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Article ; Conference proceedings: Symposium: Clinically Relevant Strategies for Treating Cartilage and Meniscal Pathology

Hung, Clark T.

Clinical orthopaedics and related research 469 ,10, S. 2677 - 2823 : Ill., graph. Darst.

[circa 2011]

2011

Title variant	Clinically relevant strategies for treating cartilage and meniscal pathology
Event/congress	Symposium Clinically Relevant Strategies for Treating Cartilage and Meniscal Pathology (2011)
Author's details	guest ed.: Clark T. Hung
Collection	Clinical orthopaedics and related research
Language	English
Publishing place	New York, NY
Publishing country	United States
Document type	Article ; Conference proceedings
HBZ-ID	HT017020729
Database	Catalogue ZB MED Medicine, Health

In stock of ZB MED Cologne/Königswinter

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Article: Modeling Inelastic Responses Using Constrained Reactive Mixtures.

Ateshian, Gerard A / Hung, Clark T / Weiss, Jeffrey A / Zimmerman, Brandon K

European journal of mechanics. A, Solids

2023 Volume 100

Abstract: This study reviews the progression of our research, from modeling growth theories for cartilage tissue engineering, to the formulation of constrained reactive mixture theories to model inelastic responses in any solid material, such as theories for ... ...

Abstract	This study reviews the progression of our research, from modeling growth theories for cartilage tissue engineering, to the formulation of constrained reactive mixture theories to model inelastic responses in any solid material, such as theories for damage mechanics, viscoelasticity, plasticity, and elasto-plastic damage. In this framework, multiple solid generations
Language	English
Publishing date	2023-05-06
Publishing country	France
Document type	Journal Article
ISSN	0997-7538
ISSN	0997-7538
DOI	10.1016/j.euromechsol.2023.105009
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Article ; Online: In vitro

Marrero-Berrios, Ileana / Salter, S Elina / Hirday, Rishabh / Rabolli, Charles P / Tan, Andrea / Hung, Clark T / Schloss, Rene S / Yarmush, Martin L

Osteoarthritis and cartilage open

2024 Volume 6, Issue 1, Page(s) 100432

Abstract: Objective: Osteoarthritis (OA) is a chronic joint disease, with limited treatment options, characterized by inflammation and matrix degradation, and resulting in severe pain or disability. Progressive inflammatory interaction among key cell types, ... ...

Abstract	Objective: Osteoarthritis (OA) is a chronic joint disease, with limited treatment options, characterized by inflammation and matrix degradation, and resulting in severe pain or disability. Progressive inflammatory interaction among key cell types, including chondrocytes and macrophages, leads to a cascade of intra- and inter-cellular events which culminate in OA induction. In order to investigate these interactions, we developed a multi-cellular Methods: We compared macrophages, chondrocytes and their co-culture responses to "low" Interleukin-1 (IL-1) or "high" IL-1/tumor necrosis factor (IL-1/TNF) levels of inflammation. We also investigated response changes following the administration of dexamethasone (DEX) or mesenchymal stromal cell (MSC) treatment via a combination of gene expression and secretory changes, reflecting not only inflammation, but also chondrocyte function. Results: Inflamed chondrocytes presented an osteoarthritic-like phenotype characterized by high gene expression of pro-inflammatory cytokines and chemokines, up-regulation of ECM degrading proteases, and down-regulation of chondrogenic genes. Our results indicate that while MSC treatment attenuates macrophage inflammation directly, it does not reduce chondrocyte inflammatory responses, unless macrophages are present as well. DEX however, can directly attenuate chondrocyte inflammation. Conclusions: Our results highlight the importance of considering multi-cellular interactions when studying complex systems such as the articular joint. In addition, our approach, using a panel of both inflammatory and chondrocyte functional genes, provides a more comprehensive approach to investigate disease biomarkers, and responses to treatment.
Language	English
Publishing date	2024-01-05
Publishing country	England
Document type	Journal Article
ISSN	2665-9131
ISSN (online)	2665-9131
DOI	10.1016/j.ocarto.2023.100432
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Article ; Online: Red blood cell exposure increases chondrocyte susceptibility to oxidative stress following hemarthrosis.

