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Peng L, Li R, Xu S, Ding K, Wu Y, Li H, Wang Y. Harnessing joint distraction for the treatment of osteoarthritis: a bibliometric and visualized analysis. Front Bioeng Biotechnol 2023; 11:1309688. [PMID: 38026890 PMCID: PMC10666289 DOI: 10.3389/fbioe.2023.1309688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2023] [Accepted: 10/30/2023] [Indexed: 12/01/2023] Open
Abstract
Osteoarthritis (OA) stands as a prevalent degenerative joint ailment, demanding immediate attention towards the development of efficacious therapeutic interventions. Presently, a definitive cure for OA remains elusive, and when conservative treatment modalities prove ineffective, resorting to a joint prosthesis becomes imperative. Temporary distraction emerges as a pivotal joint-preserving intervention in human OA patients, conferring both clinical amelioration and structural enhancements. Although extant clinical investigations exist, they are characterized by relatively modest sample sizes. Nonetheless, these studies furnish compelling evidence affirming that joint distraction engenders sustained clinical amelioration and structural refinement. Despite substantial strides in the last decade, a bibliometric analysis of joint distraction within the realm of osteoarthritis treatment research has been conspicuously absent. In this context, we have undertaken a comparative investigation utilizing bibliometric methodologies to scrutinize the landscape of joint distraction within osteoarthritis treatment. Our comprehensive analysis encompassed 469 scholarly articles. Our findings evince a consistent escalation in global research interest and publication output pertaining to this subject. The United States emerged as the frontrunner in international collaboration, publication count, and citation frequency, underscoring its preeminence in this domain. The journal "Osteoarthritis and Cartilage" emerged as the principal platform for disseminating research output on this subject. Notably, Mastbergen SC emerged as the most prolific contributor in terms of authorship. The identified keywords predominantly revolved around non-surgical interventions and joint arthroscopy procedures. This bibliometric analysis, augmented by visual representations, furnishes invaluable insights into the evolutionary trajectory of joint distraction as an osteoarthritis treatment modality spanning from 2003 to 2023. These insights will serve as a compass for the scientific community, facilitating further exploration in this promising domain.
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Affiliation(s)
- Liqing Peng
- Department of Orthopedics, First People’s Hospital of Shuangliu District, Chengdu, China
| | - Runmeng Li
- School of Medicine, Nankai University, Tianjin, China
| | - Shengxi Xu
- Department of Orthopedics, First People’s Hospital of Shuangliu District, Chengdu, China
| | - Keyuan Ding
- Department of Orthopedics, First People’s Hospital of Shuangliu District, Chengdu, China
| | - Yan Wu
- Department of Orthopedics, First People’s Hospital of Shuangliu District, Chengdu, China
| | - Hao Li
- School of Medicine, Nankai University, Tianjin, China
| | - Yong Wang
- Department of Orthopedics, First People’s Hospital of Shuangliu District, Chengdu, China
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Moser LB, Bauer C, Otahal A, Kern D, Dammerer D, Zantop T, Nehrer S. Mincing bovine articular cartilage with commercially available shavers reduces the viability of chondrocytes compared to scalpel mincing. J Exp Orthop 2023; 10:97. [PMID: 37768416 PMCID: PMC10539273 DOI: 10.1186/s40634-023-00661-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2023] [Accepted: 09/17/2023] [Indexed: 09/29/2023] Open
Abstract
PURPOSE The study aimed to compare the effect of mincing bovine articular cartilage with different shaver blades on chondrocyte viability. METHODS Bovine articular cartilage was harvested either with a scalpel or with three different shaver blades (2.5 mm, 3.5 mm, or 4.2 mm) from a commercially available shaver. The cartilage harvested with a scalpel was then minced into fragments smaller than 1 mm3 with a scalpel. All four conditions were cultivated in a culture medium for seven days. After Day 1 and Day 7, the following measurements were performed: metabolic activity, RNA isolation, and gene expression of anabolic (COL2A1 and ACAN) and catabolic genes (MMP1 and MMP13), live/dead staining and visualization using confocal microscopy, and flow cytometric characterization of minced cartilage chondrocytes. RESULTS Mincing the cartilage with shavers significantly reduced metabolic activity after one and seven days compared to scalpel mincing (p < 0.001). Gene expression of anabolic genes (COL2A1 and ACAN) was reduced, while catabolic genes (MMP1 and MMP13) were increased after day 7 in all shaver conditions. Confocal microscopy showed a thin line of dead cells at the lesion side with viable cells beneath for the scalpel mincing and a higher number of dead cells diffusely distributed in the shaver conditions. After seven days, there was a significant decrease in viable cells in the shaver conditions compared to scalpel mincing (p < 0.05). Flow cytometric characterization revealed fewer intact cells and proportionally more dead cells in all shaver conditions compared to the scalpel mincing. CONCLUSION Mincing bovine articular cartilage with commercially available shavers reduces the viability of chondrocytes compared to scalpel mincing immediately after harvest and after seven days in culture. This suggests that mincing cartilage with a shaver should be considered a matrix rather than a cell therapy. LEVEL OF EVIDENCE Level II therapeutic study.
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Affiliation(s)
- Lukas B Moser
- Center for Regenerative Medicine, Department for Health Sciences, Medicine and Research, University for Continuing Education Krems, Dr.-Karl-Dorrek-Straße 30, 3500, Krems, Austria.
- Department of Orthopaedics and Traumatology, University Hospital Krems, 3500, Krems, Austria.
| | - Christoph Bauer
- Center for Regenerative Medicine, Department for Health Sciences, Medicine and Research, University for Continuing Education Krems, Dr.-Karl-Dorrek-Straße 30, 3500, Krems, Austria
| | - Alexander Otahal
- Center for Regenerative Medicine, Department for Health Sciences, Medicine and Research, University for Continuing Education Krems, Dr.-Karl-Dorrek-Straße 30, 3500, Krems, Austria
| | - Daniela Kern
- Center for Regenerative Medicine, Department for Health Sciences, Medicine and Research, University for Continuing Education Krems, Dr.-Karl-Dorrek-Straße 30, 3500, Krems, Austria
| | - Dietmar Dammerer
- Department of Orthopaedics and Traumatology, University Hospital Krems, 3500, Krems, Austria
| | - Thore Zantop
- Center for Regenerative Medicine, Department for Health Sciences, Medicine and Research, University for Continuing Education Krems, Dr.-Karl-Dorrek-Straße 30, 3500, Krems, Austria
- Sporthopaedicum Straubing, Straubing, Germany
- Department for Health Sciences, Medicine and Research, University for Continuing Education Krems, 3500, Krems, Austria
| | - Stefan Nehrer
- Center for Regenerative Medicine, Department for Health Sciences, Medicine and Research, University for Continuing Education Krems, Dr.-Karl-Dorrek-Straße 30, 3500, Krems, Austria
- Department of Orthopaedics and Traumatology, University Hospital Krems, 3500, Krems, Austria
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Salinas EY, Otarola GA, Kwon H, Wang D, Hu JC, Athanasiou KA. Topographical Characterization of the Young, Healthy Human Femoral Medial Condyle. Cartilage 2023; 14:338-350. [PMID: 36537020 PMCID: PMC10601569 DOI: 10.1177/19476035221141421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 10/26/2022] [Accepted: 11/01/2022] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVE The medial femoral condyle of the knee exhibits some of the highest incidences of chondral degeneration. However, a dearth of healthy human tissues has rendered it difficult to ascertain whether cartilage in this compartment possesses properties that predispose it to injuries. Assessment of young, healthy tissue would be most representative of the tissue's intrinsic properties. DESIGN This work examined the topographical differences in tribological, tensile, and compressive properties of young (n = 5, 26.2 ± 5.6 years old), healthy, human medial femoral condyles, obtained from viable allograft specimens. Corresponding to clinical incidences of pathology, it was hypothesized that the lowest mechanical properties would be found in the posterior region of the medial condyle, and that tissue composition would correspond to the established structure-function relationships of cartilage. RESULTS Young's modulus, ultimate tensile strength, aggregate modulus, and shear modulus in the posterior region were 1.0-, 2.8-, 1.1-, and 1.0-fold less than the values in the anterior region, respectively. Surprisingly, although glycosaminoglycan content is thought to correlate with compressive properties, in this study, the aggregate and shear moduli correlated more robustly to the amount of pyridinoline crosslinks per collagen. Also, the coefficient of friction was anisotropic and ranged 0.22-0.26 throughout the condyle. CONCLUSION This work showed that the posteromedial condyle displays lower tensile and compressive properties, which correlate to collagen crosslinks and may play a role in this region's predisposition to injuries. Furthermore, new structure-function relationships may need to be developed to account for the role of collagen crosslinks in compressive properties.
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Affiliation(s)
- Evelia Y. Salinas
- Department of Biomedical Engineering, University of California Irvine, Irvine, CA, USA
| | - Gaston A. Otarola
- Department of Biomedical Engineering, University of California Irvine, Irvine, CA, USA
| | - Heenam Kwon
- Department of Biomedical Engineering, University of California Irvine, Irvine, CA, USA
| | - Dean Wang
- Department of Orthopaedic Surgery, University of California Irvine Medical Center, Orange, CA, USA
- Department of Orthopaedic Surgery, University of California Irvine Health, Orange, CA, USA
| | - Jerry C. Hu
- Department of Biomedical Engineering, University of California Irvine, Irvine, CA, USA
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Karnik S, Noori-Dokht H, Williams T, Joukar A, Trippel SB, Sankar U, Wagner DR. Decreased SIRT1 Activity Is Involved in the Acute Injury Response of Chondrocytes to Ex Vivo Injurious Mechanical Overload. Int J Mol Sci 2023; 24:ijms24076521. [PMID: 37047494 PMCID: PMC10095502 DOI: 10.3390/ijms24076521] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2023] [Revised: 03/17/2023] [Accepted: 03/27/2023] [Indexed: 04/03/2023] Open
Abstract
A better understanding of molecular events following cartilage injury is required to develop treatments that prevent or delay the onset of trauma-induced osteoarthritis. In this study, alterations to SIRT1 activity in bovine articular cartilage explants were evaluated in the 24 h following a mechanical overload, and the effect of pharmacological SIRT1 activator SRT1720 on acute chondrocyte injury was assessed. SIRT1 enzymatic activity decreased as early as 5 min following the mechanical overload, and remained suppressed for at least 24 h. The chondrocyte injury response, including apoptosis, oxidative stress, secretion of inflammatory mediators, and alterations in cartilage matrix expression, was prevented with pharmacological activation of SIRT1 in a dose-dependent manner. Overall, the results implicate SIRT1 deactivation as a key molecular event in chondrocyte injury following a mechanical impact overload. As decreased SIRT1 signaling is associated with advanced age, these findings suggest that downregulated SIRT1 activity may be common to both age-related and injury-induced osteoarthritis.
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Affiliation(s)
- Sonali Karnik
- Department of Mechanical and Energy Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, USA
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Hessam Noori-Dokht
- Department of Mechanical and Energy Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, USA
- School of Mechanical Engineering, Purdue University, West Lafayette, IN 47907, USA
| | - Taylor Williams
- Department of Biomedical Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, USA
| | - Amin Joukar
- Department of Mechanical and Energy Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, USA
- School of Mechanical Engineering, Purdue University, West Lafayette, IN 47907, USA
| | - Stephen B. Trippel
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Uma Sankar
- Department of Anatomy, Cell Biology and Physiology, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Diane R. Wagner
- Department of Mechanical and Energy Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, USA
- Department of Orthopaedic Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA
- Department of Biomedical Engineering, Indiana University-Purdue University Indianapolis, Indianapolis, IN 46202, USA
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He C, Clark KL, Tan J, Zhou H, Tuan RS, Lin H, Wu S, Alexander PG. Modeling early changes associated with cartilage trauma using human-cell-laden hydrogel cartilage models. Stem Cell Res Ther 2022; 13:400. [PMID: 35927702 PMCID: PMC9351070 DOI: 10.1186/s13287-022-03022-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 07/14/2022] [Indexed: 05/18/2024] Open
Abstract
BACKGROUND Traumatic impacts to the articular joint surface are known to lead to cartilage degeneration, as in post-traumatic osteoarthritis (PTOA). Limited progress in the development of disease-modifying OA drugs (DMOADs) may be due to insufficient mechanistic understanding of human disease onset/progression and insufficient in vitro models for disease and therapeutic modeling. In this study, biomimetic hydrogels laden with adult human mesenchymal stromal cells (MSC) are used to examine the effects of traumatic impacts as a model of PTOA. We hypothesize that MSC-based, engineered cartilage models will respond to traumatic impacts in a manner congruent with early PTOA pathogenesis observed in animal models. METHODS Engineered cartilage constructs were fabricated by encapsulating adult human bone marrow-derived mesenchymal stem cells in a photocross-linkable, biomimetic hydrogel of 15% methacrylated gelatin and promoting chondrogenic differentiation for 28 days in a defined medium and TGF-β3. Constructs were subjected to traumatic impacts with different strains or 10 ng/ml IL-1β, as a common comparative method of modeling OA. Cell viability and metabolism, elastic modulus, gene expression, matrix protein production and activation of catabolic enzymes were assessed. RESULTS Cell viability staining showed that traumatic impacts of 30% strain caused an appropriate level of cell death in engineered cartilage constructs. Gene expression and histo/immunohistochemical analyses revealed an acute decrease in anabolic activities, such as COL2 and ACAN expression, and a rapid increase in catabolic enzyme expression, e.g., MMP13, and inflammatory modulators, e.g., COX2. Safranin O staining and GAG assays together revealed a transient decrease in matrix production 24 h after trauma that recovered within 7 days. The decrease in elastic modulus of engineered cartilage constructs was coincident with GAG loss and mediated by the encapsulated cells. The acute and transient changes observed after traumatic impacts contrasted with progressive changes observed using continual IL-1β treatment. CONCLUSIONS Traumatic impacts delivered to engineered cartilage constructs induced PTOA-like changes in the encapsulated cells. While IL-1b may be appropriate in modeling OA pathogenesis, the results of this study indicate it may not be appropriate in understanding the etiology of PTOA. The development of a more physiological in vitro PTOA model may contribute to the more rapid development of DMOADs.
