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Koshkarev MA. [Prospects and modern possibilities of non-surgical treatment of intervertebral hernias with neurological manifestations. (Literature review)]. VOPROSY KURORTOLOGII, FIZIOTERAPII, I LECHEBNOI FIZICHESKOI KULTURY 2025; 102:52-60. [PMID: 40421861 DOI: 10.17116/kurort202510202152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/28/2025]
Abstract
The problem of non-specific pain in the spinal area is important today in society due to a number of reasons, including features of the modern human's lifestyle, tendency to increase in life expectancy and «aging» of population. There is a continuing debate about the sources of this pain and reasonableness of search for them. There is no doubt that discogenic pain prevails over other probable sources of pain in the spinal area and intervertebral hernias play the primary role here. Patients can immediately look for a solution to the problem by a neurosurgeon at the time of «intervertebral disc herniation» diagnosis establishment and in the presence of a pronounced reflex or radicular pain syndrome. It is the «intervertebral disc herniation» wording which often leads patients to a neurosurgeon. There are many methods of intervertebral hernias conservative treatment. This article is focused on the technology of spinal traction therapy, which has a scientific evidence base, including in the question of natural reduction of intervertebral hernias' dimensions. Cyclic local traction therapy is the latest and realizing all important principles of tractive impact on the spine method.
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Marshall W, Baum B, Fairhall A, Heisenberg CP, Koslover E, Liu A, Mao Y, Mogilner A, Nelson CM, Paluch EK, Trepat X, Yap A. Where physics and biology meet. Curr Biol 2024; 34:R950-R960. [PMID: 39437734 DOI: 10.1016/j.cub.2024.08.022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2024]
Abstract
As part of this special issue on physics and biology, we invited several leading experts that bridge these disciplines to provide their views on the reciprocal contributions of each field and the benefits and challenges of working across physics and biology: introduction provided by Wallace Marshall.
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Rego BV, Murtada SI, Li G, Tellides G, Humphrey JD. Multiscale insights into postnatal aortic development. Biomech Model Mechanobiol 2024; 23:687-701. [PMID: 38151614 PMCID: PMC11419831 DOI: 10.1007/s10237-023-01800-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2023] [Accepted: 11/27/2023] [Indexed: 12/29/2023]
Abstract
Despite its vital importance for establishing proper cardiovascular function, the process through which the vasculature develops and matures postnatally remains poorly understood. From a clinical perspective, an ability to mechanistically model the developmental time course in arteries and veins, as well as to predict how various pathologies and therapeutic interventions alter the affected vessels, promises to improve treatment strategies and long-term clinical outcomes, particularly in pediatric patients suffering from congenital heart defects. In the present study, we conducted a multiscale investigation into the postnatal development of the murine thoracic aorta, examining key allometric relations as well as relationships between in vivo mechanical stresses, collagen and elastin expression, and the gradual accumulation of load-bearing constituents within the aortic wall. Our findings suggest that the production of fibrillar collagens in the developing aorta associates strongly with the ratio of circumferential stresses between systole and diastole, hence emphasizing the importance of a pulsatile mechanobiological stimulus. Moreover, rates of collagen turnover and elastic fiber compaction can be inferred directly by synthesizing transcriptional data and quantitative histological measurements of evolving collagen and elastin content. Consistent with previous studies, we also observed that wall shear stresses acting on the aorta are similar at birth and in maturity, supporting the hypothesis that at least some stress targets are established early in development and maintained thereafter, thus providing a possible homeostatic basis to guide future experiments and inform future predictive modeling.
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Affiliation(s)
- Bruno V Rego
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA
- Department of Biological & Agricultural Engineering, Louisiana State University, Baton Rouge, LA, USA
| | - Sae-Il Murtada
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA
| | - Guangxin Li
- Department of Surgery, Yale School of Medicine, New Haven, CT, USA
| | - George Tellides
- Department of Surgery, Yale School of Medicine, New Haven, CT, USA
- Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT, USA
| | - Jay D Humphrey
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA.
- Vascular Biology and Therapeutics Program, Yale School of Medicine, New Haven, CT, USA.
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Barrett JM, Callaghan JP. Strain inhibition of bacterial collagenase is consistent with a collagen fibril uncrimping mechanism in rat tail tendons. J Biomech 2024; 162:111892. [PMID: 38061208 DOI: 10.1016/j.jbiomech.2023.111892] [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: 04/06/2023] [Revised: 11/23/2023] [Accepted: 11/28/2023] [Indexed: 01/16/2024]
Abstract
Mechanical strain inhibits bacterial collagenase from cleaving collagen. Additionally, the toe region of a soft tissue's force-elongation curve arises from sequentially engaging collagen fibrils as the tissue lengthens. Together, these phenomena suggest that mechanical strain may gradually inhibit collagenase activity through a soft tissue's toe region. Therefore, this investigation sought to test this hypothesis. 92 rat tail tendon fascicles from 3 female sentinel animals underwent preliminary stiffness tests, and their force-elongation curves were fit to a collagen distribution model. This distribution-based model calculated the force magnitude corresponding to p% of collagen fibril engagement. Specimens were separated into one of five levels of p, and that level of force was maintained for two hours while being exposed to 0.054 U/mL of bacterial collagenase from C. histolyticum. The specimens were strained to failure following the creep test, and the relative reduction in stiffness was quantified to estimate the fraction of digested fibrils. Every 10% additional collagen engagement corresponded to a 6.3% (97% highest density interval: 4.3 - 8.4%) retention of stiffness, which indicated collagenase inhibition. The results of this investigation were consistent with a strain-inhibition hypothesis along with the established uncrimping mechanism in the toe region. These results support an interaction between mechanical strain and collagenolysis, which may be valuable for disease prevention or treatment.
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Affiliation(s)
- Jeff M Barrett
- Department of Kinesiology and Health Sciences, University of Waterloo, Canada.
| | - Jack P Callaghan
- Department of Kinesiology and Health Sciences, University of Waterloo, Canada.
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Koshkarev MA. [Sanogenetic mechanisms of cyclic local traction therapy in the treatment of neurological manifestations of degenerative diseases in the spine. (Literature review)]. VOPROSY KURORTOLOGII, FIZIOTERAPII, I LECHEBNOI FIZICHESKOI KULTURY 2024; 101:74-83. [PMID: 39487622 DOI: 10.17116/kurort202410105174] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/04/2024]
Abstract
New information on the results of scientific research may change the understanding of the etiology and pathogenesis of diseases, which makes adjustments in treatment approaches. Cyclic local traction therapywas created in USA by the group of scientists for NASA (Axiom Worldwide, Tampa, FL) and approved by FDA in 2003. The year 2023 is the 20th anniversary of its successful application in practical medicine. Evaluating the effectiveness of the method, it has been shown that after undergoing treatment in patients with chronic back pain, the height of the intervertebral discs increases, pain syndrome and frequency of taking pain medications decreases, daily activity and duration of walking without pain increases. It is assumed that the treatment effect was achieved due to the «vacuum» effect, which could contribute to the regeneration of the intervertebral disc. It is also known about the possibility of intervertebral disc herniation reduction after a course of traction therapy and it was believed that this was ensured by «retraction» of the hernia back into the intervertebral space under the influence of the longitudinal ligament. However, fundamental studies of the past century and the present indicate the presence of other mechanisms affecting the structures of the vertebral motor segment, especially the processes occurring inside the intervertebral disc and contributing to the regression of the intervertebral disc herniation.
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Saini K, Cho S, Tewari M, Jalil AR, Wang M, Kasznel AJ, Yamamoto K, Chenoweth DM, Discher DE. Pan-tissue scaling of stiffness versus fibrillar collagen reflects contractility-driven strain that inhibits fibril degradation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.09.27.559759. [PMID: 37808742 PMCID: PMC10557712 DOI: 10.1101/2023.09.27.559759] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/10/2023]
Abstract
Polymer network properties such as stiffness often exhibit characteristic power laws in polymer density and other parameters. However, it remains unclear whether diverse animal tissues, composed of many distinct polymers, exhibit such scaling. Here, we examined many diverse tissues from adult mouse and embryonic chick to determine if stiffness ( E tissue ) follows a power law in relation to the most abundant animal protein, Collagen-I, even with molecular perturbations. We quantified fibrillar collagen in intact tissue by second harmonic generation (SHG) imaging and from tissue extracts by mass spectrometry (MS), and collagenase-mediated decreases were also tracked. Pan-tissue power laws for tissue stiffness versus Collagen-I levels measured by SHG or MS exhibit sub-linear scaling that aligns with results from cellularized gels of Collagen-I but not acellular gels. Inhibition of cellular myosin-II based contraction fits the scaling, and combination with inhibitors of matrix metalloproteinases (MMPs) show collagenase activity is strain - not stress- suppressed in tissues, consistent with past studies of gels and fibrils. Beating embryonic hearts and tendons, which differ in both collagen levels and stiffness by >1000-fold, similarly suppressed collagenases at physiological strains of ∼5%, with fiber-orientation regulating degradation. Scaling of E tissue based on 'use-it-or-lose-it' kinetics provides insight into scaling of organ size, microgravity effects, and regeneration processes while suggesting contractility-driven therapeutics.
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Yeganegi A, Whitehead K, de Castro Brás LE, Richardson WJ. Mechanical strain modulates extracellular matrix degradation and byproducts in an isoform-specific manner. Biochim Biophys Acta Gen Subj 2023; 1867:130286. [PMID: 36464138 PMCID: PMC9852084 DOI: 10.1016/j.bbagen.2022.130286] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 11/09/2022] [Accepted: 11/22/2022] [Indexed: 12/03/2022]
Abstract
Many studies have shown that mechanical forces can alter collagen degradation by proteases, and this mechanochemical effect may potentially serve an important role in determining extracellular matrix content and organization in load-bearing tissues. However, it is not yet known whether mechano-sensitive degradation depends on particular protease isoforms, nor is it yet known whether particular degradation byproducts can be altered by mechanical loading. In this study, we tested the hypothesis that different types of proteases exhibit different sensitivities to mechanical loading both in degradation rates and byproducts. Decellularized porcine pericardium samples were treated with human recombinant matrix metalloproteinases-1, -8, -9, cathepsin K, or a protease-free control while subjected to different levels of strain in a planar, biaxial mechanical tester. Tissue degradation was monitored by tracking the decay in mechanical stresses during displacement control tests, and byproducts were assessed by mass spectrometry analysis of the sample supernatant after degradation. Our key finding shows that cathepsin K-mediated degradation of collagenous tissue was enhanced with increasing strain, while MMP1-, MMP8-, and MMP9-mediated degradation were first decreased and then increased by strain. Degradation induced changes in tissue mechanical properties, and proteomic analysis revealed strain-sensitive degradome signatures with different ECM byproducts released at low vs. high strains. This evidence suggests a potentially new type of mechanobiology wherein mechanical forces alter the degradation products that can provide important signaling feedback functions during tissue remodeling.
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Affiliation(s)
- Amirreza Yeganegi
- Department of Bioengineering, Clemson University, Clemson, SC, United States of America
| | - Kaitlin Whitehead
- Department of Physiology, East Carolina University, Greenville, NC, United States of America
| | | | - William J Richardson
- Department of Chemical Engineering, University of Arkansas, Fayetteville, AR, United States of America.
