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Gullbrand SE, Kiapour A, Barrett C, Fainor M, Orozco BS, Hilliard R, Mauck RL, Hast MW, Schaer TP, Smith HE. Restoration of physiologic loading after engineered disc implantation mitigates immobilization-induced facet joint and paraspinal muscle degeneration. Acta Biomater 2025; 192:128-139. [PMID: 39653318 PMCID: PMC11735281 DOI: 10.1016/j.actbio.2024.12.014] [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: 08/05/2024] [Revised: 11/05/2024] [Accepted: 12/04/2024] [Indexed: 12/15/2024]
Abstract
Intervertebral disc degeneration is commonly associated with back and neck pain, and standard surgical treatments do not restore spine function. Replacement of the degenerative disc with a living, tissue-engineered construct has the potential to restore normal structure and function to the spine. Toward this goal, our group developed endplate-modified disc-like angle-ply structures (eDAPS) that recapitulate the native structure and function of the disc. While our initial large animal studies utilized rigid internal fixation of the eDAPS implanted level to ensure retention of the eDAPS, chronic immobilization does not restore full function and is detrimental to the spinal motion segment. The purpose of this study was to utilize a goat cervical disc replacement model coupled with finite element modeling of goat cervical motion segments to investigate the effects of remobilization (removal of fixation) on the eDAPS, the facet joints and the adjacent paraspinal muscle. Our results demonstrated that chronic immobilization caused notable degeneration of the facet joints and paraspinal muscles adjacent to eDAPS implants. Remobilization improved eDAPS composition and integration and mitigated, but did not fully reverse, facet joint osteoarthritis and paraspinal muscle atrophy and fibrosis. Finite element modeling revealed that these changes were likely due to reduced range of motion and reduced facet loading, highlighting the importance of maintaining normal spine biomechanical function with any tissue engineered disc replacement. STATEMENT OF SIGNIFICANCE: Back and neck pain are ubiquitous in modern society, and the gold standard surgical treatment of spinal fusion limits patient function. This study advances our understanding of the response of the spinal motion segment to tissue engineered disc replacement with provisional fixation in a large animal model, further advancing the clinical translation of this technology.
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Affiliation(s)
- Sarah E Gullbrand
- Department of Orthopaedic Surgery, McKay Orthopaedic Research Laboratory, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
| | - Ali Kiapour
- Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Caitlin Barrett
- Department of Orthopaedic Surgery, McKay Orthopaedic Research Laboratory, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA
| | - Matthew Fainor
- Department of Orthopaedic Surgery, McKay Orthopaedic Research Laboratory, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA
| | - Brianna S Orozco
- Department of Orthopaedic Surgery, McKay Orthopaedic Research Laboratory, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA
| | - Rachel Hilliard
- Department of Clinical Studies, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Robert L Mauck
- Department of Orthopaedic Surgery, McKay Orthopaedic Research Laboratory, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA; Department of Bioengineering, University of Pennsylvania, Philadelphia, PA, USA
| | - Michael W Hast
- Department of Orthopaedic Surgery, McKay Orthopaedic Research Laboratory, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Thomas P Schaer
- Department of Clinical Studies, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Harvey E Smith
- Department of Orthopaedic Surgery, McKay Orthopaedic Research Laboratory, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
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Dhiman MS, Bader TJ, Ponjevic D, Salo PT, Hart DA, Swamy G, Matyas JR, Duncan NA. Collagen integrity of the annulus fibrosus in degenerative disc disease individuals quantified with collagen hybridizing peptide. JOR Spine 2024; 7:e1359. [PMID: 39092166 PMCID: PMC11291301 DOI: 10.1002/jsp2.1359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2024] [Revised: 05/27/2024] [Accepted: 07/03/2024] [Indexed: 08/04/2024] Open
Abstract
Introduction Degenerative disc disease (DDD) is accompanied by structural changes in the intervertebral discs (IVD). Extra-cellular matrix degradation of the annulus fibrosus (AF) has been linked with degeneration of the IVD. Collagen is a vital component of the IVD. Collagen hybridizing peptide (CHP) is an engineered protein that binds to degraded collagen, which we used to quantify collagen damage in AF. This method was used to compare AF samples obtained from donors with no DDD to AF samples from patients undergoing surgery for symptomatic DDD. Methods Fresh AF tissue was embedded in an optimal cutting temperature compound and cryosectioned at a thickness of 8 μm. Hematoxylin and Eosin staining was performed on sections for general histomorphological assessment. Serial sections were stained with Cy3-conjugated CHP and the mean fluorescence intensity and areal fraction of Cy3-positive staining were averaged for three regions of interest (ROI) on each CHP-stained section. Results Increases in mean fluorescence intensity (p = 0.0004) and percentage of positively stained area (p = 0.00008) with CHP were detected in DDD samples compared to the non-DDD samples. Significant correlations were observed between mean fluorescence intensity and percentage of positively stained area for both non-DDD (R = 0.98, p = 5E-8) and DDD (R = 0.79, p = 0.0012) samples. No significant differences were detected between sex and the lumbar disc level subgroups of the non-DDD and DDD groups. Only tissue pathology (non-DDD versus DDD) influenced the measured parameters. No three-way interactions between tissue pathology, sex, and lumbar disc level were observed. Discussion and Conclusions These findings suggest that AF collagen degradation is greater in DDD samples compared to non-DDD samples, as evidenced by the increased CHP staining. Strong positive correlations between the two measured parameters suggest that when collagen degradation occurs, it is detected by this technique and is widespread throughout the tissue. This study provides new insights into the structural alterations associated with collagen degradation in the AF that occur during DDD.
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Affiliation(s)
- Manmeet S. Dhiman
- Department of Biomedical EngineeringUniversity of CalgaryCalgaryAlbertaCanada
- McCaig Institute for Bone and Joint HealthUniversity of CalgaryCalgaryAlbertaCanada
| | - Taylor J. Bader
- McCaig Institute for Bone and Joint HealthUniversity of CalgaryCalgaryAlbertaCanada
- Department of Medical SciencesUniversity of CalgaryCalgaryAlbertaCanada
| | - Dragana Ponjevic
- McCaig Institute for Bone and Joint HealthUniversity of CalgaryCalgaryAlbertaCanada
- Faculty of Veterinary MedicineUniversity of CalgaryCalgaryAlbertaCanada
| | - Paul T. Salo
- McCaig Institute for Bone and Joint HealthUniversity of CalgaryCalgaryAlbertaCanada
- Department of Surgery, Cumming School of MedicineUniversity of CalgaryCalgaryAlbertaCanada
| | - David A. Hart
- McCaig Institute for Bone and Joint HealthUniversity of CalgaryCalgaryAlbertaCanada
- Department of Surgery, Cumming School of MedicineUniversity of CalgaryCalgaryAlbertaCanada
- Faculty of KinesiologyUniversity of CalgaryCalgaryAlbertaCanada
| | - Ganesh Swamy
- McCaig Institute for Bone and Joint HealthUniversity of CalgaryCalgaryAlbertaCanada
- Department of Surgery, Cumming School of MedicineUniversity of CalgaryCalgaryAlbertaCanada
| | - John R. Matyas
- McCaig Institute for Bone and Joint HealthUniversity of CalgaryCalgaryAlbertaCanada
- Faculty of Veterinary MedicineUniversity of CalgaryCalgaryAlbertaCanada
| | - Neil A. Duncan
- McCaig Institute for Bone and Joint HealthUniversity of CalgaryCalgaryAlbertaCanada
- Department of Civil EngineeringUniversity of CalgaryCalgaryAlbertaCanada
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Sun Z, Mi C. Biomechanics of annulus fibrosus: Elastic fiber simplification and degenerative impact on damage initiation and propagation. J Mech Behav Biomed Mater 2024; 157:106628. [PMID: 38878651 DOI: 10.1016/j.jmbbm.2024.106628] [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: 01/08/2024] [Revised: 05/19/2024] [Accepted: 06/08/2024] [Indexed: 07/30/2024]
Abstract
This study addresses three primary objectives related to lumbar intervertebral disc (IVD) biomechanics under ramping quasi-static loading conditions. First, we explore the conditions justifying the simplification of axisymmetric elastic fiber families into single fiber bundles through discretized strain energy functions. Simulations reveal that a concentration factor exceeding 10 allows for a consistent deviation below 10% between simplified and non-simplified responses. Second, we investigate the impact of elastic fibers on the physiological stiffness in IVDs, revealing minimal influence on biological motions but significant effects on degeneration. Lastly, we examine the initiation and progression of annulus fibrosus (AF) damage. Our findings confirm the validity of simplifying elastic fiber families and underscore the necessity of considering elastic fiber damage in biomechanical studies of AF tissues. Elastic fibers contribute to increased biaxial stretch stiffness, and their damage significantly affects the loading capacity of the inner AF. Additionally, degeneration significantly alters the susceptibility to damage in the AF, with specific regions exhibiting higher vulnerability. Damage tends to extend circumferentially and radially, emphasizing the regional variations in collagen and elastic fiber properties. This study offers useful insights for refining biomechanical models, paving the way for a more comprehensive understanding of IVD responses and potential clinical implications.
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Affiliation(s)
- Zhongwei Sun
- Jiangsu Key Laboratory of Mechanical Analysis for Infrastructure and Advanced Equipment, School of Civil Engineering, Southeast University, Nanjing, Jiangsu 210096, China
| | - Changwen Mi
- Jiangsu Key Laboratory of Mechanical Analysis for Infrastructure and Advanced Equipment, School of Civil Engineering, Southeast University, Nanjing, Jiangsu 210096, China.
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Sreeja CK, Devi VKNPM, Aneesh MK, Sreekanth KS. A digital volume pulse device-finger photo pulse plethysmography to trace the vascular integrity amongst the low back pain subjects with lumbar disc degenerative diseases diagnosed by MRI analysis. RADIATION PROTECTION DOSIMETRY 2024; 200:1163-1166. [PMID: 39016498 DOI: 10.1093/rpd/ncae014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 10/21/2023] [Accepted: 12/15/2023] [Indexed: 07/18/2024]
Abstract
Finger photo pulse plethysmography is a simple, inexpensive and non-invasive method for measurement of arterial stiffness. The objective is to assess the correlation of arterial stiffness in low back pain subjects with lumbar disc degeneration. Thirty-four back pain patients of both sexes in age group of 30-65 were included. Anthropometric measures like height, body weight, body mass index (BMI) were included. Stiffness index (SI) and reflection index (RI) were measured from the digital volume pulse waveform. There was a negative correlation between SI/RI and no correlation between SI and RI with BMI in both sexes. A significant correlation found between weight and BMI in both sexes. Arterial stiffness may not have any influence on disc degeneration. BMI showed some influence on disc degeneration and back pain.
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Affiliation(s)
- Chidambaran K Sreeja
- Department of Physics, Noorul Islam Centre for Higher Education, Kumaracoil, Kanyakumari, India
| | - Vimala K N P M Devi
- Department of Physics, Noorul Islam Centre for Higher Education, Kumaracoil, Kanyakumari, India
| | - Mangalasseril K Aneesh
- Department of Radiology, Jubilee Mission Medical College & Research Institute, Thrissur, Kerala 680005, India
| | - Kavitha S Sreekanth
- Department of Biochemistry, Sree Gokulam Medical College & Research Foundation, Trivandrum 695607, India
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de Oliveira CAA, Oliveira BS, Theodoro R, Wang J, Santos GS, Rodrigues BL, Rodrigues IJ, Jorge DDMF, Jeyaraman M, Everts PA, Navani A, Lana JF. Orthobiologic Management Options for Degenerative Disc Disease. Bioengineering (Basel) 2024; 11:591. [PMID: 38927827 PMCID: PMC11200769 DOI: 10.3390/bioengineering11060591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 05/20/2024] [Accepted: 05/22/2024] [Indexed: 06/28/2024] Open
Abstract
Degenerative disc disease (DDD) is a pervasive condition that limits quality of life and burdens economies worldwide. Conventional pharmacological treatments primarily aimed at slowing the progression of degeneration have demonstrated limited long-term efficacy and often do not address the underlying causes of the disease. On the other hand, orthobiologics are regenerative agents derived from the patient's own tissue and represent a promising emerging therapy for degenerative disc disease. This review comprehensively outlines the pathophysiology of DDD, highlighting the inadequacies of existing pharmacological therapies and detailing the potential of orthobiologic approaches. It explores advanced tools such as platelet-rich plasma and mesenchymal stem cells, providing a historical overview of their development within regenerative medicine, from foundational in vitro studies to preclinical animal models. Moreover, the manuscript delves into clinical trials that assess the effectiveness of these therapies in managing DDD. While the current clinical evidence is promising, it remains insufficient for routine clinical adoption due to limitations in study designs. The review emphasizes the need for further research to optimize these therapies for consistent and effective clinical outcomes, potentially revolutionizing the management of DDD and offering renewed hope for patients.
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Affiliation(s)
| | - Bernardo Scaldini Oliveira
- Orthopedics, ABCOliveira Medical Clinic, São Paulo 03310-000, SP, Brazil; (C.A.A.d.O.); (B.S.O.); (R.T.)
| | - Rafael Theodoro
- Orthopedics, ABCOliveira Medical Clinic, São Paulo 03310-000, SP, Brazil; (C.A.A.d.O.); (B.S.O.); (R.T.)
| | - Joshua Wang
- Learning and Teaching Unit, Queensland University of Technology, Brisbane, QLD 4059, Australia;
| | - Gabriel Silva Santos
- Department of Orthopedics, Brazilian Institute of Regenerative Medicine (BIRM), Indaiatuba 13334-170, SP, Brazil; (B.L.R.); (I.J.R.); (D.d.M.F.J.); (J.F.L.)
- Regenerative Medicine, Orthoregen International Course, Indaiatuba 13334-170, SP, Brazil; (M.J.); (P.A.E.); (A.N.)
| | - Bruno Lima Rodrigues
- Department of Orthopedics, Brazilian Institute of Regenerative Medicine (BIRM), Indaiatuba 13334-170, SP, Brazil; (B.L.R.); (I.J.R.); (D.d.M.F.J.); (J.F.L.)
- Regenerative Medicine, Orthoregen International Course, Indaiatuba 13334-170, SP, Brazil; (M.J.); (P.A.E.); (A.N.)
| | - Izair Jefthé Rodrigues
- Department of Orthopedics, Brazilian Institute of Regenerative Medicine (BIRM), Indaiatuba 13334-170, SP, Brazil; (B.L.R.); (I.J.R.); (D.d.M.F.J.); (J.F.L.)
| | - Daniel de Moraes Ferreira Jorge
- Department of Orthopedics, Brazilian Institute of Regenerative Medicine (BIRM), Indaiatuba 13334-170, SP, Brazil; (B.L.R.); (I.J.R.); (D.d.M.F.J.); (J.F.L.)
- Regenerative Medicine, Orthoregen International Course, Indaiatuba 13334-170, SP, Brazil; (M.J.); (P.A.E.); (A.N.)
| | - Madhan Jeyaraman
- Regenerative Medicine, Orthoregen International Course, Indaiatuba 13334-170, SP, Brazil; (M.J.); (P.A.E.); (A.N.)
- Department of Orthopaedics, ACS Medical College and Hospital, Dr MGR Educational and Research Institute, Chennai 600077, Tamil Nadu, India
| | - Peter Albert Everts
- Regenerative Medicine, Orthoregen International Course, Indaiatuba 13334-170, SP, Brazil; (M.J.); (P.A.E.); (A.N.)
- Medical School, Max Planck University Center (UniMAX), Indaiatuba 13343-060, SP, Brazil
| | - Annu Navani
- Regenerative Medicine, Orthoregen International Course, Indaiatuba 13334-170, SP, Brazil; (M.J.); (P.A.E.); (A.N.)
- Medical Director, Le Reve, San Jose, CA 95124, USA
- Chief Medical Officer, Boomerang Healthcare, Walnut Creek, CA 94598, USA
| | - José Fábio Lana
- Department of Orthopedics, Brazilian Institute of Regenerative Medicine (BIRM), Indaiatuba 13334-170, SP, Brazil; (B.L.R.); (I.J.R.); (D.d.M.F.J.); (J.F.L.)
- Regenerative Medicine, Orthoregen International Course, Indaiatuba 13334-170, SP, Brazil; (M.J.); (P.A.E.); (A.N.)
- Medical School, Max Planck University Center (UniMAX), Indaiatuba 13343-060, SP, Brazil
- Medical School, Jaguariúna University Center (UniFAJ), Jaguariúna 13918-110, SP, Brazil
- Clinical Research, Anna Vitória Lana Institute (IAVL), Indaiatuba 13334-170, SP, Brazil
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Fainor M, Orozco BS, Muir VG, Mahindroo S, Gupta S, Mauck RL, Burdick JA, Smith HE, Gullbrand SE. Mechanical crosstalk between the intervertebral disc, facet joints, and vertebral endplate following acute disc injury in a rabbit model. JOR Spine 2023; 6:e1287. [PMID: 38156057 PMCID: PMC10751980 DOI: 10.1002/jsp2.1287] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 07/21/2023] [Accepted: 09/06/2023] [Indexed: 12/30/2023] Open
Abstract
Background Vertebral endplate sclerosis and facet osteoarthritis have been documented in animals and humans. However, it is unclear how these adjacent pathologies engage in crosstalk with the intervertebral disc. This study sought to elucidate this crosstalk by assessing each compartment individually in response to acute disc injury. Methods Eleven New Zealand White rabbits underwent annular disc puncture using a 16G or 21G needle. At 4 and 10 weeks, individual compartments of the motion segment were analyzed. Discs underwent T 1 relaxation mapping with MRI contrast agent gadodiamide as well T 2 mapping. Both discs and facets underwent mechanical testing via vertebra-disc-vertebra tension-compression creep testing and indentation testing, respectively. Endplate bone density was quantified via μCT. Discs and facets were sectioned and stained for histology scoring. Results Intervertebral discs became more degenerative with increasing needle diameter and time post-puncture. Bone density also increased in endplates adjacent to both 21G and 16G punctured discs leading to reduced gadodiamide transport at 10 weeks. The facet joints, however, did not follow this same trend. Facets adjacent to 16G punctured discs were less degenerative than facets adjacent to 21G punctured discs at 10 weeks. 16G facets were more degenerative at 4 weeks than at 10, suggesting the cartilage had recovered. The formation of severe disc osteophytes in 16G punctured discs between 4 and 10 weeks likely offloaded the facet cartilage, leading to the recovery observed. Conclusions Overall, this study supports that degeneration spans the whole spinal motion segment following disc injury. Vertebral endplate thickening occurred in response to disc injury, which limited the diffusion of small molecules into the disc. This work also suggests that altered disc mechanics can induce facet degeneration, and that extreme bony remodeling adjacent to the disc may promote facet cartilage recovery through offloading of the articular cartilage.