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Affiliation(s)
- Chunrong He
- Department of Orthopaedic Surgery, Center for Cellular and Molecular Engineering, University of Pittsburgh School of Medicine, 450 Technology Drive, Room 213, Pittsburgh, PA, 15219, USA
- The Third Hospital of Xiangya, Central South University, Changsha, 410013, Hunan, China
| | - Karen L Clark
- Department of Orthopaedic Surgery, Center for Cellular and Molecular Engineering, University of Pittsburgh School of Medicine, 450 Technology Drive, Room 213, Pittsburgh, PA, 15219, USA
| | - Jian Tan
- Department of Orthopaedic Surgery, Center for Cellular and Molecular Engineering, University of Pittsburgh School of Medicine, 450 Technology Drive, Room 213, Pittsburgh, PA, 15219, USA
| | - Hecheng Zhou
- Department of Orthopaedic Surgery, Center for Cellular and Molecular Engineering, University of Pittsburgh School of Medicine, 450 Technology Drive, Room 213, Pittsburgh, PA, 15219, USA
- The Third Hospital of Xiangya, Central South University, Changsha, 410013, Hunan, China
| | - Rocky S Tuan
- Institute for Tissue Engineering and Regenerative Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China
| | - Hang Lin
- Department of Orthopaedic Surgery, Center for Cellular and Molecular Engineering, University of Pittsburgh School of Medicine, 450 Technology Drive, Room 213, Pittsburgh, PA, 15219, USA
| | - Song Wu
- The Third Hospital of Xiangya, Central South University, Changsha, 410013, Hunan, China
| | - Peter G Alexander
- Department of Orthopaedic Surgery, Center for Cellular and Molecular Engineering, University of Pittsburgh School of Medicine, 450 Technology Drive, Room 213, Pittsburgh, PA, 15219, USA.
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Kerkhof F, Kenney D, Ogle M, Shelby T, Ladd A. The biomechanics of osteoarthritis in the hand: Implications and prospects for hand therapy. J Hand Ther 2022; 35:367-376. [PMID: 36509610 DOI: 10.1016/j.jht.2022.11.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
BACKGROUND The unique anatomy of the human hand makes it possible to carefully manipulate tools, powerfully grasp objects, and even throw items with precision. These apparent contradictory functions of the hand, high mobility for manual dexterity vs high stability during forceful grasping, imply that daily activities impose a high strain on a relatively instable joint. This makes the hand susceptible to joint disorders such as osteoarthritis. Both systemic (eg, genetics, hormones) and mechanical factors (eg, joint loading) are important in the development of osteoarthritis, but the precise pathomechanism remains largely unknown. This paper focuses on the biomechanical factors in the disease process and how hand therapists can use this knowledge to improve treatment and research. CONCLUSION Multiple factors are involved in the onset and development of osteoarthritis in the hand. Comprehension of the biomechanics helps clinicians establish best practices for orthotics intervention, exercise, and joint protection programs even in de absence of clear evidence-based guidelines. The effect and reach of hand therapy for OA patients can be expanded substantially when intervention parameters are optimized and barriers to early referrals, access reimbursement, and adherence are addressed. Close and early collaboration between hand therapists and primary care, women's health, rheumatology, and hand surgery providers upon diagnosis, and with hand surgeons pre and postoperatively, combined with advances in the supporting science and strategies to enhance adherence, appear to be a promising way forward.
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Affiliation(s)
- Faes Kerkhof
- Chase Hand and Upper Limb Center, Stanford University, Palo Alto, CA, USA.
| | - Deborah Kenney
- Chase Hand and Upper Limb Center, Stanford University, Palo Alto, CA, USA
| | - Miranda Ogle
- Chase Hand and Upper Limb Center, Stanford University, Palo Alto, CA, USA
| | - Tara Shelby
- Chase Hand and Upper Limb Center, Stanford University, Palo Alto, CA, USA
| | - Amy Ladd
- Chase Hand and Upper Limb Center, Stanford University, Palo Alto, CA, USA
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Urocortin-1 Is Chondroprotective in Response to Acute Cartilage Injury via Modulation of Piezo1. Int J Mol Sci 2022; 23:ijms23095119. [PMID: 35563508 PMCID: PMC9105101 DOI: 10.3390/ijms23095119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/27/2022] [Accepted: 04/30/2022] [Indexed: 02/01/2023] Open
Abstract
Post-traumatic OA (PTOA) is often triggered by injurious, high-impact loading events which result in rapid, excessive chondrocyte cell death and a phenotypic shift in residual cells toward a more catabolic state. As such, the identification of a disease-modifying OA drug (DMOAD) that can protect chondrocytes from death following impact injury, and thereby prevent cartilage degradation and progression to PTOA, would offer a novel intervention. We have previously shown that urocortin-1 (Ucn) is an essential endogenous pro-survival factor that protects chondrocytes from OA-associated pro-apoptotic stimuli. Here, using a drop tower PTOA-induction model, we demonstrate the extent of Ucn's chondroprotective role in cartilage explants exposed to excessive impact load. Using pathway-specific agonists and antagonists, we show that Ucn acts to block load-induced intracellular calcium accumulation through blockade of the non-selective cation channel Piezo1 rather than TRPV4. This protective effect is mediated primarily through the Ucn receptor CRF-R1 rather than CRF-R2. Crucially, we demonstrate that the chondroprotective effect of Ucn is maintained whether it is applied pre-impact or post-impact, highlighting the potential of Ucn as a novel DMOAD for the prevention of injurious impact overload-induced PTOA.
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8
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Hodgkinson T, Amado IN, O'Brien FJ, Kennedy OD. The role of mechanobiology in bone and cartilage model systems in characterizing initiation and progression of osteoarthritis. APL Bioeng 2022. [DOI: 10.1063/5.0068277] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Affiliation(s)
- Tom Hodgkinson
- Department of Anatomy and Regenerative Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Isabel N. Amado
- Department of Anatomy and Regenerative Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Fergal J. O'Brien
- Department of Anatomy and Regenerative Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
- Advanced Materials Bio-Engineering Research Centre (AMBER), Dublin, Ireland
- Trinity Centre for Biomedical Engineering, Trinity College Dublin, Dublin, Ireland
| | - Oran D. Kennedy
- Department of Anatomy and Regenerative Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
- Advanced Materials Bio-Engineering Research Centre (AMBER), Dublin, Ireland
- Trinity Centre for Biomedical Engineering, Trinity College Dublin, Dublin, Ireland
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9
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Jansen MP, Mastbergen SC. Joint distraction for osteoarthritis: clinical evidence and molecular mechanisms. Nat Rev Rheumatol 2022; 18:35-46. [PMID: 34616035 DOI: 10.1038/s41584-021-00695-y] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/06/2021] [Indexed: 12/20/2022]
Abstract
Joint distraction, the prolonged mechanical separation of the bones at a joint, has emerged as a joint-preserving treatment for end-stage osteoarthritis, with the gradually growing promise of implementation in regular clinical practice. Joint distraction of the knee has been most extensively studied, with these studies showing prolonged symptomatic improvement in combination with repair of cartilage tissue in degenerated knee joints, supporting the concept that cartilage repair can translate into real clinical benefit. The reversal of tissue degeneration observed with joint distraction could be the result of one or a combination of various proposed mechanisms, including partial unloading, synovial fluid pressure oscillation, mechanical and biochemical changes in subchondral bone, adhesion and chondrogenic commitment of joint-derived mesenchymal stem cells or a change in the molecular milieu of the joint. The overall picture that emerges from the combined evidence is relevant for future research and treatment-related improvements of joint distraction and for translation of the insights gained about tissue repair to other joint-preserving techniques. It remains to be elucidated whether optimizing the biomechanical conditions during joint distraction can actually cure osteoarthritis rather than only providing temporary symptomatic relief, but even temporary relief might be relevant for society and patients, as it will delay joint replacement with a prosthesis at an early age and thereby avert revision surgery later in life. Most importantly, improved insights into the underlying mechanisms of joint repair might provide new leads for more targeted treatment options.
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Affiliation(s)
- Mylène P Jansen
- Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Simon C Mastbergen
- Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht, The Netherlands.
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Henao-Murillo L, Pastrama MI, Ito K, van Donkelaar CC. The Relationship Between Proteoglycan Loss, Overloading-Induced Collagen Damage, and Cyclic Loading in Articular Cartilage. Cartilage 2021; 13:1501S-1512S. [PMID: 31729263 PMCID: PMC8721617 DOI: 10.1177/1947603519885005] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
OBJECTIVE The interaction between proteoglycan loss and collagen damage in articular cartilage and the effect of mechanical loading on this interaction remain unknown. The aim of this study was to answer the following questions: (1) Is proteoglycan loss dependent on the amount of collagen damage and does it depend on whether this collagen damage is superficial or internal? (2) Does repeated loading further increase the already enhanced proteoglycan loss in cartilage with collagen damage? DESIGN Fifty-six bovine osteochondral plugs were equilibrated in phosphate-buffered saline for 24 hours, mechanically tested in compression for 8 hours, and kept in phosphate-buffered saline for another 48 hours. The mechanical tests included an overloading step to induce collagen damage, creep steps to determine tissue stiffness, and cyclic loading to induce convection. Proteoglycan release was measured before and after mechanical loading, as well as 48 hours post-loading. Collagen damage was scored histologically. RESULTS Histology revealed different collagen damage grades after the application of mechanical overloading. After 48 hours in phosphate-buffered saline postloading, proteoglycan loss increased linearly with the amount of total collagen damage and was dependent on the presence but not the amount of internal collagen damage. In samples without collagen damage, repeated loading also resulted in increased proteoglycan loss. However, repeated loading did not further enhance the proteoglycan loss induced by damaged collagen. CONCLUSION Proteoglycan loss is enhanced by collagen damage and it depends on the presence of internal collagen damage. Cyclic loading stimulates proteoglycan loss in healthy cartilage but does not lead to additional loss in cartilage with damaged collagen.
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Affiliation(s)
- Lorenza Henao-Murillo
- Orthopaedic Biomechanics, Department of
Biomedical Engineering, Eindhoven University of Technology, Eindhoven, Noord
Brabant, the Netherlands,Department of Electronics and Industrial
Automation, Universidad Autónoma de Manizales, Manizales, Colombia
| | - Maria-Ioana Pastrama
- Orthopaedic Biomechanics, Department of
Biomedical Engineering, Eindhoven University of Technology, Eindhoven, Noord
Brabant, the Netherlands
| | - Keita Ito
- Orthopaedic Biomechanics, Department of
Biomedical Engineering, Eindhoven University of Technology, Eindhoven, Noord
Brabant, the Netherlands
| | - Corrinus C. van Donkelaar
- Orthopaedic Biomechanics, Department of
Biomedical Engineering, Eindhoven University of Technology, Eindhoven, Noord
Brabant, the Netherlands,Corrinus C. van Donkelaar, Orthopaedic
Biomechanics, Department of Biomedical Engineering, Eindhoven University of
Technology, Gemini-Zuid 1.106, P.O. Box 513, Eindhoven, Noord Brabant 5600 MB,
the Netherlands.