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Mechanochemistry of collagen. Acta Biomater 2023; 163:50-62. [PMID: 36669548 DOI: 10.1016/j.actbio.2023.01.025] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 01/02/2023] [Accepted: 01/10/2023] [Indexed: 01/18/2023]
Abstract
The collagen molecular family is the result of nearly one billion years of evolution. It is a unique family of proteins, the majority of which provide general mechanical support to biological tissues. Fibril forming collagens are the most abundant collagens in vertebrate animals and are generally found in positions that resist tensile loading. In animals, cells produce fibril-forming collagen molecules that self-assemble into larger structures known as collagen fibrils. Collagen fibrils are the fundamental, continuous, load-bearing elements in connective tissues, but are often further aggregated into larger load-bearing structures, fascicles in tendon, lamellae in cornea and in intervertebral disk. We know that failure to form fibrillar collagen is embryonic lethal, and excessive collagen formation/growth (fibrosis) or uncontrolled enzymatic remodeling (type II collagen: osteoarthritis) is pathological. Collagen is thus critical to vertebrate viability and instrumental in maintaining efficient mechanical structures. However, despite decades of research, our understanding of collagen matrix formation is not complete, and we know still less about the detailed mechanisms that drive collagen remodeling, growth, and pathology. In this perspective, we examine the known role of mechanical force on the formation and development of collagenous structure. We then discuss a mechanochemical mechanism that has the potential to unify our understanding of collagenous tissue assembly dynamics, which preferentially deposits and grows collagen fibrils directly in the path of mechanical force, where the energetics should be dissuasive and where collagen fibrils are most required. We term this mechanism: Mechanochemical force-structure causality. STATEMENT OF SIGNIFICANCE: Our mechanochemical-force structure causality postulate suggests that collagen molecules are components of mechanochemically-sensitive and dynamically-responsive fibrils. Collagen molecules assemble preferentially in the path of applied strain, can be grown in place by mechanical extension, and are retained in the path of force through strain-stabilization. The mechanisms that drive this behavior operate at the level of the molecules themselves and are encoded into the structure of the biomaterial. The concept might change our understanding of structure formation, enhance our ability to treat injuries, and accelerate the development of therapeutics to prevent pathologies such as fibrosis. We suggest that collagen is a mechanochemically responsive dynamic element designed to provide a substantial "material assist" in the construction of adaptive carriers of mechanical signals.
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Benage LG, Sweeney JD, Giers MB, Balasubramanian R. Dynamic Load Model Systems of Tendon Inflammation and Mechanobiology. Front Bioeng Biotechnol 2022; 10:896336. [PMID: 35910030 PMCID: PMC9335371 DOI: 10.3389/fbioe.2022.896336] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Accepted: 06/22/2022] [Indexed: 11/25/2022] Open
Abstract
Dynamic loading is a shared feature of tendon tissue homeostasis and pathology. Tendon cells have the inherent ability to sense mechanical loads that initiate molecular-level mechanotransduction pathways. While mature tendons require physiological mechanical loading in order to maintain and fine tune their extracellular matrix architecture, pathological loading initiates an inflammatory-mediated tissue repair pathway that may ultimately result in extracellular matrix dysregulation and tendon degeneration. The exact loading and inflammatory mechanisms involved in tendon healing and pathology is unclear although a precise understanding is imperative to improving therapeutic outcomes of tendon pathologies. Thus, various model systems have been designed to help elucidate the underlying mechanisms of tendon mechanobiology via mimicry of the in vivo tendon architecture and biomechanics. Recent development of model systems has focused on identifying mechanoresponses to various mechanical loading platforms. Less effort has been placed on identifying inflammatory pathways involved in tendon pathology etiology, though inflammation has been implicated in the onset of such chronic injuries. The focus of this work is to highlight the latest discoveries in tendon mechanobiology platforms and specifically identify the gaps for future work. An interdisciplinary approach is necessary to reveal the complex molecular interplay that leads to tendon pathologies and will ultimately identify potential regenerative therapeutic targets.
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Affiliation(s)
- Lindsay G. Benage
- School of Chemical, Biological and Environmental Engineering, Oregon State University, Corvallis, OR, United States
| | - James D. Sweeney
- School of Chemical, Biological and Environmental Engineering, Oregon State University, Corvallis, OR, United States
| | - Morgan B. Giers
- School of Chemical, Biological and Environmental Engineering, Oregon State University, Corvallis, OR, United States
- *Correspondence: Morgan B. Giers,
| | - Ravi Balasubramanian
- School of Chemical, Biological and Environmental Engineering, Oregon State University, Corvallis, OR, United States
- School of Mechanical, Industrial and Manufacturing Engineering, Oregon State University, Corvallis, OR, United States
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Chu J, Shieh JS, Wu K, Guan H, Roche S, Held MFG, Yang H, Guo JJ. Simultaneous or Staged Bilateral Arthroscopic Rotator Cuff Repair: An Observational Study of Intraoperative and Postoperative Outcomes. Orthop J Sports Med 2021; 9:23259671211041994. [PMID: 34708140 PMCID: PMC8543723 DOI: 10.1177/23259671211041994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Accepted: 05/19/2021] [Indexed: 11/18/2022] Open
Abstract
Background: Bilateral arthroscopic rotator cuff repair (ARCR) is frequently performed in
patients with symptomatic bilateral rotator cuff tears. Purpose: To compare patient-reported outcomes and mobility between simultaneous and
staged bilateral ARCR. Study Design: Cohort study; Level of evidence, 3. Methods: Included were 51 patients who underwent simultaneous (anesthetized once) and
42 patients who underwent staged (anesthetized twice) bilateral ARCR between
January 2014 and January 2018; for the staged group, the interval between
procedures was at least 12 months. All operations were performed by the same
surgeon, and all patients had minimum 24-month follow up in both shoulders.
Patient-reported outcomes and range of motion (ROM) were assessed
preoperatively and postoperatively and compared between groups. Outcome
measures included the Constant-Murley score (CMS) and American Shoulder and
Elbow Surgeons (ASES) score as well as measures of psychological status,
health-related quality of life, activities of daily living (ADL), and
patient satisfaction with the state of one’s shoulders. Results: The mean follow-up times for the staged and simultaneous ARCR groups were
44.1 months (range, 36-60 months) and 37.5 months (range, 25-59 months),
respectively. There were no significant differences in age, tear size, or
fatty degeneration of rotator cuff muscles between the groups. The
cumulative length of hospital stay in the staged group was significantly
longer than in the simultaneous group (P < .001). At the
final follow-up, both groups showed significant improvement in ROM, CMS, and
ASES scores (P < .05). No significant differences
between the groups were observed in terms of ROM, CMS, and ASES scores
postoperatively. At 24 months postoperatively, psychological status and
health-related quality of life in both groups improved significantly
(P < .05), and there were no significant
between-group differences. Patients were able to perform most essential ADL.
Both groups had high patient satisfaction, but patient satisfaction for the
second shoulder of the staged group was lower than that of the simultaneous
group (P = .039). Conclusion: Simultaneous bilateral ARCR was shown to be effective, resulting in similar
improvements in clinical outcomes to staged bilateral ARCR at 2-year
follow-up. In addition to higher patient satisfaction, simultaneous
bilateral ARCR also had a shorter treatment cycle.
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Affiliation(s)
- Jiabao Chu
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Ju-Sheng Shieh
- Center for Health Policy and Management Studies, Nanjing University, China
| | - Kailun Wu
- Department of Orthopedics, Dushu Lake Hospital Affiliated to Soochow University, Suzhou, China
| | - Huaqing Guan
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Stephen Roche
- Orthopaedic Research Unit, Department of Orthopaedic Surgery, Groote Schuur Hospital and Red Cross Children's Hospital, University of Cape Town, Cape Town, South Africa
| | - Michael F G Held
- Orthopaedic Research Unit, Department of Orthopaedic Surgery, Groote Schuur Hospital and Red Cross Children's Hospital, University of Cape Town, Cape Town, South Africa
| | - Huilin Yang
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jiong Jiong Guo
- Department of Orthopedics, The First Affiliated Hospital of Soochow University, Suzhou, China
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Wagner FC, Reese S, Gerlach K, Böttcher P, Mülling CKW. Cyclic tensile tests of Shetland pony superficial digital flexor tendons (SDFTs) with an optimized cryo-clamp combined with biplanar high-speed fluoroscopy. BMC Vet Res 2021; 17:223. [PMID: 34172051 PMCID: PMC8229380 DOI: 10.1186/s12917-021-02914-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 05/24/2021] [Indexed: 01/20/2023] Open
Abstract
Background Long-term cyclic tensile testing with equine palmar/plantar tendons have not yet been performed due to problems in fixing equine tendons securely and loading them cyclically. It is well established that the biomechanical response of tendons varies during cyclic loading over time. The aim of this study was to develop a clamping device that enables repetitive cyclic tensile testing of equine superficial digital flexor tendon for at least 60 loading cycles and for 5 min. Results A novel cryo-clamp was developed and built. Healthy and collagenase-treated pony SDFTs were mounted in the custom-made cryo-clamp for the proximal tendon end and a special clamping device for the short pastern bone (os coronale). Simultaneously with tensile testing, we used a biplanar high-speed fluoroscopy system (FluoKin) to track tendon movement. The FluoKin system was additionally validated in precision measurements. During the cyclic tensile tests of the SDFTs, the average maximal force measured was 325 N and 953 N for a length variation of 2 and 4 % respectively. The resulting stress averaged 16 MPa and 48 MPa respectively, while the modulus of elasticity was 828 MPa and 1212 MPa respectively. Length variation of the metacarpal region was, on average, 4.87 % higher after incubation with collagenase. The precision of the FluoKin tracking was 0.0377 mm, defined as the standard deviation of pairwise intermarker distances embedded in rigid bodies. The systems accuracy was 0.0287 mm, which is the difference between the machined and mean measured distance. Conclusion In this study, a good performing clamping technique for equine tendons under repetitive cyclic loading conditions is described. The presented cryo-clamps were tested up to 50 min duration and up to the machine maximal capacity of 10 kN. With the possibility of repetitive loading a stabilization of the time-force-curve and changes of hysteresis and creep became obvious after a dozen cycles, which underlines the necessity of repetitive cyclical testing. Furthermore, biplanar high-speed fluoroscopy seems an appropriate and highly precise measurement tool for analysis of tendon behaviour under repetitive load in equine SDFTs. Supplementary Information The online version contains supplementary material available at 10.1186/s12917-021-02914-w.
