Strain-Dependent Diffusivity of Small and Large Molecules in Meniscus.

Due to lack of full vascularization, the meniscus relies on diffusion through the extracellular matrix to deliver small (e.g., nutrients) and large (e.g., proteins) to resident cells. Under normal physiological conditions, the meniscus undergoes up to 20% compressive strains. While previous studies characterized solute diffusivity in the uncompressed meniscus, to date, little is known about the diffusive transport under physiological strain levels. This information is crucial to fully understand the pathophysiology of the meniscus. The objective of this study was to investigate strain-dependent diffusive properties of the meniscus fibrocartilage. Tissue samples were harvested from the central portion of porcine medial menisci and tested via fluorescence recovery after photobleaching to measure diffusivity of fluorescein (332 Da) and 40 K Da dextran (D40K) under 0%, 10%, and 20% compressive strain. Specifically, average diffusion coefficient and anisotropic ratio, defined as the ratio of the diffusion coefficient in the direction of the tissue collagen fibers to that orthogonal, were determined. For all the experimental conditions investigated, fluorescein diffusivity was statistically faster than that of D40K. Also, for both molecules, diffusion coefficients significantly decreased, up to ∼45%, as the strain increased. In contrast, the anisotropic ratios of both molecules were similar and not affected by the strain applied to the tissue. This suggests that compressive strains used in this study did not alter the diffusive pathways in the meniscus. Our findings provide new knowledge on the transport properties of the meniscus fibrocartilage that can be leveraged to further understand tissue pathophysiology and approaches to tissue restoration.

An Aboriginal and Torres Strait Islander Cardiac Rehabilitation program delivered in a non-Indigenous health service (Yeddung Gauar): a mixed methods feasibility study.

BACKGROUND: There is limited evidence of Aboriginal and Torres Strait Islander people attending cardiac rehabilitation (CR) programs despite high levels of heart disease. One key enabler for CR attendance is a culturally safe program. This study evaluates improving access for Aboriginal and Torres Strait Islander women to attend a CR program in a non-Indigenous health service, alongside improving health workforce cultural safety. METHODS: An 18-week mixed-methods feasibility study was conducted, with weekly flexible CR sessions delivered by a multidisciplinary team and an Aboriginal and/or Torres Strait Islander Health Worker (AHW) at a university health centre. Aboriginal and Torres Strait Islander women who were at risk of, or had experienced, a cardiac event were recruited. Data was collected from participants at baseline, and at every sixth-session attended, including measures of disease risk, quality-of-life, exercise capacity and anxiety and depression. Cultural awareness training was provided for health professionals before the program commenced. Assessment of health professionals' cultural awareness pre- and post-program was evaluated using a questionnaire (n = 18). Qualitative data from participants (n = 3), the AHW, health professionals (n = 4) and referrers (n = 4) was collected at the end of the program using yarning methodology and analysed thematically using Charmaz's constant comparative approach. RESULTS: Eight referrals were received for the CR program and four Aboriginal women attended the program, aged from 24 to 68 years. Adherence to the weekly sessions ranged from 65 to 100%. At the program's conclusion, there was a significant change in health professionals' perception of social policies implemented to 'improve' Aboriginal people, and self-reported changes in health professionals' behaviours and skills. Themes were identified for recruitment, participants, health professionals and program delivery, with cultural safety enveloping all areas. Trust was a major theme for recruitment and adherence of participants. The AHW was a key enabler of cultural authenticity, and the flexibility of the program contributed greatly to participant perceptions of cultural safety. Barriers for attendance were not unique to this population. CONCLUSION: The flexible CR program in a non-Indigenous service provided a culturally safe environment for Aboriginal women but referrals were low. Importantly, the combination of cultural awareness training and participation in the program delivery improved health professionals' confidence in working with Aboriginal people. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) 12618000581268, http://www.ANZCTR.org.au/ACTRN12618000581268.aspx , registered 16 April 2018.

Connecting With Trauma Patients After Discharge: A Phone Call Follow-Up Study.