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Affiliation(s)
- Matthew Fainor
- Department of Orthopaedic Surgery, McKay Orthopaedic Research Laboratory, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Translational Musculoskeletal Research CenterCorporal Michael J. Crescenz VA Medical CenterPhiladelphiaPennsylvaniaUSA
| | - Brianna S. Orozco
- Department of Orthopaedic Surgery, McKay Orthopaedic Research Laboratory, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Translational Musculoskeletal Research CenterCorporal Michael J. Crescenz VA Medical CenterPhiladelphiaPennsylvaniaUSA
| | - Victoria G. Muir
- Department of BioengineeringUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Sonal Mahindroo
- Translational Musculoskeletal Research CenterCorporal Michael J. Crescenz VA Medical CenterPhiladelphiaPennsylvaniaUSA
- Department of BiologySt. Bonaventure UniversitySt. BonaventureNew YorkUSA
| | - Sachin Gupta
- Department of Orthopaedic Surgery, McKay Orthopaedic Research Laboratory, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Translational Musculoskeletal Research CenterCorporal Michael J. Crescenz VA Medical CenterPhiladelphiaPennsylvaniaUSA
| | - Robert L. Mauck
- Department of Orthopaedic Surgery, McKay Orthopaedic Research Laboratory, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Translational Musculoskeletal Research CenterCorporal Michael J. Crescenz VA Medical CenterPhiladelphiaPennsylvaniaUSA
- Department of BioengineeringUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Jason A. Burdick
- Department of BioengineeringUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- BioFrontiers Institute and Department of Chemical and Biological EngineeringUniversity of Colorado BoulderBoulderColoradoUSA
| | - Harvey E. Smith
- Department of Orthopaedic Surgery, McKay Orthopaedic Research Laboratory, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Translational Musculoskeletal Research CenterCorporal Michael J. Crescenz VA Medical CenterPhiladelphiaPennsylvaniaUSA
| | - Sarah E. Gullbrand
- Department of Orthopaedic Surgery, McKay Orthopaedic Research Laboratory, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Translational Musculoskeletal Research CenterCorporal Michael J. Crescenz VA Medical CenterPhiladelphiaPennsylvaniaUSA
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King S, Magnussen J, Elliott J, Hancock MJ. Development of normalized quantitative measures of lumbar disc degeneration. JOR Spine 2023; 6:e1278. [PMID: 37780819 PMCID: PMC10540817 DOI: 10.1002/jsp2.1278] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 06/25/2023] [Accepted: 07/27/2023] [Indexed: 10/03/2023] Open
Abstract
Background Lumbar disc degeneration (DD) is widely regarded as a likely contributor to low back pain (LBP), but the association between DD and LBP is relatively weak. No known studies have normalized quantitative measures of DD severity relative to multiple variables such as age, height, and disc level. This study developed normalized quantitative measures (z-scores) of disc signal intensity (DSI) and disc height (DH) to rate relative severity of DD. Methods Raw (unnormalized) quantitative measures of DSI and DH alongside potential normalization variables were acquired from MRI scans and clinical data of 76 patients. The associations between the raw quantitative measures and potential normalization variables were investigated to develop the normalized quantitative measures (z-scores) of DSI and DH. Construct validity was assessed by comparing the normalized measures to an experienced radiologist's subjective measures of relative severity of DSI and DH loss. Results CSF signal intensity, age, and disc level were significantly associated with raw DSI (R 2 = 0.06, 0.25, and 0.09, respectively). Lumbar height and disc level were significantly associated with raw DH (R 2 = 0.13 and 0.31). Normalizing DSI and DH by these variables resulted in stronger relationships (R 2 = 0.39 and 0.37) than raw DSI and DH (R 2 = 0.24 and 0.31) with the radiologist's subjective measures. Normalized DSI and DH were both normally distributed (p = 0.32 and 0.12). Conclusions Construct validity and the distributions suggested that normalized quantitative measures of DSI and DH are better than existing measures of DSI and DH at rating relative DD severity. Determining whether normalized quantitative measures are more predictive of clinical outcomes is important future research.
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Affiliation(s)
- Samuel King
- Faculty of Medicine, Health and Human SciencesMacquarie UniversitySydneyAustralia
| | - John Magnussen
- Faculty of Medicine, Health and Human SciencesMacquarie UniversitySydneyAustralia
| | - James Elliott
- Faculty of Medicine and Health, The Kolling InstituteThe University of SydneySt LeonardsAustralia
- Feinberg School of MedicineNorthwestern UniversityChicagoIllinoisUSA
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Lorio MP, Beall DP, Calodney AK, Lewandrowski KU, Block JE, Mekhail N. Defining the Patient with Lumbar Discogenic Pain: Real-World Implications for Diagnosis and Effective Clinical Management. J Pers Med 2023; 13:821. [PMID: 37240991 PMCID: PMC10224560 DOI: 10.3390/jpm13050821] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Revised: 05/08/2023] [Accepted: 05/10/2023] [Indexed: 05/28/2023] Open
Abstract
There is an enormous body of literature that has identified the intervertebral disc as a potent pain generator. However, with regard to lumbar degenerative disc disease, the specific diagnostic criteria lack clarity and fail to capture the primary components which include axial midline low back pain with or without non-radicular/non-sciatic referred leg pain in a sclerotomal distribution. In fact, there is no specific ICD-10-CM diagnostic code to classify and define discogenic pain as a unique source of pain distinct from other recognized sources of chronic low back pain including facetogenic, neurocompressive including herniation and/or stenosis, sacroiliac, vertebrogenic, and psychogenic. All of these other sources have well-defined ICD-10-CM codes. Corresponding codes for discogenic pain remain absent from the diagnostic coding vernacular. The International Society for the Advancement of Spine Surgery (ISASS) has proposed a modernization of ICD-10-CM codes to specifically define pain associated with lumbar and lumbosacral degenerative disc disease. The proposed codes would also allow the pain to be characterized by location: lumbar region only, leg only, or both. Successful implementation of these codes would benefit both physicians and payers in distinguishing, tracking, and improving algorithms and treatments for discogenic pain associated with intervertebral disc degeneration.
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Affiliation(s)
- Morgan P. Lorio
- Advanced Orthopedics, 499 E. Central Pkwy., Ste. 130, Altamonte Springs, FL 32701, USA;
| | - Douglas P. Beall
- Clinical Radiology of Oklahoma, 1800 S. Renaissance Blvd., Ste. 110, Edmond, OK 73013, USA;
| | | | - Kai-Uwe Lewandrowski
- Center for Advanced Spine Care of Southern Arizona, 4787 E. Camp Lowell Drive, Tucson, AZ 85712, USA;
| | - Jon E. Block
- Independent Consultant, 2210 Jackson Street, Ste. 401, San Francisco, CA 94115, USA
| | - Nagy Mekhail
- Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195, USA;
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Lin M, Hu Y, An H, Guo T, Gao Y, Peng K, Zhao M, Zhang X, Zhou H. Silk fibroin-based biomaterials for disc tissue engineering. Biomater Sci 2023; 11:749-776. [PMID: 36537344 DOI: 10.1039/d2bm01343f] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Low back pain is the major cause of disability worldwide, and intervertebral disc degeneration (IVDD) is one of the most important causes of low back pain. Currently, there is no method to treat IVDD that can reverse or regenerate intervertebral disc (IVD) tissue, but the recent development of disc tissue engineering (DTE) offers a new means of addressing these disadvantages. Among numerous biomaterials for tissue engineering, silk fibroin (SF) is widely used due to its easy availability and excellent physical/chemical properties. SF is usually used in combination with other materials to construct biological scaffolds or bioactive substance delivery systems, or it can be used alone. The present article first briefly outlines the anatomical and physiological features of IVD, the associated etiology and current treatment modalities of IVDD, and the current status of DTE. Then, it highlights the characteristics of SF biomaterials and their latest research advances in DTE and discusses the prospects and challenges in the application of SF in DTE, with a view to facilitating the clinical process of developing interventions related to IVD-derived low back pain caused by IVDD.
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Affiliation(s)
- Maoqiang Lin
- Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou 730030, Gansu, China. .,Key Laboratory of Bone and Joint Disease Research of Gansu Province, Lanzhou 730030, Gansu, China
| | - Yicun Hu
- Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou 730030, Gansu, China. .,Key Laboratory of Bone and Joint Disease Research of Gansu Province, Lanzhou 730030, Gansu, China
| | - Haiying An
- Department of Laboratory Medicine, Zhongnan Hospital, Wuhan University, Wuhan 430000, Hubei, China
| | - Taowen Guo
- Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou 730030, Gansu, China. .,Key Laboratory of Bone and Joint Disease Research of Gansu Province, Lanzhou 730030, Gansu, China
| | - Yanbing Gao
- Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou 730030, Gansu, China. .,Key Laboratory of Bone and Joint Disease Research of Gansu Province, Lanzhou 730030, Gansu, China
| | - Kaichen Peng
- Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou 730030, Gansu, China. .,Key Laboratory of Bone and Joint Disease Research of Gansu Province, Lanzhou 730030, Gansu, China
| | - Meiling Zhao
- Key Laboratory of Bone and Joint Disease Research of Gansu Province, Lanzhou 730030, Gansu, China
| | - Xiaobo Zhang
- Department of Orthopedics, Honghui Hospital, Xi'an Jiaotong University, Xi'an 710000, Shaanxi, China.
| | - Haiyu Zhou
- Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou 730030, Gansu, China. .,Key Laboratory of Bone and Joint Disease Research of Gansu Province, Lanzhou 730030, Gansu, China
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10
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Yuksel Y, Ergun T, Torun E. The relationship between the flexor and extensor muscle areas and the presence and degree of intervertebral disc degeneration in the cervical region. Medicine (Baltimore) 2022; 101:e31132. [PMID: 36281108 PMCID: PMC9592502 DOI: 10.1097/md.0000000000031132] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND This study aimed to investigate the relationship between the presence and degree of cervical intervertebral disc degeneration (IVDD) and the cervical region muscle areas. METHODS The magnetic resonance imaging (MRI) examination of the patients who were sent to our clinic for investigation of neck pain between 2019 and 2020 years were evaluated retrospectively. 143 Turkish women patients between 30 and 40 ages were examined in the study. The presence and degree of IVDD was evaluated for each patient. The areas of the cervical flexor and extensor paravertebral muscles were measured. RESULTS No cervical disc degeneration was present in 44 (30.76%) patients (grade 1). The cervical intervertebral disc degeneration was grade 2 in 28 (19.58%), grade-3 in 41 (28.67%), and grade 4 in 30 (20.97%) patients. In early stage degeneration (grade 2), an increase was observed in the area of all cervical paravertebral flexor and extensor muscles examined. As the degree of degeneration increased (grades 3 and 4), a decrease was observed in the areas of all muscles. Statistical significance was found for musculus (m) sternocleidomastoideus, m. levator scapulae, m. splenius capitis, m. semispinalis capitis, and m. multifidus muscles (P = .009, r = -0.261; P = .014, r = -0.248; P = .008, r = -0.267; P = .002, r = -0.307; P = .028, r = -0.222, respectively). CONCLUSIONS IVDD is common in middle-aged females with neck pain. An increase in muscles areas is observed in the early stages of cervical disc degeneration but progressive decrease develops in all cervical paraspinal muscles areas as the degree of disc degeneration increases.
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Affiliation(s)
- Yavuz Yuksel
- Department of Radiology, Faculty of Medicine, Alaaddin Keykubat University, Alanya, Turkey
- *Correspondence: Yavuz Yuksel, Department of Radiology, Alaaddin Keykubat University School of Medicine, 07400 Alanya, Antalya, Turkey (e-mail: )
| | - Tarkan Ergun
- Department of Radiology, Faculty of Medicine, Alaaddin Keykubat University, Alanya, Turkey
| | - Ebru Torun
- Department of Radiology, Faculty of Medicine, Alaaddin Keykubat University, Alanya, Turkey
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11
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Han F, Yu Q, Chu G, Li J, Zhu Z, Tu Z, Liu C, Zhang W, Zhao R, Mao H, Han F, Li B. Multifunctional Nanofibrous Scaffolds with Angle-Ply Microstructure and Co-Delivery Capacity Promote Partial Repair and Total Replacement of Intervertebral Disc. Adv Healthc Mater 2022; 11:e2200895. [PMID: 35834429 DOI: 10.1002/adhm.202200895] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 06/17/2022] [Indexed: 01/27/2023]
Abstract
There is an urgent clinical need for the treatment of annulus fibrosus (AF) impairment caused by intervertebral disc (IVD) degeneration or surgical injury. Although repairing injured AF through tissue engineering is promising, the approach is limited by the complicated angle-ply microstructure, inflammatory microenvironment, poor self-repairing ability of AF cells and deficient matrix production. In this study, electrospinning technology is used to construct aligned core-shell nanofibrous scaffolds loaded with transforming growth factor-β3 (TGFβ3) and ibuprofen (IBU), respectively. The results confirm that the rapid IBU release improves the inflammatory microenvironment, while sustained TGFβ3 release enhances nascent extracellular matrix (ECM) formation. Biomaterials for clinical applications must repair local AF defects during herniectomy and enable AF regeneration during disc replacement, so a box defect model and total IVD replacement model in rat tail are constructed. The dual-drug delivering electrospun scaffolds are assembled into angle-ply structure to form a highly biomimetic AF that is implanted into the box defect or used to replace the disc. In two animal models, it is found that biomimetic scaffolds with good anti-inflammatory ability enhance ECM formation and maintain the mechanical properties of IVD. Findings from this study demonstrate that the multifunctional nanofibrous scaffolds provide inspirations for IVD repair.
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Affiliation(s)
- Feng Han
- Orthopaedic Institute, Department of Orthopaedic Surgery, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, 215006, China
| | - Qifan Yu
- Orthopaedic Institute, Department of Orthopaedic Surgery, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, 215006, China
| | - Genglei Chu
- Orthopaedic Institute, Department of Orthopaedic Surgery, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, 215006, China
| | - Jiaying Li
- Orthopaedic Institute, Department of Orthopaedic Surgery, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, 215006, China
| | - Zhuang Zhu
- Orthopaedic Institute, Department of Orthopaedic Surgery, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, 215006, China
| | - Zhengdong Tu
- Orthopaedic Institute, Department of Orthopaedic Surgery, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, 215006, China
| | - Changjiang Liu
- Orthopaedic Institute, Department of Orthopaedic Surgery, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, 215006, China
| | - Weidong Zhang
- Orthopaedic Institute, Department of Orthopaedic Surgery, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, 215006, China
| | - Runze Zhao
- Orthopaedic Institute, Department of Orthopaedic Surgery, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, 215006, China
| | - Haijiao Mao
- The Affiliated Hospital of Medical School, Ningbo University, Ningbo, Zhejiang, 315000, China
| | - Fengxuan Han
- Orthopaedic Institute, Department of Orthopaedic Surgery, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, 215006, China
| | - Bin Li
- Orthopaedic Institute, Department of Orthopaedic Surgery, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, 215006, China.,The Affiliated Hospital of Medical School, Ningbo University, Ningbo, Zhejiang, 315000, China.,China Orthopaedic Regenerative Medicine Group (CORMed), Hangzhou, Zhejiang, 310000, China.,Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu, 215000, China
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12
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Laagland LT, Bach FC, Creemers LB, Le Maitre CL, Poramba-Liyanage DW, Tryfonidou MA. Hyperosmolar expansion medium improves nucleus pulposus cell phenotype. JOR Spine 2022; 5:e1219. [PMID: 36203869 PMCID: PMC9520765 DOI: 10.1002/jsp2.1219] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2022] [Revised: 07/21/2022] [Accepted: 07/21/2022] [Indexed: 12/02/2022] Open
Abstract
Background Repopulating the degenerated intervertebral disc (IVD) with tissue-specific nucleus pulposus cells (NPCs) has already been shown to promote regeneration in various species. Yet the applicability of NPCs as cell-based therapy has been hampered by the low cell numbers that can be extracted from donor IVDs and their potentially limited regenerative capacity due to their degenerated phenotype. To optimize the expansion conditions, we investigated the effects of increasing culture medium osmolarity during expansion on the phenotype of dog NPCs and their ability to produce a healthy extracellular matrix (ECM) in a 3D culture model. Methods Dog NPCs were expanded in expansion medium with a standard osmolarity of 300 mOsm/L or adjusted to 400 or 500 mOsm/L in both normoxic and hypoxic conditions. Following expansion, NPCs were cultured in a 3D culture model in chondrogenic culture medium with a standard osmolarity. Read-out parameters included cell proliferaton rate, morphology, phenotype and healthy ECM production. Results Increasing the expansion medium osmolarity from 300 to 500 mOsm/L resulted in NPCs with a more rounded morphology and a lower cell proliferation rate accompanied by the expression of several healthy NPC and progenitor markers at gene (KRT18, ACAN, COL2, CD73, CD90) and protein (ACAN, PAX1, CD24, TEK, CD73) level. The NPCs expanded at 500 mOsm/L were able to retain most of their phenotypic markers and produce healthy ECM during 3D culture independent of the oxygen level used during expansion. Conclusions Altogether, our findings show that increasing medium osmolarity during expansion results in an NPC population with improved phenotype, which could enhance the potential of cell-based therapies for IVD regeneration.