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Affiliation(s)
- Franziska C Wagner
- Institute of Veterinary Anatomy, Histology and Embryology, Faculty of Veterinary Medicine, Leipzig University, An den Tierkliniken 43, 04103, Leipzig, Germany.
| | - Sven Reese
- Chair of Anatomy, Histology and Embryology, Department of Veterinary Sciences, LMU Munich, Veterinärstraße 13, 80539, Munich, Germany
| | - Kerstin Gerlach
- Department for Horses, Faculty of Veterinary Medicine, Leipzig University, An den Tierkliniken 21, 04103, Leipzig, Germany
| | - Peter Böttcher
- Small Animal Clinic, Department of Veterinary Medicine, Freie Universität Berlin, Oertzenweg 19 b, 14163, Berlin, Germany
| | - Christoph K W Mülling
- Institute of Veterinary Anatomy, Histology and Embryology, Faculty of Veterinary Medicine, Leipzig University, An den Tierkliniken 43, 04103, Leipzig, Germany
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Wagner FC, Gerlach K, Geiger SM, Gittel C, Böttcher P, Mülling CKW. Biplanar High-Speed Fluoroscopy of Pony Superficial Digital Flexor Tendon (SDFT)-An In Vivo Pilot Study. Vet Sci 2021; 8:vetsci8060092. [PMID: 34072030 PMCID: PMC8228745 DOI: 10.3390/vetsci8060092] [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: 04/27/2021] [Revised: 05/22/2021] [Accepted: 05/24/2021] [Indexed: 11/16/2022] Open
Abstract
The superficial digital flexor tendon (SDFT) is the most frequently injured structure of the musculoskeletal system in sport horses and a common cause for early retirement. This project's aim was to visualize and measure the strain of the sound, injured, and healing SDFTs in a pony during walk and trot. For this purpose, biplanar high-speed fluoroscopic kinematography (FluoKin), as a high precision X-ray movement analysis tool, was used for the first time in vivo with equine tendons. The strain in the metacarpal region of the sound SDFT was 2.86% during walk and 6.78% during trot. When injured, the strain increased to 3.38% during walk and decreased to 5.96% during trot. The baseline strain in the mid-metacarpal region was 3.13% during walk and 6.06% during trot and, when injured, decreased to 2.98% and increased to 7.61%, respectively. Following tendon injury, the mid-metacarpal region contributed less to the overall strain during walk but showed increased contribution during trot. Using this marker-based FluoKin technique, direct, high-precision, and long-term strain measurements in the same individual are possible. We conclude that FluoKin is a powerful tool for gaining deeper insight into equine tendon biomechanics.
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Affiliation(s)
- Franziska C. Wagner
- Institute of Veterinary Anatomy, Histology and Embryology, Faculty of Veterinary Medicine, Leipzig University, An den Tierkliniken 43, 04103 Leipzig, Germany; (S.M.G.); (C.K.W.M.)
- Correspondence: ; Tel.: +49-341-97-38054
| | - Kerstin Gerlach
- Department for Horses, Faculty of Veterinary Medicine, Leipzig University, An den Tierkliniken 43, 04103 Leipzig, Germany; (K.G.); (C.G.)
| | - Sandra M. Geiger
- Institute of Veterinary Anatomy, Histology and Embryology, Faculty of Veterinary Medicine, Leipzig University, An den Tierkliniken 43, 04103 Leipzig, Germany; (S.M.G.); (C.K.W.M.)
| | - Claudia Gittel
- Department for Horses, Faculty of Veterinary Medicine, Leipzig University, An den Tierkliniken 43, 04103 Leipzig, Germany; (K.G.); (C.G.)
| | - Peter Böttcher
- Small Animal Clinic, Department of Veterinary Medicine, Freie Universität Berlin, Oertzenweg 19b, 14163 Berlin, Germany;
| | - Christoph K. W. Mülling
- Institute of Veterinary Anatomy, Histology and Embryology, Faculty of Veterinary Medicine, Leipzig University, An den Tierkliniken 43, 04103 Leipzig, Germany; (S.M.G.); (C.K.W.M.)
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Ashinsky B, Smith HE, Mauck RL, Gullbrand SE. Intervertebral disc degeneration and regeneration: a motion segment perspective. Eur Cell Mater 2021; 41:370-380. [PMID: 33763848 PMCID: PMC8607668 DOI: 10.22203/ecm.v041a24] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Back and neck pain have become primary reasons for disability and healthcare spending globally. While the causes of back pain are multifactorial, intervertebral disc degeneration is frequently cited as a primary source of pain. The annulus fibrosus (AF) and nucleus pulposus (NP) subcomponents of the disc are common targets for regenerative therapeutics. However, disc degeneration is also associated with degenerative changes to adjacent spinal tissues, and successful regenerative therapies will likely need to consider and address the pathology of adjacent spinal structures beyond solely the disc subcomponents. This review summarises the current state of knowledge in the field regarding associations between back pain, disc degeneration, and degeneration of the cartilaginous and bony endplates, the AF-vertebral body interface, the facet joints and spinal muscles, in addition to a discussion of regenerative strategies for treating pain and degeneration from a whole motion segment perspective.
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Affiliation(s)
| | | | | | - S E Gullbrand
- Corporal Michael J. Crescenz VA Medical Centre, Research, Building 21, Rm A214, 3900 Woodland Ave, Philadelphia, PA 19104,
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Dyment NA, Barrett JG, Awad H, Bautista CA, Banes A, Butler DL. A brief history of tendon and ligament bioreactors: Impact and future prospects. J Orthop Res 2020; 38:2318-2330. [PMID: 32579266 PMCID: PMC7722018 DOI: 10.1002/jor.24784] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2020] [Revised: 05/28/2020] [Accepted: 06/12/2020] [Indexed: 02/04/2023]
Abstract
Bioreactors are powerful tools with the potential to model tissue development and disease in vitro. For nearly four decades, bioreactors have been used to create tendon and ligament tissue-engineered constructs in order to define basic mechanisms of cell function, extracellular matrix deposition, tissue organization, injury, and tissue remodeling. This review provides a historical perspective of tendon and ligament bioreactors and their contributions to this advancing field. First, we demonstrate the need for bioreactors to improve understanding of tendon and ligament function and dysfunction. Next, we detail the history and evolution of bioreactor development and design from simple stretching of explants to fabrication and stimulation of two- and three-dimensional constructs. Then, we demonstrate how research using tendon and ligament bioreactors has led to pivotal basic science and tissue-engineering discoveries. Finally, we provide guidance for new basic, applied, and clinical research utilizing these valuable systems, recognizing that fundamental knowledge of cell-cell and cell-matrix interactions combined with appropriate mechanical and chemical stimulation of constructs could ultimately lead to functional tendon and ligament repairs in the coming decades.
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Affiliation(s)
- Nathaniel A. Dyment
- McKay Orthopaedic Research Laboratory, University of Pennsylvania, Philadelphia, PA
| | - Jennifer G. Barrett
- Department of Large Animal Clinical Sciences, Marion duPont Scott Equine Medical Center, Virginia Tech, Leesburg, VA
| | - Hani Awad
- Department of Biomedical Engineering, The Center for Musculoskeletal Research, University of Rochester, Rochester, NY 14627
| | | | - Albert Banes
- Flexcell International Corp., 2730 Tucker St., Suite 200, Burlington, 27215, NC
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Chapel Hill, NC
| | - David L. Butler
- Department of Biomedical Engineering, University of Cincinnati, Cincinnati, OH, 45221
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Steered molecular dynamic simulations reveal Marfan syndrome mutations disrupt fibrillin-1 cbEGF domain mechanosensitive calcium binding. Sci Rep 2020; 10:16844. [PMID: 33033378 PMCID: PMC7545174 DOI: 10.1038/s41598-020-73969-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Accepted: 09/02/2020] [Indexed: 12/20/2022] Open
Abstract
Marfan syndrome (MFS) is a highly variable genetic connective tissue disorder caused by mutations in the calcium binding extracellular matrix glycoprotein fibrillin-1. Patients with the most severe form of MFS (neonatal MFS; nMFS) tend to have mutations that cluster in an internal region of fibrillin-1 called the neonatal region. This region is predominantly composed of eight calcium-binding epidermal growth factor-like (cbEGF) domains, each of which binds one calcium ion and is stabilized by three highly conserved disulfide bonds. Crucially, calcium plays a fundamental role in stabilizing cbEGF domains. Perturbed calcium binding caused by cbEGF domain mutations is thus thought to be a central driver of MFS pathophysiology. Using steered molecular dynamics (SMD) simulations, we demonstrate that cbEGF domain calcium binding decreases under mechanical stress (i.e. cbEGF domains are mechanosensitive). We further demonstrate the disulfide bonds in cbEGF domains uniquely orchestrate protein unfolding by showing that MFS disulfide bond mutations markedly disrupt normal mechanosensitive calcium binding dynamics. These results point to a potential mechanosensitive mechanism for fibrillin-1 in regulating extracellular transforming growth factor beta (TGFB) bioavailability and microfibril integrity. Such mechanosensitive “smart” features may represent novel mechanisms for mechanical hemostasis regulation in extracellular matrix that are pathologically activated in MFS.
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16
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Wang HN, Huang YC, Ni GX. Mechanotransduction of stem cells for tendon repair. World J Stem Cells 2020; 12:952-965. [PMID: 33033557 PMCID: PMC7524696 DOI: 10.4252/wjsc.v12.i9.952] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2020] [Revised: 05/06/2020] [Accepted: 07/19/2020] [Indexed: 02/06/2023] Open
Abstract
Tendon is a mechanosensitive tissue that transmits force from muscle to bone. Physiological loading contributes to maintaining the homeostasis and adaptation of tendon, but aberrant loading may lead to injury or failed repair. It is shown that stem cells respond to mechanical loading and play an essential role in both acute and chronic injuries, as well as in tendon repair. In the process of mechanotransduction, mechanical loading is detected by mechanosensors that regulate cell differentiation and proliferation via several signaling pathways. In order to better understand the stem-cell response to mechanical stimulation and the potential mechanism of the tendon repair process, in this review, we summarize the source and role of endogenous and exogenous stem cells active in tendon repair, describe the mechanical response of stem cells, and finally, highlight the mechanotransduction process and underlying signaling pathways.
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Affiliation(s)
- Hao-Nan Wang
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China
| | - Yong-Can Huang
- Shenzhen Engineering Laboratory of Orthopaedic Regenerative Technologies, Department of Spine Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, Guangdong Province, China
| | - Guo-Xin Ni
- School of Sport Medicine and Rehabilitation, Beijing Sport University, Beijing 100084, China.
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17
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Gaul RT, Nolan DR, Ristori T, Bouten CV, Loerakker S, Lally C. Pressure-induced collagen degradation in arterial tissue as a potential mechanism for degenerative arterial disease progression. J Mech Behav Biomed Mater 2020; 109:103771. [DOI: 10.1016/j.jmbbm.2020.103771] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 03/26/2020] [Accepted: 04/01/2020] [Indexed: 12/12/2022]
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18
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Atluri K, Chinnathambi S, Mendenhall A, Martin JA, Sander EA, Salem AK. Targeting Cell Contractile Forces: A Novel Minimally Invasive Treatment Strategy for Fibrosis. Ann Biomed Eng 2020; 48:1850-1862. [PMID: 32236751 PMCID: PMC7286797 DOI: 10.1007/s10439-020-02497-x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Accepted: 03/23/2020] [Indexed: 10/24/2022]
Abstract
Fibrosis is a complication of tendon injury where excessive scar tissue accumulates in and around the injured tissue, leading to painful and restricted joint motion. Unfortunately, fibrosis tends to recur after surgery, creating a need for alternative approaches to disrupt scar tissue. We posited a strategy founded on mechanobiological principles that collagen under tension generated by fibroblasts is resistant to degradation by collagenases. In this study, we tested the hypothesis that blebbistatin, a drug that inhibits cellular contractile forces, would increase the susceptibility of scar tissue to collagenase degradation. Decellularized tendon scaffolds (DTS) were treated with bacterial collagenase with or without external or cell-mediated internal tension. External tension producing strains of 2-4% significantly reduced collagen degradation compared with non-tensioned controls. Internal tension exerted by human fibroblasts seeded on DTS significantly reduced the area of the scaffolds compared to acellular controls and inhibited collagen degradation compared to free-floating DTS. Treatment of cell-seeded DTS with 50 mM blebbistatin restored susceptibility to collagenase degradation, which was significantly greater than in untreated controls (p < 0.01). These findings suggest that therapies combining collagenases with drugs that reduce cell force generation should be considered in cases of tendon fibrosis that do not respond to physiotherapy.
