritic tissue, e.g., during arthroscopic repair surgeries.Peer reviewe

Identification and functional characterisation of DNA methylation differences between East- and West-originating Finns

Eastern and Western Finns show a striking difference in coronary heart disease-related mortality; genetics is a known contributor for this discrepancy. Here, we discuss the potential role of DNA methylation in mediating the discrepancy in cardiometabolic disease-risk phenotypes between the sub-populations. We used data from the Young Finns Study (n = 969) to compare the genome-wide DNA methylation levels of East- and West-originating Finns. We identified 21 differentially methylated loci (FDR 2.5%) and 7 regions (smoothed FDR < 0.05; CpGs ≥ 5). Methylation at all loci and regions associates with genetic variants (p < 5 × 10−8). Independently of genetics, methylation at 11 loci and 4 regions associates with transcript expression, including genes encoding zinc finger proteins. Similarly, methylation at 5 loci and 4 regions associates with cardiometabolic disease-risk phenotypes including triglycerides, glucose, cholesterol, as well as insulin treatment. This analysis was also performed in LURIC (n = 2371), a German cardiovascular patient cohort, and results replicated for the association of methylation at cg26740318 and DMR_11p15 with diabetes-related phenotypes and methylation at DMR_22q13 with triglyceride levels. Our results indicate that DNA methylation differences between East and West Finns may have a functional role in mediating the cardiometabolic disease discrepancy between the sub-populations.Peer reviewe

Mitochondrial genome-wide analysis of nuclear DNA methylation quantitative trait loci

Mitochondria have a complex communication network with the surrounding cell and can alter nuclear DNA methylation (DNAm). Variation in the mitochondrial DNA (mtDNA) has also been linked to differential DNAm. Genome-wide association studies have identified numerous DNAm quantitative trait loci, but these studies have not examined the mitochondrial genome. Herein, we quantified nuclear DNAm from blood and conducted a mitochondrial genome-wide association study of DNAm, with an additional emphasis on sex- and prediabetes-specific heterogeneity. We used the Young Finns Study (n = 926) with sequenced mtDNA genotypes as a discovery sample and sought replication in the Ludwigshafen Risk and Cardiovascular Health study (n = 2317). We identified numerous significant associations in the discovery phase (P < 10(-9)), but they were not replicated when accounting for multiple testing. In total, 27 associations were nominally replicated with a P < 0.05. The replication analysis presented no evidence of sex- or prediabetes-specific heterogeneity. The 27 associations were included in a joint meta-analysis of the two cohorts, and 19 DNAm sites associated with mtDNA variants, while four other sites showed haplogroup associations. An expression quantitative trait methylation analysis was performed for the identified DNAm sites, pinpointing two statistically significant associations. This study provides evidence of a mitochondrial genetic control of nuclear DNAm with little evidence found for sex- and prediabetes-specific effects. The lack of a comparable mtDNA data set for replication is a limitation in our study and further studies are needed to validate our results.</p