BACKGROUND: Traumatic injury is sudden and unexpected. It may lead to long-standing physical and physiological consequences. Approximately 10% of the world's disease burden is attributable to traumatic injuries. At the commencement of the study, there was limited information regarding civilian trauma patients' recovery following discharge from the hospital. There are several reasons for this including lack of available resources for follow-up by clinical staff and often trauma patients have multiple injuries, which can result in fragmented care. This limits the ability to assess a patient's recovery following discharge from the hospital. OBJECTIVE: This phone call follow-up study was conducted to assess the number of trauma patients who may be showing symptoms of physical and psychological distress after traumatic injury. METHODS: The study was carried out in New South Wales (Australia) Metropolitan major (Level 1) trauma center. Consented patients were contacted at 72 hr, 1 month, and 3 months after discharge from the hospital. RESULTS: Many patients at all time points had difficulty coping with activities of daily living from pain (183 patients [64%], 121 patients [43%], and 58 patients [23%]), fatigue and sleep disturbance (110 patients [38%], 79 patients [28%], and 49 patients [20%]), as well as anxiety and frustration (38 patients [13%], 79 patients [28%], and 98 patients [39%]) regarding their recovery and returning to their preinjury activities. CONCLUSION: The research indicates that some trauma patients do not recover quickly physically or emotionally. These patients require identification and appropriate management of the consequences of trauma to enable them to return to their preinjury quality of life.

Effect of Strain, Region, and Tissue Composition on Glucose Partitioning in Meniscus Fibrocartilage.

A nearly avascular tissue, the knee meniscus relies on diffusive transport for nutritional supply to cells. Nutrient transport depends on solute partitioning in the tissue, which governs the amount of nutrients that can enter a tissue. The purpose of the present study was to investigate the effects of mechanical strain, tissue region, and tissue composition on the partition coefficient of glucose in meniscus fibrocartilage. A simple partitioning experiment was employed to measure glucose partitioning in porcine meniscus tissues from two regions (horn and central), from both meniscal components (medial and lateral), and at three levels of compression (0%, 10%, and 20%). Partition coefficient values were correlated to strain level, water volume fraction, and glycosaminoglycan (GAG) content of tissue specimens. Partition coefficient values ranged from 0.47 to 0.91 (n = 48). Results show that glucose partition coefficient is significantly (p < 0.001) affected by compression, decreasing with increasing strain. Furthermore, we did not find a statistically significant effect of tissue when comparing medial versus lateral (p = 0.181) or when comparing central and horn regions (p = 0.837). There were significant positive correlations between tissue water volume fraction and glucose partitioning for all groups. However, the correlation between GAG content and partitioning was only significant in the lateral horn group. Determining how glucose partitioning is affected by tissue composition and loading is necessary for understanding nutrient availability and related tissue health and/or degeneration. Therefore, this study is important for better understanding the transport and nutrition-related mechanisms of meniscal degeneration.

Effect of Static Compressive Strain, Anisotropy, and Tissue Region on the Diffusion of Glucose in Meniscus Fibrocartilage.

Osteoarthritis (OA) is a significant socio-economic concern, affecting millions of individuals each year. Degeneration of the meniscus of the knee is often associated with OA, yet the relationship between the two is not well understood. As a nearly avascular tissue, the meniscus must rely on diffusive transport for nutritional supply to cells. Therefore, quantifying structure-function relations for transport properties in meniscus fibrocartilage is an important task. The purpose of the present study was to determine how mechanical loading, tissue anisotropy, and tissue region affect glucose diffusion in meniscus fibrocartilage. A one-dimensional (1D) diffusion experiment was used to measure the diffusion coefficient of glucose in porcine meniscus tissues. Results show that glucose diffusion is strain-dependent, decreasing significantly with increased levels of compression. It was also determined that glucose diffusion in meniscus tissues is anisotropic, with the diffusion coefficient in the circumferential direction being significantly higher than that in the axial direction. Finally, the effect of tissue region was not statistically significant, comparing axial diffusion in the central and horn regions of the tissue. This study is important for better understanding the transport and nutrition-related mechanisms of meniscal degeneration and related OA in the knee.