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Affiliation(s)
- Lisanne T Laagland
- Department of Clinical Sciences, Faculty of Veterinary Medicine Utrecht University Utrecht The Netherlands
| | - Frances C Bach
- Department of Clinical Sciences, Faculty of Veterinary Medicine Utrecht University Utrecht The Netherlands
| | - Laura B Creemers
- Department of Orthopedics University Medical Centre Utrecht Utrecht The Netherlands
| | | | - Deepani W Poramba-Liyanage
- Department of Clinical Sciences, Faculty of Veterinary Medicine Utrecht University Utrecht The Netherlands
| | - Marianna A Tryfonidou
- Department of Clinical Sciences, Faculty of Veterinary Medicine Utrecht University Utrecht The Netherlands
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13
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Machino M, Nakashima H, Ito K, Tsushima M, Ando K, Kobayashi K, Imagama S. Influence of Age and Gender on Intervertebral Disk Degeneration and Height in the Thoracolumbar Spine. Spine Surg Relat Res 2022; 6:379-387. [PMID: 36051683 PMCID: PMC9381080 DOI: 10.22603/ssrr.2021-0187] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 11/02/2021] [Indexed: 11/20/2022] Open
Abstract
Introduction Intervertebral disk degeneration is a universal and natural process. However, no reports have summarized anatomical age-related intervertebral disk height and disk degenerative changes in the thoracolumbar spine or examined sex-specific differences. This study aimed to establish age-related changes and gender-specific differences of intervertebral disk height and disk degeneration of the thoracolumbar spine in a large cohort of relatively healthy subjects and also to evaluate the relationship between the degree of thoracolumbar disk height and disk degeneration. Methods Six hundred and twenty-seven relatively healthy subjects (307 males and 320 females; average age, 49.6±16.5 years) were enrolled. We included at least 50 males and 50 females in each decade of life between the 20s and the 70s. We measured intervertebral disk height from T10/T11 to L5/S1, vertebral body height from T10 to S1 on lateral neutral radiographs. Lumbar disk degeneration was defined according to the Pfirrmann classification in sagittal plane magnetic resonance imaging. Results Age-related decreases in intervertebral disk height were most prominent at L4/L5 in middle-aged and elderly individuals of both sexes. The grade of disk degeneration significantly increased with age in both genders at every level. Mild disk degeneration was observed even in the 20s. The disk degeneration occurred around the L4/L5 level. Although grade V disk degeneration was not identified for males in the 20s and the 30s, it appeared after the 40s and then increased further with age. The intervertebral disk height at the lower lumbar disks decreased with a progression in the disk degeneration grade in both genders. Conclusions This large-scale cross-sectional analysis of the thoracolumbar spine in relatively healthy subjects demonstrated that lumbar disk height narrowing progresses with age and is correlated with the progression of disk degeneration.
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Affiliation(s)
- Masaaki Machino
- Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine
| | - Hiroaki Nakashima
- Department of Orthopedic Surgery, Chubu Rosai Hospital, Japan Organization of Occupational Health and Safety
| | - Keigo Ito
- Department of Orthopedic Surgery, Chubu Rosai Hospital, Japan Organization of Occupational Health and Safety
| | - Mikito Tsushima
- Department of Orthopedic Surgery, Chubu Rosai Hospital, Japan Organization of Occupational Health and Safety
| | - Kei Ando
- Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine
| | - Kazuyoshi Kobayashi
- Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine
| | - Shiro Imagama
- Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine
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14
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González-Cubero E, González-Fernández ML, Olivera ER, Villar-Suárez V. Extracellular vesicle and soluble fractions of adipose tissue-derived mesenchymal stem cells secretome induce inflammatory cytokines modulation in an in vitro model of discogenic pain. Spine J 2022; 22:1222-1234. [PMID: 35121152 DOI: 10.1016/j.spinee.2022.01.012] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 12/23/2021] [Accepted: 01/24/2022] [Indexed: 02/03/2023]
Abstract
BACKGROUND CONTEXT Mesenchymal stem cells (MSCs) secretome or conditioned medium (CM) is a complex cocktail of different molecules, some of which, particularly those contained in extracellular vesicles, already have proven therapeutic applications. PURPOSE CM may well represent promising therapy for discogenic pain and the intention of this work is to assess its therapeutic potential using an in vitro model of this condition. STUDY DESIGN This is an experimental study. METHODS Our in vitro model comprised nucleus pulposus (NP) and annulus fibrosus (AF) cells inflamed with TNF. To assess the potential therapeutic value of CM and its components, extracellular vesicles (EVs) and soluble culture fraction (SF), cell inflammation took place under 3 different conditions: either in the presence of whole CM, isolated EVs or SF, and concentrations of pro-inflammatory cytokines, metalloproteinases (MMPs) and neurotrophic factors produced in all 3 cases were compared. RESULTS In the presence of whole CM, both in vitro gene expression by the NP and AF test cells and analysis of their protein content showed high modulatory effects on inflammation and MMP inhibition. The presence of EVs and SF showed similar but much smaller effects, and this was particularly marked in the case of NP cells. CONCLUSIONS Our results show that, compared to EVs and SF, the presence of whole CM has the greatest positive effect on the modulation of pro-inflammatory and catabolic factors. These observations suggest that CM could protect against inflammation and the resulting intervertebral disc (IVD) degeneration that leads to discogenic pain. CLINICAL SIGNIFICANCE Many patients' expectations are not met by current non-operative and surgical treatments for discogenic low back pain. We propose the use of the MSCs secretome for assessing its potential as cell-free therapy to treat degenerative disc disease modulating the inflammatory response.
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Affiliation(s)
- Elsa González-Cubero
- Departmento de Anatomía, Facultad de Veterinaria, University of León-Universidad de León, Campus de Vegazana s/n, 24007, León, Spain
| | - María L González-Fernández
- Departmento de Anatomía, Facultad de Veterinaria, University of León-Universidad de León, Campus de Vegazana s/n, 24007, León, Spain
| | - Elias R Olivera
- Departamento de Bioquímica y Biología Molecular, Facultad de Veterinaria, Universidad de León Campus de Vegazana s/n, 24007, León, Spain
| | - Vega Villar-Suárez
- Departmento de Anatomía, Facultad de Veterinaria, University of León-Universidad de León, Campus de Vegazana s/n, 24007, León, Spain; Institute of Biomedicine (IBIOMED), University of León-Universidad de León, Campus de Vegazana s/n, 24007, León, Spain.
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15
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Lee S, Chae DS, Song BW, Lim S, Kim SW, Kim IK, Hwang KC. ADSC-Based Cell Therapies for Musculoskeletal Disorders: A Review of Recent Clinical Trials. Int J Mol Sci 2021; 22:10586. [PMID: 34638927 PMCID: PMC8508846 DOI: 10.3390/ijms221910586] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Revised: 09/24/2021] [Accepted: 09/25/2021] [Indexed: 01/04/2023] Open
Abstract
Recently published clinical trials involving the use of adipose-derived stem cells (ADSCs) indicated that approximately one-third of the studies were conducted on musculoskeletal disorders (MSD). MSD refers to a wide range of degenerative conditions of joints, bones, and muscles, and these conditions are the most common causes of chronic disability worldwide, being a major burden to the society. Conventional treatment modalities for MSD are not sufficient to correct the underlying structural abnormalities. Hence, ADSC-based cell therapies are being tested as a form of alternative, yet more effective, therapies in the management of MSDs. Therefore, in this review, MSDs subjected to the ADSC-based therapy were further categorized as arthritis, craniomaxillofacial defects, tendon/ligament related disorders, and spine disorders, and their brief characterization as well as the corresponding conventional therapeutic approaches with possible mechanisms with which ADSCs produce regenerative effects in disease-specific microenvironments were discussed to provide an overview of under which circumstances and on what bases the ADSC-based cell therapy was implemented. Providing an overview of the current status of ADSC-based cell therapy on MSDs can help to develop better and optimized strategies of ADSC-based therapeutics for MSDs as well as help to find novel clinical applications of ADSCs in the near future.
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Affiliation(s)
- Seahyoung Lee
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung 210-701, Korea; (S.L.); (B.-W.S.); (S.L.); (S.W.K.)
| | - Dong-Sik Chae
- Department of Orthopedic Surgery, International St. Mary’s Hospital, Catholic Kwandong University, Gangneung 210-701, Korea;
| | - Byeong-Wook Song
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung 210-701, Korea; (S.L.); (B.-W.S.); (S.L.); (S.W.K.)
| | - Soyeon Lim
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung 210-701, Korea; (S.L.); (B.-W.S.); (S.L.); (S.W.K.)
| | - Sang Woo Kim
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung 210-701, Korea; (S.L.); (B.-W.S.); (S.L.); (S.W.K.)
| | - Il-Kwon Kim
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung 210-701, Korea; (S.L.); (B.-W.S.); (S.L.); (S.W.K.)
| | - Ki-Chul Hwang
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung 210-701, Korea; (S.L.); (B.-W.S.); (S.L.); (S.W.K.)
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16
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Le Maitre CL, Dahia CL, Giers M, Illien‐Junger S, Cicione C, Samartzis D, Vadala G, Fields A, Lotz J. Development of a standardized histopathology scoring system for human intervertebral disc degeneration: an Orthopaedic Research Society Spine Section Initiative. JOR Spine 2021; 4:e1167. [PMID: 34337340 PMCID: PMC8313169 DOI: 10.1002/jsp2.1167] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 05/25/2021] [Accepted: 06/07/2021] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Histopathological analysis of intervertebral disc (IVD) tissues is a critical domain of back pain research. Identification, description, and classification of attributes that distinguish abnormal tissues form a basis for probing disease mechanisms and conceiving novel therapies. Unfortunately, lack of standardized methods and nomenclature can limit comparisons of results across studies and prevent organizing information into a clear representation of the hierarchical, spatial, and temporal patterns of IVD degeneration. Thus, the following Orthopaedic Research Society (ORS) Spine Section Initiative aimed to develop a standardized histopathology scoring scheme for human IVD degeneration. METHODS Guided by a working group of experts, this prospective process entailed a series of stages that consisted of reviewing and assessing past grading schemes, surveying IVD researchers globally on current practice and recommendations for a new grading system, utilizing expert opinion a taxonomy of histological grading was developed, and validation performed. RESULTS A standardized taxonomy was developed, which showed excellent intra-rater reliability for scoring nucleus pulposus (NP), annulus fibrosus (AF), and cartilaginous end plate (CEP) regions (interclass correlation [ICC] > .89). The ability to reliably detect subtle changes varied by IVD region, being poorest in the NP (ICC: .89-.95) where changes at the cellular level were important, vs the AF (ICC: .93-.98), CEP (ICC: .97-.98), and boney end plate (ICC: .96-.99) where matrix and structural changes varied more dramatically with degeneration. CONCLUSIONS The proposed grading system incorporates more comprehensive descriptions of degenerative features for all the IVD sub-tissues than prior criteria. While there was excellent reliability, our results reinforce the need for improved training, particularly for novice raters. Future evaluation of the proposed system in real-world settings (eg, at the microscope) will be needed to further refine criteria and more fully evaluate utility. This improved taxonomy could aid in the understanding of IVD degeneration phenotypes and their association with back pain.
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Affiliation(s)
| | - Chitra L. Dahia
- Orthopaedic Soft Tissue Research ProgramHospital for Special SurgeryNew YorkNew YorkUSA
- Department of Cell and Developmental BiologyWeill Cornell Medicine, Graduate School of Medical SciencesNew YorkNew YorkUSA
| | - Morgan Giers
- School of Chemical, Biological, and Environmental EngineeringOregon State UniversityCorvallisOregonUSA
| | | | - Claudia Cicione
- Laboratory of Regenerative Orthopaedics, Department of Orthopaedic and Trauma SurgeryCampus Bio‐Medico University of RomeRomeItaly
| | - Dino Samartzis
- Department of Orthopaedic SurgeryRush University Medical CenterChicagoIllinoisUSA
- International Spine Research and Innovation InitiativeRush University Medical CenterChicagoIllinoisUSA
| | - Gianluca Vadala
- Laboratory of Regenerative Orthopaedics, Department of Orthopaedic and Trauma SurgeryCampus Bio‐Medico University of RomeRomeItaly
| | - Aaron Fields
- Department of Orthopaedic SurgeryUniversity of California at San FranciscoSan FranciscoCaliforniaUSA
| | - Jeffrey Lotz
- Department of Orthopaedic SurgeryUniversity of California at San FranciscoSan FranciscoCaliforniaUSA
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17
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Roberts S, Gardner C, Jiang Z, Abedi A, Buser Z, Wang JC. Analysis of trends in lumbar disc degeneration using kinematic MRI. Clin Imaging 2021; 79:136-141. [PMID: 33940491 DOI: 10.1016/j.clinimag.2021.04.028] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 03/16/2021] [Accepted: 04/12/2021] [Indexed: 01/08/2023]
Abstract
OBJECTIVE The aim of the current study was to classify and analyze trends in lumbar disc degeneration across age, sex, and disc level using weightbearing kinematic MRI. MATERIALS AND METHODS Between January 2019 and July 2019, 1198 cases were retrospectively analyzed with kinematic MRI. Patients were divided into 5 groups based on age (20-29, 30-39, 40-49, 50-59, and 60+) and evaluated using the Pfirrmann classification to assess for disc degeneration at 5 vertebral levels: L1/2, L2/3, L3/4, L4/5, and L5/S1. Trends in degeneration were analyzed with regression and time series. RESULTS The L5/S1 vertebral disc had the highest prevalence of severe degeneration across all age groups. The most common multi-level degeneration combinations were L4/5 and L5/S1 for two levels and L3/4, L4/5, and L5/S1 for three levels. All vertebral levels showed significant difference in mean Pfirrmann grade among the age groups (p < 0.001 at all levels). Statistically significant differences in mean Pfirmmann grade among males and females were found only in ages 20-29 and 30-39, in which males showed more degeneration. CONCLUSION Our findings using kinematic MRI demonstrate that degeneration increases with age and is most severe in the L5/S1 disc. In multi-level degeneration the most prevalent combinations are those that are contiguous and include L5/S1. Young males were more likely to have degeneration than young females, but there was no significant difference from the fifth decade of life on.
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Affiliation(s)
- Sidney Roberts
- Department Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Carson Gardner
- Department Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Zhenhuan Jiang
- Department Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Aidin Abedi
- Department Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
| | - Zorica Buser
- Department Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
| | - Jeffrey C Wang
- Department Orthopaedic Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
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18
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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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19
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Guo Z, Qiu C, Mecca C, Zhang Y, Bian J, Wang Y, Wu X, Wang T, Su W, Li X, Zhang W, Chen B, Xiang H. Elevated lymphotoxin-α (TNFβ) is associated with intervertebral disc degeneration. BMC Musculoskelet Disord 2021; 22:77. [PMID: 33441130 PMCID: PMC7807514 DOI: 10.1186/s12891-020-03934-7] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 12/28/2020] [Indexed: 11/25/2022] Open
Abstract
Background Intervertebral disc degeneration (IVDD) is a primary cause of degenerative disc diseases; however, the mechanisms underlying the degeneration remain unclear. The immunoinflammatory response plays an important role in IVDD progression. The inflammatory cytokine lymphotoxin-α (LTα), formerly known as TNFβ, is associated with various pathological conditions, while its role in the pathogenesis of IVDD remains elusive. Methods Real-time quantitative polymerase chain reaction (RT-qPCR), Western blotting (WB), and enzyme-linked immunosorbent assays were used to assess the levels of LTα in human nucleus pulposus (NP) tissues between degeneration and control groups. The plasma concentrations of LTα and C-reactive protein (CRP) were compared between healthy and IVDD patients. Rat primary NP cells were cultured and identified via immunofluorescence. Methyl-thiazolyl-tetrazolium assays and flow cytometry were used to evaluate the effects of LTα on rat NP cell viability. After NP cells were treated with LTα, degeneration-related molecules (Caspase-3, Caspase-1, matrix metalloproteinase (MMP) -3, aggrecan and type II collagen) were measured via RT-qPCR and WB. Results The levels of both the mRNA and protein of LTα in human degenerated NP tissue significantly increased. Plasma LTα and CRP did not differ between healthy controls and IVDD patients. Rat primary NP cells were cultured, and the purity of primary NP cells was > 90%. Cell experiments showed inversely proportional relationships among the LTα dose, treatment time, and cell viability. The optimal conditions (dose and time) for LTα treatment to induce rat NP cell degeneration were 5 μg/ml and 48 ~ 72 h. The apoptosis rate and the levels of Caspase-3, Caspase-1, and MMP-3 significantly increased after LTα treatment, while the levels of type II collagen and aggrecan were decreased, and the protein expression levels were consistent with their mRNA expression levels. Conclusions This study demonstrated that elevated LTα is closely associated with IVDD and that LTα may induce NP cell apoptosis and reduce important extracellular matrix (ECM) proteins, which cause adverse effects on IVDD progress. Moreover, the optimal conditions for LTα treatment to induce NP cell degeneration were determined. Supplementary Information The online version contains supplementary material available at 10.1186/s12891-020-03934-7.
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Affiliation(s)
- Zhu Guo
- Department of Orthopedic Surgery, the Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Chensheng Qiu
- Department of Orthopedic Surgery, the Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China.,Department of Orthopedic Surgery, Qingdao Municipal Hospital (Group), Qingdao, 266011, Shandong, China
| | - Christina Mecca
- Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA
| | - Yang Zhang
- Department of Spine Surgery, Weifang People's Hospital, Weifang, 261041, Shandong, China
| | - Jiang Bian
- Qingdao Eye Hospital of Shandong First Medical University, Qingdao, 266000, Shandong, China
| | - Yan Wang
- Department of Orthopedic Surgery, the Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Xiaolin Wu
- Department of Orthopedic Surgery, the Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Tianrui Wang
- Department of Orthopedic Surgery, the Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Weiliang Su
- Department of Orthopedic Surgery, the Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China
| | - Xianglin Li
- School of Medical Imaging, Bin Zhou Medical University, Yantai, 264003, China
| | - Wei Zhang
- School of Medical Imaging, Bin Zhou Medical University, Yantai, 264003, China
| | - Bohua Chen
- Department of Orthopedic Surgery, the Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China.
| | - Hongfei Xiang
- Department of Orthopedic Surgery, the Affiliated Hospital of Qingdao University, Qingdao, 266000, Shandong, China.