Lee, Andy J / Gangi, Lianna R / Zandkarimi, Fereshteh / Stockwell, Brent R / Hung, Clark T

Osteoarthritis and cartilage

2023 Volume 31, Issue 10, Page(s) 1365–1376

Abstract: Objective: The detrimental effects of blood exposure on articular tissues are well characterized, but the individual contributions of specific whole blood components are yet to be fully elucidated. Better understanding of mechanisms that drive cell and ... ...

Abstract	Objective: The detrimental effects of blood exposure on articular tissues are well characterized, but the individual contributions of specific whole blood components are yet to be fully elucidated. Better understanding of mechanisms that drive cell and tissue damage in hemophilic arthropathy will inform novel therapeutic strategies. The studies here aimed to identify the specific contributions of intact and lysed red blood cells (RBCs) on cartilage and the therapeutic potential of Ferrostatin-1 in the context of lipid changes, oxidative stress, and ferroptosis. Methods: Changes to biochemical and mechanical properties following intact RBC treatment were assessed in human chondrocyte-based tissue-engineered cartilage constructs and validated against human cartilage explants. Chondrocyte monolayers were assayed for changes to intracellular lipid profiles and the presence of oxidative and ferroptotic mechanisms. Results: Markers of tissue breakdown were observed in cartilage constructs without parallel losses in DNA (control: 786.3 (102.2) ng/mg; RBC Conclusions: Intact RBCs induce intracellular phenotypic changes to chondrocytes that increase vulnerability to tissue damage while lysed RBCs have a more direct influence on chondrocyte death by mechanisms that are representative of ferroptosis.
MeSH term(s)	Humans ; Chondrocytes/metabolism ; Hemarthrosis/metabolism ; Cartilage, Articular/metabolism ; Erythrocytes/metabolism ; Oxidative Stress ; Lipids
Chemical Substances	Lipids
Language	English
Publishing date	2023-06-25
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1167809-4
ISSN	1522-9653 ; 1063-4584
ISSN (online)	1522-9653
ISSN	1063-4584
DOI	10.1016/j.joca.2023.06.007
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Article ; Online: Biophysical Modulation of Mesenchymal Stem Cell Differentiation in the Context of Skeletal Repair.

Hung, Clark T / Racine-Avila, Jennifer / Pellicore, Matthew J / Aaron, Roy

International journal of molecular sciences

2022 Volume 23, Issue 7

Abstract: A prominent feature of the skeleton is its ability to remodel in response to biophysical stimuli and to repair under varied biophysical conditions. This allows the skeleton considerable adaptation to meet its physiological roles of stability and movement. ...

Abstract	A prominent feature of the skeleton is its ability to remodel in response to biophysical stimuli and to repair under varied biophysical conditions. This allows the skeleton considerable adaptation to meet its physiological roles of stability and movement. Skeletal cells and their mesenchymal precursors exist in a native environment rich with biophysical signals, and they sense and respond to those signals to meet organismal demands of the skeleton. While mechanical strain is the most recognized of the skeletal biophysical stimuli, signaling phenomena also include fluid flow, hydrostatic pressure, shear stress, and ion-movement-related electrokinetic phenomena including, prominently, streaming potentials. Because of the complex interactions of these electromechanical signals, it is difficult to isolate the significance of each. The application of external electrical and electromagnetic fields allows an exploration of the effects of these stimuli on cell differentiation and extra-cellular matrix formation in the absence of mechanical strain. This review takes a distinctly translational approach to mechanistic and preclinical studies of differentiation and skeletal lineage commitment of mesenchymal cells under biophysical stimulation. In vitro studies facilitate the examination of isolated cellular responses while in vivo studies permit the observation of cell differentiation and extracellular matrix synthesis.
MeSH term(s)	Cell Differentiation ; Extracellular Matrix/physiology ; Mesenchymal Stem Cells ; Osteogenesis/physiology ; Stress, Mechanical
Language	English
Publishing date	2022-04-01
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms23073919
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Article ; Online: Directed differentiation of human iPSCs into mesenchymal lineages by optogenetic control of TGF-β signaling.