Development of Improved Confined Compression Testing Setups for Use in Stress Relaxation Testing of Viscoelastic Biomaterials.

The development of cell-based biomaterial alternatives holds significant promise in tissue engineering applications, but it requires accurate mechanical assessment. Herein, we present the development of a novel 3D-printed confined compression apparatus, fabricated using clear resin, designed to cater to the unique demands of biomaterial developers. Our objective was to enhance the precision of force measurements and improve sample visibility during compression testing. We compared the performance of our innovative 3D-printed confined compression setup to a conventional setup by performing stress relaxation testing on hydrogels with variable degrees of crosslinking. We assessed equilibrium force, aggregate modulus, and peak force. This study demonstrates that our revised setup can capture a larger range of force values while simultaneously improving accuracy. We were able to detect significant differences in force and aggregate modulus measurements of hydrogels with variable degrees of crosslinking using our revised setup, whereas these were indistinguishable with the convectional apparatus. Further, by incorporating a clear resin in the fabrication of the compression chamber, we improved sample visibility, thus enabling real-time monitoring and informed assessment of biomaterial behavior under compressive testing.

Assessing the role of surface layer and molecular probe size in diffusion within meniscus tissue.

Diffusion within extracellular matrix is essential to deliver nutrients and larger metabolites to the avascular region of the meniscus. It is well known that both structure and composition of the meniscus vary across its regions; therefore, it is crucial to fully understand how the heterogenous meniscal architecture affects its diffusive properties. The objective of this study was to investigate the effect of meniscal region (core tissue, femoral, and tibial surface layers) and molecular weight on the diffusivity of several molecules in porcine meniscus. Tissue samples were harvested from the central area of porcine lateral menisci. Diffusivity of fluorescein (MW 332 Da) and three fluorescence-labeled dextrans (MW 3k, 40k, and 150k Da) was measured via fluorescence recovery after photobleaching. Diffusivity was affected by molecular size, decreasing as the Stokes' radius of the solute increased. There was no significant effect of meniscal region on diffusivity for fluorescein, 3k and 40k dextrans (p>0.05). However, region did significantly affect the diffusivity of 150k Dextran, with that in the tibial surface layer being larger than in the core region (p = 0.001). Our findings contribute novel knowledge concerning the transport properties of the meniscus fibrocartilage. This data can be used to advance the understanding of tissue pathophysiology and explore effective approaches for tissue restoration.

The association of race, ethnicity, and socioeconomic status on the severity of menopause symptoms: a study of 68,864 women.

