391 research outputs found
Response of mature meniscal tissue to a single injurious compression and interleukin-1 in vitro
No full textObjective:
To study mechanical overload of mature meniscal tissue under normal and pro-inflammatory conditions in vitro.
Method:
Three days after a single unconfined compression (strain: 25–75%, strain rate 1/s) of meniscal explants from 16 to 24 months-old cattle combined with interleukin-1-treatment (IL-1, 10 ng/ml) release of glycosaminoglycans (GAGs; dimethylmethylene blue (DMMB) assay), lactate dehydrogenase (LDH; cytotoxicity detection kit), and nitric oxide (NO; Griess assay), as well as gene transcription (quantitative reverse transcription polymerase chain reaction (RT-PCR)) and numbers of cells with condensed nuclei (CN; histomorphometry) were determined.
Results:
Mean peak stresses during compression were about five (25%), 11 (50%), and 30 MPa (75%), respectively. GAG and LDH release and numbers of CN increased whereas NO production and mRNA levels of matrix metalloproteinase (MMP)-2, -3 and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4 decreased strain-dependently after compression. IL-1 induced an increase in GAG and NO release as well as MMP-2, -3 and ADAMTS-4 levels, but had no impact on the LDH release and slightly increased numbers of CN. However, in combination with compression the tissue responses were reduced and LDH and CN levels were increased compared to IL-1 alone.
Conclusion:
Our data suggest that a single impact compression induces cell damage and release of GAG and reduces the NO production and transcription of certain matrix-degrading enzymes. It also reduces the capacity of meniscal tissue to respond to IL-1, which might be related to the cell damage and suggests that the compression-related GAG release might rather be the result of immediate extracellular matrix-damage than a cell-mediated event. This, however, needs to be confirmed in future studies.ENDO-Stiftung (Hamburg, Germany)ENDO-Klinik (Hamburg, Germany
Quantitative analysis of T2 relaxation times of the patellofemoral joint cartilage 3 years after anterior cruciate ligament reconstruction
No full textObjective: To evaluate patient-specific patellofemoral joint (PFJ) cartilage 3 years postoperatively using T2 mapping magnetic resonance imaging and the uninjured contralateral side as control.
Hypothesis: The cartilage of the PFJ in the anterior cruciate ligament (ACL) reconstructed knees would show increased T2 values compared to the uninjured contralateral knees at 3-year follow-up, and the femoral (trochlear) cartilage would be more susceptible than the patella in degeneration in ACL-reconstructed knees.
Methods: Ten patients with clinically successful ACL-reconstructed knees were prospectively enrolled 3 years postoperatively. Sagittal images of both knees were obtained using T2 mapping. Cartilage over the medial, central, and lateral regions of the trochlea and patella was divided into superficial and deep regions. Average T2 values of the cartilage at each region of interest of the ACL-reconstructed and uninjured contralateral knees were compared for each individual patient.
Results: Overall, the T2 values at the superficial layers of the medial and central trochlear cartilage of the ACL-reconstructed knees were significantly higher than those of the uninjured contralateral knees by 4.23 ± 9.09 milliseconds (8.9%; p = 0.043) and 5.94 ± 8.12 milliseconds (10.9%; p = 0.019), respectively. No significant difference was found in other cartilage areas of the trochlea and patella. In individual patient analysis, increased T2 values of ACL-reconstructed knees were found in all 10 patients in at least one superficial region and eight patients in at least one deep region of the trochlear cartilage, five patients in at least one superficial region, and eight patients in at least one deep region of the patellar cartilage.
Conclusion: Despite a clinically satisfactory ACL reconstruction (with negative anteroposterior drawer and pivot shift tests), all patients showed at least one region with increased T2 value of the PFJ cartilage 3 years after ACL reconstruction, especially at the medial compartment of the trochlear cartilage.