Wu, Josephine Y / Yeager, Keith / Tavakol, Daniel Naveed / Morsink, Margaretha / Wang, Bryan / Soni, Rajesh Kumar / Hung, Clark T / Vunjak-Novakovic, Gordana

Cell reports

2023 Volume 42, Issue 5, Page(s) 112509

Abstract: In tissue development and homeostasis, transforming growth factor (TGF)-β signaling is finely coordinated by latent forms and matrix sequestration. Optogenetics can offer precise and dynamic control of cell signaling. We report the development of an ... ...

Abstract	In tissue development and homeostasis, transforming growth factor (TGF)-β signaling is finely coordinated by latent forms and matrix sequestration. Optogenetics can offer precise and dynamic control of cell signaling. We report the development of an optogenetic human induced pluripotent stem cell system for TGF-β signaling and demonstrate its utility in directing differentiation into the smooth muscle, tenogenic, and chondrogenic lineages. Light-activated TGF-β signaling resulted in expression of differentiation markers at levels close to those in soluble factor-treated cultures, with minimal phototoxicity. In a cartilage-bone model, light-patterned TGF-β gradients allowed the establishment of hyaline-like layer of cartilage tissue at the articular surface while attenuating with depth to enable hypertrophic induction at the osteochondral interface. By selectively activating TGF-β signaling in co-cultures of light-responsive and non-responsive cells, undifferentiated and differentiated cells were simultaneously maintained in a single culture with shared medium. This platform can enable patient-specific and spatiotemporally precise studies of cellular decision making.
MeSH term(s)	Humans ; Transforming Growth Factor beta/metabolism ; Optogenetics ; Induced Pluripotent Stem Cells/metabolism ; Mesenchymal Stem Cells/metabolism ; Cell Differentiation ; Signal Transduction ; Chondrogenesis ; Cells, Cultured ; Chondrocytes
Chemical Substances	Transforming Growth Factor beta
Language	English
Publishing date	2023-05-12
Publishing country	United States
Document type	Journal Article ; Research Support, U.S. Gov't, Non-P.H.S. ; Research Support, N.I.H., Extramural
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2023.112509
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Article ; Online: Superficial zone chondrocytes can get compacted under physiological loading: A multiscale finite element analysis.

Kroupa, Kimberly R / Gangi, Lianna R / Zimmerman, Brandon K / Hung, Clark T / Ateshian, Gerard A

Acta biomaterialia

2022 Volume 163, Page(s) 248–258

Abstract: Recent in vivo and in vitro studies have demonstrated that superficial zone (SZ) chondrocytes within articular layers of diarthrodial joints die under normal physiologic loading conditions. In order to further explore the implications of this observation ...

Abstract	Recent in vivo and in vitro studies have demonstrated that superficial zone (SZ) chondrocytes within articular layers of diarthrodial joints die under normal physiologic loading conditions. In order to further explore the implications of this observation in future investigations, we first needed to understand the mechanical environment of SZ chondrocytes that might cause them to die under physiological sliding contact conditions. In this study we performed a multiscale finite element analysis of articular contact to track the temporal evolution of a SZ chondrocyte's interstitial fluid pressure, hydraulic permeability, and volume under physiologic loading conditions. The effect of the pericellular matrix modulus and permeability was parametrically investigated. Results showed that SZ chondrocytes can lose ninety percent of their intracellular fluid after several hours of intermittent or continuous contact loading, resulting in a reduction of intracellular hydraulic permeability by more than three orders of magnitude. These findings are consistent with loss of cell viability due to the impediment of cellular metabolic pathways induced by the loss of fluid. They suggest that there is a simple mechanical explanation for the vulnerability of SZ chondrocytes to sustained physiological loading conditions. Future studies will focus on validating these specific findings experimentally. STATEMENT OF SIGNIFICANCE: As with any mechanical system, normal 'wear and tear' of cartilage tissue lining joints is expected. Yet incidences of osteoarthritis are uncommon in individuals younger than 45. This counter-intuitive observation suggests there must be an intrinsic repair mechanism compensating for this wear and tear over many decades of life. Recent experimental studies have shown superficial zone chondrocytes die under physiologic loading conditions, suggesting that this repair mechanism may involve cell replenishment. To better understand the mechanical environment of these cells, we performed a multiscale computational analysis of articular contact under loading. Results indicated that normal activities like walking or standing can induce significant loss of intracellular fluid volume, potentially hindering metabolic activity and fluid transport properties, and causing cell death.
MeSH term(s)	Humans ; Chondrocytes/metabolism ; Cartilage, Articular/metabolism ; Finite Element Analysis ; Models, Biological ; Osteoarthritis/metabolism ; Stress, Mechanical
Language	English
Publishing date	2022-10-13
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2173841-5
ISSN	1878-7568 ; 1742-7061
ISSN (online)	1878-7568
ISSN	1742-7061
DOI	10.1016/j.actbio.2022.10.013
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Article: Pulsed Electromagnetic Field Therapy and Direct Current Electric Field Modulation Promote the Migration of Fibroblast-like Synoviocytes to Accelerate Cartilage Repair In Vitro.