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20
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Fu F, Bao R, Yao S, Zhou C, Luo H, Zhang Z, Zhang H, Li Y, Yan S, Yu H, Du W, Yang Y, Jin H, Tong P, Sun ZT, Yue M, Chen D, Wu C, Ruan H. Aberrant spinal mechanical loading stress triggers intervertebral disc degeneration by inducing pyroptosis and nerve ingrowth. Sci Rep 2021; 11:772. [PMID: 33437038 PMCID: PMC7804398 DOI: 10.1038/s41598-020-80756-6] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 12/28/2020] [Indexed: 01/08/2023] Open
Abstract
Aberrant mechanical factor is one of the etiologies of the intervertebral disc (IVD) degeneration (IVDD). However, the exact molecular mechanism of spinal mechanical loading stress-induced IVDD has yet to be elucidated due to a lack of an ideal and stable IVDD animal model. The present study aimed to establish a stable IVDD mouse model and evaluated the effect of aberrant spinal mechanical loading on the pathogenesis of IVDD. Eight-week-old male mice were treated with lumbar spine instability (LSI) surgery to induce IVDD. The progression of IVDD was evaluated by μCT and Safranin O/Fast green staining analysis. The metabolism of extracellular matrix, ingrowth of sensory nerves, pyroptosis in IVDs tissues were determined by immunohistological or real-time PCR analysis. The apoptosis of IVD cells was tested by TUNEL assay. IVDD modeling was successfully produced by LSI surgery, with substantial reductions in IVD height, BS/TV, Tb.N. and lower IVD score. LSI administration led to the histologic change of disc degeneration, disruption of the matrix metabolism, promotion of apoptosis of IVD cells and invasion of sensory nerves into annulus fibrosus, as well as induction of pyroptosis. Moreover, LSI surgery activated Wnt signaling in IVD tissues. Mechanical instability caused by LSI surgery accelerates the disc matrix degradation, nerve invasion, pyroptosis, and eventually lead to IVDD, which provided an alternative mouse IVDD model.
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Affiliation(s)
- Fangda Fu
- Institute of Orthopaedics and Traumatology, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China.,The First Clinical College, Zhejiang Chinese Medical University, Hangzhou, 310051, Zhejiang, China
| | - Ronghua Bao
- Hangzhou Fuyang Hospital of TCM Orthopedics and Traumatology, Hangzhou, 311400, Zhejiang, China
| | - Sai Yao
- Institute of Orthopaedics and Traumatology, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China.,The First Clinical College, Zhejiang Chinese Medical University, Hangzhou, 310051, Zhejiang, China
| | - Chengcong Zhou
- Institute of Orthopaedics and Traumatology, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China.,The First Clinical College, Zhejiang Chinese Medical University, Hangzhou, 310051, Zhejiang, China
| | - Huan Luo
- Department of Pharmacy, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310009, Zhejiang, China
| | - Zhiguo Zhang
- Institute of Orthopaedics and Traumatology, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China.,The First Clinical College, Zhejiang Chinese Medical University, Hangzhou, 310051, Zhejiang, China
| | - Huihao Zhang
- Institute of Orthopaedics and Traumatology, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China.,The First Clinical College, Zhejiang Chinese Medical University, Hangzhou, 310051, Zhejiang, China
| | - Yan Li
- The First Clinical College, Zhejiang Chinese Medical University, Hangzhou, 310051, Zhejiang, China
| | - Shuxin Yan
- The First Clinical College, Zhejiang Chinese Medical University, Hangzhou, 310051, Zhejiang, China
| | - Huan Yu
- Institute of Orthopaedics and Traumatology, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China.,Research Center for Human Tissues and Organs Degeneration, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.,The First Clinical College, Zhejiang Chinese Medical University, Hangzhou, 310051, Zhejiang, China
| | - Weibin Du
- Research Institute of Orthopedics, the Affiliated JiangNan Hospital of Zhejiang Chinese Medical University, Hangzhou, 311200, Zhejiang, China
| | - Yanping Yang
- Longhua Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China
| | - Hongting Jin
- Institute of Orthopaedics and Traumatology, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China
| | - Peijian Tong
- Institute of Orthopaedics and Traumatology, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China
| | - Zhi-Tao Sun
- Department of Orthopedics, Shenzhen Traditional Chinese Hospital, Guangzhou University of Chinese Medicine, Shenzhen, 518055, China
| | - Ming Yue
- Department of Physiology, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Di Chen
- Research Center for Human Tissues and Organs Degeneration, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
| | - Chengliang Wu
- Institute of Orthopaedics and Traumatology, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China.
| | - Hongfeng Ruan
- Institute of Orthopaedics and Traumatology, the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310053, Zhejiang, China. .,Longhua Hospital, Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200032, China.
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21
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Che YJ, Hou JJ, Guo JB, Liang T, Zhang W, Lu Y, Yang HL, Hao YF, Luo ZP. Low energy extracorporeal shock wave therapy combined with low tension traction can better reshape the microenvironment in degenerated intervertebral disc regeneration and repair. Spine J 2021; 21:160-177. [PMID: 32800896 DOI: 10.1016/j.spinee.2020.08.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2020] [Revised: 08/07/2020] [Accepted: 08/07/2020] [Indexed: 02/03/2023]
Abstract
BACKGROUND Low-tension traction is more effective than high-tension traction in restoring the height and rehydration of a degenerated disc and to some extent the bony endplate. This might better reshape the microenvironment for disc regeneration and repair. However, the repair of the combination of endplate sclerosis, osteophyte formation, and even collapse leading to partial or nearly complete occlusion of the nutrient channel is greatly limited. PURPOSE To evaluate the effectiveness of low-intensity extracorporeal shock wave therapy (ESWT) combined with low tension traction for regeneration and repair of moderately and severely degenerated discs; to explore the possible mechanism of action. STUDY DESIGN Animal study of a rat model of degenerated discs. METHODS A total of thirty-five 6-month old male Sprague-Dawley rats were randomly assigned to one of five groups (n=7, each group). In Group A (model group), caudal vertebrae were immobilized using a custom-made external device to fix four caudal vertebrae (Co7-Co10) whereas Co8-Co9 underwent 4 weeks of compression to induce moderate disc degeneration. In Group B (experimental control group), as in Group A, disc degeneration was successfully induced after which the fixed device was removed for 8 weeks of self-recovery. The remaining three groups of rats represented the intervention Groups (C-E): after successful generation of disc degeneration in Group C (com - 4w/tra - 4w) and Group D (com - 4w/ESWT), as described for group A, low-tension traction (in-situ traction) or low-energy ESWT was administered for 4 weeks (ESWT parameters: intensity: 0.15 Mpa; frequency: 1 Hz; impact: 1,000 each time; once/week, 4 times in total); Group E (com - 4w/tra - 4w/ESWT): disc degeneration as described for group A, low-tension traction combined with low-energy ESWT was conducted (ESWT parameters as Group D). After experimentation, caudal vertebrae were harvested and disc height, T2 signal intensity, disc morphology, total glycosaminoglycan (GAG) content, gene expression, structure of the Co8-Co9 bony endplates and elastic moduli of the discs were measured. RESULTS After continuous low-tension traction, low energy ESWT intervention or combined intervention, the degenerated discs effectively recovered their height and became rehydrated. However, the response in Group D was weaker than in the other intervention groups in terms of restoration of intervertebral disc (IVD) height, whereas Group E was superior in disc rehydration. Tissue regeneration was evident in Groups C to E using different interventions. No apparent tissue regeneration was observed in the experimental control group (Group B). The histological scores of the three intervention groups (Groups C-E) were lower than those of Groups A or B (p<.0001), and the scores of Groups C and E were significantly lower than those of Group D (p<.05), but not Group C versus Group E (p>.05). Compared with the intervention groups (Groups C-E), total GAG content of the nucleus pulposus (NP) in Group B did not increase significantly (p>.05). There was also no significant difference in the total GAG content between Groups A and B (p>.05). Of the three intervention groups, the recovery of NP GAG content was greatest in Group E. The expression of collagen I and II, and aggrecan in the annulus fibrosus (AF) was up-regulated (p<.05), whereas the expression of MMP-3, MMP-13, and ADAMTS-4 was down-regulated (p<.05). Of the groups, Group E displayed the greatest degree of regulation. The trend in regulation of gene expression in the NP was essentially consistent with that of the AF, of which Group E was the greatest. In the intervention groups (Groups C-E), compared with Group A, the pore structure of the bony endplate displayed clear changes. The number of pores in the endplate in Groups C to E was significantly higher than in Group A (p<.0001), among which Group C versus Group D (p=.9724), and Group C versus Group E (p=.0116). There was no significant difference between Groups A and B (p=.5261). In addition, the pore diameter also increased, the trend essentially the same as that of pore density. There was no significant difference between the three intervention groups (p=.7213). It is worth noting that, compared with Groups A and B, peripheral pore density and size in Groups D and E of the three intervention groups recovered significantly. The elastic modulus and diameter of collagen fibers in the AF and NP varied with the type of intervention. Low tension traction combined with ESWT resulted in the greatest impact on the diameter and modulus of collagen fibers. CONCLUSIONS Low energy ESWT combined with low tension traction provided a more stable intervertebral environment for the regeneration and repair of moderate and severe degenerative discs. Low energy ESWT promoted the regeneration of disc matrix by reducing MMP-3, MMP-13, and ADAMTS-4 resulting in inhibition of collagen degradation. Although axial traction promoted the recovery of height and rehydration of the IVD, combined with low energy ESWT, the micro-nano structure of the bony endplate underwent positive reconstruction, tension in the annulus of the AF and nuclear stress of the NP declined, and the biomechanical microenvironment required for IVD regeneration and repair was reshaped.
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Affiliation(s)
- Yan-Jun Che
- Orthopaedic Institute, Department of Orthopaedics, The First Affiliated Hospital of SooChow University, 708 Renmin Rd, Suzhou, Jiangsu 215007, People's Republic of China; Department of Orthopedics, Heping Hospital Affiliated to Changzhi Medical College, Changzhi, Shanxi, People's Republic of China
| | - Jun-Jun Hou
- Department of Geriatrics, Xinghu Hospital, SuZhou industrial park, Suzhou, Jiangsu, People's Republic of China; Department of Endocrinology, The First Affiliated Hospital of SooChow University, Suzhou, Jiangsu, People's Republic of China
| | - Jiang-Bo Guo
- Orthopaedic Institute, Department of Orthopaedics, The First Affiliated Hospital of SooChow University, 708 Renmin Rd, Suzhou, Jiangsu 215007, People's Republic of China
| | - Ting Liang
- Orthopaedic Institute, Department of Orthopaedics, The First Affiliated Hospital of SooChow University, 708 Renmin Rd, Suzhou, Jiangsu 215007, People's Republic of China
| | - Wen Zhang
- Orthopaedic Institute, Department of Orthopaedics, The First Affiliated Hospital of SooChow University, 708 Renmin Rd, Suzhou, Jiangsu 215007, People's Republic of China
| | - Yan Lu
- Department of Endocrinology, The First Affiliated Hospital of SooChow University, Suzhou, Jiangsu, People's Republic of China
| | - Hui-Lin Yang
- Orthopaedic Institute, Department of Orthopaedics, The First Affiliated Hospital of SooChow University, 708 Renmin Rd, Suzhou, Jiangsu 215007, People's Republic of China
| | - Yue Feng Hao
- Orthopedics and Sports medicine center, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou 215000, Jiangsu, People's Republic of China
| | - Zong-Ping Luo
- Orthopaedic Institute, Department of Orthopaedics, The First Affiliated Hospital of SooChow University, 708 Renmin Rd, Suzhou, Jiangsu 215007, People's Republic of China.
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22
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Zeldin L, Mosley GE, Laudier D, Gallate ZS, Gansau J, Hoy RC, Poeran J, Iatridis JC. Spatial mapping of collagen content and structure in human intervertebral disk degeneration. JOR Spine 2020; 3:e1129. [PMID: 33392461 PMCID: PMC7770200 DOI: 10.1002/jsp2.1129] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 10/13/2020] [Accepted: 10/18/2020] [Indexed: 12/11/2022] Open
Abstract
Collagen plays a key structural role in both the annulus fibrosus (AF) and nucleus pulposus (NP) of intervertebral disks (IVDs). Changes in collagen content with degeneration suggest a shift from collagen type II to type I within the NP, and the activation of pro-inflammatory factors is indicative of fibrosis throughout. While IVD degeneration is considered a fibrotic process, an increase in collagen content with degeneration, reflective of fibrosis, has not been demonstrated. Additionally, changes in collagen content and structure in human IVDs with degeneration have not been characterized with high spatial resolution. The collagen content of 23 human lumbar L2/3 or L3/4 IVDs was quantified using second harmonic generation imaging (SHG) and multiple image processing algorithms, and these parameters were correlated with the Rutges histological degeneration grade. In the NP, SHG intensity increased with degeneration grade, suggesting fibrotic collagen deposition. In the AF, the entropy of SHG intensity was reduced with degeneration indicating increased collagen uniformity and suggesting less-organized lamellar structure. Collagen orientation entropy decreased throughout most IVD regions with increasing degeneration grade, further supporting a loss in collagen structural complexity. Overall, SHG imaging enabled visualization and quantification of IVD collagen content and organization with degeneration. There was an observed shift from an initially complex structure to more uniform structure with loss of microstructural elements and increased NP collagen polarity, suggesting fibrotic remodeling.
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Affiliation(s)
- Lawrence Zeldin
- Leni & Peter W. May Department of OrthopedicsIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Grace E. Mosley
- Leni & Peter W. May Department of OrthopedicsIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Damien Laudier
- Leni & Peter W. May Department of OrthopedicsIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Zachary S. Gallate
- Leni & Peter W. May Department of OrthopedicsIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Jennifer Gansau
- Leni & Peter W. May Department of OrthopedicsIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Robert C. Hoy
- Leni & Peter W. May Department of OrthopedicsIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Jashvant Poeran
- Leni & Peter W. May Department of OrthopedicsIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
- Department of Population Health Science and PolicyIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - James C. Iatridis
- Leni & Peter W. May Department of OrthopedicsIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
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23
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Kangari P, Talaei-Khozani T, Razeghian-Jahromi I, Razmkhah M. Mesenchymal stem cells: amazing remedies for bone and cartilage defects. Stem Cell Res Ther 2020; 11:492. [PMID: 33225992 PMCID: PMC7681994 DOI: 10.1186/s13287-020-02001-1] [Citation(s) in RCA: 157] [Impact Index Per Article: 31.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 10/27/2020] [Indexed: 12/15/2022] Open
Abstract
Skeletal disorders are among the leading debilitating factors affecting millions of people worldwide. The use of stem cells for tissue repair has raised many promises in various medical fields, including skeletal disorders. Mesenchymal stem cells (MSCs) are multipotent stromal cells with mesodermal and neural crest origin. These cells are one of the most attractive candidates in regenerative medicine, and their use could be helpful in repairing and regeneration of skeletal disorders through several mechanisms including homing, angiogenesis, differentiation, and response to inflammatory condition. The most widely studied sources of MSCs are bone marrow (BM), adipose tissue, muscle, umbilical cord (UC), umbilical cord blood (UCB), placenta (PL), Wharton's jelly (WJ), and amniotic fluid. These cells are capable of differentiating into osteoblasts, chondrocytes, adipocytes, and myocytes in vitro. MSCs obtained from various sources have diverse capabilities of secreting many different cytokines, growth factors, and chemokines. It is believed that the salutary effects of MSCs from different sources are not alike in terms of repairing or reformation of injured skeletal tissues. Accordingly, differential identification of MSCs' secretome enables us to make optimal choices in skeletal disorders considering various sources. This review discusses and compares the therapeutic abilities of MSCs from different sources for bone and cartilage diseases.
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Affiliation(s)
- Parisa Kangari
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Tahereh Talaei-Khozani
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
- Tissue Engineering Laboratory, Department of Anatomy, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Mahboobeh Razmkhah
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
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24
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Ashinsky BG, Gullbrand SE, Wang C, Bonnevie ED, Han L, Mauck RL, Smith HE. Degeneration alters structure-function relationships at multiple length-scales and across interfaces in human intervertebral discs. J Anat 2020; 238:986-998. [PMID: 33205444 DOI: 10.1111/joa.13349] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Revised: 09/19/2020] [Accepted: 10/08/2020] [Indexed: 12/19/2022] Open
Abstract
Intervertebral disc (IVD) degeneration and associated back pain place a significant burden on the population. IVD degeneration is a progressive cascade of cellular, compositional, and structural changes, which results in a loss of disc height, disorganization of extracellular matrix architecture, tears in the annulus fibrosus which may involve herniation of the nucleus pulposus, and remodeling of the bony and cartilaginous endplates (CEP). These changes to the IVD often occur concomitantly, across the entire motion segment from the disc subcomponents to the CEP and vertebral bone, making it difficult to determine the causal initiating factor of degeneration. Furthermore, assessments of the subcomponents of the IVD have been largely qualitative, with most studies focusing on a single attribute, rather than multiple adjacent IVD substructures. The objective of this study was to perform a multiscale and multimodal analysis of human lumbar motion segments across various length scales and degrees of degeneration. We performed multiple assays on every sample and identified several correlations between structural and functional measurements of disc subcomponents. Our results demonstrate that with increasing Pfirrmann grade there is a reduction in disc height and nucleus pulposus T2 relaxation time, in addition to alterations in motion segment macromechanical function, disc matrix composition and cellular morphology. At the cartilage endplate-vertebral bone interface, substantial remodeling was observed coinciding with alterations in micromechanical properties. Finally, we report significant relationships between vertebral bone and nucleus pulposus metrics, as well as between micromechanical properties of the endplate and whole motion segment biomechanical parameters, indicating the importance of studying IVD degeneration as a whole organ.