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11
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Early JO, Fagan LE, Curtis AM, Kennedy OD. Mitochondria in Injury, Inflammation and Disease of Articular Skeletal Joints. Front Immunol 2021; 12:695257. [PMID: 34539627 PMCID: PMC8448207 DOI: 10.3389/fimmu.2021.695257] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2021] [Accepted: 07/30/2021] [Indexed: 12/14/2022] Open
Abstract
Inflammation is an important biological response to tissue damage caused by injury, with a crucial role in initiating and controlling the healing process. However, dysregulation of the process can also be a major contributor to tissue damage. Related to this, although mitochondria are typically thought of in terms of energy production, it has recently become clear that these important organelles also orchestrate the inflammatory response via multiple mechanisms. Dysregulated inflammation is a well-recognised problem in skeletal joint diseases, such as rheumatoid arthritis. Interestingly osteoarthritis (OA), despite traditionally being known as a ‘non-inflammatory arthritis’, now appears to involve an element of chronic inflammation. OA is considered an umbrella term for a family of diseases stemming from a range of aetiologies (age, obesity etc.), but all with a common presentation. One particular OA sub-set called Post-Traumatic OA (PTOA) results from acute mechanical injury to the joint. Whether the initial mechanical tissue damage, or the subsequent inflammatory response drives disease, is currently unclear. In the former case; mechanobiological properties of cells/tissues in the joint are a crucial consideration. Many such cell-types have been shown to be exquisitely sensitive to their mechanical environment, which can alter their mitochondrial and cellular function. For example, in bone and cartilage cells fluid-flow induced shear stresses can modulate cytoskeletal dynamics and gene expression profiles. More recently, immune cells were shown to be highly sensitive to hydrostatic pressure. In each of these cases mitochondria were central to these responses. In terms of acute inflammation, mitochondria may have a pivotal role in linking joint tissue injury with chronic disease. These processes could involve the immune cells recruited to the joint, native/resident joint cells that have been damaged, or both. Taken together, these observations suggest that mitochondria are likely to play an important role in linking acute joint tissue injury, inflammation, and long-term chronic joint degeneration - and that the process involves mechanobiological factors. In this review, we will explore the links between mechanobiology, mitochondrial function, inflammation/tissue-damage in joint injury and disease. We will also explore some emerging mitochondrial therapeutics and their potential for application in PTOA.
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Affiliation(s)
- James Orman Early
- Department of Anatomy and Regenerative Medicine and Tissue Engineering Research Group, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Lauren E Fagan
- Department of Anatomy and Regenerative Medicine and Tissue Engineering Research Group, Royal College of Surgeons in Ireland, Dublin, Ireland.,School of Pharmacy and Biomolecular Sciences and Tissue Engineering Research Group, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Annie M Curtis
- School of Pharmacy and Biomolecular Sciences and Tissue Engineering Research Group, Royal College of Surgeons in Ireland, Dublin, Ireland
| | - Oran D Kennedy
- Department of Anatomy and Regenerative Medicine and Tissue Engineering Research Group, Royal College of Surgeons in Ireland, Dublin, Ireland.,Department of Mechanical and Manufacturing Engineering, Trinity College Dublin, Dublin, Ireland
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12
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The mechanical influence of bone spicules in the osteochondral junction: A finite element modelling study. Biomech Model Mechanobiol 2021; 20:2335-2351. [PMID: 34468916 DOI: 10.1007/s10237-021-01510-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 08/13/2021] [Indexed: 10/20/2022]
Abstract
While much has been done to study how cartilage responds to mechanical loading, as well as modelling such responses, arguably less has been accomplished around the mechanics of the cartilage-bone junction. Previously, it has been reported that the presence of bony spicules invading the zone of calcified cartilage, preceded the formation of new subchondral bone and the advancing of the cement line (Thambyah and Broom in Osteoarthr Cartil 17:456-463, 2009). In this study, the morphology and frequency of bone spicules in the cartilage-bone interface of osteochondral beams subjected to three-point bending were modelled, and the results are discussed within the context of biomechanical theories on bone formation. It was found that the stress and strain magnitudes, and their distribution were sensitive to the presence and number of spicules. Spicule numbers and shape were shown to affect the strain energy density (SED) distribution in the areas of the cement line adjacent to spicules. Stresses, strains and SED analyses thus provided evidence that the mechanical environment with the addition of spicules promotes bone formation in the cartilage-bone junction.
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13
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Espinosa MG, Otarola GA, Hu JC, Athanasiou KA. Cartilage Assessment Requires a Surface Characterization Protocol: Roughness, Friction, and Function. Tissue Eng Part C Methods 2021; 27:276-286. [PMID: 33678002 DOI: 10.1089/ten.tec.2020.0367] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
The surface of articular cartilage is integral to smooth, low-friction joint articulation. However, the majority of cartilage literature rarely includes measurements of surface characteristics and function. This may, in part, be due to a shortage of or unfamiliarity with fast, nondestructive, and, preferably, noncontact methods that can be applied to large cartilage surfaces for evaluating cartilage surface characteristics. A comprehensive methodology for characterizing cartilage surfaces is useful in determining changes in tissue function, as for example, in cases where the quality of cartilage grafts needs to be assessed. With cartilage storage conditions being an area of ongoing and active research, this study used interferometry and tribology methods as efficient and nondestructive ways of evaluating changes in cartilage surface topography, roughness, and coefficient of friction (CoF) resulting from various storage temperatures and durations. Standard, destructive testing for bulk mechanical and biochemical properties, as well as immunohistochemistry, were also performed. For the first time, interferometry was used to show cartilage topographical anisotropy through an anterior-posterior striated pattern in the same direction as joint articulation. Another novel observation enabled by tribology was frictional anisotropy, illustrated by a 53% increase in CoF in the medial-lateral direction compared to the anterior-posterior direction. Of the storage conditions examined, 37°C, 4°C, -20°C, and -80°C for 1 day, 1 week, and 1 month, a 49% decrease in CoF was observed at 1 week in -80°C. Interestingly, prolonged storage at 37°C resulted in up to an 83% increase in the compressive aggregate modulus by 1 month, with a corresponding increase in the glycosaminoglycan (GAG) bulk content. This study illustrates the differential effects of storage conditions on cartilage: freezing tends to target surface properties, while nonfreezing storage impacts the tissue bulk. These data show that a bulk-only analysis of cartilage function is not sufficient or representative. The nondestructive surface characterization assays described here enable improvement in cartilage functionality assessment by considering both surface and bulk cartilage properties; this methodology may thus provide a new angle to explore in future cartilage research and tissue engineering endeavors.
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Affiliation(s)
- M Gabriela Espinosa
- Department of Biomedical Engineering, University of California, Irvine, Irvine, California, USA
| | - Gaston A Otarola
- Department of Biomedical Engineering, University of California, Irvine, Irvine, California, USA
| | - Jerry C Hu
- Department of Biomedical Engineering, University of California, Irvine, Irvine, California, USA
| | - Kyriacos A Athanasiou
- Department of Biomedical Engineering, University of California, Irvine, Irvine, California, USA
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14
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Human articular cartilage is orthotropic where microstructure, micromechanics, and chemistry vary with depth and split-line orientation. Osteoarthritis Cartilage 2020; 28:1362-1372. [PMID: 32645403 PMCID: PMC7697147 DOI: 10.1016/j.joca.2020.06.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 06/25/2020] [Accepted: 06/27/2020] [Indexed: 02/02/2023]
Abstract
OBJECTIVE Quantitative, micrometer length scale assessment of human articular cartilage is essential to enable progress toward new functional tissue engineering approaches, including utilization of emerging 3D bioprinting technologies, and for improved computational modeling of the osteochondral unit. Thus the objective of this study was to characterize the structural organization, material properties, and chemical composition of human skeletally mature articular cartilage with respect to depth and defined morphological features: normal to the articulating surface, parallel to the split-line, and transverse to the split-line. METHOD Three samples from the lateral femoral condyles of 4 healthy adult donors (55-61 years old) were evaluated via histology, second harmonic generation, microindentation, and Raman spectroscopy. All metrics were evaluated as a function of depth and direction relative to the split-line. RESULTS All donors presented with intact and healthy tissue. Collagen fiber orientation varied significantly between testing directions and with increasing depth from the articular surface. Both compressive and tensile modulus increased significantly with depth and differed across the middle and deep zones and depended on orthogonal direction relative to the split-line. Similarly, matrix components varied with both depth and direction, where chondroitin sulfate steadily increased with depth while collagen prevalence was highest in the surface layer. CONCLUSIONS Microscale measurements of human articular cartilage demonstrate that properties are both depth-dependent and orthotropic and depend on the underlying tissue structure and composition. These findings improve upon existing knowledge establishing more accurate measurements, with greater degree of depth and spatial specificity, as inputs for tissue engineering and computational modeling.
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15
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Walsh SK, Shelley JC, Henak CR. Mechanobiology of Cartilage Impact Via Real-Time Metabolic Imaging. J Biomech Eng 2020; 142:100802. [PMID: 32542333 DOI: 10.1115/1.4047534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Indexed: 11/08/2022]
Abstract
Cartilage loading is important in both structural and biological contexts, with overloading known to cause osteoarthritis (OA). Cellular metabolism, which can be evaluated through the relative measures of glycolysis and oxidative phosphorylation, is important in disease processes across tissues. Details of structural damage coupled with cellular metabolism in cartilage have not been evaluated. Therefore, the aim of this study was to characterize the time- and location-dependent metabolic response to traumatic impact loading in articular cartilage. Cartilage samples from porcine femoral condyles underwent a single traumatic injury that created cracks in most samples. Before and up to 30 min after loading, samples underwent optical metabolic imaging. Optical metabolic imaging measures the fluorescent intensity of byproducts of the two metabolic pathways, flavin adenine dinucleotide for oxidative phosphorylation and nicotinamide adenine dinucleotide ± phosphate for glycolysis, as well as the redox ratio between them. Images were taken at varied distances from the center of the impact. Shortly after impact, fluorescence intensity in both channels decreased, while redox ratio was unchanged. The most dramatic metabolic response was measured closest to the impact center, with suppressed fluorescence in both channels relative to baseline. Redox ratio varied nonlinearly as a function of distance from the impact. Finally, both lower and higher magnitude loading reduced flavin adenine dinucleotide fluorescence, whereas reduced nicotinamide adenine dinucleotide ± phosphate fluorescence was associated only with low strain loads and high contact pressure loads, respectively. In conclusion, this study performed novel analysis of metabolic activity following induction of cartilage damage and demonstrated time-, distance-, and load-dependent response to traumatic impact loading.
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Affiliation(s)
- Shannon K Walsh
- Comparative Biomedical Sciences Program, University of Wisconsin-Madison, Madison, WI 53706
| | - Joshua C Shelley
- Department of Mechanical Engineering, University of Wisconsin-Madison, Madison, WI 53706
| | - Corinne R Henak
- Department of Mechanical Engineering, University of Wisconsin-Madison, 3031 Mechanical Engineering Building, 1513 University Ave. Madison, WI 53706; Department of Biomedical Engineering, University of Wisconsin-Madison, 3031 Mechanical Engineering Building, 1513 University Ave. Madison, WI 53706; Department of Orthopedics and Rehabilitation, University of Wisconsin-Madison, 3031 Mechanical Engineering Building, 1513 University Ave. Madison, WI 53705
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16
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Papagiannaki M, Samoladas E, Maropoulos S, Arabatzi F. Running-Related Injury From an Engineering, Medical and Sport Science Perspective. Front Bioeng Biotechnol 2020; 8:533391. [PMID: 33117776 PMCID: PMC7561420 DOI: 10.3389/fbioe.2020.533391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2020] [Accepted: 08/28/2020] [Indexed: 11/30/2022] Open
Abstract
Etiologic factors associated to running injuries are reviewed, with an emphasis on the transient shock waves experienced during foot strike. In these terms, impact mechanics are analyzed from both, a biomechanical and medical standpoint and evaluated with respect injury etiology, precursors and morbidity. The complex interaction of runner specific characteristics on the employed footwear system are examined, providing insight into footwear selection that could act as a preventive measure against non-acute trauma incidence. In conclusion, and despite the vast literature on running-related injury-risks, only few records could be identified to consider the effect of shoe cushioning and anthropometric data on injury prevalence. Based on this literature, we would stress the importance of such considerations in future studies aspiring to provide insight into running related injury etiology and prevention.
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Affiliation(s)
- Maria Papagiannaki
- Department of Physical Education and Sport Science, Serres, Aristotle University of Thessaloniki, Thessalonik, Greece
| | - Efthimios Samoladas
- Department of Orthopaedics, Medical School, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Stergios Maropoulos
- Department of Mechanical Engineering, University of Western Macedonia, Kozani, Greece
| | - Fotini Arabatzi
- Department of Physical Education and Sport Science, Serres, Aristotle University of Thessaloniki, Thessalonik, Greece
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17
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Xiang S, Li Z, Bian Y, Weng X. RNA sequencing reveals the circular RNA expression profiles of osteoarthritic synovium. J Cell Biochem 2019; 120:18031-18040. [PMID: 31190410 DOI: 10.1002/jcb.29106] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2018] [Revised: 05/04/2019] [Accepted: 05/07/2019] [Indexed: 01/15/2023]
Abstract
The role of circular RNAs (circRNAs) in regulating cartilage homeostasis in osteoarthritis (OA) has been reported. However, the regulatory mechanisms of circRNAs in OA synovium remains basically unidentified. The current study intended to divulge the expression profile of circRNAs in OA synovium and investigate the possible molecular mechanisms of circRNAs in synovitis in OA through an integrated bioinformatics analysis. A total of 35 synovium samples were collected, including 17 from patients with knee OA and 18 from controls. circRNA sequencing was then carried out on five OA synovium samples as well as five controls to explore the expression pattern of the circRNAs. Real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was done to confirm the manifestation levels of six differentially expressed circRNAs. Gene Ontology (GO) as well as Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses were done for differentially expressed circRNAs using the DAVID database to annotate the functions. The circRNA-miRNA coexpression network was then created to estimate the probable molecular regulatory mechanisms of specifically expressed circRNAs in OA synovium. Total of 122 circRNAs were found to be differentially expressed in OA synovium through RNA sequencing. The expressions of five downregulated circRNAs as well as an upregulated circRNA were confirmed through the use of qRT-PCR. The circRNA-miRNA network was created to annotate the probable molecular regulatory mechanisms of specifically expressed circRNAs. Our outcomes revealed that circRNAs might be incorporated in the initiation as well as development of OA synovitis and might have prospective importance in OA diagnosis and therapy.