The Translational Potential of this Article: Little data has been reported on PFJ cartilage condition after ACL reconstruction. This study could help develop noninvasive diagnostic methods for detection of early PFJ cartilage degeneration after ACL reconstruction
Macromolecular drug release from porous implants : sources of matrix tortuosity
No full textThesis (Sc.D.)--Massachusetts Institute of Technology, Dept. of Electrical Engineering and Computer Science, 1984.MICROFICHE COPY AVAILABLE IN ARCHIVES AND ENGINEERING.Vita.Includes bibliographical references.by Ronald Alan Siegel.Sc.D
Relevance of collagen piezoelectricity to "Wolff's Law": A critical review
No full textAccording to “Wolff's Law”, bone is deposited and reinforced at areas of greatest stress. From a clinical perspective, this “law” is supported by the strong association between bone density and physical activity. From a mechanistic standpoint, however, the law presents a challenge to scientists seeking to understand how osteocytes and osteoblasts sense the mechanical load. In the 1960s, collagen piezoelectricity was invoked as a potential mechanism by which osteocytes could detect areas of greater stress but piezoelectricity diminished in importance as more compelling mechanisms, such as streaming potential, were identified. In addition, accumulating evidence for the role of fluid-related shear stress in osteocyte's mechanosensory function has made piezoelectricity seemingly more obsolete in bone physiology. This review critically evaluates the role of collagen piezoelectricity (if any) in Wolff's Law—specifically, the evidence regarding its involvement in strain-generated potentials, existing alternate mechanisms, the present understanding of bone mechanosensation, and whether piezoelectricity serves an influential role within the context of this newly proposed mechanism. In addition to reviewing the literature, this review generates several hypotheses and proposes future research to fully address the relevance of piezoelectricity in bone physiology.National Center for Complementary and Alternative Medicine (U.S.) (grant K23-AT003238
Systems Based Study of the Therapeutic Potential of Small Charged Molecules for the Inhibition of IL-1 Mediated Cartilage Degradation
No full textInflammatory cytokines are key drivers of cartilage degradation in post-traumatic osteoarthritis. Cartilage degradation mediated by these inflammatory cytokines has been extensively investigated using in vitro experimental systems. Based on one such study, we have developed a computational model to quantitatively assess the impact of charged small molecules intended to inhibit IL-1 mediated cartilage degradation. We primarily focus on the simplest possible computational model of small molecular interaction with the IL-1 system—direct binding of the small molecule to the active site on the IL-1 molecule itself. We first use the model to explore the uptake and release kinetics of the small molecule inhibitor by cartilage tissue. Our results show that negatively charged small molecules are excluded from the negatively charged cartilage tissue and have uptake kinetics in the order of hours. In contrast, the positively charged small molecules are drawn into the cartilage with uptake and release timescales ranging from hours to days. Using our calibrated computational model, we subsequently explore the effect of small molecule charge and binding constant on the rate of cartilage degradation. The results from this analysis indicate that the small molecules are most effective in inhibiting cartilage degradation if they are either positively charged and/or bind strongly to IL-1α, or both. Furthermore, our results showed that the cartilage structural homeostasis can be restored by the small molecule if administered within six days following initial tissue exposure to IL-1α. We finally extended the scope of the computational model by simulating the competitive inhibition of cartilage degradation by the small molecule. Results from this model show that small molecules are more efficient in inhibiting cartilage degradation by binding directly to IL-1α rather than binding to IL-1α receptors. The results from this study can be used as a template for the design and development of more pharmacologically effective osteoarthritis drugs, and to investigate possible therapeutic options
Osteoarthritis year in review 2015: mechanics
No full textSummaryMotivated by the conceptual framework of multi-scale biomechanics, this narrative review highlights recent major advances with a focus on gait and joint kinematics, then tissue-level mechanics, cell mechanics and mechanotransduction, matrix mechanics, and finally the nanoscale mechanics of matrix macromolecules. A literature review was conducted from January 2014 to April 2015 using PubMed to identify major developments in mechanics related to osteoarthritis (OA). Studies of knee adduction, flexion, rotation, and contact mechanics have extended our understanding of medial compartment loading. In turn, advances in measurement methodologies have shown how injuries to both the meniscus and ligaments, together, can alter joint kinematics. At the tissue scale, novel findings have emerged regarding the mechanics of the meniscus as well as cartilage superficial zone. Moving to the cell level, poroelastic and poro-viscoelastic mechanisms underlying chondrocyte deformation have been reported, along with the response to osmotic stress. Further developments have emerged on the role of calcium signaling in chondrocyte mechanobiology, including exciting findings on the function of mechanically activated cation channels newly found to be expressed in chondrocytes. Finally, AFM-based nano-rheology systems have enabled studies of thin murine tissues and brush layers of matrix molecules over a wide range of loading rates including high rates corresponding to impact injury. With OA acknowledged to be a disease of the joint as an organ, understanding mechanical behavior at each length scale helps to elucidate the connections between cell biology, matrix biochemistry and tissue structure/function that may play a role in the pathomechanics of OA
Computational model for the analysis of cartilage and cartilage tissue constructs