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Tan GK, Pryce BA, Stabio A, Brigande JV, Wang C, Xia Z, Tufa SF, Keene DR, Schweitzer R. Tgfβ signaling is critical for maintenance of the tendon cell fate. eLife 2020; 9:52695. [PMID: 31961320 PMCID: PMC7025861 DOI: 10.7554/elife.52695] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Accepted: 01/17/2020] [Indexed: 12/12/2022] Open
Abstract
Studies of cell fate focus on specification, but little is known about maintenance of the differentiated state. In this study, we find that the mouse tendon cell fate requires continuous maintenance in vivo and identify an essential role for TGFβ signaling in maintenance of the tendon cell fate. To examine the role of TGFβ signaling in tenocyte function the TGFβ type II receptor (Tgfbr2) was targeted in the Scleraxis-expressing cell lineage using the ScxCre deletor. Tendon development was not disrupted in mutant embryos, but shortly after birth tenocytes lost differentiation markers and reverted to a more stem/progenitor state. Viral reintroduction of Tgfbr2 to mutants prevented and even rescued tenocyte dedifferentiation suggesting a continuous and cell autonomous role for TGFβ signaling in cell fate maintenance. These results uncover the critical importance of molecular pathways that maintain the differentiated cell fate and a key role for TGFβ signaling in these processes.
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Affiliation(s)
- Guak-Kim Tan
- Research Division, Shriners Hospital for Children, Portland, United States
| | - Brian A Pryce
- Research Division, Shriners Hospital for Children, Portland, United States
| | - Anna Stabio
- Research Division, Shriners Hospital for Children, Portland, United States
| | - John V Brigande
- Oregon Hearing Research Center, Oregon Health & Science University, Portland, United States
| | - ChaoJie Wang
- Computational Biology Program, Oregon Health & Science University, Portland, United States
| | - Zheng Xia
- Computational Biology Program, Oregon Health & Science University, Portland, United States
| | - Sara F Tufa
- Research Division, Shriners Hospital for Children, Portland, United States
| | - Douglas R Keene
- Research Division, Shriners Hospital for Children, Portland, United States
| | - Ronen Schweitzer
- Research Division, Shriners Hospital for Children, Portland, United States.,Department of Orthopedics, Oregon Health & Science University, Portland, United States
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20
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A multi-chamber tissue culture device for load-dependent parallel evaluation of tendon explants. BMC Musculoskelet Disord 2019; 20:549. [PMID: 31739778 PMCID: PMC6862789 DOI: 10.1186/s12891-019-2896-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2018] [Accepted: 10/14/2019] [Indexed: 11/29/2022] Open
Abstract
Background Injuries in the musculoskeletal system, such as tendon and ligament ruptures, are challenging to manage and often require surgical reconstructions with limited long-term success. Thus, characterizations of these tissues are urgently needed to better understand cellular mechanisms that regulate tissue homeostasis and healing. Explant culturing systems allow for ex vivo analysis of tissues in an environment that mimics the native microenvironment in vivo. Methods Collaborative efforts within our institution facilitated the establishment of a novel explant culturing system. Tissue specimens cultured in single wells, with individual applied loading and/or biological environment, allowed characterization of tissue cultured under a variety of biological loading conditions. Quantitative PCR analysis for selected gene markers was our primary outcome. Results Data were stratified for analysis by either culture environment or loading condition. Our gene expression results show that specimens clustered by culture condition may differ in molecular markers related to ECM production (e.g., Col1a1, Adamts4) and/or organization (e.g., Tnc, Dnc). In contrast, loading condition did significantly alter the median gene expression levels of tissues in comparison to unloaded control samples, although gene expression values related to ECM degradation (e.g., Mmp1, Mmp10) were altered in tendons cultured under tension in the device. Conclusion Our study demonstrates promising utility of a novel explant culturing system for further characterization of musculoskeletal tissues such as native tendons and ligaments, as well as pathologic fibrotic tissues resulting from arthrofibrosis or Dupuytren’s disease.
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A Prospective Randomized Trial Comparing Suture Bridge and Medially Based Single-Row Rotator Cuff Repair in Medium-Sized Supraspinatus Tears. Arthroscopy 2019; 35:2803-2813. [PMID: 31604496 DOI: 10.1016/j.arthro.2019.05.026] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2019] [Revised: 05/12/2019] [Accepted: 05/12/2019] [Indexed: 02/02/2023]
Abstract
PURPOSE To compare the clinical and imaging outcomes between the suture bridge technique (SB) and the medially based single-row technique (medSR) in patients with 1- to 3-cm tear sizes. METHODS All patients were evaluated preoperatively and postoperatively (at 12 and 24 months) using the modified University of California, Los Angeles scoring system; active range of motion (flexion and external rotation); and a visual analog scale for pain. Healing status was examined by postoperative magnetic resonance imaging. RESULTS Clinical and imaging evaluations were completed by 92 patients at 1-year follow-up and by 74 patients at 2 years. No significant differences were found between the 2 groups across all measures at final follow-up: The University of California, Los Angeles scores were 33.4 points in SB patients and 33.0 points in medSR patients (P = .58); the visual analog scale scores were 6 mm and 7 mm, respectively (P = .38); the active flexion angles were 161° and 159°, respectively (P = .34); and the external rotation angles were 49° and 52°, respectively (P = .37). Retears were observed in 6.5% of SB patients and 2.1% of medSR patients (P = .31). Medial cuff failure was observed only in SB patients (4.3%, 2 cases), whereas incomplete healing (deep-layer retraction pattern) was observed only in medSR patients (8.7%, 4 cases). Neo-tendon regeneration in the medSR group was observed in 93% of patients. CONCLUSIONS This study did not show any significant differences in the clinical outcomes and cuff integrity between the 2 treatment groups at final follow-up; however, medial cuff failure was observed only in the SB group, and incomplete healing was more frequent in the medSR group. One should consider the risk of medial cuff failure and incomplete healing of the repaired cuff before choosing the repair technique for medium-sized supraspinatus tears. LEVEL OF EVIDENCE Level I, therapeutic, prospective, randomized trial.
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22
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Water-content related alterations in macro and micro scale tendon biomechanics. Sci Rep 2019; 9:7887. [PMID: 31133713 PMCID: PMC6536550 DOI: 10.1038/s41598-019-44306-z] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Accepted: 05/14/2019] [Indexed: 11/17/2022] Open
Abstract
Though it is known that the water content of biological soft tissues alters mechanical properties, little attempt has been made to adjust the tissue water content prior to biomechanical testing as part of standardization procedures. The objective of this study was to examine the effects of altered water content on the macro and micro scale mechanical tissues properties. Human iliotibial band samples were obtained during autopsies to osmotically adapt their water content. Macro mechanical tensile testing of the samples was conducted with digital image correlation, and micro mechanical tests using atomic force microscopy. Analyses were conducted for elastic moduli, tensile strength, and strain at maximum force, and correlations for water content, anthropometric data, and post-mortem interval. Different mechanical properties exist at different water concentrations. Correlations to anthropometric data are more likely to be found at water concentrations close to the native state. These data underline the need for adapting the water content of soft tissues for macro and micro biomechanical experiments to optimize their validity. The osmotic stress protocol provides a feasible and reliable standardization approach to adjust for water content-related differences induced by age at death, post-mortem interval and tissue processing time with known impact on the stress-strain properties.
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23
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Gaul R, Nolan D, Ristori T, Bouten C, Loerakker S, Lally C. Strain mediated enzymatic degradation of arterial tissue: Insights into the role of the non-collagenous tissue matrix and collagen crimp. Acta Biomater 2018; 77:301-310. [PMID: 30126592 DOI: 10.1016/j.actbio.2018.06.037] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2018] [Revised: 06/04/2018] [Accepted: 06/29/2018] [Indexed: 02/07/2023]
Abstract
Collagen fibre remodelling is a strain dependent process which is stimulated by the degradation of existing collagen. To date, literature has focussed on strain dependent degradation of pure collagen or structurally simple collagenous tissues, often overlooking degradation within more complex, heterogenous soft tissues. The aim of this study is to identify, for the first time, the strain dependent degradation behaviour and mechanical factors influencing collagen degradation in arterial tissue using a combined experimental and numerical approach. To achieve this, structural analysis was carried out using small angle light scattering to determine the fibre level response due to strain induced degradation. Next, strain dependent degradation rates were determined from stress relaxation experiments in the presence of crude and purified collagenase to determine the tissue level degradation response. Finally, a 1D theoretical model was developed, incorporating matrix stiffness and a gradient of collagen fibre crimp to decouple the mechanism behind strain dependent arterial degradation. SALS structural analysis identified a strain mediated degradation response in arterial tissue at the fibre level not dissimilar to that found in literature for pure collagen. Interestingly, two distinctly different strain mediated degradation responses were identified experimentally at the tissue level, not seen in other collagenous tissues. Our model was able to accurately predict these experimental findings, but only once the load bearing matrix, its degradation response and the gradient of collagen fibre crimp across the arterial wall were incorporated. These findings highlight the critical role that the various tissue constituents play in the degradation response of arterial tissue. STATEMENT OF SIGNIFICANCE Collagen fibre architecture is the dominant load bearing component of arterial tissue. Remodelling of this architecture is a strain dependent process stimulated by the degradation of existing collagen. Despite this, degradation of arterial tissue and in particular, arterial collagen, is not fully understood or studied. In the current study, we identified for the first time, the strain dependent degradation response of arterial tissue, which has not been observed in other collagenous tissues in literature. We hypothesised that this unique degradation response was due to the complex structure observed in arterial tissue. Based on this hypothesis, we developed a novel numerical model capable of explaining this unique degradation response which may provide critical insights into disease development and aid in the design of interventional medical devices.