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Affiliation(s)
- Shuai Xiang
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China
| | - Zeng Li
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China
| | - Yanyan Bian
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China
| | - Xisheng Weng
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing, China
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18
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Xiang S, Li Z, Bian Y, Weng X. Identification of changed expression of mRNAs and lncRNAs in osteoarthritic synovium by RNA-sequencing. Gene 2018; 685:55-61. [PMID: 30393192 DOI: 10.1016/j.gene.2018.10.076] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 05/25/2018] [Accepted: 10/26/2018] [Indexed: 01/15/2023]
Abstract
Long non-coding RNAs (lncRNAs) are recently reported to regulate the homeostasis of cartilage in osteoarthritis (OA), but their regulatory roles in OA synovium remain elusive. This study aimed to identify the differentially expressed mRNAs and lncRNAs in OA synovium and further explore the function of differentially expressed lncRNAs in OA progression through bioinformatics analysis. We started with RNA-sequencing in 5 OA synovium samples and 5 healthy controls to compare the expression of mRNAs and lncRNAs. GO analysis and KEGG pathway analysis were performed to annotate the function of differentially expressed mRNAs. Then real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was admitted in 17 osteoarthritic synovium and 18 healthy controls to confirm the changes of the expression of the selected lncRNAs. LncRNA-mRNA co-expression network was constructed to predict the potential molecular regulatory mechanisms of specifically expressed lncRNAs in OA synovium. 384 mRNAs and 17 lncRNAs were detected to be differentially expressed in OA synovium. The expressions of 4 lncRNAs were confirmed by qRT-PCR. We found the differentially expression lncRNAs could potentially regulate OA progression through pathways regarding to immune response through the lncRNA-mRNA network and further annotation for co-expression mRNAs. Our results indicated that lncRNAs may play key roles in OA synovitis and may have potential value in OA diagnosis.
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Affiliation(s)
- Shuai Xiang
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing 100730, China
| | - Zeng Li
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing 100730, China
| | - Yanyan Bian
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing 100730, China
| | - Xisheng Weng
- Department of Orthopaedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Science, Beijing 100730, China.
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19
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Nickien M, Heuijerjans A, Ito K, van Donkelaar CC. Comparison between in vitro and in vivo cartilage overloading studies based on a systematic literature review. J Orthop Res 2018; 36:2076-2086. [PMID: 29644716 PMCID: PMC6120482 DOI: 10.1002/jor.23910] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2017] [Accepted: 03/27/2018] [Indexed: 02/04/2023]
Abstract
Methodological differences between in vitro and in vivo studies on cartilage overloading complicate the comparison of outcomes. The rationale of the current review was to (i) identify consistencies and inconsistencies between in vitro and in vivo studies on mechanically-induced structural damage in articular cartilage, such that variables worth interesting to further explore using either one of these approaches can be identified; and (ii) suggest how the methodologies of both approaches may be adjusted to facilitate easier comparison and therewith stimulate translation of results between in vivo and in vitro studies. This study is anticipated to enhance our understanding of the development of osteoarthritis, and to reduce the number of in vivo studies. Generally, results of in vitro and in vivo studies are not contradicting. Both show subchondral bone damage and intact cartilage above a threshold value of impact energy. At lower loading rates, excessive loads may cause cartilage fissuring, decreased cell viability, collagen network de-structuring, decreased GAG content, an overall damage increase over time, and low ability to recover. This encourages further improvement of in vitro systems, to replace, reduce, and/or refine in vivo studies. However, differences in experimental set up and analyses complicate comparison of results. Ways to bridge the gap include (i) bringing in vitro set-ups closer to in vivo, for example, by aligning loading protocols and overlapping experimental timeframes; (ii) synchronizing analytical methods; and (iii) using computational models to translate conclusions from in vitro results to the in vivo environment and vice versa. © 2018 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals, Inc. J Orthop Res 9999:1-11, 2018.
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Affiliation(s)
- Mieke Nickien
- Department of Biomedical Engineering, Orthopaedic BiomechanicsEindhoven University of TechnologyP.O. Box 513, 5600MBEindhovenThe Netherlands
| | - Ashley Heuijerjans
- Department of Biomedical Engineering, Orthopaedic BiomechanicsEindhoven University of TechnologyP.O. Box 513, 5600MBEindhovenThe Netherlands
| | - Keita Ito
- Department of Biomedical Engineering, Orthopaedic BiomechanicsEindhoven University of TechnologyP.O. Box 513, 5600MBEindhovenThe Netherlands
| | - Corrinus C. van Donkelaar
- Department of Biomedical Engineering, Orthopaedic BiomechanicsEindhoven University of TechnologyP.O. Box 513, 5600MBEindhovenThe Netherlands
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20
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Henak CR, Bartell LR, Cohen I, Bonassar LJ. Multiscale Strain as a Predictor of Impact-Induced Fissuring in Articular Cartilage. J Biomech Eng 2017; 139:2571657. [PMID: 27760253 DOI: 10.1115/1.4034994] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2016] [Indexed: 11/08/2022]
Abstract
Mechanical damage is central to both initiation and progression of osteoarthritis (OA). However, specific causal links between mechanics and cartilage damage are incompletely understood, which results in an inability to predict failure. The lack of understanding is primarily due to the difficulty in simultaneously resolving the high rates and small length scales relevant to the problem and in correlating such measurements to the resulting fissures. This study leveraged microscopy and high-speed imaging to resolve mechanics on the previously unexamined time and length scales of interest in cartilage damage, and used those mechanics to develop predictive models. The specific objectives of this study were to: first, quantify bulk and local mechanics during impact-induced fissuring; second, develop predictive models of fissuring based on bulk mechanics and local strain; and third, evaluate the accuracy of these models in predicting fissures. To achieve these three objectives, bovine tibial cartilage was impacted using a custom spring-loaded device mounted on an inverted microscope. The occurrence of fissures was modulated by varying impact energy. For the first objective, during impact, deformation was captured at 10,000 frames per second and bulk and local mechanics were analyzed. For the second objective, data from samples impacted with a 1.2 mm diameter rod were fit to logistic regression functions, creating models of fissure probability based on bulk and local mechanics. Finally, for the third objective, data from samples impacted with a 0.8 mm diameter rod were used to test the accuracy of model predictions. This study provides a direct comparison between bulk and local mechanical thresholds for the prediction of fissures in cartilage samples, and demonstrates that local mechanics provide more accurate predictions of local failure than bulk mechanics provide. Bulk mechanics were accurate predictors of fissure for the entire sample cohort, but poor predictors of fissure for individual samples. Local strain fields were highly heterogeneous and significant differences were determined between fissured and intact samples, indicating the presence of damage thresholds. In particular, first principal strain rate and maximum shear strain were the best predictors of local failure, as determined by concordance statistics. These data provide an important step in establishing causal links between local mechanics and cartilage damage; ultimately, data such as these can be used to link macro- and micro-scale mechanics and thereby predict mechanically mediated disease on a subject-specific basis.
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Affiliation(s)
- Corinne R Henak
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853
| | - Lena R Bartell
- Department of Applied and Engineering Physics, Cornell University, Ithaca, NY 14853
| | - Itai Cohen
- Department of Physics, Cornell University, Ithaca, NY 14853
| | - Lawrence J Bonassar
- Meinig School of Biomedical Engineering, 149 Weill Hall, Cornell University, Ithaca, NY 14853; Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, NY 14853 e-mail:
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21
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DAMPs Synergize with Cytokines or Fibronectin Fragment on Inducing Chondrolysis but Lose Effect When Acting Alone. Mediators Inflamm 2017; 2017:2642549. [PMID: 28804219 PMCID: PMC5540522 DOI: 10.1155/2017/2642549] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2017] [Revised: 05/03/2017] [Accepted: 05/29/2017] [Indexed: 11/17/2022] Open
Abstract
OBJECTIVE AND DESIGN To investigate whether endogenous damage-associated molecular patterns (DAMPs) or alarmins originated from mitochondria or nucleus stimulates inflammatory response in articular chondrocytes to cause chondrolysis which leads to cartilage degradation featured in posttraumatic osteoarthritis (PTOA). MATERIALS Primary cultures of bovine or human chondrocytes isolated from cartilage of weight-bearing joints. TREATMENT Chondrocytes were subjected to mitochondrial DAMPs (MTDs) or HMGB1, a nuclear DAMP (NuD), with or without the presence of an N-terminal 29 kDa fibronectin fragment (Fn-f) or proinflammatory cytokines (IL-1β and TNF-α). Injured cartilage-conditioned culturing medium containing a mixture of DAMPs was employed as a control. After 24 hrs, the protein expression of cartilage degrading metalloproteinases and iNOS in culture medium or cell lysates was examined with Western blotting, respectively. RESULTS HMGB1 was synergized with IL-1β in upregulating expression of MMP-3, MMP-13, ADAMTS-5, ADAM-8, and iNOS. Moreover, a moderate synergistic effect was detected between HMGB1 and Fn-f or between MTDs and TNF-α on MMP-3 expression. However, when acting alone, MTDs or HMGB1 did not upregulate cartilage degrading enzymes or iNOS. CONCLUSION MTDs or HMGB1 could only stimulate inflammatory response in chondrocytes with the presence of cytokines or Fn-f.
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22
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Hubbard-Turner T, Wikstrom EA, Guderian S, Turner MJ. Acute Ankle Sprain in a Mouse Model: Changes in Knee-Joint Space. J Athl Train 2017; 52:587-591. [PMID: 28437129 DOI: 10.4085/1062-6050-52.3.07] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
CONTEXT Ankle sprains remain the most common orthopaedic injury. Conducting long-term studies in humans is difficult and costly, so the long-term consequences of an ankle sprain are not entirely known. OBJECTIVE To measure knee-joint space after a single surgically induced ankle sprain in mice. DESIGN Randomized controlled trial. SETTING University research laboratory. PATIENTS OR OTHER PARTICIPANTS Thirty male mice (CBA/2J) were randomly placed into 1 of 3 surgical groups: the transected calcaneofibular ligament (CFL) group, the transected anterior talofibular ligament/CFL group, or a sham treatment group. The right ankle was operated on in all mice. MAIN OUTCOME MEASURE(S) Three days after surgery, all of the mice were individually housed in cages containing a solid-surface running wheel, and daily running-wheel measurements were recorded. Before surgery and every 6 weeks after surgery, a diagnostic ultrasound was used to measure medial and lateral knee-joint space in both hind limbs. RESULTS Right medial (P = .003), right lateral (P = .002), left medial (P = .03), and left lateral (P = .002) knee-joint spaces decreased across the life span. The mice in the anterior talofibular ligament/CFL group had decreased right medial (P = .004) joint space compared with the sham and CFL groups starting at 24 weeks of age and continuing throughout the life span. No differences occurred in contralateral knee-joint degeneration among any of the groups. CONCLUSIONS Based on current data, mice that sustained a surgically induced severe ankle sprain developed greater joint degeneration in the ipsilateral knee. Knee degeneration could result from accommodation to the laxity of the ankle or biomechanical alterations secondary to ankle instability. A single surgically induced ankle sprain could significantly affect knee-joint function.
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Affiliation(s)
| | - Erik A Wikstrom
- Department of Exercise and Sport Science, University of North Carolina at Chapel Hill
| | | | - Michael J Turner
- Department of Kinesiology, University of North Carolina at Charlotte
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23
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van Haaften EE, Ito K, van Donkelaar CC. The initial repair response of articular cartilage after mechanically induced damage. J Orthop Res 2017; 35:1265-1273. [PMID: 27500885 DOI: 10.1002/jor.23382] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Accepted: 08/05/2016] [Indexed: 02/04/2023]
Abstract
The regenerative potential of articular cartilage (AC) defects is limited and depends on defect size, biomechanical conditions, and age. Early events after overloading might be predictive for cartilage degeneration in the long term. Therefore, the present aim is to investigate the temporal response of cartilage to overloading at cell, matrix, and tissue level during the first period after mechanical overloading. In the present study, the effect of high loading (∼8 MPa) at a high rate (∼14 MPa/s) at day 0 during a 9 day period on collagen damage, gene expression, cell death, and biochemical composition in AC was investigated. A model system was developed which enabled culturing osteochondral explants after loading. Proteoglycan content was repeatedly monitored over time using μCT, whereas other evaluations required destructive measurements. Changes in matrix related gene expressions indicated a degenerative response during the first 6 h after loading. After 24 h, this was restored and data suggested an initial repair response. Cell death and microscopic damage increased after 24 h following loading. These degradative changes were not restored within the 9 day culture period, and were accompanied by a slight loss of proteoglycans at the articular surface that extended into the middle zones. The combined findings indicate that high magnitude loading of articular cartilage at a high rate induces an initial damage that later initiates a healing response that can probably not be retained due to loss of cell viability. Consequently, the matrix cannot be restored in the short term. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1265-1273, 2017.