No full textWe propose a new non-linear poroelastic model that is suited to the analysis of soft tissues. In this paper the model is tailored to the analysis of cartilage and the engineering design of cartilage constructs. The proposed continuum formulation of the governing equations enables the strain of the individual material components within the extracellular matrix (ECM) to be followed over time, as the individual material components are synthesized, assembled and incorporated within the ECM or lost through passive transport or degradation. The material component analysis developed here naturally captures the effect of time-dependent changes of ECM composition on the deformation and internal stress states of the ECM. For example, it is shown that increased synthesis of aggrecan by chondrocytes embedded within a decellularized cartilage matrix initially devoid of aggrecan results in osmotic expansion of the newly synthesized proteoglycan matrix and tension within the structural collagen network. Specifically, we predict that the collagen network experiences a tensile strain, with a maximum of ~2% at the fixed base of the cartilage. The analysis of an example problem demonstrates the temporal and spatial evolution of the stresses and strains in each component of a self-equilibrating composite tissue construct, and the role played by the flux of water through the tissue
A mathematical model for targeting chemicals to tissues by exploiting complex degradation
No full textBackground In many biological and therapeutic contexts, it is highly desirable to target a chemical specifically to a particular tissue where it exerts its biological effect. In this paper, we present a simple, generic, mathematical model that elucidates a general method for targeting a chemical to particular tissues. The model consists of coupled reaction-diffusion equations to describe the evolution within the tissue of the concentrations of three chemical species: a (concentration of free chemical), b (binding protein) and their complex, c (chemical bound to binding protein). We assume that all species are free to diffuse, and that a and b undergo a reversible reaction to form c. In addition, the complex, c, can be broken down by a process (e.g. an enzyme in the tissue) that results in the release of the chemical, a, which is then free to exert its biological action. Results For simplicity, we consider a one-dimensional geometry. In the special case where the rate of complex formation is small (compared to the diffusion timescale of the species within the tissue) the system can be solved analytically. This analytic solution allows us to show how the concentration of free chemical, a, in the tissue can be increased over the concentration of free chemical at the tissue boundary. We show that, under certain conditions, the maximum concentration of a can occur at the centre of the tissue, and give an upper bound on this maximum level. Numerical simulations are then used to determine how the behaviour of the system changes when the assumption of negligible complex formation rate is relaxed. Conclusions We have shown, using our mathematical model, how complex degradation can potentially be exploited to target a chemical to a particular tissue, and how the level of the active chemical depends on factors such as the diffusion coefficients and degradation/production rates of each species. The biological significance of these results in terms of potential applications in cartilage tissue engineering and chemotherapy is discussed. In particular, we believe these results may be of use in determining the most promising prodrug candidates.National Institutes of Health (U.S.) (NIH Grant AR33236)Australian Research Council (DP50192)University of Melbourn
Mechanical motion promotes expression of Prg4 in articular cartilage via multiple CREB-dependent, fluid flow shear stress-induced signaling pathways
No full textLubricin is a secreted proteoglycan encoded by the Prg4 locus that is abundantly expressed by superficial zone articular chondrocytes and has been noted to both be sensitive to mechanical loading and protect against the development of osteoarthritis. In this study, we document that running induces maximal expression of Prg4 in the superficial zone of knee joint articular cartilage in a COX-2-dependent fashion, which correlates with augmented levels of phospho-S133 CREB and increased nuclear localization of CREB-regulated transcriptional coactivators (CRTCs) in this tissue. Furthermore, we found that fluid flow shear stress (FFSS) increases secretion of extracellular PGE2, PTHrP, and ATP (by epiphyseal chondrocytes), which together engage both PKA- and Ca++-regulated signaling pathways that work in combination to promote CREB-dependent induction of Prg4, specifically in superficial zone articular chondrocytes. Because running and FFSS both boost Prg4 expression in a COX-2-dependent fashion, our results suggest that mechanical motion may induce Prg4 expression in the superficial zone of articular cartilage by engaging the same signaling pathways activated in vitro by FFSS that promote CREB-dependent gene expression in this tissue.National Institute of Arthritis and Musculoskeletal and Skin Diseases (U.S.) (Grant AR60331
Effects of insulin-like growth factor-1 and dexamethasone on cytokine-challenged cartilage: relevance to post-traumatic osteoarthritis
No full textObjective: Interleukin-1 is one of the inflammatory cytokines elevated after traumatic joint injury that plays a critical role in mediating cartilage tissue degradation, suppressing matrix biosynthesis, and inducing chondrocyte apoptosis, events associated with progression to post-traumatic osteoarthritis (PTOA). We studied the combined use of insulin-like growth factor-1 (IGF-1) and dexamethasone (Dex) to block these multiple degradative effects of cytokine challenge to articular cartilage.
Methods: Young bovine and adult human articular cartilage explants were treated with IL-1α in the presence or absence of IGF-1, Dex, or their combination. Loss of sulfated glycosaminoglycans (sGAG) and collagen were evaluated by the DMMB and hydroxyproline assays, respectively. Matrix biosynthesis was measured via radiolabel incorporation, chondrocyte gene expression by qRT-PCR, and cell viability by fluorescence staining.
Results: In young bovine cartilage, the combination of IGF-1 and Dex significantly inhibited the loss of sGAG and collagen, rescued the suppression of matrix biosynthesis, and inhibited the loss of chondrocyte viability caused by IL-1α treatment. In adult human cartilage, only IGF-1 rescued matrix biosynthesis and only Dex inhibited sGAG loss and improved cell viability. Thus, the combination of IGF-1 + Dex together showed combined beneficial effects in human cartilage.
Conclusions: Our findings suggest that the combination of IGF-1 and Dex has greater beneficial effects than either molecule alone in preventing cytokine-mediated cartilage degradation in adult human and young bovine cartilage. Our results support the use of such a combined approach as a potential treatment relevant to early cartilage degradative changes associated with joint injury.Singapore. Agency for Science, Technology and Research (National Science Scholarship)Massachusetts Institute of Technology. Office of the Dean for Graduate Education (Chyn Duog Shiah Memorial Graduate Student Fellowship
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