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24
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Biomaterials in Tendon and Skeletal Muscle Tissue Engineering: Current Trends and Challenges. MATERIALS 2018; 11:ma11071116. [PMID: 29966303 PMCID: PMC6073924 DOI: 10.3390/ma11071116] [Citation(s) in RCA: 90] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 06/20/2018] [Accepted: 06/25/2018] [Indexed: 12/17/2022]
Abstract
Tissue engineering is a promising approach to repair tendon and muscle when natural healing fails. Biohybrid constructs obtained after cells’ seeding and culture in dedicated scaffolds have indeed been considered as relevant tools for mimicking native tissue, leading to a better integration in vivo. They can also be employed to perform advanced in vitro studies to model the cell differentiation or regeneration processes. In this review, we report and analyze the different solutions proposed in literature, for the reconstruction of tendon, muscle, and the myotendinous junction. They classically rely on the three pillars of tissue engineering, i.e., cells, biomaterials and environment (both chemical and physical stimuli). We have chosen to present biomimetic or bioinspired strategies based on understanding of the native tissue structure/functions/properties of the tissue of interest. For each tissue, we sorted the relevant publications according to an increasing degree of complexity in the materials’ shape or manufacture. We present their biological and mechanical performances, observed in vitro and in vivo when available. Although there is no consensus for a gold standard technique to reconstruct these musculo-skeletal tissues, the reader can find different ways to progress in the field and to understand the recent history in the choice of materials, from collagen to polymer-based matrices.
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25
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Rakhsha M, Smith CR, Recuero A, Brandon SCE, Vignos MF, Thelen DG, Negrut D. Simulation of surface strain in tibiofemoral cartilage during walking for the prediction of collagen fiber orientation. COMPUTER METHODS IN BIOMECHANICS AND BIOMEDICAL ENGINEERING. IMAGING & VISUALIZATION 2018; 7:396-405. [PMID: 31886037 PMCID: PMC6934360 DOI: 10.1080/21681163.2018.1442751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/16/2017] [Accepted: 02/15/2018] [Indexed: 06/10/2023]
Abstract
The collagen fibers in the superficial layer of tibiofemoral articular cartilage exhibit distinct patterns in orientation revealed by split lines. In this study, we introduce a simulation framework to predict cartilage surface loading during walking to investigate if split line orientations correspond with principal strain directions in the cartilage surface. The two-step framework uses a multibody musculoskeletal model to predict tibiofemoral kinematics which are then imposed on a deformable surface model to predict surface strains. The deformable surface model uses absolute nodal coordinate formulation (ANCF) shell elements to represent the articular surface and a system of spring-dampers and internal pressure to represent the underlying cartilage. Simulations were performed to predict surface strains due to osmotic pressure, loading induced by walking, and the combination of both loading due to pressure and walking. Time-averaged magnitude-weighted first principal strain directions agreed well with split line maps from the literature for both the osmotic pressure and combined cases. This result suggests there is indeed a connection between collagen fiber orientation and mechanical loading, and indicates the importance of accounting for the pre-strain in the cartilage surface due to osmotic pressure.
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Affiliation(s)
- Milad Rakhsha
- Simulation Based Engineering Laboratory (SBEL), Department of Mechanical Engineering, University of Wisconsin-Madison, Madison, Wisconsin 53706
| | - Colin R Smith
- Neuromuscular Biomechanics Laboratory (NMBL), Department of Mechanical Engineering, University of Wisconsin-Madison, Madison, Wisconsin 53706
| | - Antonio Recuero
- Simulation Based Engineering Laboratory (SBEL), Department of Mechanical Engineering, University of Wisconsin-Madison, Madison, Wisconsin 53706
| | - Scott C E Brandon
- Neuromuscular Biomechanics Laboratory (NMBL), Department of Mechanical Engineering, University of Wisconsin-Madison, Madison, Wisconsin 53706
| | - Michael F Vignos
- Neuromuscular Biomechanics Laboratory (NMBL), Department of Mechanical Engineering, University of Wisconsin-Madison, Madison, Wisconsin 53706
| | - Darryl G Thelen
- Neuromuscular Biomechanics Laboratory (NMBL), Department of Mechanical Engineering, University of Wisconsin-Madison, Madison, Wisconsin 53706
| | - Dan Negrut
- Simulation Based Engineering Laboratory (SBEL), Department of Mechanical Engineering, University of Wisconsin-Madison, Madison, Wisconsin 53706
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26
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Growth Description for Vessel Wall Adaptation: A Thick-Walled Mixture Model of Abdominal Aortic Aneurysm Evolution. MATERIALS 2017; 10:ma10090994. [PMID: 28841196 PMCID: PMC5615649 DOI: 10.3390/ma10090994] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Revised: 08/21/2017] [Accepted: 08/23/2017] [Indexed: 12/20/2022]
Abstract
(1) Background: Vascular tissue seems to adapt towards stable homeostatic mechanical conditions, however, failure of reaching homeostasis may result in pathologies. Current vascular tissue adaptation models use many ad hoc assumptions, the implications of which are far from being fully understood; (2) Methods: The present study investigates the plausibility of different growth kinematics in modeling Abdominal Aortic Aneurysm (AAA) evolution in time. A structurally motivated constitutive description for the vessel wall is coupled to multi-constituent tissue growth descriptions; Constituent deposition preserved either the constituent’s density or its volume, and Isotropic Volume Growth (IVG), in-Plane Volume Growth (PVG), in-Thickness Volume Growth (TVG) and No Volume Growth (NVG) describe the kinematics of the growing vessel wall. The sensitivity of key modeling parameters is explored, and predictions are assessed for their plausibility; (3) Results: AAA development based on TVG and NVG kinematics provided not only quantitatively, but also qualitatively different results compared to IVG and PVG kinematics. Specifically, for IVG and PVG kinematics, increasing collagen mass production accelerated AAA expansion which seems counterintuitive. In addition, TVG and NVG kinematics showed less sensitivity to the initial constituent volume fractions, than predictions based on IVG and PVG; (4) Conclusions: The choice of tissue growth kinematics is of crucial importance when modeling AAA growth. Much more interdisciplinary experimental work is required to develop and validate vascular tissue adaption models, before such models can be of any practical use.
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27
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Mazzocca AD, Arciero RA, Shea KP, Apostolakos JM, Solovyova O, Gomlinski G, Wojcik KE, Tafuto V, Stock H, Cote MP. The Effect of Early Range of Motion on Quality of Life, Clinical Outcome, and Repair Integrity After Arthroscopic Rotator Cuff Repair. Arthroscopy 2017; 33:1138-1148. [PMID: 28111006 DOI: 10.1016/j.arthro.2016.10.017] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Revised: 10/04/2016] [Accepted: 10/20/2016] [Indexed: 02/06/2023]
Abstract
PURPOSE To compare the effect of early versus delayed motion protocols on quality of life, clinical outcomes, and repair integrity in patients who have undergone arthroscopic single-tendon rotator cuff repair. METHODS This was a prospective, randomized, investigator-blinded clinical trial. Seventy-three patients from a single surgeon's practice who underwent arthroscopic repair of a single-tendon rotator cuff tear were randomized to either an early motion protocol (starting 2 to 3 days after surgery) or a delayed motion protocol (starting 28 days after surgery). The primary outcome measure was the Western Ontario Rotator Cuff index (WORC). Secondary outcome measures included clinical outcome scores, integrity of the repair on 6-month magnetic resonance imaging scans, pain scores, physical examination data, and ultrasonography. Study participants were followed up at 3, 6, and 12 weeks; 6 months; and 1 year postoperatively. RESULTS There was no statistically significant difference in WORC scores at 6 months (529 ± 472 in delayed group vs 325 ± 400 in early group, P = .08). Mixed-effects analysis indicated the early group maintained lower WORC scores throughout the postoperative period (estimated difference of 191, P = .04). The proportions of patients with tears on the 6-month postoperative magnetic resonance imaging scan were comparable (31% in delayed group vs 34% in early group, P = .78). CONCLUSIONS There was no difference between the delayed and early motion groups in WORC scores at 6 months after surgery. Early motion was associated with lower WORC scores throughout the postoperative period; however, both groups had a similar trajectory of improvement, suggesting both protocols have the same effect on patient-reported improvement. Although failure rates were similar between the groups, the sample size was not sufficient to support a statement regarding the relation between tear morphology and the rehabilitation protocol. LEVEL OF EVIDENCE Level II, lesser-quality randomized controlled trial.
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Affiliation(s)
| | - Robert A Arciero
- University of Connecticut Health Center, Farmington, Connecticut, U.S.A
| | - Kevin P Shea
- University of Connecticut Health Center, Farmington, Connecticut, U.S.A
| | | | - Olga Solovyova
- University of Connecticut Health Center, Farmington, Connecticut, U.S.A
| | - Gregg Gomlinski
- University of Connecticut Health Center, Farmington, Connecticut, U.S.A
| | - Karen E Wojcik
- University of Connecticut Health Center, Farmington, Connecticut, U.S.A
| | - Vincent Tafuto
- University of Connecticut Health Center, Farmington, Connecticut, U.S.A
| | - Harlan Stock
- University of Connecticut Health Center, Farmington, Connecticut, U.S.A
| | - Mark P Cote
- University of Connecticut Health Center, Farmington, Connecticut, U.S.A..
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28
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Gasser TC, Grytsan A. Biomechanical modeling the adaptation of soft biological tissue. CURRENT OPINION IN BIOMEDICAL ENGINEERING 2017. [DOI: 10.1016/j.cobme.2017.03.004] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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29
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Huang S, Huang HYS. Biaxial stress relaxation of semilunar heart valve leaflets during simulated collagen catabolism: Effects of collagenase concentration and equibiaxial strain state. Proc Inst Mech Eng H 2016; 229:721-31. [PMID: 26405097 DOI: 10.1177/0954411915604336] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Heart valve leaflet collagen turnover and remodeling are innate to physiological homeostasis; valvular interstitial cells routinely catabolize damaged collagen and affect repair. Moreover, evidence indicates that leaflets can adapt to altered physiological (e.g. pregnancy) and pathological (e.g. hypertension) mechanical load states, tuning collagen structure and composition to changes in pressure and flow. However, while valvular interstitial cell-secreted matrix metalloproteinases are considered the primary effectors of collagen catabolism, the mechanisms by which damaged collagen fibers are selectively degraded remain unclear. Growing evidence suggests that the collagen fiber strain state plays a key role, with the strain-dependent configuration of the collagen molecules either masking or presenting proteolytic sites, thereby protecting or accelerating collagen proteolysis. In this study, the effects of equibiaxial strain state on collagen catabolism were investigated in porcine aortic valve and pulmonary valve tissues. Bacterial collagenase (0.2 and 0.5 mg/mL) was utilized to simulate endogenous matrix metalloproteinases, and biaxial stress relaxation and biochemical collagen concentration served as functional and compositional measures of collagen catabolism, respectively. At a collagenase concentration of 0.5 mg/mL, increasing the equibiaxial strain imposed during stress relaxation (0%, 37.5%, and 50%) yielded significantly lower median collagen concentrations in the aortic valve (p = 0.0231) and pulmonary valve (p = 0.0183), suggesting that relatively large strain magnitudes may enhance collagen catabolism. Collagen concentration decreases were paralleled by trends of accelerated normalized stress relaxation rate with equibiaxial strain in aortic valve tissues. Collectively, these in vitro results indicate that biaxial strain state is capable of affecting the susceptibility of valvular collagens to catabolism, providing a basis for further investigation of how such phenomena may manifest at different strain magnitudes or in vivo.