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Affiliation(s)
- Eline E van Haaften
- Orthopaedic Biomechanics, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands
| | - Keita Ito
- Orthopaedic Biomechanics, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands
| | - Corrinus C van Donkelaar
- Orthopaedic Biomechanics, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands
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24
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The Effect of Body Mass on the Shoe-Athlete Interaction. Appl Bionics Biomech 2017; 2017:7136238. [PMID: 28465660 PMCID: PMC5390569 DOI: 10.1155/2017/7136238] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2016] [Revised: 01/20/2017] [Accepted: 02/07/2017] [Indexed: 11/29/2022] Open
Abstract
Long-distance running is known to induce joint overloading and elevate cytokine levels, which are the hallmarks for a variety of running-related injuries. To address this, footwear systems incorporate cushioning midsoles to mitigate injurious mechanical loading. The aim of this study was to evaluate the effect of athlete body mass on the cushioning capacity of technical footwear. An artificial heel was prototyped to fit the impact pattern of a heel-strike runner and used to measure shock attenuation by an automated drop test. Impact mass and velocity were modulated to simulate runners of various body mass and speeds. The investigation provided refined insight on running-induced impact transmission to the human body. The examined midsole system was optimized around anthropometric data corresponding to an average (normal) body mass. The results suggest that although modern footwear is capable of attenuating the shock waves occurring during foot strike, improper shoe selection could expose an athlete to high levels of peak stress that could provoke an abnormal cartilage response. The selection of a weight-specific cushioning system could provide optimum protection and could thus prolong the duration of physical exercise beneficial to maintaining a simulated immune system.
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Kaleem B, Maier F, Drissi H, Pierce DM. Low-energy impact of human cartilage: predictors for microcracking the network of collagen. Osteoarthritis Cartilage 2017; 25:544-553. [PMID: 27903450 DOI: 10.1016/j.joca.2016.11.009] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2016] [Revised: 11/08/2016] [Accepted: 11/21/2016] [Indexed: 02/02/2023]
Abstract
OBJECTIVE We aimed to determine the minimum mechanical impact to cause microstructural damage in the network of collagen (microcracking) within human cartilage and hypothesized that energies below 0.1 J or 1 mJ/mm3 would suffice. DESIGN We completed 108 low-energy impact tests (0.05, 0.07, or 0.09 J; 0.75 or 1.0 m/s2) using healthy cartilage specimens from six male donors (30.2 ± 8.8 yrs old). Before and after impact we acquired, imaging the second harmonic generation (SHG), ten images from each specimen (50 μm depth, 5 μm step size), resulting in 2160 images. We quantified both the presence and morphology of microcracks. We then correlated test parameters (predictors) impact energy/energy dissipation density, nominal stress/stress rate, and strain/strain rate to microcracking and tested for significance. Where predictors significantly correlated with microstructural outcomes we fitted binary logistic regression plots with 95% confidence intervals (CIs). RESULTS No specimens presented visible damage following impact. We found that impact energy/energy dissipation density and nominal stress/stress rate were significant (P < 0.05) predictors of microcracking while both strain and strain rate were not. In our test configuration, an impact energy density of 2.93 mJ/mm3, an energy dissipation density of 1.68 mJ/mm3, a nominal stress of 4.18 MPa, and a nominal stress rate of 689 MPa/s all corresponded to a 50% probability of microcracking in the network of collagen. CONCLUSIONS An impact energy density of 1.0 mJ/mm3 corresponded to a ∼20% probability of microcracking. Such changes may initiate a degenerative cascade leading to post-traumatic osteoarthritis.
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Affiliation(s)
- B Kaleem
- University of Connecticut, Department of Biomedical Engineering, Storrs, CT, USA
| | - F Maier
- Department of Mechanical Engineering, University of Connecticut, Storrs, CT, USA
| | - H Drissi
- University of Connecticut Health Center, Orthopedic Surgery, Farmington, CT, USA
| | - D M Pierce
- University of Connecticut, Department of Biomedical Engineering, Storrs, CT, USA; Department of Mechanical Engineering, University of Connecticut, Storrs, CT, USA.
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Paschos NK. Anterior cruciate ligament reconstruction and knee osteoarthritis. World J Orthop 2017; 8:212-217. [PMID: 28361013 PMCID: PMC5359756 DOI: 10.5312/wjo.v8.i3.212] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Revised: 10/12/2016] [Accepted: 12/14/2016] [Indexed: 02/06/2023] Open
Abstract
Anterior cruciate ligament (ACL) injury is a traumatic event that can lead to significant functional impairment and inability to participate in high-level sports-related activities. ACL reconstruction is considered the treatment of choice for symptomatic ACL-deficient patients and can assist in full functional recovery. Furthermore, ACL reconstruction restores ligamentous stability to normal, and, therefore, can potentially fully reinstate kinematics of the knee joint. As a consequence, the natural history of ACL injury could be potentially reversed via ACL reconstruction. Evidence from the literature is controversial regarding the effectiveness of ACL reconstruction in preventing the development of knee cartilage degeneration. This editorial aims to present recent high-level evidence in an attempt to answer whether ACL injury inevitably leads to osteoarthritis and whether ACL reconstruction can prevent this development or not.
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Workman J, Thambyah A, Broom N. The influence of early degenerative changes on the vulnerability of articular cartilage to impact-induced injury. Clin Biomech (Bristol, Avon) 2017; 43:40-49. [PMID: 28199881 DOI: 10.1016/j.clinbiomech.2017.01.003] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2016] [Revised: 11/01/2016] [Accepted: 01/03/2017] [Indexed: 02/07/2023]
Abstract
BACKGROUND Recently, the structural changes in a bovine model of early degeneration were validated by our research group to be analogous to that in early human osteoarthritis. The hypothesis of this study was that the structural changes associated with increasing levels of degeneration would lead to higher levels of tissue damage in response to impact induced injury. METHODS A total of forty bovine patellae were obtained for this study. Cartilage-on-bone samples were extracted from the distal lateral quarter, a region known to be affected by varying levels of degeneration. A single impact drop test was applied to these samples delivering 2.3J of energy. A dynamic load cell and image capture at 2000fps allowed for the calculation of the reaction stress and coefficient of restitution. The extent of tissue damage was examined from the micro to ultrastructural levels using differential interference contrast optical microscopy and scanning electron microscopy respectively. FINDINGS The impact mechanical properties of mildly degenerate articular cartilage were not significantly different but showed a significantly larger amount of structural damage. From comparing the mechanical and structural response of intact and mildly degenerate cartilage, to tissue showing increased macro-scale tissue degeneration, the significance of the surface layer and fibrillar scale transverse interconnectivity in effectively attenuating impact loads is demonstrated in this study. INTERPRETATION This study shows that even though articular cartilage can appear visibly normal under macroscopic observation, the micro-scale structural changes associated with very early stage osteoarthritis can have a significant effect on its vulnerability to impact damage.
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Affiliation(s)
- Joshua Workman
- University of Auckland, 2-6 Park Ave, Grafton, Auckland 1023, New Zealand
| | - Ashvin Thambyah
- University of Auckland, 2-6 Park Ave, Grafton, Auckland 1023, New Zealand.
| | - Neil Broom
- University of Auckland, 2-6 Park Ave, Grafton, Auckland 1023, New Zealand
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Bonnevie ED, Delco ML, Galesso D, Secchieri C, Fortier LA, Bonassar LJ. Sub-critical impact inhibits the lubricating mechanisms of articular cartilage. J Biomech 2017; 53:64-70. [DOI: 10.1016/j.jbiomech.2016.12.034] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Revised: 12/06/2016] [Accepted: 12/22/2016] [Indexed: 12/27/2022]
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Vundelinckx B, Herman B, Getgood A, Litchfield R. Surgical Indications and Technique for Anterior Cruciate Ligament Reconstruction Combined with Lateral Extra-articular Tenodesis or Anterolateral Ligament Reconstruction. Clin Sports Med 2016; 36:135-153. [PMID: 27871655 DOI: 10.1016/j.csm.2016.08.009] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
After anterior cruciate ligament (ACL) rupture, anteroposterior and rotational laxity in the knee causes instability, functional symptoms, and damage to other intra-articular structures. Surgical reconstruction aims to restore the stability in the knee, and to improve function and ability to participate in sports. It also protects cartilage and menisci from secondary injuries. Because of persistent rotational instability after ACL reconstruction, combined intra-articular and extra-articular procedures are more commonly performed. In this article, an overview of anatomy, biomechanical studies, current gold standard procedures, techniques, and research topics are summarized.
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Affiliation(s)
- Bart Vundelinckx
- Department of Surgery, Fowler Kennedy Sport Medicine Clinic, Western University, 3M Centre, 1151 Richmond Street, London, Ontario N6A 3K7, Canada
| | - Benjamin Herman
- Department of Surgery, Fowler Kennedy Sport Medicine Clinic, Western University, 3M Centre, 1151 Richmond Street, London, Ontario N6A 3K7, Canada
| | - Alan Getgood
- Department of Surgery, Fowler Kennedy Sport Medicine Clinic, Western University, 3M Centre, 1151 Richmond Street, London, Ontario N6A 3K7, Canada
| | - Robert Litchfield
- Department of Surgery, Fowler Kennedy Sport Medicine Clinic, Western University, 3M Centre, 1151 Richmond Street, London, Ontario N6A 3K7, Canada.
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Vernon LL, Vance DD, Wang L, Rampersaud E, Vance JM, Pericak-Vance M, Huang CYC, Kaplan LD. Regional Differential Genetic Response of Human Articular Cartilage to Impact Injury. Cartilage 2016; 7:163-73. [PMID: 27047639 PMCID: PMC4797239 DOI: 10.1177/1947603515618483] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
OBJECTIVE Normal physiological movement creates different weightbearing zones within a human knee: the medial condyle bearing the highest and the trochlea bearing the lowest weight. Adaptation to different physiological loading conditions results in different tissue and cellular properties within a knee. The objective of this study was to use microarray analysis to examine gene expression differences among three anatomical regions of human knee articular cartilage at baseline and following induction of an acute impact injury. DESIGN Cartilage explants were harvested from 7 cadaveric knees (12 plugs per knee). A drop tower was utilized to introduce injury. Plugs were examined 24 hours after impact for gene expression using microarray. The primary analysis is the comparison of baseline versus impacted samples within each region separately. In addition, pairwise comparisons among the three regions were performed at baseline and after impact. False discovery rate (FDR) was used to evaluate significance of differential gene expression. RESULTS In the comparison of before and after injury, the trochlear had 130 differentially expressed genes (FDR ≤ 0.05) while the condyles had none. In the comparison among regions, smaller sets of differentially expressed genes (n ≤ 21) were found, with trochlea being more different than the condyles. Most of more frequently expressed genes in trochlea are developmental genes. CONCLUSIONS Within the experimental setup of this study, only the trochlea was displaying an acute genetic response on injury. Our data demonstrated the regional-specific response to injury in human articular cartilage.
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Affiliation(s)
- Lauren L. Vernon
- Department of Biomedical Engineering, University of Miami, Coral Gables, FL, USA,Division of Sports Medicine, UHealth Sports Performance and Wellness Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Danica D. Vance
- Division of Sports Medicine, UHealth Sports Performance and Wellness Institute, University of Miami Miller School of Medicine, Miami, FL, USA,John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Liyong Wang
- John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Evadnie Rampersaud
- John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Jeffery M. Vance
- John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Margaret Pericak-Vance
- John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA
| | - C.-Y. Charles Huang
- Department of Biomedical Engineering, University of Miami, Coral Gables, FL, USA
| | - Lee D. Kaplan
- Department of Biomedical Engineering, University of Miami, Coral Gables, FL, USA,Division of Sports Medicine, UHealth Sports Performance and Wellness Institute, University of Miami Miller School of Medicine, Miami, FL, USA,Lee D. Kaplan, Division of Sports Medicine, UHealth Sports Performance and Wellness Institute, University of Miami, 1400 NW 12th Avenue, First Floor Sports Medicine Clinic, Miami, FL 33136, USA.
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Lewis R, Barrett-Jolley R. Changes in Membrane Receptors and Ion Channels as Potential Biomarkers for Osteoarthritis. Front Physiol 2015; 6:357. [PMID: 26648874 PMCID: PMC4664663 DOI: 10.3389/fphys.2015.00357] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2015] [Accepted: 11/11/2015] [Indexed: 01/01/2023] Open
Abstract
Osteoarthritis (OA), a degenerative joint condition, is currently difficult to detect early enough for any of the current treatment options to be completely successful. Early diagnosis of this disease could increase the numbers of patients who are able to slow its progression. There are now several diseases where membrane protein biomarkers are used for early diagnosis. The numbers of proteins in the membrane is vast and so it is a rich source of potential biomarkers for OA but we need more knowledge of these before they can be considered practical biomarkers. How are they best measured and are they selective to OA or even certain types of OA? The first step in this process is to identify membrane proteins that change in OA. Here, we summarize several ion channels and receptors that change in OA models and/or OA patients, and may thus be considered candidates as novel membrane biomarkers of OA.