OBJECTIVE: This study aimed to evaluate if and how race, ethnicity, and socioeconomic status (SES) are associated with the severity of menopause symptoms in a large, diverse sample of women. METHODS: For this cross-sectional study conducted between March 24, 2019, and January 13, 2023, a total of 68,864 women were enrolled from the Evernow online telehealth platform. Participants underwent a clinical intake survey, which encompassed demographic information, detailed medical questionnaires, and a modified Menopause Rating Scale. The modified scale was adapted for ease of use online and is available in the supplementary material along with the full intake. Symptom severity was evaluated using a multivariate binomial generalized linear model, accounting for factors such as race, ethnicity, age, body mass index, smoking status, bilateral oophorectomy status, and SES. Odds ratios (OR) and CIs were calculated based on the linear regression coefficients. RESULTS: Of the participants, 67,867 (98.6%) were included in the analysis after excluding outliers and those with unknown oophorectomy status. The majority of respondents identified as White (77.4%), followed by Hispanic (9.0%), Black (6.7%), two or more races/ethnicities (4.4%), Asian (1.2%), Indigenous/First Nations (0.8%), Middle Eastern (0.3%), and South Asian (0.2%). Notably, individuals identifying as Black (hot flashes OR, 1.91; 97.5% CI, 1.75-2.09; P < 0.001), Hispanic (skin/hair changes OR, 1.58; 97.5% CI, 1.45-1.71; P < 0.001), Indigenous/First Nations (painful sex OR, 1.39; 97.5% CI, 1.19-2.75; P = 0.007), Middle Eastern (weight changes OR, 2.22; 97.5% CI, 1.25-4.37; P = 0.01), or with two or more races/ethnicities (skin/hair changes OR, 1.41; 97.5% CI, 1.26-1.58; P < 0.001) reported higher levels of symptom severity compared with their White counterparts. Conversely, Asian and South Asian participants reported lower symptom severity. Even after incorporating SES into the linear model, racial and ethnic groups with lower SES (Black, Hispanic, Indigenous, and multiple ethnicities) exhibited slight shifts in OR while maintaining high statistical significance (Black [hot flashes OR, 1.87; 97.5% CI, 1.72-2.04; P < 0.001], Hispanic [skin/hair changes OR, 1.54; 97.5% CI, 1.42-1.68; P < 0.001], Indigenous/First Nations [painful sex OR, 1.74; 97.5% CI, 1.17-2.70; P = 0.009], multiple ethnicities [skin/hair changes OR, 1.41; 97.5% CI, 1.26-1.58; P < 0.001]). CONCLUSIONS: Our study suggests that the relationship between race and ethnicity and the severity of menopause symptoms is not solely explained by differences in SES but is itself an independent factor. Understanding and addressing social, cultural, and economic factors are crucial to reduce disparities in menopausal symptoms.

Effect of molecular weight and tissue layer on solute partitioning in the knee meniscus.

Objective: Knee meniscus tissue is partly vascularized, meaning that nutrients must be transported through the extracellular matrix of the avascular portion to reach resident cells. Similarly, drugs used as therapeutic agents to treat meniscal pathologies rely on transport through the tissue. The driving force of diffusive transport is the gradient of concentration, which depends on molecular solubility. The meniscus is organized into a core region sandwiched between the tibial and femoral superficial layers. Structural differences exist across meniscal regions; therefore, regional differences in solubility are also hypothesized. Methods: Samples from the core, tibial and femoral layers were obtained from 5 medial and 5 lateral porcine menisci. The partition coefficient (K) of fluorescein, 3 â€‹kDa and 40 â€‹kDa dextrans in the layers of the meniscus was measured using an equilibration experiment. The effect of meniscal compartment, layer, and solute molecular weight on K was analyzed using a three-way ANOVA. Results: K ranged from a high of ∼2.9 in fluorescein to a low of ∼0.1 in 40 â€‹kDa dextran and was inversely related to the solute molecular weight across all tissue regions. Tissue layer only had a significant effect on partitioning of 40k Dex solute, which was lower in the tibial surface layer relative to the core (p â€‹= â€‹0.032). Conclusion: This study provides insight into depth-dependent partitioning in the meniscus, indicating the limiting effect of the meniscus superficial layer on solubility increases with solute molecular size. This illustrates how the surface layers could potentially reduce the effectiveness of drug delivery therapies incorporating large molecules (>40 â€‹kDa).

Biomechanical properties of porcine meniscus as determined via AFM: Effect of region, compartment and anisotropy.