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Affiliation(s)
- Siyao Huang
- Department of Mechanical & Aerospace Engineering, North Carolina State University, Raleigh, NC, USA
| | - Hsiao-Ying Shadow Huang
- Department of Mechanical & Aerospace Engineering, North Carolina State University, Raleigh, NC, USA
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30
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Tonge TK, Ruberti JW, Nguyen TD. Micromechanical Modeling Study of Mechanical Inhibition of Enzymatic Degradation of Collagen Tissues. Biophys J 2016; 109:2689-2700. [PMID: 26682825 DOI: 10.1016/j.bpj.2015.10.051] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2015] [Revised: 10/22/2015] [Accepted: 10/27/2015] [Indexed: 02/07/2023] Open
Abstract
This study investigates how the collagen fiber structure influences the enzymatic degradation of collagen tissues. We developed a micromechanical model of a fibrous collagen tissue undergoing enzymatic degradation based on two central hypotheses. The collagen fibers are crimped in the undeformed configuration. Enzymatic degradation is an energy activated process and the activation energy is increased by the axial strain energy density of the fiber. We determined the intrinsic degradation rate and characteristic energy for mechanical inhibition from fibril-level degradation experiments and applied the parameters to predict the effect of the crimped fiber structure and fiber properties on the degradation of bovine cornea and pericardium tissues under controlled tension. We then applied the model to examine the effect of the tissue stress state on the rate of tissue degradation and the anisotropic fiber structures that developed from enzymatic degradation.
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Affiliation(s)
- Theresa K Tonge
- Department of Mechanical Engineering, The Johns Hopkins University, Baltimore, Maryland
| | - Jeffrey W Ruberti
- Department of Bioengineering, Northeastern University, Boston, Massachusetts
| | - Thao D Nguyen
- Department of Mechanical Engineering, The Johns Hopkins University, Baltimore, Maryland.
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31
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Internal strain drives spontaneous periodic buckling in collagen and regulates remodeling. Proc Natl Acad Sci U S A 2016; 113:8436-41. [PMID: 27402741 DOI: 10.1073/pnas.1523228113] [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: 02/08/2023] Open
Abstract
Fibrillar collagen, an essential structural component of the extracellular matrix, is remarkably resistant to proteolysis, requiring specialized matrix metalloproteinases (MMPs) to initiate its remodeling. In the context of native fibrils, remodeling is poorly understood; MMPs have limited access to cleavage sites and are inhibited by tension on the fibril. Here, single-molecule recordings of fluorescently labeled MMPs reveal cleavage-vulnerable binding regions arrayed periodically at ∼1-µm intervals along collagen fibrils. Binding regions remain periodic even as they migrate on the fibril, indicating a collective process of thermally activated and self-healing defect formation. An internal strain relief model involving reversible structural rearrangements quantitatively reproduces the observed spatial patterning and fluctuations of defects and provides a mechanism for tension-dependent stabilization of fibrillar collagen. This work identifies internal-strain-driven defects that may have general and widespread regulatory functions in self-assembled biological filaments.
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32
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Susilo ME, Paten JA, Sander EA, Nguyen TD, Ruberti JW. Collagen network strengthening following cyclic tensile loading. Interface Focus 2016; 6:20150088. [PMID: 26855760 PMCID: PMC4686249 DOI: 10.1098/rsfs.2015.0088] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2025] Open
Abstract
The bulk mechanical properties of tissues are highly tuned to the physiological loads they experience and reflect the hierarchical structure and mechanical properties of their constituent parts. A thorough understanding of the processes involved in tissue adaptation is required to develop multi-scale computational models of tissue remodelling. While extracellular matrix (ECM) remodelling is partly due to the changing cellular metabolic activity, there may also be mechanically directed changes in ECM nano/microscale organization which lead to mechanical tuning. The thermal and enzymatic stability of collagen, which is the principal load-bearing biopolymer in vertebrates, have been shown to be enhanced by force suggesting that collagen has an active role in ECM mechanical properties. Here, we ask how changes in the mechanical properties of a collagen-based material are reflected by alterations in the micro/nanoscale collagen network following cyclic loading. Surprisingly, we observed significantly higher tensile stiffness and ultimate tensile strength, roughly analogous to the effect of work hardening, in the absence of network realignment and alterations to the fibril area fraction. The data suggest that mechanical loading induces stabilizing changes internal to the fibrils themselves or in the fibril-fibril interactions. If such a cell-independent strengthening effect is operational in vivo, then it would be an important consideration in any multiscale computational approach to ECM growth and remodelling.
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Affiliation(s)
| | | | - Edward A. Sander
- Biomedical Engineering,
University of Iowa, Iowa City, IA
52242, USA
| | - Thao D. Nguyen
- Mechanical Engineering,
Johns Hopkins, Baltimore, MD
21218, USA
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33
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Yamakado K. The suprascapular notch narrows with aging: a preliminary solution of the old conjecture based on a 3D-CT evaluation. Surg Radiol Anat 2016; 38:693-7. [PMID: 26732771 DOI: 10.1007/s00276-015-1614-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2015] [Accepted: 12/22/2015] [Indexed: 10/22/2022]
Abstract
PURPOSE The purpose of this study was to describe the morphology of the suprascapular notch in terms of age distribution. We hypothesized that the notch narrows with aging. METHODS Seven hundred and sixty consecutive patients (465 men and 295 women) scheduled for a shoulder surgery were retrospectively reviewed. A 3D-CT of the shoulder was taken to evaluate the shape of the notch according to the Rengachary classification. The six types of Rengachary classification were arranged into three major categories according to transverse scapular ligament ossification and notch size as follows: the wide notch (type 1 and type 2); the narrow notch (type 3 and type 4); and the ossified notch (type 5 and type 6). Comparisons between categories were done with a one-way analysis of variance. RESULTS There was a statistically significant difference among the three categories (P < .01): the narrow notch group (n = 442, 63.4 ± 12.8 years) and the ossified notch group (n = 66, 65.9 ± 10.6 years) were significantly older than the wide notch group (n = 252, 57.5 ± 17.8 years), respectively. In patients with Rengachary type 5 shoulders, ossification was dominant on the medial side of the notch in 37 of 39 shoulders (92.3 %). CONCLUSION The current study showed that morphological changes of the scapular notch are related to aging. The narrow notch and the ossified notch are seemed to be developed from the wide notch in terms of the ossification starting from the medial side.
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Affiliation(s)
- Kotaro Yamakado
- Department of Orthopaedics, Fukui General Hospital, 58-16-1 Egami, Fukui, Fukui, 9108561, Japan.
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34
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Wang T, Lin Z, Ni M, Thien C, Day RE, Gardiner B, Rubenson J, Kirk TB, Smith DW, Wang A, Lloyd DG, Wang Y, Zheng Q, Zheng MH. Cyclic mechanical stimulation rescues achilles tendon from degeneration in a bioreactor system. J Orthop Res 2015; 33:1888-96. [PMID: 26123799 DOI: 10.1002/jor.22960] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2015] [Accepted: 05/30/2015] [Indexed: 02/04/2023]
Abstract
Physiotherapy is one of the effective treatments for tendinopathy, whereby symptoms are relieved by changing the biomechanical environment of the pathological tendon. However, the underlying mechanism remains unclear. In this study, we first established a model of progressive tendinopathy-like degeneration in the rabbit Achilles. Following ex vivo loading deprivation culture in a bioreactor system for 6 and 12 days, tendons exhibited progressive degenerative changes, abnormal collagen type III production, increased cell apoptosis, and weakened mechanical properties. When intervention was applied at day 7 for another 6 days by using cyclic tensile mechanical stimulation (6% strain, 0.25 Hz, 8 h/day) in a bioreactor, the pathological changes and mechanical properties were almost restored to levels seen in healthy tendon. Our results indicated that a proper biomechanical environment was able to rescue early-stage pathological changes by increased collagen type I production, decreased collagen degradation and cell apoptosis. The ex vivo model developed in this study allows systematic study on the effect of mechanical stimulation on tendon biology.
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Affiliation(s)
- Tao Wang
- Division of Orthopaedic Surgery, Department of Surgery, Guangdong General Hospital, Guangdong Academy of Medicine Science, Guangzhou, Guangdong, China.,Centre for Orthopaedic Translational Research, School of Surgery, University of Western Australia, Nedlands, Australia
| | - Zhen Lin
- Centre for Orthopaedic Translational Research, School of Surgery, University of Western Australia, Nedlands, Australia
| | - Ming Ni
- Department of Orthopaedics, The General Hospital of Chinese People's Liberation Army, Beijing, China
| | - Christine Thien
- Centre for Orthopaedic Translational Research, School of Surgery, University of Western Australia, Nedlands, Australia
| | - Robert E Day
- Department of Medical Engineering and Physics, Royal Perth Hospital, Perth, Australia
| | - Bruce Gardiner
- School of Computer Science and Software Engineering, University of Western Australia, Crawley, Australia
| | - Jonas Rubenson
- School of Sport Science, Exercise and Health, University of Western Australia, Crawley, Australia
| | | | - David W Smith
- School of Computer Science and Software Engineering, University of Western Australia, Crawley, Australia
| | - Allan Wang
- Sir Charles Gairdner Hospital, Perth, Australia
| | - David G Lloyd
- Centre for Musculoskeletal Research, Griffith Health Institute, Griffith University, Gold Coast, Australia
| | - Yan Wang
- Department of Orthopaedics, The General Hospital of Chinese People's Liberation Army, Beijing, China
| | - Qiujian Zheng
- Division of Orthopaedic Surgery, Department of Surgery, Guangdong General Hospital, Guangdong Academy of Medicine Science, Guangzhou, Guangdong, China
| | - Ming H Zheng
- Centre for Orthopaedic Translational Research, School of Surgery, University of Western Australia, Nedlands, Australia
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35
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Chang EY, Du J, Biswas R, Statum S, Pauli C, Bae WC, Chung CB. Off-resonance saturation ratio obtained with ultrashort echo time-magnetization transfer techniques is sensitive to changes in static tensile loading of tendons and degeneration. J Magn Reson Imaging 2015; 42:1064-71. [PMID: 25808266 DOI: 10.1002/jmri.24881] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2014] [Accepted: 02/18/2015] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND To determine if off-saturation ratio (OSR) measured with the ultrashort echo time magnetization transfer (UTE-MT) sequence could differentiate between tendons under different states of tensile load and to compare these changes between normal versus degenerated tendons. METHODS Fourteen tendons were imaged at 3 Tesla before and during the application of 0.5-1 kg tension. A two-dimensional (2D) -UTE-MT sequence with 1.5, 3, and 5 kHz frequency offsets was used on nine tendons and a 3D-UTE-MT sequence with 1.5 kHz frequency offset was used on five tendons. OSR was calculated and compared for each condition. Histologic correlation was performed using light microscopy. RESULTS In general, OSR increased after the application of tension. Mean increase of 2D OSR was 0.035 (95% confidence interval [CI], 0.013-0.056) at 1.5 kHz offset (P < 0.01), 0.031 (95% CI, 0.023-0.040) at 3 kHz offset (P < 0.01), and 0.013 (95% CI, -0.013-0.027) at 5 kHz offset (P = 0.07) from pre- to posttension states. Mean increase of 3D OSR was 0.026 (95% CI, 0.008-0.044) at a 1.5 kHz offset (P = 0.02) from pre- to posttension states. Mean decrease of 2D OSR at 1.5 kHz offset was 0.074-0.087 when comparing normal versus degenerated tendons (P < 0.01). CONCLUSION OSR as measured with 2D or 3D UTE-MT sequences can detect the changes in hydration seen when tendons are placed under two different states of tensile load, but these changes are smaller than those encountered when comparing between normal versus pathologic tendons. Lower off-resonance saturation frequencies (3 kHz or less) are more sensitive to these changes than higher off-resonance saturation frequencies.