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Affiliation(s)
- Rebecca Lewis
- Faculty of Health and Medical Sciences, School of Veterinary Medicine and Science, University of Surrey Guildford, UK
| | - Richard Barrett-Jolley
- Department of Musculoskeletal Biology, Faculty of Health and Life Sciences, Institute of Ageing and Chronic Disease, University of Liverpool Liverpool, UK
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Novakofski K, Berg L, Bronzini I, Bonnevie E, Poland S, Bonassar L, Fortier L. Joint-dependent response to impact and implications for post-traumatic osteoarthritis. Osteoarthritis Cartilage 2015; 23:1130-7. [PMID: 25725390 PMCID: PMC4778978 DOI: 10.1016/j.joca.2015.02.023] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2014] [Revised: 02/13/2015] [Accepted: 02/18/2015] [Indexed: 02/02/2023]
Abstract
OBJECTIVE The prevalence of osteoarthritis (OA) varies between joints. Cartilage in eight different joints was evaluated to elucidate the disparate susceptibilities between joints to post-traumatic OA (PTOA) and provide evidence for joint-specific clinical treatments. The hypothesis was that cartilage in different joints would have varying cell death and anabolic gene expression profiles after injury. METHODS Adult equine cartilage explants were harvested from shoulder (SH), elbow (EL), carpal (CA), metacarpophalangeal (MC), patellofemoral (FP), tarsal (TA), metatarsophalangeal (MT), and proximal interphalangeal (PP) joints, and injured by loading with 30 MPa within 1 s. Fractional dissipated energy, cell density, cell death, and gene expression were quantified. RESULTS PP had the highest fractional dissipated energy (94%, 95% confidence interval [CI] 88 to 101%). Cell density was highest in the superficial zone in all samples, with MC and MT having the highest peak density. Injured samples had significantly increased cell death (13.5%, 95% CI 9.1 to 17.9%) than non-injured samples (6.8%, 95% CI 2.5 to 11.1%, P = 0.016); however, cell death after injury was not significantly different between joints. Gene expression was significantly different between joints. CD-RAP expression in normal cartilage was lowest in FP (Cp = 21, 95% CI -80 to 122). After injury, the change in CD-RAP expression increased and was highest in FP (147% relative increase after injury, 95% CI 64 to 213). CONCLUSION Different joints have different baseline characteristics, including cell density and gene expression, and responses to injury, including energy dissipation and gene expression. These unique characteristics may explain differences in OA prevalence and suggest differences in susceptibility to PTOA. CLINICAL RELEVANCE Understanding differences in the response to injury and potential susceptibility to OA can lead to the development of preventative or treatment strategies. KEY TERMS Gene expression, cartilage injury, chondrocyte, multiphoton microscopy, cartilage biomechanical properties, PTOA. WHAT IS KNOWN ABOUT THE SUBJECT The prevalence of OA is variable among joints; however, most laboratory studies are performed on a single joint - most commonly the knee, and extrapolated to other joints such as the ankle or shoulder. A small number of studies have compared knee and ankle cartilage and reported differences in mechanical properties and gene expression. WHAT THIS STUDY ADDS TO EXISTING KNOWLEDGE There are differences in baseline cell density and gene expression, and differences in response to injury, including gene expression and cell death. This suggests that there are inherent differences leading to varying susceptibilities in OA prevalence among joints. Joint-specific treatments may improve OA therapies.
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Affiliation(s)
- K.D. Novakofski
- Department of Clinical Sciences, Cornell University, Ithaca, NY, USA
| | - L.C. Berg
- Department of Clinical Veterinary and Animal Science, University of Copenhagen, København, Denmark
| | - I. Bronzini
- Department of Comparative Biomedicine and Food Science, University of Padova, Padova, Italy
| | - E.D. Bonnevie
- Department of Biomedical Engineering, Cornell University, Ithaca, NY, USA
| | - S.G. Poland
- Department of Clinical Sciences, Cornell University, Ithaca, NY, USA
| | - L.J. Bonassar
- Department of Biomedical Engineering, Cornell University, Ithaca, NY, USA
| | - L.A. Fortier
- Department of Clinical Sciences, Cornell University, Ithaca, NY, USA,Address correspondence and reprint requests to: L.A. Fortier, C3-181 Veterinary Medical Center, Cornell University, Ithaca, NY 14853, USA. Tel: 1-607-253-3102; Fax: 1-607-253-3497. (L.A. Fortier)
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Evaluation of Single-Impact-Induced Cartilage Degeneration by Optical Coherence Tomography. BIOMED RESEARCH INTERNATIONAL 2015; 2015:486794. [PMID: 26229959 PMCID: PMC4502276 DOI: 10.1155/2015/486794] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/08/2015] [Revised: 06/01/2015] [Accepted: 06/10/2015] [Indexed: 01/19/2023]
Abstract
Posttraumatic osteoarthritis constitutes a major cause of disability in our increasingly elderly population. Unfortunately, current imaging modalities are too insensitive to detect early degenerative changes of this disease. Optical coherence tomography (OCT) is a promising nondestructive imaging technique that allows surface and subsurface imaging of cartilage, at near-histological resolution, and is principally applicable in vivo during arthroscopy. Thirty-four macroscopically normal human cartilage-bone samples obtained from total joint replacements were subjected to standardized single impacts in vitro (range: 0.25 J to 0.98 J). 3D OCT measurements of impact area and adjacent tissue were performed prior to impaction, directly after impaction, and 1, 4, and 8 days later. OCT images were assessed qualitatively (DJD classification) and quantitatively using established parameters (OII, Optical Irregularity Index; OHI, Optical Homogeneity Index; OAI, Optical Attenuation Index) and compared to corresponding histological sections. While OAI and OHI scores were not significantly changed in response to low- or moderate-impact energies, high-impact energies significantly increased mean DJD grades (histology and OCT) and OII scores. In conclusion, OCT-based parameterization and quantification are able to reliably detect loss of cartilage surface integrity after high-energy traumatic insults and hold potential to be used for clinical screening of early osteoarthritis.
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Bartell LR, Fortier LA, Bonassar LJ, Cohen I. Measuring microscale strain fields in articular cartilage during rapid impact reveals thresholds for chondrocyte death and a protective role for the superficial layer. J Biomech 2015; 48:3440-6. [PMID: 26150096 DOI: 10.1016/j.jbiomech.2015.05.035] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Revised: 05/11/2015] [Accepted: 05/26/2015] [Indexed: 10/23/2022]
Abstract
Articular cartilage is a heterogeneous soft tissue that dissipates and distributes loads in mammalian joints. Though robust, cartilage is susceptible to damage from loading at high rates or magnitudes. Such injurious loads have been implicated in degenerative changes, including chronic osteoarthritis (OA), which remains a leading cause of disability in developed nations. Despite decades of research, mechanisms of OA initiation after trauma remain poorly understood. Indeed, although bulk cartilage mechanics are measurable during impact, current techniques cannot access microscale mechanics at those rapid time scales. We aimed to address this knowledge gap by imaging the microscale mechanics and corresponding acute biological changes of cartilage in response to rapid loading. In this study, we utilized fast-camera and confocal microscopy to achieve roughly 85 µm spatial resolution of both the cartilage deformation during a rapid (~3 ms), localized impact and the chondrocyte death following impact. Our results showed that, at these high rates, strain and chondrocyte death were highly correlated (p<0.001) with a threshold of 8% microscale strain norm before any cell death occurred. Additionally, chondrocyte death had developed by two hours after impact, suggesting a time frame for clinical therapeutics. Moreover, when the superficial layer was removed, strain - and subsequently chondrocyte death - penetrated deeper into the samples (p<0.001), suggesting a protective role for the superficial layer of articular cartilage. Combined, these results provide insight regarding the detailed biomechanics that drive early chondrocyte damage after trauma and emphasize the importance of understanding cartilage and its mechanics on the microscale.
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Affiliation(s)
- Lena R Bartell
- School of Applied and Engineering Physics, C7 Clark Hall, Cornell University, Ithaca, NY 14853, USA.
| | - Lisa A Fortier
- Department of Clinical Sciences, Cornell University, Ithaca, NY, USA
| | - Lawrence J Bonassar
- Department of Biomedical Engineering, Cornell University, Ithaca, NY, USA; Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, NY, USA
| | - Itai Cohen
- Department of Physics, Cornell University, Ithaca, NY, USA
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Abstract
Articular cartilage injuries and degenerative joint diseases are responsible for progressive pain and disability in millions of people worldwide, yet there is currently no treatment available to restore full joint functionality. As the tissue functions under mechanical load, an understanding of the physiologic or pathologic effects of biomechanical factors on cartilage physiology is of particular interest. Here, we highlight studies that have measured cartilage deformation at scales ranging from the macroscale to the microscale, as well as the responses of the resident cartilage cells, chondrocytes, to mechanical loading using in vitro and in vivo approaches. From these studies, it is clear that there exists a complex interplay among mechanical, inflammatory, and biochemical factors that can either support or inhibit cartilage matrix homeostasis under normal or pathologic conditions. Understanding these interactions is an important step toward developing tissue engineering approaches and therapeutic interventions for cartilage pathologies, such as osteoarthritis.
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Li H, Pei BQ, Yang JC, Hai Y, Li DY, Wu SQ. Load rate of facet joints at the adjacent segment increased after fusion. Chin Med J (Engl) 2015; 128:1042-6. [PMID: 25881597 PMCID: PMC4832943 DOI: 10.4103/0366-6999.155080] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Background: The cause of the adjacent segment degeneration (ASD) after fusion remains unknown. It is reported that adjacent facet joint stresses increase after anterior cervical discectomy and fusion. This increase of stress rate may lead to tissue injury. Thus far, the load rate of the adjacent segment facet joint after fusion remains unclear. Methods: Six C2–C7 cadaveric spine specimens were loaded under four motion modes: Flexion, extension, rotation, and lateral bending, with a pure moment using a 6° robot arm combined with an optical motion analysis system. The Tecscan pressure test system was used for testing facet joint pressure. Results: The contact mode of the facet joints and distributions of the force center during different motions were recorded. The adjacent segment facet joint forces increased faster after fusion, compared with intact conditions. While the magnitude of pressures increased, there was no difference in distribution modes before and after fusion. No pressures were detected during flexion. The average growth velocity during extension was the fastest and was significantly faster than lateral bending. Conclusions: One of the reasons for cartilage injury was the increasing stress rate of loading. This implies that ASD after fusion may be related to habitual movement before and after fusion. More and faster extension is disadvantageous for the facet joints and should be reduced as much as possible.
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Affiliation(s)
| | | | - Jin-Cai Yang
- Department of Orthopedics, Beijing Chao-Yang Hospital, Beijing 100020, China
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Blalock D, Miller A, Tilley M, Wang J. Joint instability and osteoarthritis. CLINICAL MEDICINE INSIGHTS-ARTHRITIS AND MUSCULOSKELETAL DISORDERS 2015; 8:15-23. [PMID: 25741184 PMCID: PMC4337591 DOI: 10.4137/cmamd.s22147] [Citation(s) in RCA: 90] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/26/2014] [Revised: 01/11/2015] [Accepted: 01/11/2015] [Indexed: 12/26/2022]
Abstract
Joint instability creates a clinical and economic burden in the health care system. Injuries and disorders that directly damage the joint structure or lead to joint instability are highly associated with osteoarthritis (OA). Thus, understanding the physiology of joint stability and the mechanisms of joint instability-induced OA is of clinical significance. The first section of this review discusses the structure and function of major joint tissues, including periarticular muscles, which play a significant role in joint stability. Because the knee, ankle, and shoulder joints demonstrate a high incidence of ligament injury and joint instability, the second section summarizes the mechanisms of ligament injury-associated joint instability of these joints. The final section highlights the recent advances in the understanding of the mechanical and biological mechanisms of joint instability-induced OA. These advances may lead to new opportunities for clinical intervention in the prevention and early treatment of OA.
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Affiliation(s)
- Darryl Blalock
- Department of Orthopedic Surgery, University of Kansas Medical Center, Kansas City, KS, USA
| | - Andrew Miller
- Department of Orthopedic Surgery, University of Kansas Medical Center, Kansas City, KS, USA
| | - Michael Tilley
- Department of Orthopedic Surgery, University of Kansas Medical Center, Kansas City, KS, USA
| | - Jinxi Wang
- Department of Orthopedic Surgery, University of Kansas Medical Center, Kansas City, KS, USA
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Athanasiou KA, Responte DJ, Brown WE, Hu JC. Harnessing biomechanics to develop cartilage regeneration strategies. J Biomech Eng 2015; 137:020901. [PMID: 25322349 DOI: 10.1115/1.4028825] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2014] [Indexed: 12/24/2022]
Abstract
As this review was prepared specifically for the American Society of Mechanical Engineers H.R. Lissner Medal, it primarily discusses work toward cartilage regeneration performed in Dr. Kyriacos A. Athanasiou's laboratory over the past 25 years. The prevalence and severity of degeneration of articular cartilage, a tissue whose main function is largely biomechanical, have motivated the development of cartilage tissue engineering approaches informed by biomechanics. This article provides a review of important steps toward regeneration of articular cartilage with suitable biomechanical properties. As a first step, biomechanical and biochemical characterization studies at the tissue level were used to provide design criteria for engineering neotissues. Extending this work to the single cell and subcellular levels has helped to develop biochemical and mechanical stimuli for tissue engineering studies. This strong mechanobiological foundation guided studies on regenerating hyaline articular cartilage, the knee meniscus, and temporomandibular joint (TMJ) fibrocartilage. Initial tissue engineering efforts centered on developing biodegradable scaffolds for cartilage regeneration. After many years of studying scaffold-based cartilage engineering, scaffoldless approaches were developed to address deficiencies of scaffold-based systems, resulting in the self-assembling process. This process was further improved by employing exogenous stimuli, such as hydrostatic pressure, growth factors, and matrix-modifying and catabolic agents, both singly and in synergistic combination to enhance neocartilage functional properties. Due to the high cell needs for tissue engineering and the limited supply of native articular chondrocytes, costochondral cells are emerging as a suitable cell source. Looking forward, additional cell sources are investigated to render these technologies more translatable. For example, dermis isolated adult stem (DIAS) cells show potential as a source of chondrogenic cells. The challenging problem of enhanced integration of engineered cartilage with native cartilage is approached with both familiar and novel methods, such as lysyl oxidase (LOX). These diverse tissue engineering strategies all aim to build upon thorough biomechanical characterizations to produce functional neotissue that ultimately will help combat the pressing problem of cartilage degeneration. As our prior research is reviewed, we look to establish new pathways to comprehensively and effectively address the complex problems of musculoskeletal cartilage regeneration.