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Affiliation(s)
- Beth G Ashinsky
- McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA, USA.,Drexel University School of Biomedical Engineering, Science and Health Systems, Philadelphia, PA, USA.,Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA
| | - Sarah E Gullbrand
- McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA, USA.,Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA
| | - Chao Wang
- Drexel University School of Biomedical Engineering, Science and Health Systems, Philadelphia, PA, USA
| | - Edward D Bonnevie
- McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA, USA.,Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA
| | - Lin Han
- Drexel University School of Biomedical Engineering, Science and Health Systems, Philadelphia, PA, USA
| | - Robert L Mauck
- McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA, USA.,Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA
| | - Harvey E Smith
- McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, PA, USA.,Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA
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25
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Laurent A, Hirt-Burri N, Scaletta C, Michetti M, de Buys Roessingh AS, Raffoul W, Applegate LA. Holistic Approach of Swiss Fetal Progenitor Cell Banking: Optimizing Safe and Sustainable Substrates for Regenerative Medicine and Biotechnology. Front Bioeng Biotechnol 2020; 8:557758. [PMID: 33195124 PMCID: PMC7644790 DOI: 10.3389/fbioe.2020.557758] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Accepted: 08/21/2020] [Indexed: 12/17/2022] Open
Abstract
Safety, quality, and regulatory-driven iterative optimization of therapeutic cell source selection has constituted the core developmental bedrock for primary fetal progenitor cell (FPC) therapy in Switzerland throughout three decades. Customized Fetal Transplantation Programs were pragmatically devised as straightforward workflows for tissue procurement, traceability maximization, safety, consistency, and robustness of cultured progeny cellular materials. Whole-cell bioprocessing standardization has provided plethoric insights into the adequate conjugation of modern biotechnological advances with current restraining legislative, ethical, and regulatory frameworks. Pioneer translational advances in cutaneous and musculoskeletal regenerative medicine continuously demonstrate the therapeutic potential of FPCs. Extensive technical and clinical hindsight was gathered by managing pediatric burns and geriatric ulcers in Switzerland. Concomitant industrial transposition of dermal FPC banking, following good manufacturing practices, demonstrated the extensive potential of their therapeutic value. Furthermore, in extenso, exponential revalorization of Swiss FPC technology may be achieved via the renewal of integrative model frameworks. Consideration of both longitudinal and transversal aspects of simultaneous fetal tissue differential processing allows for a better understanding of the quasi-infinite expansion potential within multi-tiered primary FPC banking. Multiple fetal tissues (e.g., skin, cartilage, tendon, muscle, bone, lung) may be simultaneously harvested and processed for adherent cell cultures, establishing a unique model for sustainable therapeutic cellular material supply chains. Here, we integrated fundamental, preclinical, clinical, and industrial developments embodying the scientific advances supported by Swiss FPC banking and we focused on advances made to date for FPCs that may be derived from a single organ donation. A renewed model of single organ donation bioprocessing is proposed, achieving sustained standards and potential production of billions of affordable and efficient therapeutic doses. Thereby, the aim is to validate the core therapeutic value proposition, to increase awareness and use of standardized protocols for translational regenerative medicine, potentially impacting millions of patients suffering from cutaneous and musculoskeletal diseases. Alternative applications of FPC banking include biopharmaceutical therapeutic product manufacturing, thereby indirectly and synergistically enhancing the power of modern therapeutic armamentariums. It is hypothesized that a single qualifying fetal organ donation is sufficient to sustain decades of scientific, medical, and industrial developments, as technological optimization and standardization enable high efficiency.
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Affiliation(s)
- Alexis Laurent
- Regenerative Therapy Unit, Lausanne University Hospital, University of Lausanne, Épalinges, Switzerland
- Tec-Pharma SA, Bercher, Switzerland
- LAM Biotechnologies SA, Épalinges, Switzerland
| | - Nathalie Hirt-Burri
- Regenerative Therapy Unit, Lausanne University Hospital, University of Lausanne, Épalinges, Switzerland
| | - Corinne Scaletta
- Regenerative Therapy Unit, Lausanne University Hospital, University of Lausanne, Épalinges, Switzerland
| | - Murielle Michetti
- Regenerative Therapy Unit, Lausanne University Hospital, University of Lausanne, Épalinges, Switzerland
| | - Anthony S. de Buys Roessingh
- Children and Adolescent Surgery Service, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
| | - Wassim Raffoul
- Plastic, Reconstructive and Hand Surgery Service, Lausanne University Hospital, University of Lausanne, Lausanne, Switzerland
| | - Lee Ann Applegate
- Regenerative Therapy Unit, Lausanne University Hospital, University of Lausanne, Épalinges, Switzerland
- Oxford Suzhou Center for Advanced Research, Science and Technology Co., Ltd., Oxford University, Suzhou, China
- Competence Center for Applied Biotechnology and Molecular Medicine, University of Zurich, Zurich, Switzerland
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Augusto A, Dias RG, Wajchenberg M, Martins D. EXTREME LATERAL INTERBODY FUSION IN PACIENTS WITH CHRONIC LOW BACK PAIN. ACTA ORTOPEDICA BRASILEIRA 2020; 28:256-260. [PMID: 33144843 PMCID: PMC7580297 DOI: 10.1590/1413-785220202805233621] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
OBJECTIVE To evaluate the effect of lateral lumbar interbody fusion (LLIF) or oblique interbody fusion (OLIF) on low back pain due to degenerative intervertebral disc disease. METHODS We systematically reviewed articles on surgical treatment of low back pain by LLIF and OLIF, according to the Cochrane Handbook for Systematic Reviews of Interventions. We searched through electronic databases, including Medline via PubMed, Lilacs through the Virtual Health Library (VHL), Cochrane Collaboration/Central and Cohrane/Dare Cochrane Controlled Trials Register, without language or publication date restrictions and with design for prospective cohorts and randomized clinical trials. RESULTS We have selected and presented three studies. CONCLUSION The literature review showed great relevance in the improvement of the new surgical approach (LLIF) in relation to TLIF, but greater content availability in the databases is necessary to reach a satisfactory conclusion regarding the efficiency of the lateral approach and its advantages over other traditional procedures. Level of Evidence II, Systematic review of Level II studies.
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Affiliation(s)
| | | | - Marcelo Wajchenberg
- Hospital Israelita Albert Einstein, São Paulo, SP, Brazil.,Universidade Federal de São Paulo, Paulista School of Medicine, Department of Orthopedics and Traumatology, São Paulo, SP, Brazil
| | - Delio Martins
- Universidade Anhembi Morumbi, São Paulo, SP, Brazil.,Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
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Lin H, Wang Y, Jing K, Wu T, Niu Y, Wei J. Nuclear factor erythroid-2 related factor 2 inhibits human disc nucleus pulpous cells apoptosis induced by excessive hydrogen peroxide. ACTA ACUST UNITED AC 2020; 66:986-991. [PMID: 32844924 DOI: 10.1590/1806-9282.66.7.986] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Accepted: 02/23/2020] [Indexed: 12/25/2022]
Abstract
OBJECTIVE Nuclear factor erythroid-2 related factor 2 (Nrf2)/ antioxidant response element (ARE) is a novel defensive pathway involved in the oxidative and chemical stress of cells. The aim of the study was to explore the role of Nrf2 on the apoptosis of human disc nucleus pulpous cells induced by hydrogen peroxide (H2O2). METHODS The degeneration model of human intervertebral disc nucleus pulpous cells was established. The expression of Nrf2 was interfered with using sulforaphane (SFN); for that end, three groups were established: a blank group (H2O2-/SFN-), control group (H2O2+/SFN-), and an experimental group (H2O2+/SFN+). CCK8, Hoechst 33258 living cell staining was used to detect reactive oxygen species (ROS) content. RESULTS The apoptotic rates of the three groups were [(0.40±0.46)%], [(25.98±11.28)%], and [(3.83±2.06)%, respectively. The difference was statistically significant (p<0.05). The relative content of ROS in the three groups was [(100±7)%], [(1538±91)%], and [(818±63)%]; the difference was statistically significant (p<0.05). In Western blotting, Nrf2 content in the experimental group was higher than that in the control group. CONCLUSION Nrf2 exists in the nucleus pulpous cells of human intervertebral discs, which is related to the degeneration of the intervertebral disc. It has negative feedback regulation and can prevent the degeneration of the intervertebral disc by inhibiting the apoptosis of nucleus pulpous cells of human intervertebral discs caused by excessive ROS, which provides a new intervention strategy for the prevention and treatment of the degeneration of intervertebral discs.
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Affiliation(s)
- Hao Lin
- Orthopaedic Center, Affiliated Hospital, Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Yingxin Wang
- Orthopaedic Center, Affiliated Hospital, Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Kaipeng Jing
- Department of Nephrology, Affiliated Hospital, Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Tingrui Wu
- Orthopaedic Center, Affiliated Hospital, Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Yanru Niu
- Orthopaedic Center, Affiliated Hospital, Guangdong Medical University, Zhanjiang, Guangdong, China
| | - Jinsong Wei
- Orthopaedic Center, Affiliated Hospital, Guangdong Medical University, Zhanjiang, Guangdong, China
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Ashinsky BG, Gullbrand SE, Bonnevie ED, Wang C, Kim DH, Han L, Mauck RL, Smith HE. Sacrificial Fibers Improve Matrix Distribution and Micromechanical Properties in a Tissue-Engineered Intervertebral Disc. Acta Biomater 2020; 111:232-241. [PMID: 32447064 DOI: 10.1016/j.actbio.2020.05.019] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Revised: 05/13/2020] [Accepted: 05/14/2020] [Indexed: 12/19/2022]
Abstract
Tissue-engineered replacement discs are an area of intense investigation for the treatment of end-stage intervertebral disc (IVD) degeneration. These living implants can integrate into the IVD space and recapitulate native motion segment function. We recently developed a multiphasic tissue-engineered disc-like angle-ply structure (DAPS) that models the micro-architectural and functional features of native tissue. While these implants resulted in functional restoration of the motion segment in rat and caprine models, we also noted deficiencies in cell infiltration and homogeneity of matrix deposition in the electrospun poly(ε-caprolactone) outer region (annulus fibrosus, AF) of the DAPS. To address this limitation, here, we incorporated a sacrificial water-soluble polymer, polyethylene oxide (PEO), as a second fiber fraction within the AF region to increase porosity of the implant. Maturation of these PEO-modified DAPS were evaluated after 5 and 10 weeks of in vitro culture in terms of AF biochemical content, MRI T2 values, overall construct mechanical properties, AF micromechanical properties and cell and matrix distribution. To assess the performance of the PEO-modified DAPS in vivo, precultured constructs were implanted into the rat caudal IVD space for 10 weeks. Results showed that matrix distribution was more homogenous in PCL/PEO DAPS, as evidenced by more robust histological staining, organized collagen deposition and micromechanical properties, compared to standard PCL-only DAPS in vitro. Cell and matrix infiltration were also improved in vivo, but no differences in macromechanical properties and a trend towards improved micromechanical properties were observed. These findings demonstrate that the inclusion of a sacrificial PEO fiber fraction in the DAPS AF region improves cellular colonization, matrix elaboration, and in vitro and in vivo function of an engineered IVD implant. STATEMENT OF SIGNIFICANCE: This work establishes a method for improving cell infiltration and matrix distribution within tissue-engineered dense fibrous scaffolds for intervertebral disc replacement. Tissue-engineered whole disc replacements are an attractive alternative to the current gold standard (mechanical disc arthroplasty or vertebral fusion) for the clinical treatment of patients with advanced disc degeneration.
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Qiu C, Wu X, Bian J, Ma X, Zhang G, Guo Z, Wang Y, Ci Y, Wang Q, Xiang H, Chen B. Differential proteomic analysis of fetal and geriatric lumbar nucleus pulposus: immunoinflammation and age-related intervertebral disc degeneration. BMC Musculoskelet Disord 2020; 21:339. [PMID: 32487144 PMCID: PMC7265631 DOI: 10.1186/s12891-020-03329-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 05/05/2020] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Intervertebral disc degeneration (IVDD) is a major cause of low back pain. Although the mechanism of degeneration remains unclear, aging has been recognized as a key risk factor for IVDD. Most studies seeking to identify IVDD-associated molecular alterations in the context of human age-related IVDD have focused only on a limited number of proteins. Differential proteomic analysis is an ideal method for comprehensively screening altered protein profiles and identifying the potential pathways related to pathological processes such as disc degeneration. METHODS In this study, tandem mass tag (TMT) labeling was combined with liquid chromatography-tandem mass spectrometry (LC-MS/MS) for differential proteomic analysis of human fetal and geriatric lumbar disc nucleus pulposus (NP) tissue. Parallel reaction monitoring (PRM) and Western blotting (WB) techniques were used to identify target proteins. Bioinformatic analyses, including Gene Ontology (GO) annotation, domain annotation, pathway annotation, subcellular localization and functional enrichment analyses, were used to interpret the potential significance of the protein alterations in the mechanism of IVDD. Student's t-tests and two-tailed Fisher's exact tests were used for statistical analysis. RESULTS Six hundred forty five proteins were significantly upregulated and 748 proteins were downregulated in the geriatric group compared with the fetal group. Twelve proteins were verified to have significant differences in abundance between geriatric and fetal NP tissue; most of these have not been previously identified as being associated with human IVDD. The potential significance of the differentially expressed proteins in age-related IVDD was analyzed from multiple perspectives, especially with regard to the association of the immunoinflammatory response with IVDD. CONCLUSIONS Differential proteomic analysis was used as a comprehensive strategy for elucidating the protein alterations associated with age-related IVDD. The findings of this study will aid in the screening of new biomarkers and molecular targets for the diagnosis and therapy of IVDD. The results may also significantly enhance our understanding of the pathophysiological process and mechanism of age-related IVDD.
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Affiliation(s)
- Chensheng Qiu
- Medical College of Qingdao University, Qingdao, 266000, China.,Department of Orthopedic Surgery, Affiliated Hospital of Qingdao University, Qingdao, 266000, China.,Department of Orthopedic Surgery, Qingdao Municipal Hospital (Group), Qingdao, 266011, China
| | - Xiaolin Wu
- Medical College of Qingdao University, Qingdao, 266000, China
| | - Jiang Bian
- Qingdao Eye Hospital of Shandong First Medical University, Qingdao, 266000, China
| | - Xuexiao Ma
- Department of Orthopedic Surgery, Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Guoqing Zhang
- Department of Orthopedic Surgery, Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Zhu Guo
- Department of Orthopedic Surgery, Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Yan Wang
- Department of Orthopedic Surgery, Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Yandong Ci
- The Eighth People's Hospital of Qingdao, Qingdao, 266000, China
| | - Qizun Wang
- Department of Orthopedic Surgery, Affiliated Hospital of Qingdao University, Qingdao, 266000, China
| | - Hongfei Xiang
- Department of Orthopedic Surgery, Affiliated Hospital of Qingdao University, Qingdao, 266000, China.
| | - Bohua Chen
- Department of Orthopedic Surgery, Affiliated Hospital of Qingdao University, Qingdao, 266000, China.
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Gullbrand SE, Kim DH, Ashinsky BG, Bonnevie ED, Smith HE, Mauck RL. Restoration of physiologic loading modulates engineered intervertebral disc structure and function in an in vivo model. JOR Spine 2020; 3:e1086. [PMID: 32613161 PMCID: PMC7323465 DOI: 10.1002/jsp2.1086] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2019] [Revised: 03/24/2020] [Accepted: 03/25/2020] [Indexed: 12/12/2022] Open
Abstract
Tissue-engineered whole disc replacements are an emerging treatment strategy for advanced intervertebral disc degeneration. A challenge facing the translation of tissue-engineered disc replacement to clinical use are the opposing needs of initial immobilization to advantage integration contrasted with physiologic loading and its anabolic effects. Here, we utilize our established rat tail model of tissue engineered disc replacement with external fixation to study the effects of remobilization at two time points postimplantation on engineered disc structure, composition, and function. Our results suggest that the restoration of mechanical loading following immobilization enhanced collagen and proteoglycan content within the nucleus pulposus and annulus fibrosus of the engineered discs, in addition to improving the integration of the endplate region of the construct with native bone. Despite these benefits, angulation of the vertebral bodies at the implanted level occurred following remobilization at both early and late time points, reducing tensile failure properties in the remobilized groups compared to the fixed group. These results demonstrate the necessity of restoring physiologic mechanical loading to engineered disc implants in vivo, and the need to transition toward their evaluation in larger animal models with more human-like anatomy and motion compared to the rat tail.