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Affiliation(s)
- Eric Y Chang
- Radiology Service, VA San Diego Healthcare System, San Diego, California, USA.,Department of Radiology, University of California, San Diego Medical Center, San Diego, California, USA
| | - Jiang Du
- Department of Radiology, University of California, San Diego Medical Center, San Diego, California, USA
| | - Reni Biswas
- Department of Radiology, University of California, San Diego Medical Center, San Diego, California, USA
| | - Sheronda Statum
- Department of Radiology, University of California, San Diego Medical Center, San Diego, California, USA
| | - Chantal Pauli
- Institute of Surgical Pathology, University Hospital Zurich, Zurich, Switzerland
| | - Won C Bae
- Department of Radiology, University of California, San Diego Medical Center, San Diego, California, USA
| | - Christine B Chung
- Radiology Service, VA San Diego Healthcare System, San Diego, California, USA.,Department of Radiology, University of California, San Diego Medical Center, San Diego, California, USA
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36
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Heck TAM, Wilson W, Foolen J, Cilingir AC, Ito K, van Donkelaar CC. A tissue adaptation model based on strain-dependent collagen degradation and contact-guided cell traction. J Biomech 2014; 48:823-31. [PMID: 25560271 DOI: 10.1016/j.jbiomech.2014.12.023] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/26/2014] [Indexed: 02/02/2023]
Abstract
Soft biological tissues adapt their collagen network to the mechanical environment. Collagen remodeling and cell traction are both involved in this process. The present study presents a collagen adaptation model which includes strain-dependent collagen degradation and contact-guided cell traction. Cell traction is determined by the prevailing collagen structure and is assumed to strive for tensional homeostasis. In addition, collagen is assumed to mechanically fail if it is over-strained. Care is taken to use principally measurable and physiologically meaningful relationships. This model is implemented in a fibril-reinforced biphasic finite element model for soft hydrated tissues. The versatility and limitations of the model are demonstrated by corroborating the predicted transient and equilibrium collagen adaptation under distinct mechanical constraints against experimental observations from the literature. These experiments include overloading of pericardium explants until failure, static uniaxial and biaxial loading of cell-seeded gels in vitro and shortening of periosteum explants. In addition, remodeling under hypothetical conditions is explored to demonstrate how collagen might adapt to small differences in constraints. Typical aspects of all essentially different experimental conditions are captured quantitatively or qualitatively. Differences between predictions and experiments as well as new insights that emerge from the present simulations are discussed. This model is anticipated to evolve into a mechanistic description of collagen adaptation, which may assist in developing load-regimes for functional tissue engineered constructs, or may be employed to improve our understanding of the mechanisms behind physiological and pathological collagen remodeling.
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Affiliation(s)
- T A M Heck
- Orthopaedic Biomechanics, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands
| | - W Wilson
- Orthopaedic Biomechanics, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands
| | - J Foolen
- Orthopaedic Biomechanics, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands
| | - A C Cilingir
- Mechanical Engineering Department, Sakarya University, Sakarya, Turkey
| | - K Ito
- Orthopaedic Biomechanics, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands
| | - C C van Donkelaar
- Orthopaedic Biomechanics, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands.
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37
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Chang EY, Du J, Iwasaki K, Biswas R, Statum S, He Q, Bae WC, Chung CB. Single- and Bi-component T2* analysis of tendon before and during tensile loading, using UTE sequences. J Magn Reson Imaging 2014; 42:114-20. [PMID: 25223714 DOI: 10.1002/jmri.24758] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2014] [Accepted: 08/28/2014] [Indexed: 11/07/2022] Open
Abstract
BACKGROUND To determine if the application of tensile force alters the single- or bi-component T2* values of human tendons as measured on a clinical MRI scanner with ultrashort echo time (UTE sequences and if single- or bi-component T2* values differ when measured with 2D-UTE, 3D-UTE, or 3D-UTE-Cones sequences. METHODS Ten tendons were imaged before and during the application of tension using various UTE sequences at 3 Tesla. Single and bi-component T2* analysis was performed pre- and posttension and compared with Bonferroni-corrected paired Wilcoxon tests. RESULTS Range of mean pre- and posttension T2* analysis values were: short T2* fraction (78.6-79.7% and 77.3-79.7%, respectively; P = 1.0 for all sequences), long T2* fraction (20.3-21.4% and 20.3-22.7%, respectively; P = 1.0 for all sequences), short T2* (0.9-1.0 ms and 0.9 ms, respectively; P = 1.0 for all sequences), long T2* (19.9-20.4 ms and 21.9-24.0 ms, respectively; P = 0.9 for 2D-UTE and P = 1.0 for 3D-UTE and 3D-UTE-Cones), and single-component T2* (2.3-2.5 ms and 2.5-3.2 ms, respectively; P = 1.0 for all sequences). CONCLUSION No significant difference in single- or bi-component results was found after the application of tension to tendons. Results are similar regardless of UTE sequence used for acquisition.
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Affiliation(s)
- Eric Y Chang
- Radiology Service, VA San Diego Healthcare System, San Diego, California, USA.,Department of Radiology, University of California, San Diego Medical Center, San Diego, California, USA
| | - Jiang Du
- Department of Radiology, University of California, San Diego Medical Center, San Diego, California, USA
| | - Kenyu Iwasaki
- Department of Radiology, University of California, San Diego Medical Center, San Diego, California, USA
| | - Reni Biswas
- Department of Radiology, University of California, San Diego Medical Center, San Diego, California, USA
| | - Sheronda Statum
- Department of Radiology, University of California, San Diego Medical Center, San Diego, California, USA
| | - Qun He
- Department of Radiology, University of California, San Diego Medical Center, San Diego, California, USA
| | - Won C Bae
- Department of Radiology, University of California, San Diego Medical Center, San Diego, California, USA
| | - Christine B Chung
- Radiology Service, VA San Diego Healthcare System, San Diego, California, USA.,Department of Radiology, University of California, San Diego Medical Center, San Diego, California, USA
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38
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Abstract
Degradation of fibrillar collagen is critical for tissue maintenance. Yet, understanding collagen catabolism has been challenging partly due to a lack of atomistic picture for its load-dependent conformational dynamics, as both mechanical load and local unfolding of collagen affect its cleavage by matrix metalloproteinase (MMP). We use molecular dynamics simulation to find the most cleavage-prone arrangement of α chains in a collagen triple helix and find amino acids that modulate stability of the MMP cleavage domain depending on the chain registry within the molecule. The native-like state is mechanically inhomogeneous, where the cleavage site interfaces a stiff region and a locally unfolded and flexible region along the molecule. In contrast, a triple helix made of the stable glycine-proline-hydroxyproline motif is uniformly flexible and is dynamically stabilized by short-lived, low-occupancy hydrogen bonds. These results provide an atomistic basis for the mechanics, conformation, and stability of collagen that affect catabolism.
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Affiliation(s)
- Xiaojing Teng
- Department of Biomedical Engineering and ‡Department of Materials Science and Engineering, Texas A&M University , College Station, Texas 77843, United States
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39
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Lanir Y. Mechanistic micro-structural theory of soft tissues growth and remodeling: tissues with unidirectional fibers. Biomech Model Mechanobiol 2014; 14:245-66. [DOI: 10.1007/s10237-014-0600-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2013] [Accepted: 05/23/2014] [Indexed: 10/25/2022]
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40
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Khoshgoftar M, Wilson W, Ito K, van Donkelaar CC. Influence of the Temporal Deposition of Extracellular Matrix on the Mechanical Properties of Tissue-Engineered Cartilage. Tissue Eng Part A 2014; 20:1476-85. [DOI: 10.1089/ten.tea.2013.0345] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Mehdi Khoshgoftar
- Orthopaedic Biomechanics, Department of Biomedical Engineering, Eindhoven University of Technology, Eindhoven, The Netherlands
| | - Wouter Wilson
- 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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41
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Bourne JW, Lippell JM, Torzilli PA. Glycation cross-linking induced mechanical-enzymatic cleavage of microscale tendon fibers. Matrix Biol 2013; 34:179-84. [PMID: 24316373 DOI: 10.1016/j.matbio.2013.11.005] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2013] [Revised: 11/27/2013] [Accepted: 11/28/2013] [Indexed: 01/26/2023]
Abstract
Recent molecular modeling data using collagen peptides predicted that mechanical force transmitted through intermolecular cross-links resulted in collagen triple helix unwinding. These simulations further predicted that this unwinding, referred to as triple helical microunfolding, occurred at forces well below canonical collagen damage mechanisms. Based in large part on these data, we hypothesized that mechanical loading of glycation cross-linked tendon microfibers would result in accelerated collagenolytic enzyme damage. This hypothesis is in stark contrast to reports in literature that indicated that individually mechanical loading or cross-linking each retards enzymatic degradation of collagen substrates. Using our Collagen Enzyme Mechano-Kinetic Automated Testing (CEMKAT) System we mechanically loaded collagen-rich tendon microfibers that had been chemically cross-linked with sugar and tested for degrading enzyme susceptibility. Our results indicated that cross-linked fibers were >5 times more resistant to enzymatic degradation while unloaded but became highly susceptible to enzyme cleavage when they were stretched by an applied mechanical deformation.
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Affiliation(s)
- Jonathan W Bourne
- Laboratory for Soft Tissue Research, Tissue Engineering, Regeneration and Repair Program, Hospital for Special Surgery, 535 East 70th Street, New York, New York 10021, United States; Physiology, Biophysics & Systems Biology Program, Weill Graduate School of Medical Sciences, Cornell University, 1300 York Avenue, New York, New York 10065, United States.
| | - Jared M Lippell
- Laboratory for Soft Tissue Research, Tissue Engineering, Regeneration and Repair Program, Hospital for Special Surgery, 535 East 70th Street, New York, New York 10021, United States
| | - Peter A Torzilli
- Laboratory for Soft Tissue Research, Tissue Engineering, Regeneration and Repair Program, Hospital for Special Surgery, 535 East 70th Street, New York, New York 10021, United States; Physiology, Biophysics & Systems Biology Program, Weill Graduate School of Medical Sciences, Cornell University, 1300 York Avenue, New York, New York 10065, United States
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42
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Key S, Adams MA, Stefanakis M. Healing of painful intervertebral discs: implications for physiotherapy Part 2 — pressure change therapy: a proposed clinical model to stimulate disc healing. PHYSICAL THERAPY REVIEWS 2013. [DOI: 10.1179/1743288x12y.0000000038] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2022]
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43
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Galloway MT, Lalley AL, Shearn JT. The role of mechanical loading in tendon development, maintenance, injury, and repair. J Bone Joint Surg Am 2013; 95:1620-8. [PMID: 24005204 PMCID: PMC3748997 DOI: 10.2106/jbjs.l.01004] [Citation(s) in RCA: 165] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Tendon injuries often result from excessive or insufficient mechanical loading, impairing the ability of the local tendon cell population to maintain normal tendon function. The resident cell population composing tendon tissue is mechanosensitive, given that the cells are able to alter the extracellular matrix in response to modifications of the local loading environment. Natural tendon healing is insufficient, characterized by improper collagen fibril diameter formation, collagen fibril distribution, and overall fibril misalignment. Current tendon repair rehabilitation protocols focus on implementing early, well-controlled eccentric loading exercises to improve repair outcome. Tissue engineers look toward incorporating mechanical loading regimens to precondition cell populations for the creation of improved biological augmentations for tendon repair.