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Progression of Gene Expression Changes following a Mechanical Injury to Articular Cartilage as a Model of Early Stage Osteoarthritis. ARTHRITIS 2014; 2014:371426. [PMID: 25478225 PMCID: PMC4248372 DOI: 10.1155/2014/371426] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2014] [Accepted: 10/29/2014] [Indexed: 01/17/2023]
Abstract
An impact injury model of early stage osteoarthritis (OA) progression was developed using a mechanical insult to an articular cartilage surface to evaluate differential gene expression changes over time and treatment. Porcine patellae with intact cartilage surfaces were randomized to one of three treatments: nonimpacted control, axial impaction (2000 N), or a shear impaction (500 N axial, with tangential displacement to induce shear forces). After impact, the patellae were returned to culture for 0, 3, 7, or 14 days. At the appropriate time point, RNA was extracted from full-thickness cartilage slices at the impact site. Quantitative real-time PCR was used to evaluate differential gene expression for 18 OA related genes from four categories: cartilage matrix, degradative enzymes and inhibitors, inflammatory response and signaling, and cell apoptosis. The shear impacted specimens were compared to the axial impacted specimens and showed that shear specimens more highly expressed type I collagen (Col1a1) at the early time points. In addition, there was generally elevated expression of degradative enzymes, inflammatory response genes, and apoptosis markers at the early time points. These changes suggest that the more physiologically relevant shear loading may initially be more damaging to the cartilage and induces more repair efforts after loading.
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Mohanraj B, Meloni GR, Mauck RL, Dodge GR. A high-throughput model of post-traumatic osteoarthritis using engineered cartilage tissue analogs. Osteoarthritis Cartilage 2014; 22:1282-90. [PMID: 24999113 PMCID: PMC4313617 DOI: 10.1016/j.joca.2014.06.032] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2014] [Revised: 05/31/2014] [Accepted: 06/25/2014] [Indexed: 02/02/2023]
Abstract
OBJECTIVE A number of in vitro models of post-traumatic osteoarthritis (PTOA) have been developed to study the effect of mechanical overload on the processes that regulate cartilage degeneration. While such frameworks are critical for the identification therapeutic targets, existing technologies are limited in their throughput capacity. Here, we validate a test platform for high-throughput mechanical injury incorporating engineered cartilage. METHOD We utilized a high-throughput mechanical testing platform to apply injurious compression to engineered cartilage and determined their strain and strain rate dependent responses to injury. Next, we validated this response by applying the same injury conditions to cartilage explants. Finally, we conducted a pilot screen of putative PTOA therapeutic compounds. RESULTS Engineered cartilage response to injury was strain dependent, with a 2-fold increase in glycosaminoglycan (GAG) loss at 75% compared to 50% strain. Extensive cell death was observed adjacent to fissures, with membrane rupture corroborated by marked increases in lactate dehydrogenase (LDH) release. Testing of established PTOA therapeutics showed that pan-caspase inhibitor [Z-VAD-FMK (ZVF)] was effective at reducing cell death, while the amphiphilic polymer [Poloxamer 188 (P188)] and the free-radical scavenger [N-Acetyl-L-cysteine (NAC)] reduced GAG loss as compared to injury alone. CONCLUSIONS The injury response in this engineered cartilage model replicated key features of the response of cartilage explants, validating this system for application of physiologically relevant injurious compression. This study establishes a novel tool for the discovery of mechanisms governing cartilage injury, as well as a screening platform for the identification of new molecules for the treatment of PTOA.
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Affiliation(s)
- Bhavana Mohanraj
- McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104,Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104
| | - Gregory R. Meloni
- McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104
| | - Robert L. Mauck
- McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104,Collaborative Research Partner Acute Cartilage Injury Program of AO the Foundation, Davos, Switzerland,Department of Bioengineering, School of Engineering and Applied Science, University of Pennsylvania, Philadelphia, PA 19104,Translational Musculoskeletal Research Center, Philadelphia Veterans Administration Medical Center, Philadelphia, PA 19104, USA
| | - George R. Dodge
- McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104,Collaborative Research Partner Acute Cartilage Injury Program of AO the Foundation, Davos, Switzerland,Translational Musculoskeletal Research Center, Philadelphia Veterans Administration Medical Center, Philadelphia, PA 19104, USA,Address for Correspondence: George R. Dodge, Ph.D., McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, 424 Stemmler Hall, 36 Street and Hamilton Walk, Philadelphia, PA 19104, Phone: (215) 898-8653, Fax: (215) 573-2133
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Riordan EA, Little C, Hunter D. Pathogenesis of post-traumatic OA with a view to intervention. Best Pract Res Clin Rheumatol 2014; 28:17-30. [PMID: 24792943 DOI: 10.1016/j.berh.2014.02.001] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Post-traumatic osteoarthritis (PTOA) subsequent to joint injury accounts for over 12% of the overall disease burden of OA, and higher in the most at-risk ankle and knee joints. Evidence suggests that the pathogenesis of PTOA may be related to inflammatory processes and alterations to the articular cartilage, menisci, muscle and subchondral bone that are initiated in the acute post-injury phase. Imaging of these early changes, as well as a number of biochemical markers, demonstrates the potential for use as predictors of future disease, and may help stratify patients on the likelihood of their developing clinical disease. This will be important in guiding future interventions, which will likely target elements of the inflammatory response within the joint, molecular abnormalities related to cartilage matrix degradation, chondrocyte function and subchondral bone remodelling. Until significant improvements are made, however, in identifying patients most at risk for developing PTOA--and therefore those who are candidates for therapy--primary prevention programmes will remain the most effective current management tools.
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Affiliation(s)
- Edward A Riordan
- School of Medicine, University of Sydney, Sydney, NSW, Australia.
| | - Christopher Little
- Raymond Purves Bone and Joint Research Laboratories, Kolling Institute of Medical Research, Institute of Bone and Joint Research, University of Sydney, Level 10 Kolling Building, St Leonards, NSW, Australia
| | - David Hunter
- Department of Rheumatology, Royal North Shore Hospital and Northern Clinical School, Kolling Institute of Medical Research, Institute of Bone and Joint Research, University of Sydney, Reserve Road, St Leonards, Sydney, NSW, Australia
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Waters NP, Stoker AM, Carson WL, Pfeiffer FM, Cook JL. Biomarkers affected by impact velocity and maximum strain of cartilage during injury. J Biomech 2014; 47:3185-95. [PMID: 25005436 DOI: 10.1016/j.jbiomech.2014.06.015] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2014] [Revised: 05/30/2014] [Accepted: 06/10/2014] [Indexed: 10/25/2022]
Abstract
Osteoarthritis is one of the most common, debilitating, musculoskeletal diseases; 12% associated with traumatic injury resulting in post-traumatic osteoarthritis (PTOA). Our objective was to develop a single impact model with cartilage "injury level" defined in terms of controlled combinations of strain rate to a maximum strain (both independent of cartilage load resistance) to study their sensitivity to articular cartilage cell viability and potential PTOA biomarkers. A servo-hydraulic test machine was used to measure canine humeral head cartilage explant thickness under repeatable pressure, then subject it (except sham and controls) to a single impact having controlled constant velocity V=1 or 100mm/s (strain rate 1.82 or 182/s) to maximum strain ε=10%, 30%, or 50%. Thereafter, explants were cultured in media for twelve days, with media changed at day 1, 2, 3, 6, 9, 12. Explant thickness was measured at day 0 (pre-injury), 6 and 12 (post-injury). Cell viability, and tissue collagen and glycosaminoglycan (GAG) were analyzed immediately post-injury and day 12. Culture media were tested for biomarkers: GAG, collagen II, chondroitin sulfate-846, nitric oxide, and prostaglandin E2 (PGE2). Detrimental effects on cell viability, and release of GAG and PGE2 to the media were primarily strain-dependent, (PGE2 being more prolonged and sensitive at lower strains). The cartilage injury model appears to be useful (possibly superior) for investigating the relationship between impact severity of injury and the onset of PTOA, specifically for discovery of biomarkers to evaluate the risk of developing clinical PTOA, and to compare effective treatments for arthritis prevention.
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Affiliation(s)
- Nicole Poythress Waters
- Comparative Orthopaedic Laboratory, University of Missouri, 900 E. Campus Drive, Columbia, MO 65211, USA.
| | - Aaron M Stoker
- Comparative Orthopaedic Laboratory, University of Missouri, 900 E. Campus Drive, Columbia, MO 65211, USA
| | - William L Carson
- Comparative Orthopaedic Laboratory, University of Missouri, 900 E. Campus Drive, Columbia, MO 65211, USA
| | - Ferris M Pfeiffer
- Comparative Orthopaedic Laboratory, University of Missouri, 900 E. Campus Drive, Columbia, MO 65211, USA
| | - James L Cook
- Comparative Orthopaedic Laboratory, University of Missouri, 900 E. Campus Drive, Columbia, MO 65211, USA
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43
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Novakofski KD, Williams RM, Fortier LA, Mohammed HO, Zipfel WR, Bonassar LJ. Identification of cartilage injury using quantitative multiphoton microscopy. Osteoarthritis Cartilage 2014; 22:355-62. [PMID: 24185113 PMCID: PMC4117377 DOI: 10.1016/j.joca.2013.10.008] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2013] [Revised: 08/27/2013] [Accepted: 10/23/2013] [Indexed: 02/02/2023]
Abstract
OBJECTIVE Cartilage injury can lead to post-traumatic osteoarthritis (PTOA). Immediate post-trauma cellular and structural changes are not widely understood. Furthermore, current cellular-resolution cartilage imaging techniques require sectioning of cartilage and/or use of dyes not suitable for patient imaging. In this study, we used multiphoton microscopy (MPM) data with FDA-approved sodium fluorescein to identify and evaluate the pattern of chondrocyte death after traumatic injury. METHOD Mature equine distal metacarpal or metatarsal osteochondral blocks (OCBs) were injured by 30 MPa compressive loading delivered over 1 s. Injured and control sites were imaged unfixed and in situ 1 h post-injury with sodium fluorescein using rasterized z-scanning. MPM data was quantified in MATLAB, reconstructed in 3-D, and projected in 2-D to determine the damage pattern. RESULTS MPM images (600 per sample) were reconstructed and analyzed for cell death. The overall distribution of cell death appeared to cluster into circular (n = 7) or elliptical (n = 4) patterns (p = 0.006). Dead cells were prevalent near cracks in the matrix, with only 26.3% (SE = 5.0%, p < 0.0001) of chondrocytes near cracks being viable. CONCLUSION This study demonstrates the first application of MPM for evaluating cellular-scale cartilage injury in situ in live tissue, with clinical potential for detecting early cartilage damage. With this technique, we were able to uniquely observe two death patterns resulting from the same compressive loading, which may be related to local variability in matrix structure. These results also demonstrate proof-of-concept MPM diagnostic use in detecting subtle and early cartilage damage not detectable in any other way.
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Affiliation(s)
- K D Novakofski
- Department of Clinical Sciences, Cornell University, Ithaca, NY, USA
| | - R M Williams
- Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA
| | - L A Fortier
- Department of Clinical Sciences, Cornell University, Ithaca, NY, USA
| | - H O Mohammed
- Population Medicine and Diagnostic Sciences, Cornell University, Ithaca, NY 14853, USA
| | - W R Zipfel
- Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA
| | - L J Bonassar
- Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA.