Sakhrani, Neeraj / Stefani, Robert M / Setti, Stefania / Cadossi, Ruggero / Ateshian, Gerard A / Hung, Clark T

Applied sciences (Basel, Switzerland)

2022 Volume 12, Issue 23

Abstract: Articular cartilage injuries are a common source of joint pain and dysfunction. As articular cartilage is avascular, it exhibits a poor intrinsic healing capacity for self-repair. Clinically, osteochondral grafts are used to surgically restore the ... ...

Abstract	Articular cartilage injuries are a common source of joint pain and dysfunction. As articular cartilage is avascular, it exhibits a poor intrinsic healing capacity for self-repair. Clinically, osteochondral grafts are used to surgically restore the articular surface following injury. A significant challenge remains with the repair properties at the graft-host tissue interface as proper integration is critical toward restoring normal load distribution across the joint. A key to addressing poor tissue integration may involve optimizing mobilization of fibroblast-like synoviocytes (FLS) that exhibit chondrogenic potential and are derived from the adjacent synovium, the specialized connective tissue membrane that envelops the diarthrodial joint. Synovium-derived cells have been directly implicated in the native repair response of articular cartilage. Electrotherapeutics hold potential as low-cost, low-risk, non-invasive adjunctive therapies for promoting cartilage healing via cell-mediated repair. Pulsed electromagnetic fields (PEMFs) and applied direct current (DC) electric fields (EFs) via galvanotaxis are two potential therapeutic strategies to promote cartilage repair by stimulating the migration of FLS within a wound or defect site. PEMF chambers were calibrated to recapitulate clinical standards (1.5 ± 0.2 mT, 75 Hz, 1.3 ms duration). PEMF stimulation promoted bovine FLS migration using a 2D in vitro scratch assay to assess the rate of wound closure following cruciform injury. Galvanotaxis DC EF stimulation assisted FLS migration within a collagen hydrogel matrix in order to promote cartilage repair. A novel tissue-scale bioreactor capable of applying DC EFs in sterile culture conditions to 3D constructs was designed in order to track the increased recruitment of synovial repair cells via galvanotaxis from intact bovine synovium explants to the site of a cartilage wound injury. PEMF stimulation further modulated FLS migration into the bovine cartilage defect region. Biochemical composition, histological analysis, and gene expression revealed elevated GAG and collagen levels following PEMF treatment, indicative of its pro-anabolic effect. Together, PEMF and galvanotaxis DC EF modulation are electrotherapeutic strategies with complementary repair properties. Both procedures may enable direct migration or selective homing of target cells to defect sites, thus augmenting natural repair processes for improving cartilage repair and healing.
Language	English
Publishing date	2022-12-04
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2704225-X
ISSN	2076-3417
ISSN	2076-3417
DOI	10.3390/app122312406
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Article ; Online: Blocking toll-like receptor 4 mitigates static loading induced pro-inflammatory expression in intervertebral disc motion segments.