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Affiliation(s)
- Sarah E. Gullbrand
- Translational Musculoskeletal Research CenterCorporal Michael J. Crescenz VA Medical CenterPhiladelphiaPennsylvaniaUSA
- McKay Orthopaedic Research Laboratory, Department of Orthopaedic SurgeryUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Dong Hwa Kim
- Translational Musculoskeletal Research CenterCorporal Michael J. Crescenz VA Medical CenterPhiladelphiaPennsylvaniaUSA
- McKay Orthopaedic Research Laboratory, Department of Orthopaedic SurgeryUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Beth G. Ashinsky
- Translational Musculoskeletal Research CenterCorporal Michael J. Crescenz VA Medical CenterPhiladelphiaPennsylvaniaUSA
- McKay Orthopaedic Research Laboratory, Department of Orthopaedic SurgeryUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- School of Biomedical Engineering, Science and Health SystemsDrexel UniversityPhiladelphiaPennsylvaniaUSA
| | - Edward D. Bonnevie
- Translational Musculoskeletal Research CenterCorporal Michael J. Crescenz VA Medical CenterPhiladelphiaPennsylvaniaUSA
- McKay Orthopaedic Research Laboratory, Department of Orthopaedic SurgeryUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Harvey E. Smith
- Translational Musculoskeletal Research CenterCorporal Michael J. Crescenz VA Medical CenterPhiladelphiaPennsylvaniaUSA
- McKay Orthopaedic Research Laboratory, Department of Orthopaedic SurgeryUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Robert L. Mauck
- Translational Musculoskeletal Research CenterCorporal Michael J. Crescenz VA Medical CenterPhiladelphiaPennsylvaniaUSA
- McKay Orthopaedic Research Laboratory, Department of Orthopaedic SurgeryUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Department of BioengineeringUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
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Yin X, Motorwala A, Vesvoranan O, Levene HB, Gu W, Huang CY. Effects of Glucose Deprivation on ATP and Proteoglycan Production of Intervertebral Disc Cells under Hypoxia. Sci Rep 2020; 10:8899. [PMID: 32483367 PMCID: PMC7264337 DOI: 10.1038/s41598-020-65691-w] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2019] [Accepted: 03/05/2020] [Indexed: 12/25/2022] Open
Abstract
As the most common cause of low back pain, the cascade of intervertebral disc (IVD) degeneration is initiated by the disappearance of notochordal cells and progressive loss of proteoglycan (PG). Limited nutrient supply in the avascular disc environment restricts the production of ATP which is an essential energy source for cell survival and function such as PG biosynthesis. The objective of this study was to examine ATP level and PG production of porcine IVD cells under prolonged exposure to hypoxia with physiological glucose concentrations. The results showed notochordal NP and AF cells responded differently to changes of oxygen and glucose. Metabolic activities (including PG production) of IVD cells are restricted under the in-vivo nutrient conditions while NP notochordal cells are likely to be more vulnerable to reduced nutrition supply. Moreover, provision of energy, together or not with genetic regulation, may govern PG production in the IVD under restricted nutrient supply. Therefore, maintaining essential levels of nutrients may reduce the loss of notochordal cells and PG in the IVD. This study provides a new insight into the metabolism of IVD cells under nutrient deprivation and the information for developing treatment strategies for disc degeneration.
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Affiliation(s)
- Xue Yin
- Department of Biomedical Engineering, University of Miami, Coral Gables, FL, USA
| | - Aarif Motorwala
- Department of Biomedical Engineering, University of Miami, Coral Gables, FL, USA
| | - Oraya Vesvoranan
- Department of Biomedical Engineering, University of Miami, Coral Gables, FL, USA
| | - Howard B Levene
- Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Weiyong Gu
- Department of Biomedical Engineering, University of Miami, Coral Gables, FL, USA.,Department of Mechanical and Aerospace Engineering, University of Miami, Coral Gables, FL, USA
| | - Chun-Yuh Huang
- Department of Biomedical Engineering, University of Miami, Coral Gables, FL, USA.
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Xu G, Liu C, Jiang J, Liang T, Yu C, Qin Z, Zhang Z, Lu Z, Zhan X. A novel mechanism of intervertebral disc degeneration: imbalance between autophagy and apoptosis. Epigenomics 2020; 12:1095-1108. [PMID: 32285684 DOI: 10.2217/epi-2020-0079] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
Aim: To identify a key competitive endogenous RNA network for intervertebral disc degeneration. Materials & methods: Based on circular RNA, microRNA and mRNA expression profiles of nucleus pulposus cells, a variety of bioinformatics methods were used to screen key molecular structures and construct competitive endogenous RNA networks. Results: 190 upregulated genes and 77 downregulated genes were identified. Gene ontology/Kyoto Encyclopedia of Genes and Genomes functional analysis showed that autophagy was out of balance with apoptosis. Nine hub genes, five hub microRNAs and eight hub circular RNAs were obtained through progressive reverse prediction and verification. Conclusion: We believe that disc degeneration is caused by an imbalance between autophagy and apoptosis in nucleus pulposus cells, which may provide nonsurgical treatment for the future delay or prevention of spinal degenerative diseases associated with intervertebral disc degeneration.
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Affiliation(s)
- Guoyong Xu
- Guangxi Collaborative Innovation Center for Biomedicine, Guangxi Medical University, Nanning 530021, PR China
| | - Chong Liu
- Guangxi Collaborative Innovation Center for Biomedicine, Guangxi Medical University, Nanning 530021, PR China.,Spine and Osteopathy Ward, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, PR China
| | - Jie Jiang
- Guangxi Collaborative Innovation Center for Biomedicine, Guangxi Medical University, Nanning 530021, PR China
| | - Tuo Liang
- Guangxi Collaborative Innovation Center for Biomedicine, Guangxi Medical University, Nanning 530021, PR China
| | - Chaojie Yu
- Guangxi Collaborative Innovation Center for Biomedicine, Guangxi Medical University, Nanning 530021, PR China
| | - Zhaojie Qin
- Guangxi Collaborative Innovation Center for Biomedicine, Guangxi Medical University, Nanning 530021, PR China
| | - Zide Zhang
- Guangxi Collaborative Innovation Center for Biomedicine, Guangxi Medical University, Nanning 530021, PR China
| | - Zhaojun Lu
- Guangxi Collaborative Innovation Center for Biomedicine, Guangxi Medical University, Nanning 530021, PR China
| | - Xinli Zhan
- Guangxi Collaborative Innovation Center for Biomedicine, Guangxi Medical University, Nanning 530021, PR China.,Spine and Osteopathy Ward, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, PR China
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Nano and micro biomechanical analyses of the nucleus pulposus after in situ immobilization in rats. Micron 2020; 130:102824. [PMID: 31927410 DOI: 10.1016/j.micron.2020.102824] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2019] [Revised: 11/20/2019] [Accepted: 01/03/2020] [Indexed: 01/07/2023]
Abstract
Immobilization can lead to intervertebral disc degeneration. The biomechanical characteristics of such discs have not so far been investigated at the micro- or nanoscale, the level at which cells sense and respond to the surrounding environment. This study aimed to characterize changes in the elastic modulus of the collagen fibrils in the nucleus pulposus at the nanoscale and correlate this with micro-biomechanical properties of the nucleus pulposus after immobilization, in addition to observation of tissue histology and its gene expressions. An immobilization system was used on the rat tail with an external fixation device. The elastic modulus was measured using both nano and micro probes for atomic force microscopy after 4 and 8 weeks of immobilization. Histology of the tissue was observed following hematoxylin and eosin staining. Gene expression in the annulus fibrosus tissue was quantified using real-time reverse transcription-polymerase chain reaction. The elastic modulus of the collagen fibrils in the nucleus pulposus at the nanoscale increased from 74.07 ± 17.06 MPa in the control to 90.06 ± 25.51 MPa after 8 weeks (P = 0.007), and from 33.51 ± 9.33 kPa to 43.18 ± 12.08 kPa at the microscale (P = 0.002). After immobilization for 8 weeks, a greater number of cells were observed by histology to be aggregated within the nucleus pulposus. Collagen II (P = 0.007) and aggrecan (P = 0.003) gene expression were downregulated whereas collagen I (P = 0.002), MMP-3 (P < 0.001), MMP-13 (P < 0.001) and ADAMTs-4 (P < 0.001) were upregulated. Immobilization not only influenced individual collagen fibrils at the nanoscale, but also altered the micro-biomechanics and cell response in the nucleus pulposus. These results suggest that significant changes occur in intervertebral discs at both scales after immobilization, a situation about which clinicians should be aware when immobilization has to be used clinically.
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Ashinsky BG, Gullbrand SE, Bonnevie ED, Mandalapu SA, Wang C, Elliott DM, Han L, Mauck RL, Smith HE. Multiscale and multimodal structure-function analysis of intervertebral disc degeneration in a rabbit model. Osteoarthritis Cartilage 2019; 27:1860-1869. [PMID: 31419488 PMCID: PMC6875634 DOI: 10.1016/j.joca.2019.07.016] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2019] [Revised: 07/11/2019] [Accepted: 07/18/2019] [Indexed: 02/02/2023]
Abstract
OBJECTIVES The objective of this study was to perform a quantitative analysis of the structural and functional alterations in the intervertebral disc during in vivo degeneration, using emerging tools that enable rigorous assessment from the microscale to the macroscale, as well as to correlate these outcomes with noninvasive, clinically relevant imaging parameters. DESIGN Degeneration was induced in a rabbit model by puncturing the annulus fibrosus (AF) with a 16-gauge needle. 2, 4, 8, and 12 weeks following puncture, degenerative changes in the discs were evaluated via magnetic resonance imaging (MRI), whole motion segment biomechanics, atomic force microscopy, histology and polarized light microscopy, immunohistochemistry, biochemical content, and second harmonic generation imaging. RESULTS Following puncture, degeneration was evident through marked changes in whole disc structure and mechanics. Puncture acutely compromised disc macro and microscale mechanics, followed by progressive stiffening and remodeling. Histological analysis showed substantial anterior fibrotic remodeling and osteophyte formation, as well as an overall reduction in disc height, and disorganization and infolding of the AF lamellae into the NP space. Increases in NP collagen content and aggrecan breakdown products were also noted within 4 weeks. On MRI, NP T2 was reduced at all post-puncture time points and correlated significantly with microscale indentation modulus. CONCLUSION This study defined the time dependent changes in disc structure-function relationships during IVD degeneration in a rabbit annular injury model and correlated degeneration severity with clinical imaging parameters. Our findings identified AF infolding and occupancy of the space as a principle mechanism of disc degeneration in response to needle puncture, and provide new insights to direct the development of novel therapeutics.
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Affiliation(s)
- Beth G. Ashinsky
- Department of Orthopaedic Surgery, McKay Orthopaedic Research Laboratory, University of Pennsylvania, Philadelphia, PA,Drexel University School of Biomedical Engineering, Philadelphia, PA,Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA
| | - Sarah E. Gullbrand
- Department of Orthopaedic Surgery, McKay Orthopaedic Research Laboratory, University of Pennsylvania, Philadelphia, PA,Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA
| | - Edward D. Bonnevie
- Department of Orthopaedic Surgery, McKay Orthopaedic Research Laboratory, University of Pennsylvania, Philadelphia, PA,Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA
| | - Sai A. Mandalapu
- Department of Orthopaedic Surgery, McKay Orthopaedic Research Laboratory, University of Pennsylvania, Philadelphia, PA,Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA
| | - Chao Wang
- Drexel University School of Biomedical Engineering, Philadelphia, PA
| | - Dawn M. Elliott
- Department of Biomedical Engineering, University of Delaware, Newark, DE
| | - Lin Han
- Drexel University School of Biomedical Engineering, Philadelphia, PA
| | - Robert L. Mauck
- Department of Orthopaedic Surgery, McKay Orthopaedic Research Laboratory, University of Pennsylvania, Philadelphia, PA,Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA
| | - Harvey E. Smith
- Department of Orthopaedic Surgery, McKay Orthopaedic Research Laboratory, University of Pennsylvania, Philadelphia, PA,Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA,Address correspondence to: Harvey E. Smith, University of Pennsylvania School of Medicine, Department of Orthopaedic Surgery, 3737 Market Street, 6 Floor, Philadelphia, PA 19104, T: 215-662-3340,
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35
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Hansen BB, Ciochon UM, Trampedach CR, Christensen AF, Rasti Z, Boesen M. Grading lumbar disc degeneration: a comparison between low- and high-field MRI. Acta Radiol 2019; 60:1636-1642. [PMID: 31003590 DOI: 10.1177/0284185119842472] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Affiliation(s)
- Bjarke B Hansen
- The Parker Institute, Copenhagen University Hospital, Frederiksberg, Denmark
| | - Urszula M Ciochon
- Department of Radiology, Copenhagen University Hospital, Frederiksberg, Denmark
| | | | | | - Zoreh Rasti
- Department of Radiology, Copenhagen University Hospital, Frederiksberg, Denmark
| | - Mikael Boesen
- The Parker Institute, Copenhagen University Hospital, Frederiksberg, Denmark
- Department of Radiology, Copenhagen University Hospital, Frederiksberg, Denmark
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Song Y, Wang Z, Liu L, Zhang S, Zhang H, Qian Y. 1,4-Dihydropyridine (DHP) suppresses against oxidative stress in nucleus pulposus via activating sirtuin-1. Biomed Pharmacother 2019; 121:109592. [PMID: 31706101 DOI: 10.1016/j.biopha.2019.109592] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2019] [Revised: 10/23/2019] [Accepted: 10/26/2019] [Indexed: 01/03/2023] Open
Abstract
Intervertebral disc degeneration (IVDD) is a major cause of many spinal diseases characterized mainly by nucleus pulposus degradation. 1,4-dihydropyridine (DHP), a new activator of sirtuin-1 (sirt1), has been reported to have anti-oxidative effects. The aim of this study is to investigate the effect of DHP on nucleus pulposus (NP) cells in vitro. NP cells were pretreated with IL-1β to establish a degenerated model, and then treated with DHP alone or DHP combined with selisistat (an inhibitor of sirt1). ROS level was analyzed by flow cytometry. Production of IL-6 and TNF-α were evaluated by the enzyme-linked immunosorbent assay (ELISA). The mRNA and protein expression were measured by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot respectively. Immunofluorescence was used to assess the expression of collagen-II and sirt1. We found that DHP inhibited IL-1β-induced upregulation of ROS, TNF-α, IL-6, MMP-3, ADAMTS-5. Besides, DHP remarkably increased the sirt1 and anti-oxidative protein SOD-1 level. Furthermore, DHP significantly protected the IL-1β-induced degradation of collagen-II and aggrecan. However, the inhibitory effect of DHP was obvious abolished by selisistat, suggesting that DHP exerts these effects in NP cells through activating sirt1. Taken together, we found that DHP inhibited the ROS, inflammatory response and ECM degradation through activating Sirt1 in human NP cells.
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Affiliation(s)
- Yuxin Song
- Department of Orthopaedics, Gansu Provincial Hospital, Lanzhou, Gansu, China
| | - Zhan Wang
- Department of Orthopaedics, Gansu Provincial Hospital, Lanzhou, Gansu, China
| | - Lin Liu
- Department of Orthopaedics, Gansu Provincial Hospital, Lanzhou, Gansu, China
| | - Suifeng Zhang
- Department of Orthopaedics, Gansu Provincial Hospital, Lanzhou, Gansu, China
| | - Hui Zhang
- Department of Orthopaedics, Gansu Provincial Hospital, Lanzhou, Gansu, China
| | - Yaowen Qian
- Department of Orthopaedics, Gansu Provincial Hospital, Lanzhou, Gansu, China; Cancer Center, Gansu Provincial Hospital, Lanzhou, Gansu, China.
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Claeson AA, Vresilovic EJ, Showalter BL, Wright AC, Gee JC, Malhotra NR, Elliott DM. Human Disc Nucleotomy Alters Annulus Fibrosus Mechanics at Both Reference and Compressed Loads. J Biomech Eng 2019; 141:1110011-11100112. [PMID: 31141601 PMCID: PMC6808005 DOI: 10.1115/1.4043874] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2018] [Revised: 05/25/2019] [Indexed: 10/19/2023]
Abstract
Nucleotomy is a common surgical procedure and is also performed in ex vivo mechanical testing to model decreased nucleus pulposus (NP) pressurization that occurs with degeneration. Here, we implement novel and noninvasive methods using magnetic resonance imaging (MRI) to study internal 3D annulus fibrosus (AF) deformations after partial nucleotomy and during axial compression by evaluating changes in internal AF deformation at reference loads (50 N) and physiological compressive loads (∼10% strain). One particular advantage of this methodology is that the full 3D disc deformation state, inclusive of both in-plane and out-of-plane deformations, can be quantified through the use of a high-resolution volumetric MR scan sequence and advanced image registration. Intact grade II L3-L4 cadaveric human discs before and after nucleotomy were subjected to identical mechanical testing and imaging protocols. Internal disc deformation fields were calculated by registering MR images captured in each loading state (reference and compressed) and each condition (intact and nucleotomy). Comparisons were drawn between the resulting three deformation states (intact at compressed load, nucleotomy at reference load, nucleotomy at compressed load) with regard to the magnitude of internal strain and direction of internal displacements. Under compressed load, internal AF axial strains averaged -18.5% when intact and -22.5% after nucleotomy. Deformation orientations were significantly altered by nucleotomy and load magnitude. For example, deformations of intact discs oriented in-plane, whereas deformations after nucleotomy oriented axially. For intact discs, in-plane components of displacements under compressive loads oriented radially outward and circumferentially. After nucleotomy, in-plane displacements were oriented radially inward under reference load and were not significantly different from the intact state at compressed loads. Re-establishment of outward displacements after nucleotomy indicates increased axial loading restores the characteristics of internal pressurization. Results may have implications for the recurrence of pain, design of novel therapeutics, or progression of disc degeneration.