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Heiner AD, Smith AD, Goetz JE, Goreham-Voss CM, Judd KT, McKinley TO, Martin JA. Cartilage-on-cartilage versus metal-on-cartilage impact characteristics and responses. J Orthop Res 2013; 31:887-93. [PMID: 23335281 PMCID: PMC3740544 DOI: 10.1002/jor.22311] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2012] [Accepted: 12/19/2012] [Indexed: 02/04/2023]
Abstract
A common in vitro model for studying acute mechanical damage in cartilage is to impact an isolated osteochondral or cartilage specimen with a metallic impactor. The mechanics of a cartilage-on-cartilage (COC) impact, as encountered in vivo, are likely different than those of a metal-on-cartilage (MOC) impact. The hypothesis of this study was that impacted in vitro COC and MOC specimens would differ in their impact behavior, mechanical properties, chondrocyte viability, cell metabolism, and histologic structural damage. Osteochondral specimens were impacted with either an osteochondral plug or a metallic cylinder at the same delivered impact energy per unit area, and processed after 14 days in culture. The COC impacts resulted in about half of the impact maximum stress and a quarter of the impact maximum stress rate of change, as compared to the MOC impacts. The impacted COC specimens had smaller changes in mechanical properties, smaller decreases in chondrocyte viability, higher total proteoglycan content, and less histologic structural damage, as compared to the impacted MOC specimens. If MOC impact conditions are to be used for modeling of articular injuries and post-traumatic osteoarthritis, the differences between COC and MOC impacts must be kept in mind.
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Affiliation(s)
- Anneliese D Heiner
- Department of Orthopaedics and Rehabilitation, University of Iowa, Iowa City, Iowa, USA.
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45
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Lee CM, Kisiday JD, McIlwraith CW, Grodzinsky AJ, Frisbie DD. Development of an in vitro model of injury-induced osteoarthritis in cartilage explants from adult horses through application of single-impact compressive overload. Am J Vet Res 2013; 74:40-7. [PMID: 23270344 DOI: 10.2460/ajvr.74.1.40] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
OBJECTIVE To develop an in vitro model of cartilage injury in full-thickness equine cartilage specimens that can be used to simulate in vivo disease and evaluate treatment efficacy. SAMPLE 15 full-thickness cartilage explants from the trochlear ridges of the distal aspect of the femur from each of 6 adult horses that had died from reasons unrelated to the musculoskeletal system. PROCEDURES To simulate injury, cartilage explants were subjected to single-impact uniaxial compression to 50%, 60%, 70%, or 80% strain at a rate of 100% strain/s. Other explants were left uninjured (control specimens). All specimens underwent a culture process for 28 days and were subsequently evaluated histologically for characteristics of injury and early stages of osteoarthritis, including articular surface damage, chondrocyte cell death, focal cell loss, chondrocyte cluster formation, and loss of the extracellular matrix molecules aggrecan and types I and II collagen. RESULTS Compression to all degrees of strain induced some amount of pathological change typical of clinical osteoarthritis in horses; however, only compression to 60% strain induced significant changes morphologically and biochemically in the extracellular matrix. CONCLUSIONS AND CLINICAL RELEVANCE The threshold strain necessary to model injury in full-thickness cartilage specimens from the trochlear ridges of the distal femur of adult horses was 60% strain at a rate of 100% strain/s. This in vitro model should facilitate study of pathophysiologic changes and therapeutic interventions for osteoarthritis.
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Affiliation(s)
- Christina M Lee
- Orthopaedic Research Center, Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523
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Ashwell MS, Gonda MG, Gray K, Maltecca C, O'Nan AT, Cassady JP, Mente PL. Changes in chondrocyte gene expression following in vitro impaction of porcine articular cartilage in an impact injury model. J Orthop Res 2013; 31:385-91. [PMID: 23027577 PMCID: PMC3553272 DOI: 10.1002/jor.22239] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/09/2011] [Accepted: 08/31/2012] [Indexed: 02/04/2023]
Abstract
Our objective was to monitor chondrocyte gene expression at 0, 3, 7, and 14 days following in vitro impaction to the articular surface of porcine patellae. Patellar facets were either axially impacted with a cylindrical impactor (25 mm/s loading rate) to a load level of 2,000 N or not impacted to serve as controls. After being placed in organ culture for 0, 3, 7, or 14 days, total RNA was isolated from full thickness cartilage slices and gene expression measured for 17 genes by quantitative real-time RT-PCR. Targeted genes included those encoding proteins involved with biological stress, inflammation, or anabolism and catabolism of cartilage extracellular matrix. Some gene expression changes were detected on the day of impaction, but most significant changes occurred at 14 days in culture. At 14 days in culture, 10 of the 17 genes were differentially expressed with col1a1 most significantly up-regulated in the impacted samples, suggesting impacted chondrocytes may have reverted to a fibroblast-like phenotype.
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Affiliation(s)
- Melissa S. Ashwell
- Animal Science Department, North Carolina State University, Raleigh, NC, USA
| | - Michael G. Gonda
- Animal Science Department, North Carolina State University, Raleigh, NC, USA
| | - Kent Gray
- Animal Science Department, North Carolina State University, Raleigh, NC, USA
| | - Christian Maltecca
- Animal Science Department, North Carolina State University, Raleigh, NC, USA
| | - Audrey T. O'Nan
- Animal Science Department, North Carolina State University, Raleigh, NC, USA
| | - Joseph P. Cassady
- Animal Science Department, North Carolina State University, Raleigh, NC, USA
| | - Peter L. Mente
- Joint Department of Biomedical Engineering, North Carolina State University, Raleigh, NC, USA and University of North Carolina, Chapel Hill, NC, USA
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47
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ProDisc cervical arthroplasty does not alter facet joint contact pressure during lateral bending or axial torsion. Spine (Phila Pa 1976) 2013; 38:E84-93. [PMID: 23132537 DOI: 10.1097/brs.0b013e31827b8a2d] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN A biomechanical study of facet joint pressure after total disc replacement using cadaveric human cervical spines during lateral bending and axial torsion. OBJECTIVE The goal was to measure the contact pressure in the facet joint in cadaveric human cervical spines subjected to physiologic lateral bending and axial torsion before and after implantation of a ProDisc-C implant. SUMMARY OF BACKGROUND DATA Changes in facet biomechanics can damage the articular cartilage in the joint, potentially leading to degeneration and painful arthritis. Few cadaveric and computational studies have evaluated the changes in facet joint loading during spinal loading with an artificial disc implanted. Computational models have predicted that the design and placement of the implant influence facet joint loading, but limited cadaveric studies document changes in facet forces and pressures during nonsagittal bending after implantation of a ProDisc. As such, little is known about the local facet joint mechanics for these complicated loading scenarios in the cervical spine. METHODS Seven osteoligamentous C2-T1 cadaveric cervical spines were instrumented with a transducer to measure the C5-C6 facet pressure profiles during physiological lateral bending and axial torsion, before and after implantation of a ProDisc-C at that level. Rotations at that level and global cervical spine motions and loads were also quantified. RESULT.: Global and segmental rotations were not altered by the disc implantation. Facet contact pressure increased after implantation during ipsilateral lateral bending and contralateral torsion, but that increase was not significant compared with the intact condition. CONCLUSION Implantation of a ProDisc-C does not significantly modify the kinematics and facet pressure at the index level in cadaveric specimens during lateral bending and axial torsion. However, changes in facet contact pressures after disc arthroplasty may have long-term effects on spinal loading and cartilage degeneration and should be monitored in vivo.
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Alexander PG, Song Y, Taboas JM, Chen FH, Melvin GM, Manner PA, Tuan RS. Development of a Spring-Loaded Impact Device to Deliver Injurious Mechanical Impacts to the Articular Cartilage Surface. Cartilage 2013; 4:52-62. [PMID: 26069650 PMCID: PMC4297114 DOI: 10.1177/1947603512455195] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
OBJECTIVE Traumatic impacts on the articular joint surface in vitro are known to lead to degeneration of the cartilage. The main objective of this study was to develop a spring-loaded impact device that can be used to deliver traumatic impacts of consistent magnitude and rate and to find whether impacts cause catabolic activities in articular cartilage consistent with other previously reported impact models and correlated with the development of osteoarthritic lesions. In developing the spring-loaded impactor, the operating hypothesis is that a single supraphysiologic impact to articular cartilage in vitro can affect cartilage integrity, cell viability, sulfated glycosaminoglycan and inflammatory mediator release in a dose-dependent manner. DESIGN Impacts of increasing force are delivered to adult bovine articular cartilage explants in confined compression. Impact parameters are correlated with tissue damage, cell viability, matrix and inflammatory mediator release, and gene expression 24 hours postimpact. RESULTS Nitric oxide release is first detected after 7.7 MPa impacts, whereas cell death, glycosaminoglycan release, and prostaglandin E2 release are first detected at 17 MPa. Catabolic markers increase linearly to maximal levels after ≥36 MPa impacts. CONCLUSIONS A single supraphysiologic impact negatively affects cartilage integrity, cell viability, and GAG release in a dose-dependent manner. Our findings showed that 7 to 17 MPa impacts can induce cell death and catabolism without compromising the articular surface, whereas a 17 MPa impact is sufficient to induce increases in most common catabolic markers of osteoarthritic degeneration.
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Affiliation(s)
- Peter G Alexander
- Cartilage Biology and Orthopaedics Branch, National Institute of Arthritis, and Musculoskeletal and Skin Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA ; Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Yingjie Song
- Cartilage Biology and Orthopaedics Branch, National Institute of Arthritis, and Musculoskeletal and Skin Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA
| | - Juan M Taboas
- Cartilage Biology and Orthopaedics Branch, National Institute of Arthritis, and Musculoskeletal and Skin Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA ; Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
| | - Faye H Chen
- Cartilage Biology and Orthopaedics Branch, National Institute of Arthritis, and Musculoskeletal and Skin Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA
| | - Gary M Melvin
- Office of Science and Technology, National Institute of Arthritis, and Musculoskeletal and Skin Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA
| | - Paul A Manner
- Department of Orthopaedics and Sports Medicine, University of Washington, Seattle, WA, USA
| | - Rocky S Tuan
- Cartilage Biology and Orthopaedics Branch, National Institute of Arthritis, and Musculoskeletal and Skin Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, MD, USA ; Center for Cellular and Molecular Engineering, Department of Orthopaedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
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Rosenzweig DH, Djap MJ, Ou SJ, Quinn TM. Mechanical injury of bovine cartilage explants induces depth-dependent, transient changes in MAP kinase activity associated with apoptosis. Osteoarthritis Cartilage 2012; 20:1591-602. [PMID: 22935788 DOI: 10.1016/j.joca.2012.08.012] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2012] [Revised: 08/13/2012] [Accepted: 08/18/2012] [Indexed: 02/02/2023]
Abstract
OBJECTIVE To characterize mitogen activated protein (MAP) kinase activity and chondrocyte apoptosis in an in vitro model of cartilage mechanical injury as a function of tissue depth and time post-injury. DESIGN Mechanically injured osteochondral explants were assessed for cell viability, MAP kinase and caspase-3 activity over 15 days using immunofluorescence microscopy and Western blot. Zonal distributions of cell viability and apoptosis were quantified in the presence of specific mitogen activated protein kinase inhibitors. RESULTS Viability rapidly decreased post-injury, most significantly in the superficial zone, with some involvement of the middle and deep zones, which correlated with increased caspase-3 activity. Transient and significant increases in extracellular-regulated protein kinase (ERK) activity were observed in middle and deep zones at 1 and 6 days post-injury, while c-Jun-amino terminal protein kinase activity increased in the deep zone at 1 and 6 days compared to uninjured controls. Changes in p38 activity were particularly pronounced, with significant increases in all three zones 30 min post-injury, but only in the middle and deep zones after 1 and 6 days. Inhibition of ERK and p38 increased chondrocyte viability which correlated with decreased apoptosis. CONCLUSIONS Spatiotemporal patterns of MAP kinase signalling in cartilage after mechanical injury strongly correlate with changes in cell viability and chondrocyte apoptosis. Importantly, these signals may be pro-survival or pro-apoptotic depending on zonal location and time post-injury. These data yield mechanistic insights which may improve the diagnosis and treatment of cartilage injuries.
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Affiliation(s)
- D H Rosenzweig
- Soft Tissue Biophysics Laboratory, Department of Chemical Engineering, McGill University, Montreal, QC, Canada
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50
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Responte DJ, Lee JK, Hu JC, Athanasiou KA. Biomechanics-driven chondrogenesis: from embryo to adult. FASEB J 2012; 26:3614-24. [PMID: 22673579 DOI: 10.1096/fj.12-207241] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Biomechanics plays a pivotal role in articular cartilage development, pathophysiology, and regeneration. During embryogenesis and cartilage maturation, mechanical stimuli promote chondrogenesis and limb formation. Mechanical loading, which has been characterized using computer modeling and in vivo studies, is crucial for maintaining the phenotype of cartilage. However, excessive or insufficient loading has deleterious effects and promotes the onset of cartilage degeneration. Informed by the prominent role of biomechanics, mechanical stimuli have been harnessed to enhance redifferentiation of chondrocytes and chondroinduction of other cell types, thus providing new chondrocyte cell sources. Biomechanical stimuli, such as hydrostatic pressure or compression, have been used to enhance the functional properties of neocartilage. By identifying pathways involved in mechanical stimulation, chemical equivalents that mimic mechanical signaling are beginning to offer exciting new methods for improving neocartilage. Harnessing biomechanics to improve differentiation, maintenance, and regeneration is emerging as pivotal toward producing functional neocartilage that could eventually be used to treat cartilage degeneration.
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Affiliation(s)
- Donald J Responte
- Department of Biomedical Engineering, University of California-Davis, Davis, California 95616, USA
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