Kenawy, Hagar M / Marshall, Samantha L / Rogot, James / Lee, Andy J / Hung, Clark T / Chahine, Nadeen O

Journal of biomechanics

2023 Volume 150, Page(s) 111491

Abstract: While the anabolic effects of mechanical loading on the intervertebral disc (IVD) have been extensively studied, inflammatory responses to loading have not been as well characterized. Recent studies have highlighted a significant role of innate immune ... ...

Abstract	While the anabolic effects of mechanical loading on the intervertebral disc (IVD) have been extensively studied, inflammatory responses to loading have not been as well characterized. Recent studies have highlighted a significant role of innate immune activation, particularly that of toll-like receptors (TLRs), in IVD degeneration. Biological responses of intervertebral disc cells to loading depend on many factors that include magnitude and frequency. The goals of this study were to characterize the inflammatory signaling changes in response to static and dynamic loading of IVD and investigate the contributions of TLR4 signaling in response to mechanical loading. Rat bone-disc-bone motion segments were loaded for 3 hr under a static load (20 % strain, 0 Hz) with or without an additional low-dynamic (4 % dynamic strain, 0.5 Hz) or high-dynamic (8 % dynamic strain, 3 Hz) strain, and results were compared to unloaded controls. Some samples were also loaded with or without TAK-242, an inhibitor of TLR4 signaling. The magnitude of NO release into the loading media (LM) was correlated with the applied frequency and strain magnitudes across different loading groups. Injurious loading profiles, such as static and high-dynamic, significantly increased Tlr4 and Hmgb1 expression while this result was not observed in the more physiologically relevant low-dynamic loading group. TAK-242 co-treatment decreased pro-inflammatory expression in static but not dynamic loaded groups, suggesting that TLR4 plays a direct role in mediating inflammatory responses of IVD to static compression. Overall, the microenvironment induced by dynamic loading diminished the protective effects of the TAK-242, suggesting that TLR4 plays a direct role in mediating inflammatory responses of IVD to static loading injury.
MeSH term(s)	Rats ; Animals ; Toll-Like Receptor 4/metabolism ; Intervertebral Disc/physiology ; Intervertebral Disc Degeneration ; Sulfonamides/metabolism ; Sulfonamides/pharmacology
Chemical Substances	ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate ; Toll-Like Receptor 4 ; Sulfonamides
Language	English
Publishing date	2023-02-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	218076-5
ISSN	1873-2380 ; 0021-9290
ISSN (online)	1873-2380
ISSN	0021-9290
DOI	10.1016/j.jbiomech.2023.111491
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Article ; Online: Biophysical Modulation of Mesenchymal Stem Cell Differentiation in the Context of Skeletal Repair

Clark T. Hung / Jennifer Racine-Avila / Matthew J. Pellicore / Roy Aaron

International Journal of Molecular Sciences, Vol 23, Iss 3919, p

2022 Volume 3919

Abstract	A prominent feature of the skeleton is its ability to remodel in response to biophysical stimuli and to repair under varied biophysical conditions. This allows the skeleton considerable adaptation to meet its physiological roles of stability and movement. Skeletal cells and their mesenchymal precursors exist in a native environment rich with biophysical signals, and they sense and respond to those signals to meet organismal demands of the skeleton. While mechanical strain is the most recognized of the skeletal biophysical stimuli, signaling phenomena also include fluid flow, hydrostatic pressure, shear stress, and ion-movement-related electrokinetic phenomena including, prominently, streaming potentials. Because of the complex interactions of these electromechanical signals, it is difficult to isolate the significance of each. The application of external electrical and electromagnetic fields allows an exploration of the effects of these stimuli on cell differentiation and extra-cellular matrix formation in the absence of mechanical strain. This review takes a distinctly translational approach to mechanistic and preclinical studies of differentiation and skeletal lineage commitment of mesenchymal cells under biophysical stimulation. In vitro studies facilitate the examination of isolated cellular responses while in vivo studies permit the observation of cell differentiation and extracellular matrix synthesis.
Keywords	stem cells ; differentiation ; osteogenesis ; chondrogenesis ; Biology (General) ; QH301-705.5 ; Chemistry ; QD1-999
Subject code	500
Language	English
Publishing date	2022-04-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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