The meniscus is a fibrocartilaginous tissue that plays an essential role in load transmission, lubrication, and stabilization of the knee. Loss of meniscus function, through degeneration or trauma, can lead to osteoarthritis in the underlying articular cartilage. To perform its crucial function, the meniscus extracellular matrix has a particular organization, including collagen fiber bundles running circumferentially, allowing the tissue to withstand tensile hoop stresses developed during axial loading. Given its critical role in preserving the health of the knee, better understanding structure-function relations of the biomechanical properties of the meniscus is critical. The main objective of this study was to measure the compressive modulus of porcine meniscus using Atomic Force Microscopy (AFM); the effects of three key factors were investigated: direction (axial, circumferential), compartment (medial, lateral) and region (inner, outer). Porcine menisci were prepared in 8 groups (= 2 directions x 2 compartments x 2 regions) with n = 9 per group. A custom AFM was used to obtain force-indentation curves, which were then curve-fit with the Hertz model to determine the tissue's compressive modulus. The compressive modulus ranged from 0.75 to 4.00 MPa across the 8 groups, with an averaged value of 2.04±0.86MPa. Only direction had a significant effect on meniscus compressive modulus (circumferential > axial, p = 0.024), in agreement with earlier studies demonstrating that mechanical properties in the tissue are anisotropic. This behavior is likely the result of the particular collagen fiber arrangement in the tissue and plays a key role in load transmission capability. This study provides important information on the micromechanical properties of the meniscus, which is crucial for understanding tissue pathophysiology, as well as for developing novel treatments for tissue repair.

A proof-of-concept randomized controlled trial of follow-up mental health care for traumatic injury patients following hospital discharge.

INTRODUCTION: Traumatic injuries account for a huge burden of disease. Many patients develop persistent mental health problems in the months following hospital discharge. This proof-of-concept trial investigated whether Stepped Care comprising follow-up assessment telephone calls and appropriate referral information would lead to better mental health and functioning in traumatic injury patients. METHODS: Patients admitted to the Trauma Service at Royal North Shore Hospital were randomized to either Stepped Care (n = 84) or Treatment as Usual (n = 90). All patients were assessed for anxiety, depression, and posttraumatic stress prior to hospital discharge. Those in Stepped Care received a telephone call at 1-month and 3-months after hospital discharge in which they were administered a brief assessment; patients who reported mental health or pain difficulties were provided with information for local specialists to address their specific problem. All patients were independently assessed by telephone interview 9- months after hospital discharge for posttraumatic stress disorder (PTSD) (primary outcome), as well as for anxiety, depression, disability, and pain. RESULTS: There were 58 (73%) patients that could be contacted at either the 1-month or 3-month assessments. Of those contacted, 28 patients (48% of those contacted) were referred for specialist assistance. There were no differences between treatment arms on PTSD symptoms at follow-up [F1,95 = 0.55, p = 0.46]. At the 9-month assessment, patients in the Stepped Care condition reported significantly less anxiety [F1,95 = 5.07, p = 0.03] and disability [F1,95 = 4.37, p = 0.04] relative to those in Treatment as Usual. At 9 months there was no difference between conditions on depression [F1,95 = 1.03, p = 0.31]. There were no differences between conditions on self-reported pain difficulties. CONCLUSIONS: This proof-of-concept trial suggests that brief screening assessments of traumatic injury patients following hospital discharge, combined with appropriate referral information, may lead to better functional outcomes. Further research is needed with larger sample sizes and greater verification of referral uptake to validate this finding.

Heterogeneity of dynamic shear properties of the meniscus: A comparison between tissue core and surface layers.

Damage to the meniscus has been associated with excessive shear loads. Aimed at elucidating meniscus pathophysiology, previous studies have investigated the shear properties of the meniscus fibrocartilaginous core. However, the meniscus is structurally inhomogeneous, with an external cartilaginous envelope (tibial and femoral surface layers) wrapping the tissue core. To date, little is known about the shear behavior of the surface layers. The objective of this study was to measure the dynamic shear properties of the surface layers and derive empirical relations with their composition. Specimens were harvested from tibial and femoral surface layers and core of porcine menisci (medial and lateral, n = 10 each). Frequency sweep tests yielded complex shear modulus (G*) and phase shifts (δ). Mechanical behavior of regions was described by a generalized Maxwell model. Correlations between shear moduli with water and glycosaminoglycans content of the tissue regions were investigated. The femoral surface had the lowest shear modulus, when compared to core and tibial regions. A 3-relaxation times Maxwell model satisfactorily interpreted the shear behavior of all tissue regions. Inhomogeneous tissue composition was also observed, with water content in the surface layers being higher when compared with tissue core. Water content negatively correlated with shear properties in all regions. The lower measured shear properties in the femoral layer may explain the higher prevalence of meniscal tears on the superior surface of the tissue. The heterogenous behavior of the tissue in shear provides insight into meniscus pathology and has important implications for efforts to tissue engineer replacement tissues.