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Affiliation(s)
- Marc T. Galloway
- Cincinnati Sports Medicine and Orthopaedic Center, 7423 Mason Montgomery Road, Cincinnati, OH 45249
| | - Andrea L. Lalley
- Engineering Research Center, University of Cincinnati, 2901 Woodside Drive, ERC Room 701, Cincinnati, OH 45221. E-mail address for A.L. Lalley:
| | - Jason T. Shearn
- Engineering Research Center, University of Cincinnati, 2901 Woodside Drive, ERC Room 701, Cincinnati, OH 45221. E-mail address for A.L. Lalley:
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44
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Toledano M, Aguilera FS, Yamauti M, Ruiz-Requena ME, Osorio R. In vitro load-induced dentin collagen-stabilization against MMPs degradation. J Mech Behav Biomed Mater 2013; 27:10-8. [PMID: 23834971 DOI: 10.1016/j.jmbbm.2013.06.002] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2013] [Revised: 05/27/2013] [Accepted: 06/06/2013] [Indexed: 11/30/2022]
Abstract
INTRODUCTION Teeth are continuously subjected to stresses during mastication, swallowing and parafunctional habits, producing a significant reduction of the bonding efficacy in adhesive restorations. The purpose of this study was to evaluate the metalloproteinases (MMPs)-mediated dentin collagen degradation of hybrid layers created by using different demineralization processes, previous resin infiltration, and in vitro mechanical loading. METHODS Human dentin beams (0.75×0.75×5.0mm) were subjected to different treatments: (1) untreated dentin; (2) demineralization by 37% phosphoric acid (PA) or by 0.5% M ethylenediaminetetraacetic acid (EDTA); (3) demineralization by PA, followed by application of Adper(™) Single Bond (SB); (4) demineralization by EDTA, followed by application of SB. In half of the specimens, mechanical loadings (100,000 cycles, 2Hz, 49N) were applied to dentin beams. Specimens were stored in artificial saliva. C-terminal telopeptide (ICTP), determinations (which indicates the amount of collagen degradation) (radioimmunoassay) were performed after 24h, 1 week and 4 weeks. RESULTS Load cycling decreased collagen degradation when dentin was untreated or PA-demineralized and EDTA-treated. ICTP values increased when both PA-demineralized and EDTA-treated and infiltrated with SB dentin beams were loaded, except in samples that were subjected to EDTA treatment and SB infiltration after 4w of storage, which showed similar values of collagenolytic activity than the non loaded specimens. Load cycling preserved the initial (24h) ICTP determination at any time point, in all groups of the study, except in PA-demineralized and SB infiltrated dentin which showed an increased of collagen degradation values, over time. This same trend was observed in all groups without loading. INTERPRETATION Mechanical loading enhances collagen's resistance to enzymatic degradation in natural and demineralized dentin. Mild acids (EDTA) lead to a lower volume of demineralized/unprotected collagen to be cleaved by MMPs. Load cycling produced an increase of collagen degradation when PA-demineralized dentin and EDTA-treated dentin were infiltrated with resin, but EDTA-treated dentin showed a constant collagenolytic degradation, over time.
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Affiliation(s)
- Manuel Toledano
- Department of Dental Materials, School of Dentistry, University of Granada, E-18071 Granada, Spain.
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Smith DW, Rubenson J, Lloyd D, Zheng M, Fernandez J, Besier T, Xu J, Gardiner BS. A conceptual framework for computational models of Achilles tendon homeostasis. WILEY INTERDISCIPLINARY REVIEWS-SYSTEMS BIOLOGY AND MEDICINE 2013; 5:523-38. [PMID: 23757159 DOI: 10.1002/wsbm.1229] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/07/2012] [Revised: 04/22/2013] [Accepted: 04/25/2013] [Indexed: 12/31/2022]
Abstract
Computational modeling of tendon lags the development of computational models for other tissues. A major bottleneck in the development of realistic computational models for Achilles tendon is the absence of detailed conceptual and theoretical models as to how the tissue actually functions. Without the conceptual models to provide a theoretical framework to guide the development and integration of multiscale computational models, modeling of the Achilles tendon to date has tended to be piecemeal and focused on specific mechanical or biochemical issues. In this paper, we present a new conceptual model of Achilles tendon tissue homeostasis, and discuss this model in terms of existing computational models of tendon. This approach has the benefits of structuring the research on relevant computational modeling to date, while allowing us to identify new computational models requiring development. The critically important functional issue for tendon is that it is continually damaged during use and so has to be repaired. From this follows the centrally important issue of homeostasis of the load carrying collagen fibrils within the collagen fibers of the Achilles tendon. Collagen fibrils may be damaged mechanically-by loading, or damaged biochemically-by proteases. Upon reviewing existing computational models within this conceptual framework of the Achilles tendon structure and function, we demonstrate that a great deal of theoretical and experimental research remains to be done before there are reliably predictive multiscale computational model of Achilles tendon in health and disease.
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Affiliation(s)
- David W Smith
- Faculty of Engineering, Computing, and Mathematics, The University of Western Australia, Crawley, Western Australia, Australia
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A novel in vitro loading system for high frequency loading of cultured tendon fascicles. Med Eng Phys 2013; 35:205-10. [DOI: 10.1016/j.medengphy.2012.08.015] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2012] [Revised: 07/05/2012] [Accepted: 08/18/2012] [Indexed: 11/24/2022]
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Torzilli PA, Bourne JW, Cigler T, Vincent CT. A new paradigm for mechanobiological mechanisms in tumor metastasis. Semin Cancer Biol 2012; 22:385-95. [PMID: 22613484 PMCID: PMC3445741 DOI: 10.1016/j.semcancer.2012.05.002] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2012] [Accepted: 05/13/2012] [Indexed: 12/24/2022]
Abstract
Tumor metastases and epithelial to mesenchymal transition (EMT) involve tumor cell invasion and migration through the dense collagen-rich extracellular matrix surrounding the tumor. Little is neither known about the mechanobiological mechanisms involved in this process, nor the role of the mechanical forces generated by the cells in their effort to invade and migrate through the stroma. In this paper we propose a new fundamental mechanobiological mechanism involved in cancer growth and metastasis, which can be both protective or destructive depending on the magnitude of the forces generated by the cells. This new mechanobiological mechanism directly challenges current paradigms that are focused mainly on biological and biochemical mechanisms associated with tumor metastasis. Our new mechanobiological mechanism describes how tumor expansion generates mechanical forces within the stroma to not only resist tumor expansion but also inhibit or enhance tumor invasion by, respectively, inhibiting or enhancing matrix metalloproteinase (MMP) degradation of the tensed interstitial collagen. While this mechanobiological mechanism has not been previously applied to the study of tumor metastasis and EMT, it may have the potential to broaden our understanding of the tumor invasive process and assist in developing new strategies for preventing or treating cancer metastasis.
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Affiliation(s)
- Peter A Torzilli
- Tissue Engineering, Regeneration and Repair Program, Hospital for Special Surgery, New York, NY 10021, United States.
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Peniston SJ, L. Burg KJ, Shalaby SW. Effect of mesh construction on the physicomechanical properties of bicomponent knit mesh using yarns derived from degradable copolyesters. J Biomed Mater Res B Appl Biomater 2012; 100:1922-34. [DOI: 10.1002/jbm.b.32759] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2012] [Revised: 05/10/2012] [Accepted: 05/20/2012] [Indexed: 01/07/2023]
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Adhikari AS, Glassey E, Dunn AR. Conformational dynamics accompanying the proteolytic degradation of trimeric collagen I by collagenases. J Am Chem Soc 2012; 134:13259-65. [PMID: 22720833 PMCID: PMC4800024 DOI: 10.1021/ja212170b] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Collagenases are the principal enzymes responsible for the degradation of collagens during embryonic development, wound healing, and cancer metastasis. However, the mechanism by which these enzymes disrupt the highly chemically and structurally stable collagen triple helix remains incompletely understood. We used a single-molecule magnetic tweezers assay to characterize the cleavage of heterotrimeric collagen I by both the human collagenase matrix metalloproteinase-1 (MMP-1) and collagenase from Clostridium histolyticum. We observe that the application of 16 pN of force causes an 8-fold increase in collagen proteolysis rates by MMP-1 but does not affect cleavage rates by Clostridium collagenase. Quantitative analysis of these data allows us to infer the structural changes in collagen associated with proteolytic cleavage by both enzymes. Our data support a model in which MMP-1 cuts a transient, stretched conformation of its recognition site. In contrast, our findings suggest that Clostridium collagenase is able to cleave the fully wound collagen triple helix, accounting for its lack of force sensitivity and low sequence specificity. We observe that the cleavage of heterotrimeric collagen is less force sensitive than the proteolysis of a homotrimeric collagen model peptide, consistent with studies suggesting that the MMP-1 recognition site in heterotrimeric collagen I is partially unwound at equilibrium.
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Affiliation(s)
| | | | - Alexander R. Dunn
- Department of Chemical Engineering, Stanford University, Stanford, CA - 94305
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Veres SP, Lee JM. Designed to fail: a novel mode of collagen fibril disruption and its relevance to tissue toughness. Biophys J 2012; 102:2876-84. [PMID: 22735538 DOI: 10.1016/j.bpj.2012.05.022] [Citation(s) in RCA: 64] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2012] [Revised: 04/13/2012] [Accepted: 05/07/2012] [Indexed: 11/16/2022] Open
Abstract
Collagen fibrils are nanostructured biological cables essential to the structural integrity of many of our tissues. Consequently, understanding the structural basis of their robust mechanical properties is of great interest. Here we present what to our knowledge is a novel mode of collagen fibril disruption that provides new insights into both the structure and mechanics of native collagen fibrils. Using enzyme probes for denatured collagen and scanning electron microscopy, we show that mechanically overloading collagen fibrils from bovine tail tendons causes them to undergo a sequential, two-stage, selective molecular failure process. Denatured collagen molecules-meaning molecules with a reduced degree of time-averaged helicity compared to those packed in undamaged fibrils-were first created within kinks that developed at discrete, repeating locations along the length of fibrils. There, collagen denaturation within the kinks was concentrated within certain subfibrils. Additional denatured molecules were then created along the surface of some disrupted fibrils. The heterogeneity of the disruption within fibrils suggests that either mechanical load is not carried equally by a fibril's subcomponents or that the subcomponents do not possess homogenous mechanical properties. Meanwhile, the creation of denatured collagen molecules, which necessarily involves the energy intensive breaking of intramolecular hydrogen bonds, provides a physical basis for the toughness of collagen fibrils.
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Affiliation(s)
- Samuel P Veres
- School of Biomedical Engineering, Dalhousie University, Halifax, Nova Scotia, Canada.
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