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Affiliation(s)
- Amy A Claeson
- Mem. ASMEBiomedical Engineering,University of Delaware,160 Colburn Lab,150 Academy Street,Newark, DE 19716e-mail:
| | - Edward J Vresilovic
- Orthopaedic and Rehabilitation,Pennsylvania State University,EC089 500 University Drive,Hershey, PA 17033e-mail:
| | - Brent L Showalter
- Bioengineering,University of Pennsylvania,242 Stemmler Hall,36th Street & Hamilton Walk,Philadelphia, PA 19104e-mail:
| | - Alexander C Wright
- Radiology,University of Pennsylvania,1st Floor Silverstein Pavilion,3400 Spruce Street,Philadelphia, PA 19104e-mail:
| | - James C Gee
- Radiology,University of Pennsylvania,6th Floor Richards,3700 Hamilton Walk,Philadelphia, PA 19104e-mail:
| | - Neil R Malhotra
- Neurosurgery,University of Pennsylvania,3rd Floor Silverstein Pavilion,3400 Spruce Street,Philadelphia, PA 19104e-mail:
| | - Dawn M Elliott
- Mem. ASMEBiomedical Engineering,University of Delaware,160 Colburn Lab,150 Academy Street,Newark, DE 19716e-mail:
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38
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Zehra U, Noel-Barker N, Marshall J, Adams MA, Dolan P. Associations Between Intervertebral Disc Degeneration Grading Schemes and Measures of Disc Function. J Orthop Res 2019; 37:1946-1955. [PMID: 31042314 DOI: 10.1002/jor.24326] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Accepted: 04/08/2019] [Indexed: 02/04/2023]
Abstract
Disc degeneration is a major cause of spinal dysfunction and pain, but grading schemes concentrate on tissue changes rather than altered function. The aim of this study was to compare disc degeneration grading systems with each other, and with biomechanical measures of disc function. Sixty-six motion segments (T8-9 to L5-S1) were dissected from cadavers aged 48-98 years. Disc function was assessed by measuring nucleus pressure (IDP) and maximum stresses in the annulus under 1 kN of compression. Detailed "scores" of disc degeneration were based on independent radiographic, macroscopic, and microscopic evaluations. For each evaluation, scores were used to assign a degeneration "grade" (I-IV), and functional measures were then correlated with degeneration scores and grades. Results showed that all measures were reliable (intraclass correlation coefficients: 0.82-0.99). Macroscopic and microscopic assessments were highly correlated with each other (r: 0.57-0.89, p < 0.001) but only weakly correlated with radiographic features. The overall macroscopic and microscopic scores of degeneration increased significantly with age and at lower spinal levels, although the influence of age was less marked in the case of the microscopic scores. IDP decreased with age and at lower spinal levels, but annulus stresses were more variable. Importantly, IDP and annulus stresses decreased consistently with all measures of disc degeneration, and these associations remained strong after controlling for age, gender, and spinal level. We conclude that radiographic and tissue-based assessments of disc degeneration are consistent with each other, and are more closely related to mechanical (dys)function than to age or spinal level. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1946-1955, 2019.
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Affiliation(s)
- Uruj Zehra
- Department of Anatomy, University of Health Sciences, Lahore, Pakistan
| | - Natasha Noel-Barker
- Centre for Applied Anatomy, Faculty of Health Sciences, University of Bristol, Southwell Street Bristol, Bristol, BS2 8EJ, UK
| | - John Marshall
- Centre for Applied Anatomy, Faculty of Health Sciences, University of Bristol, Southwell Street Bristol, Bristol, BS2 8EJ, UK
| | - Michael A Adams
- Centre for Applied Anatomy, Faculty of Health Sciences, University of Bristol, Southwell Street Bristol, Bristol, BS2 8EJ, UK
| | - Patricia Dolan
- Centre for Applied Anatomy, Faculty of Health Sciences, University of Bristol, Southwell Street Bristol, Bristol, BS2 8EJ, UK
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Wang J, Liu X, Sun B, Du W, Zheng Y, Sun Y. Upregulated miR-154 promotes ECM degradation in intervertebral disc degeneration. J Cell Biochem 2019; 120:11900-11907. [PMID: 30825225 DOI: 10.1002/jcb.28471] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Revised: 11/21/2018] [Accepted: 02/07/2019] [Indexed: 01/24/2023]
Abstract
Intervertebral disc degeneration (IDD), a common global health issue, is a major cause for low back pain (LBP). Given the complex etiology of IDD, micro RNA (miRNA) recently has been demonstrated to play essential roles in the progression of IDD. Therefore, this study aims to investigate functions of the miR-154, which is well-documented in a series of cell activities, IDD, and other relevant mechanisms. Lumbar nucleus pulposus (NP) samples were collected from patients with IDD and the control group. After solexa sequencing and bioinformatical analysis, the results showed that miR-154 was increased in NP cells of patients with IDD. Inhibition of miR-154 increased type II collagen and aggrecan and decreased mRNA expressions of collagenase-3 (MMP13) and aggrecanase-1 (ADAMTS4), whereas overexpression of miR-154 reversed such effects in NP cells. In addition, the luciferase reporter assay revealed that fibroblast growth factor 14 (FGF14) is a direct target of miR-154 and that the overexpression of FGF14 leads to similar effects as inhibition of miR-154 did. In conclusion, the results suggested that miR-154 participates in the development of IDD and its effects are mediated via targeting FGF14. Thus, miR-154 may be thought as a potential etiological factor for IDD and may provide insights into a therapeutic target to treat IDD.
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Affiliation(s)
- Jingjie Wang
- Department of Orthopedic Surgery, Qilu Hospital, Shandong University, Jinan, China.,Department of Spine, Yantaishan Hospital, Yantai, China
| | - Xiaoyan Liu
- Department of Laboratory, Yuhuangding Hospital, Yantai, China
| | - Bing Sun
- Department of Spine, Yantaishan Hospital, Yantai, China
| | - Wei Du
- Department of Spine, Yantaishan Hospital, Yantai, China
| | - Yanping Zheng
- Department of Orthopedic Surgery, Qilu Hospital, Shandong University, Jinan, China
| | - Yuanliang Sun
- Department of Spine Surgery, Affiliated Hospital of Qingdao University, Qingdao, China
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40
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Predictive Factors for Muscle Injury After Posterior Lumbar Spinal Surgery. World Neurosurg 2019; 129:e514-e521. [PMID: 31152890 DOI: 10.1016/j.wneu.2019.05.197] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Revised: 05/22/2019] [Accepted: 05/23/2019] [Indexed: 11/19/2022]
Abstract
OBJECTIVE The aims of this study were to evaluate the risk factors for muscle injury in patients undergoing posterior lumbar spinal surgery and the clearance of postoperative biochemical changes following lumbar fusion and secondarily to evaluate the timing for monitoring postoperative biochemical serum levels and potential clinical correlation. METHODS The study prospectively enrolled 39 patients with degenerative disease of the lumbar spine. Biochemical markers (creatine phosphokinase [CPK], creatinine, and hemoglobin) were analyzed in 5 predefined stages. All relevant clinical data were collected. Rhabdomyolysis (RML) was defined as a postoperative 5-fold increase of the baseline CPK value. RESULTS Patients from the lumbar fusion group had the highest postoperative CPK ratio. Overall, the rate of RML was 43.6%. CPK and creatinine activity reached their maximum on the first postoperative day in 69.2% and 87.5% of patients, respectively. Lumbar fusion (P = 0.005), surgical time >270 minutes (P = 0.028), and fall in hemoglobin levels >3 g/dL (P = 0.034) were identified as independent factors associated with higher risk of RML. CONCLUSIONS The risk of RML increases with prolonged and invasive surgery with higher bleeding potential. Knowing the clearance of postoperative biochemical changes permits a standardized strategy with measurements in precise intervals, thereby avoiding unnecessary costs. The clinical significance is still undetermined.
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Xia K, Gong Z, Zhu J, Yu W, Wang Y, Wang J, Xu A, Zhou X, Tao H, Li F, Liang C. Differentiation of Pluripotent Stem Cells into Nucleus Pulposus Progenitor Cells for Intervertebral Disc Regeneration. Curr Stem Cell Res Ther 2019; 14:57-64. [PMID: 30227822 DOI: 10.2174/1574888x13666180918095121] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2018] [Revised: 08/31/2018] [Accepted: 09/11/2018] [Indexed: 02/08/2023]
Abstract
Low back pain (LBP) is one of the world's most common musculoskeletal diseases and is frequently associated with intervertebral disc degeneration (IDD). While the main cause of IDD is commonly attributed to a reduced number of nucleus pulposus (NP) cells, current treatment strategies (both surgical and more conservative) fail to replenish NP cells or reverse the pathology. Cell replacement therapies are an attractive alternative for treating IDD. However, injecting intervertebral disc (IVD) cells, chondrocytes, or mesenchymal stem cells into various animal models of IDD indicate that transplanted cells generally fail to survive and engraft into the avascular IVD niche. Whereas pluripotent stem cells (PSCs), including induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs), hold great potential for revolutionizing regenerative medicine, current protocols for differentiating these cells into NP-like cells are inadequate. Nucleus pulposus progenitor cells (NPPCs), which are derived from the embryonic notochord, can not only survive within the harsh hypoxic environment of the IVD, but they also efficiently differentiate into NP-like cells. Here we provide an overview of the latest progress in repairing degenerated IVDs using PSCs and NPPCs. We also discuss the molecular pathways by which PSCs differentiate into NPPCs in vitro and in vivo and propose a new, in vivo IDD therapy.
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Affiliation(s)
- Kaishun Xia
- Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, No. 88 Jie Fang Road, Hangzhou, 310009, Zhejiang, China.,Orthopedics Research Institute of Zhejiang University, No. 88, Jiefang Road, Hangzhou 310009, China
| | - Zhe Gong
- Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, No. 88 Jie Fang Road, Hangzhou, 310009, Zhejiang, China.,Orthopedics Research Institute of Zhejiang University, No. 88, Jiefang Road, Hangzhou 310009, China
| | - Jian Zhu
- Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, No. 88 Jie Fang Road, Hangzhou, 310009, Zhejiang, China.,Orthopedics Research Institute of Zhejiang University, No. 88, Jiefang Road, Hangzhou 310009, China
| | - Wei Yu
- Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, No. 88 Jie Fang Road, Hangzhou, 310009, Zhejiang, China.,Orthopedics Research Institute of Zhejiang University, No. 88, Jiefang Road, Hangzhou 310009, China
| | - Yitian Wang
- Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, No. 88 Jie Fang Road, Hangzhou, 310009, Zhejiang, China.,Orthopedics Research Institute of Zhejiang University, No. 88, Jiefang Road, Hangzhou 310009, China
| | - Junjie Wang
- Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, No. 88 Jie Fang Road, Hangzhou, 310009, Zhejiang, China.,Orthopedics Research Institute of Zhejiang University, No. 88, Jiefang Road, Hangzhou 310009, China
| | - Ankai Xu
- Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, No. 88 Jie Fang Road, Hangzhou, 310009, Zhejiang, China.,Orthopedics Research Institute of Zhejiang University, No. 88, Jiefang Road, Hangzhou 310009, China
| | - Xiaopeng Zhou
- Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, No. 88 Jie Fang Road, Hangzhou, 310009, Zhejiang, China.,Orthopedics Research Institute of Zhejiang University, No. 88, Jiefang Road, Hangzhou 310009, China
| | - Huimin Tao
- Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, No. 88 Jie Fang Road, Hangzhou, 310009, Zhejiang, China.,Orthopedics Research Institute of Zhejiang University, No. 88, Jiefang Road, Hangzhou 310009, China
| | - Fangcai Li
- Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, No. 88 Jie Fang Road, Hangzhou, 310009, Zhejiang, China.,Orthopedics Research Institute of Zhejiang University, No. 88, Jiefang Road, Hangzhou 310009, China
| | - Chengzhen Liang
- Department of Orthopedics, 2nd Affiliated Hospital, School of Medicine, Zhejiang University, No. 88 Jie Fang Road, Hangzhou, 310009, Zhejiang, China.,Orthopedics Research Institute of Zhejiang University, No. 88, Jiefang Road, Hangzhou 310009, China
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42
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Ogon I, Takebayashi T, Takashima H, Morita T, Oshigiri T, Terashima Y, Yoshimoto M, Yamashita T. Multifidus Muscles Lipid Content Is Associated with Intervertebral Disc Degeneration: A Quantitative Magnetic Resonance Imaging Study. Asian Spine J 2019; 13:601-607. [PMID: 30866613 PMCID: PMC6680039 DOI: 10.31616/asj.2018.0258] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2018] [Accepted: 12/23/2018] [Indexed: 12/12/2022] Open
Abstract
Study Design Cross-sectional study. Purpose To determine the association between fatty degeneration of the multifidus muscle (Mm) and intervertebral disc degeneration (IVDD) using quantitative magnetic resonance imaging (MRI). Overview of Literature Few studies have reported on quantitative MRI analysis of the relation between the Mm and IVDD. Methods The subjects with chronic low back pain comprised 45 patients (19 males, 26 females; mean age, 63.8±2.0 years; range, 41-79 years). We analyzed the intramyocellular lipids (IMCL) and extramyocellular lipids (EMCL) of the Mm using magnetic resonance spectroscopy. The T2 values of the anterior annulus fibrosus (AF), nucleus pulposus (NP), and posterior AF were evaluated using MRI T2 mapping. We compared the possible correlations of IMCL and EMCL of the Mm with the T2 values of anterior AF, NP, and posterior AF. Results There was a significant negative correlation between IMCL and T2 values of the anterior AF (r=-0.65, p<0.01). There were no significant correlations between the IMCL and T2 values of NP (r=-0.16, p=0.30) and posterior AF (r=0.07, p=0.62). There were no significant correlations between the EMCL and T2 values of the anterior AF (r=-0.11, p=0.46), NP (r=0.15, p=0.32), and posterior AF (r=0.07, p=0.66). After adjustment for age and sex using multiple linear regression analysis, there was a significant negative correlation between the IMCL and T2 values of anterior AF (standardized partial regression coefficient=-0.65, p<0.01). Conclusions The results indicated that IMCL of the Mm might be accompanied with anterior AF degeneration. Therapeutic exercises using IMCL of the Mm as evaluation index might have the potential to identify novel targets for the treatment and prevention of IVDD.
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Affiliation(s)
- Izaya Ogon
- Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Tsuneo Takebayashi
- Department of Orthopaedic Surgery, Sapporo Maruyama Orthopaedic Hospital, Sapporo, Japan
| | - Hiroyuki Takashima
- Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Tomonori Morita
- Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Tsutomu Oshigiri
- Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Yoshinori Terashima
- Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Mitsunori Yoshimoto
- Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Toshihiko Yamashita
- Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan
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43
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Snuggs JW, Day RE, Bach FC, Conner MT, Bunning RAD, Tryfonidou MA, Le Maitre CL. Aquaporin expression in the human and canine intervertebral disc during maturation and degeneration. JOR Spine 2019; 2:e1049. [PMID: 31463463 PMCID: PMC6686802 DOI: 10.1002/jsp2.1049] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 03/01/2019] [Accepted: 03/04/2019] [Indexed: 12/13/2022] Open
Abstract
The intervertebral disc (IVD) is a highly hydrated tissue, the rich proteoglycan matrix imbibes water, enabling the disc to withstand compressive loads. During aging and degeneration increased matrix degradation leads to dehydration and loss of function. Aquaporins (AQP) are a family of transmembrane channel proteins that selectively allow the passage of water in and out of cells and are responsible for maintaining water homeostasis in many tissues. Here, the expression of all 13 AQPs at gene and protein level was investigated in human and canine nondegenerate and degenerate IVDs to develop an understanding of the role of AQPs during degeneration. Furthermore, in order to explore the transition of notochordal cells (NCs) towards nucleus pulposus (NP) cells, AQP expression was investigated in canine IVDs enriched in NCs to understand the role of AQPs in IVD maturation. AQP0, 1, 2, 3, 4, 5, 6, 7, and 9 were expressed at gene and protein level in both nondegenerate and degenerate human NP tissue. AQP2 and 7 immunopositivity increased with degeneration in human NP tissue, whereas AQP4 expression decreased with degeneration in a similar way to AQP1 and 5 shown previously. All AQP proteins that were identified in human NP tissue were also expressed in canine NP tissue. AQP2, 5, 6, and 9 were found to localize to vacuole-like membranes and cell membranes in NC cells. In conclusion, AQPs were abundantly expressed in human and canine IVDs. The expression of many AQP isotypes potentially alludes to multifaceted functions related to adaption of NP cells to the conditions they encounter within their microenvironment in health and degeneration. The presence of AQPs within the IVD may suggest an adaptive role for these water channels during the development and maintenance of the healthy, mature IVD.
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Affiliation(s)
- Joseph W. Snuggs
- Biomolecular Sciences Research CentreSheffield Hallam UniversitySheffieldUK
| | - Rebecca E. Day
- Biomolecular Sciences Research CentreSheffield Hallam UniversitySheffieldUK
| | - Frances C. Bach
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary MedicineUtrecht UniversityUtrechtThe Netherlands
| | - Matthew T. Conner
- Faculty of Science and EngineeringUniversity of WolverhamptonWolverhamptonUK
| | | | - Marianna A. Tryfonidou
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary MedicineUtrecht UniversityUtrechtThe Netherlands
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44
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[Lumbar facet joint disease : Classification, clinical diagnostics, and minimally invasive treatment]. DER ORTHOPADE 2019; 48:77-83. [PMID: 30637440 DOI: 10.1007/s00132-018-03667-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND The degeneration of the lumbar facet joint is a multi-factorial process that is closely linked to degeneration of the intervertebral discs and has been implicated as one of the causes of low-back pain of elderly patients in about 15 up to 40% of cases. Moreover, emerging data suggest that increased inflammatory features play an important role in the progression of lumbar facet joint disease and may serve as a link to the afferent pain nerve fibers. OPERATIVE TECHNIQUES Since the first description in 1975 of minimally invasive treatment of lumbar facet joint disease, different techniques have been developed and used with varying results. Today, the major techniques are thermorhizotomy, cryorhizotomy, and endoscopic or percutaneous facet debridement with different anatomical targets, such as the medial branch of the dorsal ramus or facet joint capsule.
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45
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Gullbrand SE, Ashinsky BG, Bonnevie ED, Kim DH, Engiles JB, Smith LJ, Elliott DM, Schaer TP, Smith HE, Mauck RL. Long-term mechanical function and integration of an implanted tissue-engineered intervertebral disc. Sci Transl Med 2018; 10:eaau0670. [PMID: 30463917 PMCID: PMC7380504 DOI: 10.1126/scitranslmed.aau0670] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Accepted: 10/31/2018] [Indexed: 01/09/2023]
Abstract
Tissue engineering holds great promise for the treatment of advanced intervertebral disc degeneration. However, assessment of in vivo integration and mechanical function of tissue-engineered disc replacements over the long term, in large animal models, will be necessary to advance clinical translation. To that end, we developed tissue-engineered, endplate-modified disc-like angle ply structures (eDAPS) sized for the rat caudal and goat cervical spines that recapitulate the hierarchical structure of the native disc. Here, we demonstrate functional maturation and integration of these eDAPS in a rat caudal disc replacement model, with compressive mechanical properties reaching native values after 20 weeks in vivo and evidence of functional integration under physiological loads. To further this therapy toward clinical translation, we implanted eDAPS sized for the human cervical disc space in a goat cervical disc replacement model. Our results demonstrate maintenance of eDAPS composition and structure up to 8 weeks in vivo in the goat cervical disc space and maturation of compressive mechanical properties to match native levels. These results demonstrate the translational feasibility of disc replacement with a tissue-engineered construct for the treatment of advanced disc degeneration.