Tensile energy dissipation and mechanical properties of the knee meniscus: relationship with fiber orientation, tissue layer, and water content.

Introduction: The knee meniscus distributes and dampens mechanical loads. It is composed of water (∼70%) and a porous fibrous matrix (∼30%) with a central core that is reinforced by circumferential collagen fibers enclosed by mesh-like superficial tibial and femoral layers. Daily loading activities produce mechanical tensile loads which are transferred through and dissipated by the meniscus. Therefore, the objective of this study was to measure how tensile mechanical properties and extent of energy dissipation vary by tension direction, meniscal layer, and water content. Methods: The central regions of porcine meniscal pairs (n = 8) were cut into tensile samples (4.7 mm length, 2.1 mm width, and 0.356 mm thickness) from core, femoral and tibial components. Core samples were prepared parallel (circumferential) and perpendicular (radial) to the fibers. Tensile testing consisted of frequency sweeps (0.01-1Hz) followed by quasi-static loading to failure. Dynamic testing yielded energy dissipation (ED), complex modulus (E*), and phase shift (δ) while quasi-static tests yielded Young's Modulus (E), ultimate tensile strength (UTS), and strain at UTS (εUTS). To investigate how ED is influenced by the specific mechanical parameters, linear regressions were performed. Correlations between sample water content (φw) and mechanical properties were investigated. A total of 64 samples were evaluated. Results: Dynamic tests showed that increasing loading frequency significantly reduced ED (p < 0.05). Circumferential samples had higher ED, E*, E, and UTS than radial ones (p < 0.001). Stiffness was highly correlated with ED (R2 > 0.75, p < 0.01). No differences were found between superficial and circumferential core layers. ED, E*, E, and UTS trended negatively with φw (p < 0.05). Discussion: Energy dissipation, stiffness, and strength are highly dependent on loading direction. A significant amount of energy dissipation may be associated with time-dependent reorganization of matrix fibers. This is the first study to analyze the tensile dynamic properties and energy dissipation of the meniscus surface layers. Results provide new insights on the mechanics and function of meniscal tissue.

Mechanical properties of meniscal circumferential fibers using an inverse finite element analysis approach.

The extracellular matrix (ECM) of the meniscus is a gel-like water solution of proteoglycans embedding bundles of collagen fibers mainly oriented circumferentially. Collagen fibers significantly contribute to meniscal mechanics, however little is known about their mechanical properties. The objective of this study was to propose a constitutive model for collagen fibers embedded in the ECM of the meniscus and to characterize the tissue's pertinent mechanical properties. It was hypothesized that a linear fiber reinforced viscoelastic constitutive model is suitable to describe meniscal mechanical behavior in shear. It was further hypothesized that the mechanical properties governing the model depend on the tissue's composition. Frequency sweep tests were conducted on eight porcine meniscal specimens. A first cohort of experimental data resulted from tissue specimens where collagen fibers oriented parallel with respect to the shear plane were used. This was done to eliminate the contribution of collagen fibers from the mechanical response and characterize the mechanical properties of the ECM. A second cohort with fibers orthogonally oriented with respect to the shear plane that were used to determine the elastic properties of the collagen fibers via inverse finite element analysis. Our testing protocol revealed that tissue ECM mechanical behavior could be described by a generalized Maxwell model with 3 relaxation times. The inverse finite element analysis suggested that collagen fibers can be modeled as linear elastic elements having an average elastic modulus of 287.5 ± 62.6 MPa. Magnitudes of the mechanical parameters governing the ECM and fibers were negatively related to tissue water content.

3D finite element analysis of nutrient distributions and cell viability in the intervertebral disc: effects of deformation and degeneration.

The intervertebral disc (IVD) receives important nutrients, such as glucose, from surrounding blood vessels. Poor nutritional supply is believed to play a key role in disc degeneration. Several investigators have presented finite element models of the IVD to investigate disc nutrition; however, none has predicted nutrient levels and cell viability in the disc with a realistic 3D geometry and tissue properties coupled to mechanical deformation. Understanding how degeneration and loading affect nutrition and cell viability is necessary for elucidating the mechanisms of disc degeneration and low back pain. The objective of this study was to analyze the effects of disc degeneration and static deformation on glucose distributions and cell viability in the IVD using finite element analysis. A realistic 3D finite element model of the IVD was developed based on mechano-electrochemical mixture theory. In the model, the cellular metabolic activities and viability were related to nutrient concentrations, and transport properties of nutrients were dependent on tissue deformation. The effects of disc degeneration and mechanical compression on glucose concentrations and cell density distributions in the IVD were investigated. To examine effects of disc degeneration, tissue properties were altered to reflect those of degenerated tissue, including reduced water content, fixed charge density, height, and endplate permeability. Two mechanical loading conditions were also investigated: a reference (undeformed) case and a 10% static deformation case. In general, nutrient levels decreased moving away from the nutritional supply at the disc periphery. Minimum glucose levels were at the interface between the nucleus and annulus regions of the disc. Deformation caused a 6.2% decrease in the minimum glucose concentration in the normal IVD, while degeneration resulted in an 80% decrease. Although cell density was not affected in the undeformed normal disc, there was a decrease in cell viability in the degenerated case, in which averaged cell density fell 11% compared with the normal case. This effect was further exacerbated by deformation of the degenerated IVD. Both deformation and disc degeneration altered the glucose distribution in the IVD. For the degenerated case, glucose levels fell below levels necessary for maintaining cell viability, and cell density decreased. This study provides important insight into nutrition-related mechanisms of disc degeneration. Moreover, our model may serve as a powerful tool in the development of new treatments for low back pain.

Computational Modeling Intervertebral Disc Pathophysiology: A Review.

Lower back pain is a medical condition of epidemic proportion, and the degeneration of the intervertebral disc has been identified as a major contributor. The etiology of intervertebral disc (IVD) degeneration is multifactorial, depending on age, cell-mediated molecular degradation processes and genetics, which is accelerated by traumatic or gradual mechanical factors. The complexity of such intertwined biochemical and mechanical processes leading to degeneration makes it difficult to quantitatively identify cause-effect relationships through experiments. Computational modeling of the IVD is a powerful investigative tool since it offers the opportunity to vary, observe and isolate the effects of a wide range of phenomena involved in the degenerative process of discs. This review aims at discussing the main findings of finite element models of IVD pathophysiology with a special focus on the different factors contributing to physical changes typical of degenerative phenomena. Models presented are subdivided into those addressing role of nutritional supply, progressive biochemical alterations stemming from an imbalance between anabolic and catabolic processes, aging and those considering mechanical factors as the primary source that induces morphological change within the disc. Limitations of the current models, as well as opportunities for future computational modeling work are also discussed.

Viscoelastic and equilibrium shear properties of human meniscus: Relationships with tissue structure and composition.

The meniscus is crucial in maintaining the knee function and protecting the joint from secondary pathologies, including osteoarthritis. Although most of the mechanical properties of human menisci have been characterized, to our knowledge, its dynamic shear properties have never been reported. Moreover, little is known about meniscal shear properties in relation to tissue structure and composition. This is crucial to understand mechanisms of meniscal injury, as well as, in regenerative medicine, for the design and development of tissue engineered scaffolds mimicking the native tissue. Hence, the objective of this study was to characterize the dynamic and equilibrium shear properties of human meniscus in relation to its anisotropy and composition. Specimens were prepared from the axial and the circumferential anatomical planes of medial and lateral menisci. Frequency sweeps and stress relaxation tests yielded storage (G') and loss moduli (G″), and equilibrium shear modulus (G). Correlations of moduli with water, glycosaminoglycans (GAGs), and collagen content were investigated. The meniscus exhibited viscoelastic behavior. Dynamic shear properties were related to tissue composition: negative correlations were found between G', G″ and G, and meniscal water content; positive correlations were found for G' and G″ with GAG and collagen (only in circumferential samples). Circumferential samples, with collagen fibers orthogonal to the shear plane, exhibited superior dynamic mechanical properties, with G' ~70 kPa and G″ ~10 kPa, compared to those of the axial plane ~15 kPa and ~1 kPa, respectively. Fiber orientation did not affect the values of G, which ranged from ~50 to ~100 kPa.

EFFECTS OF SOLUTE SIZE AND TISSUE COMPOSITION ON MOLECULAR AND MACROMOLECULAR DIFFUSIVITY IN HUMAN KNEE CARTILAGE.

OBJECTIVE: Articular cartilage is an avascular tissue. Accordingly, diffusivity represents a fundamental transport mechanism for nutrients and other molecular signals regulating its cell metabolism and maintenance of the extracellular matrix. Understanding how solutes spread into articular cartilage is crucial to elucidating its pathologies, and to designing treatments for repair and restoration of its extracellular matrix. As in other connective tissues, diffusivity in articular cartilage may vary depending both its composition and the specific diffusing solute. Hence, this study investigated the roles of solute size and tissue composition on molecular diffusion in knee articular cartilage. DESIGN: FRAP tests were conducted to measure diffusivity of five molecular probes, with size ranging from ~332Da to 70,000Da, in human knee articular cartilage. The measured diffusion coefficients were related to molecular size, as well as water and glycosaminoglycan (GAG) content of femoral and tibial condyle cartilage. RESULTS: Diffusivity was affected by molecular size, with the magnitude of the diffusion coefficients decreasing as the Stokes radius of the probe increased. The values of diffusion coefficients in tibial and femoral samples were not significantly different from one another, despite the fact that tibial samples exhibited significantly higher water content and lower GAG content of the femoral specimens. Water content did not affect diffusivity. In contrast, diffusivities of large molecules were sensitive to GAG content. CONCLUSIONS: This study provides new knowledge on the mechanisms of diffusion in articular cartilage. Our findings can be leveraged to further investigate osteoarthritis and to design treatments for cartilage restoration or replacement.

Compressive Properties and Hydraulic Permeability of Human Meniscus: Relationships With Tissue Structure and Composition.

The meniscus is crucial in maintaining knee function and protecting the joint from secondary pathologies, including osteoarthritis. The meniscus has been shown to absorb up to 75% of the total load on the knee joint. Mechanical behavior of meniscal tissue in compression can be predicted by quantifying the mechanical parameters including; aggregate modulus (H) and Poisson modulus (ν), and the fluid transport parameter: hydraulic permeability (K). These parameters are crucial to develop a computational model of the tissue and for the design and development of tissue engineered scaffolds mimicking the native tissue. Hence, the objective of this study was to characterize the mechanical and fluid transport properties of human meniscus and relate them to the tissue composition. Specimens were prepared from the axial and the circumferential anatomical planes of the tissue. Stress relaxation tests yielded the H, while finite element modeling was used to curve fit for ν and K. Correlations of moduli with water and glycosaminoglycans (GAGs) content were investigated. On average H was found to be 0.11 ± 0.078 MPa, ν was 0.32 ± 0.057, and K was 2.9 ± 2.27 × 10-15 m4N-1s-1. The parameters H, ν, and K were not found to be statistically different across compression orientation or compression level. Water content of the tissue was 77 ± 3.3% while GAG content was 8.79 ± 1.1%. Interestingly, a weak negative correlation was found between H and water content (R2 ~ 34%) and a positive correlation between K and GAG content (R2 ~ 53%). In conclusion, while no significant differences in transport and compressive properties can be found across sample orientation and compression levels, data trends suggest potential relationships between magnitudes of H and K, and GAG content.