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Affiliation(s)
- Sarah E Gullbrand
- Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA 19104, USA
- McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Beth G Ashinsky
- Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA 19104, USA
- McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- School of Biomedical Sciences, Drexel University, Philadelphia, PA 19104, USA
| | - Edward D Bonnevie
- Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA 19104, USA
- McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Dong Hwa Kim
- Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA 19104, USA
- McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Julie B Engiles
- Department of Clinical Studies, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19348, USA
| | - Lachlan J Smith
- Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA 19104, USA
- McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Dawn M Elliott
- Department of Biomedical Engineering, University of Delaware, Newark, DE 19716, USA
| | - Thomas P Schaer
- Department of Clinical Studies, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19348, USA
| | - Harvey E Smith
- Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA 19104, USA.
- McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Neurosurgery, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Robert L Mauck
- Translational Musculoskeletal Research Center, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA 19104, USA.
- McKay Orthopaedic Research Laboratory, Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
- Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104, USA
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Pokorny G, Marchi L, Amaral R, Jensen R, Pimenta L. Lumbar Total Disc Replacement by the Lateral Approach-Up to 10 Years Follow-Up. World Neurosurg 2018; 122:e325-e333. [PMID: 30326312 DOI: 10.1016/j.wneu.2018.10.033] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Revised: 10/03/2018] [Accepted: 10/04/2018] [Indexed: 11/27/2022]
Abstract
OBJECTIVE This study aimed to analyze radiologic and clinical results with a minimum 5 years follow-up (FUP) of lateral lumbar total disc replacement for the treatment of symptomatic lumbar degenerative disc disease. METHODS We performed a prospective, single-center, clinical, and radiologic study. Patients were treated with lumbar total disc replacement (extreme lateral total disc replacement) by a lateral transpsoas approach. From 2005 to 2012, 60 patients were enrolled (31 male, 29 female; total, 66 levels; average age, 42.8 years [standard deviation (SD), 9.7 years, range, 22-64 years]; mean body mass index, 26.0 [SD, 3.4]). Clinical end points included visual analog scale and Oswestry Disability Index questionnaires, complications, and reoperation. Radiographic end points included heterotopic ossification (McAfee classification), adjacent level disease, and prosthesis migration or subluxation. RESULTS The mean surgical duration was 122 minutes (SD, 45 minutes) with mean 58 mL (SD, 21 mL) of estimated blood loss. No intraoperative complication occurred. The exceptions were 1 patient with postanesthesia apnea and 2 patients with quadriceps motor deficit (resolved within 4 months with physiotherapy). Of 60 patients, 9 were missed to FUP and 51 (85%) were enrolled in the study, with mean FUP of 92 months (range, 60-122 months). In total, 5 levels (9%; 5 of 55) required to be fused. Both removal of the prostheses and interbody fusion were performed by the lateral transpsoas approach. One patient experienced CrCo allergy (at 2 months); 4 experienced persistent pain from different causes (at 7, 9, 24, and 88 months). Five patients (10%) presented with progression at adjacent levels and 2 (4%) required surgery. One patient required sacroiliac fusion at 63 months. There were no complications during the retrieval surgeries. One partial disc migration occurred but the patient refused retrieval. There was no bone bridging in 9% of the discs (grade 0 heterotopic ossification): grade I, 22%; grade II, 31%; grade III, 20%; grade IV (fusion), 18%. Most heterotopic ossification cases (93%) occurred in the lateral aspect of the disc space, and mostly at the contralateral side of the surgical approach. Patient-reported outcomes significantly improved (P < 0.01) at the last FUP. Visual analog scale back pain score was preoperatively 8.5, early postoperatively 2.5, and at last FUP 3.1. Oswestry Disability Index was preoperatively 55%, early postoperatively 31%, and at last FUP 21%. CONCLUSIONS This study presents mid-term to long-term results of extreme lateral total disc replacement artificial disc for the treatment of lumbar degenerative disease, with fast mobilization, sustained pain relief, and improved physical function. Despite the low rate of ALDis, some discs evolved to ankyloses and others were retrieved. Lumbar artificial disc replacement by the lateral approach seems to be a safe and effective treatment.
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Affiliation(s)
- Gabriel Pokorny
- Instituto de Patologia da Coluna (IPC), São Paulo, São Paulo, Brasil.
| | - Luís Marchi
- Instituto de Patologia da Coluna (IPC), São Paulo, São Paulo, Brasil
| | - Rodrigo Amaral
- Instituto de Patologia da Coluna (IPC), São Paulo, São Paulo, Brasil
| | - Rubens Jensen
- Instituto de Patologia da Coluna (IPC), São Paulo, São Paulo, Brasil
| | - Luiz Pimenta
- Instituto de Patologia da Coluna (IPC), São Paulo, São Paulo, Brasil; University of California, UCSD, San Diego, California, USA
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Martins DE, Medeiros VPD, Wajchenberg M, Paredes-Gamero EJ, Lima M, Reginato RD, Nader HB, Puertas EB, Faloppa F. Changes in human intervertebral disc biochemical composition and bony end plates between middle and old age. PLoS One 2018; 13:e0203932. [PMID: 30226874 PMCID: PMC6144914 DOI: 10.1371/journal.pone.0203932] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Accepted: 08/30/2018] [Indexed: 12/22/2022] Open
Abstract
Objective This study evaluates molecular, nutritional and biochemical alterations in
human intervertebral discs between middle and old age. Methods Twenty-eight human lumbar intervertebral discs from donors were evaluated and
separated into two groups: Middle-aged (35–50 years old, relatively
non-degenerate discs of Pfirrmann grades 1–3, n = 15) and Old-aged (≥80
years old, all degenerate Pfirrmann grade 4 or 5, n = 13). Parameters which
might be expected to to be related to nutrient supply and so the health of
disc cells (eg the porosity of the vertebral endplate, cell viability and
cell density) and to disc extracellular composition (ie quantification of
glycosaminoglycan disaccharides and hyaluronic acid molecular weight) and
collagen organization, were analyzed. Three regions of the intervertebral
disc (anterior annulus fibrosus, nucleus pulposus, and posterior annulus
fibrosus) were examined. Results The old-aged group showed a decrease in content of sulphated and
non-sulphated glycosaminoglycans relative to middle-aged and there were also
alterations in the proportion of GAG disaccharides and a decrease of
collagen fiber size. Hyaluronic acid molecular weight was around 200 kDa in
all regions and ages studied. The anterior annulus differed from the
posterior annulus particularly in relation to cell density and GAG content.
Additionally, there were changes in the bony endplate, with fewer openings
observed in the caudal than cranial endplates of all discs in both
groups. Conclusions Results show the cranial vertebral endplate is the main vascular source for
the intervertebral discs. Hylauronic acid molecular weight is the same
through the intervertebral disc after age of 50 years.
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Affiliation(s)
- Delio Eulalio Martins
- Department of Orthopaedics and Traumatology, Universidade Federal de Sao Paulo-UNIFESP, Sao Paulo, SP, Brazil
| | - Valquiria Pereira de Medeiros
- Department of Biochemistry, Universidade Federal de Juiz de Fora, Juiz de Fora, MG, Brazil.,Faculty of Pharmaceutical Science, Universidade Federal de Mato Grosso do Sul, Campo Grande, MS, Brazil
| | - Marcelo Wajchenberg
- Department of Orthopaedics and Traumatology, Universidade Federal de Sao Paulo-UNIFESP, Sao Paulo, SP, Brazil
| | - Edgar Julian Paredes-Gamero
- Faculty of Pharmaceutical Science, Universidade Federal de Mato Grosso do Sul, Campo Grande, MS, Brazil.,Department of Biochemistry, Universidade Federal de Sao Paulo-UNIFESP, Sao Paulo, SP, Brazil
| | - Marcelo Lima
- Department of Biochemistry, Universidade Federal de Sao Paulo-UNIFESP, Sao Paulo, SP, Brazil
| | - Rejane Daniele Reginato
- Department of Morphology and Genetics, Universidade Federal de Sao Paulo-UNIFESP, Sao Paulo, SP, Brazil
| | - Helena Bonciani Nader
- Department of Biochemistry, Universidade Federal de Sao Paulo-UNIFESP, Sao Paulo, SP, Brazil
| | - Eduardo Barros Puertas
- Department of Orthopaedics and Traumatology, Universidade Federal de Sao Paulo-UNIFESP, Sao Paulo, SP, Brazil
| | - Flavio Faloppa
- Department of Orthopaedics and Traumatology, Universidade Federal de Sao Paulo-UNIFESP, Sao Paulo, SP, Brazil
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Choi H, Tessier S, Silagi ES, Kyada R, Yousefi F, Pleshko N, Shapiro IM, Risbud MV. A novel mouse model of intervertebral disc degeneration shows altered cell fate and matrix homeostasis. Matrix Biol 2018; 70:102-122. [PMID: 29605718 PMCID: PMC6081256 DOI: 10.1016/j.matbio.2018.03.019] [Citation(s) in RCA: 93] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2018] [Revised: 03/17/2018] [Accepted: 03/18/2018] [Indexed: 12/17/2022]
Abstract
Intervertebral disc degeneration and associated low back and neck pain is a ubiquitous health condition that affects millions of people world-wide, and causes high incidence of disability and enormous medical/societal costs. However, lack of appropriate small animal models with spontaneous disease onset has impeded our ability to understand the pathogenetic mechanisms that characterize and drive the degenerative process. We report, for the first time, early onset spontaneous disc degeneration in SM/J mice known for their poor regenerative capacities compared to "super-healer" LG/J mice. In SM/J mice, degenerative process was marked by decreased nucleus pulposus (NP) cellularity and changes in matrix composition at P7, 4, and 8 weeks with increased severity by 17 weeks. Distinctions between NP and annulus fibrosus (AF) or endplate cartilage were lost, and NP and AF of SM/J mice showed higher histological grades. There was increased NP cell death in SM/J mice with decreased phenotypic marker expression. Polarized microscopy and FTIR spectroscopy demonstrated replacement of glycosaminoglycan-rich NP matrix with collagenous fibrous tissue. The levels of ARGxx were increased in, indicating higher aggrecan turnover. Furthermore, an aberrant expression of collagen X and MMP13 was observed in the NP of SM/J mice, along with elevated expression of Col10a1, Ctgf, and Runx2, markers of chondrocyte hypertrophy. Likewise, expression of Enpp1 as well as Alpl was higher, suggesting NP cells of SM/J mice promote dystrophic mineralization. There was also a decrease in several pathways necessary for NP cell survival and function including Wnt and VEGF signaling. Importantly, SM/J discs were stiffer, had decreased height, and poor vertebral bone quality, suggesting compromised motion segment mechanical functionality. Taken together, our results clearly demonstrate that SM/J mouse strain recapitulates many salient features of human disc degeneration, and serves as a novel small animal model.
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Affiliation(s)
- Hyowon Choi
- Department of Orthopaedic Surgery, Graduate Program in Cell Biology and Regenerative Medicine, Thomas Jefferson University, Philadelphia, PA, USA
| | - Steven Tessier
- Department of Orthopaedic Surgery, Graduate Program in Cell Biology and Regenerative Medicine, Thomas Jefferson University, Philadelphia, PA, USA
| | - Elizabeth S Silagi
- Department of Orthopaedic Surgery, Graduate Program in Cell Biology and Regenerative Medicine, Thomas Jefferson University, Philadelphia, PA, USA
| | - Rutvin Kyada
- Department of Bioengineering, Temple University, Philadelphia, PA, USA
| | - Farzad Yousefi
- Department of Bioengineering, Temple University, Philadelphia, PA, USA
| | - Nancy Pleshko
- Department of Bioengineering, Temple University, Philadelphia, PA, USA
| | - Irving M Shapiro
- Department of Orthopaedic Surgery, Graduate Program in Cell Biology and Regenerative Medicine, Thomas Jefferson University, Philadelphia, PA, USA
| | - Makarand V Risbud
- Department of Orthopaedic Surgery, Graduate Program in Cell Biology and Regenerative Medicine, Thomas Jefferson University, Philadelphia, PA, USA.
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Chen Q, Shi F, Yang X, Liu L, Song Y. [Comparative study on biological characteristics between different generations of rabbit nucleus pulposus cells]. ZHONGGUO XIU FU CHONG JIAN WAI KE ZA ZHI = ZHONGGUO XIUFU CHONGJIAN WAIKE ZAZHI = CHINESE JOURNAL OF REPARATIVE AND RECONSTRUCTIVE SURGERY 2018; 32:660-667. [PMID: 29905041 DOI: 10.7507/1002-1892.201707017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Objective To research the biological characteristics of different generations of rabbit nucleus pulposus cells (NPCs) that were cultured with natural culture and subculture method. Methods The thoracolumbar segments of New Zealand white rabbits (6-8 weeks old and weighing 1.5-2.5 kg) were obtained and nucleus pulposus were isolated from disc regions. And NPCs were harvested by enzymatic digestion from nucleus pulposus. Primary NPCs were counted as P0 generation. Then, NPCs were passaged by trypsin and counted as P1, P2, P3 with a totle of 4 generations. P0 to P3 generations NPCs were separately examined by observation of cell morphology and proliferation time, detection of apoptosis rates of cells by flow cytometry, and detection of hypoxia-inducible factor 1α (HIF-1α), matrix metalloproteinases 2 (MMP-2), Aggrecan, and collagen type Ⅱ proteins by immunofluorescence and Western blot. Results The morphology of NPCs transformed from triangular or polygonal in P0 generation to spindle in P3 generation; the characteristic vacuolated cells gradually disappeared; and the cell volume and cell proliferation time increased. The cell apoptosis rates were 5.47%±0.91%, 13.77%±2.42%, 33.46%±1.82%, and 38.76%±1.50% from P0 to P3 generations, with the increase of culture time, and there were significant differences between 4 generations ( P<0.05). Immunofluorescence staining showed that with the increase of cells generation, the fluorescence intensity of HIF-1α, collagen type Ⅱ, and Aggrecan decreased, and the fluorescence intensity of MMP-2 increased. Western blot results showed that the relative expression of HIF-1α protein was high in P0 generation, the P1 generation has a rising trend, and then gradually decreased; the differences between generations were significant ( P<0.05). The relative expression of collagen type Ⅱ protein decreased from P0 to P3 generations and there were significant differences between generations ( P<0.05). The relative expression of Aggrecan protein decreased from P0 to P2 generations and there were significant differences between generations ( P<0.05); but no significant difference was found between P2 and P3 generations ( P>0.05). The relative expression of MMP-2 protein increased significantly in P3 generation; except that the difference between P0 and P2 generations was not significant ( P>0.05), the significant differences were found between the other generations ( P<0.05). Conclusion Rabbit NPCs degeneration model was successfully established by the natural culture and subculture method. Transforming of NPCs morphology, increasing of cell apoptosis rates, decreasing of anabolism, and increasing of catabolism were presented in NPCs degeneration model.
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Affiliation(s)
- Qi Chen
- Department of Orthopedics, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou Zhejiang, 310014, P.R.China;Department of Orthopedics, West China Hospital, Sichuan University, Chengdu Sichuan, 610041, P.R.China
| | - Fangfang Shi
- Department of Hematology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou Zhejiang, 310014, P.R.China
| | - Xi Yang
- Department of Orthopedics, West China Hospital, Sichuan University, Chengdu Sichuan, 610041, P.R.China
| | - Limin Liu
- Department of Orthopedics, West China Hospital, Sichuan University, Chengdu Sichuan, 610041, P.R.China
| | - Yueming Song
- Department of Orthopedics, West China Hospital, Sichuan University, Chengdu Sichuan, 610041,
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Fyllos AH, Arvanitis DL, Karantanas AH, Varitimidis SE, Hantes M, Zibis AH. Magnetic resonance morphometry of the adult normal lumbar intervertebral space. Surg Radiol Anat 2018; 40:1055-1061. [PMID: 29876634 DOI: 10.1007/s00276-018-2048-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Accepted: 06/01/2018] [Indexed: 12/27/2022]
Abstract
PURPOSE This study aims to: (a) quantify and evaluate normal relationships between neighboring spinal units using MR imaging indices, (b) propose an easy-to-apply-and-reproduce method of estimating the correct amount of distraction when surgically restoring a collapsed intervertebral disc, based on individualized measurements. METHODS This is a retrospective cross-sectional MR imaging study of 119 adult subjects, aged 18-54, asymptomatic for low back pain. Each of the examinees should demonstrate two or more consecutive intervertebral discs classified as Pfirrmann grade I or II to be included. We measured and studied the relationships of disc height index, Dabbs index, Farfan index, disc convexity index and mean and posterior disc height per spinal level using multiple regression analysis. All measurements were tested for intra- and interobserver agreement by two raters. RESULTS DHI, Dabbs, Farfan, and mean disc height had a statistically significant correlation with the spinal level and age. Our results were highly reproducible, with excellent inter- and intraobserver agreement and reliability between two raters (ICC = 0.992 and 0.994, respectively). Furthermore, we expressed each intervertebral space as a percentage of its adjacent space, introducing the coefficient α factor for every intervertebral space. CONCLUSIONS Our results suggest that a normal values' database to refer during preoperative planning of correction of a degenerated intervertebral disc is feasible. Our study offers new anatomical and radiological insight in terms of spinal measurements and their potential correlation with current surgical techniques. A new approach for calculating disc space as an expression of its adjacent disc has been introduced with various potential applications.
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Affiliation(s)
- Apostolos H Fyllos
- Department of Anatomy, School of Medicine, University of Thessaly, Panepistimiou 3 (Biopolis), 41110, Larissa, Greece
- Department of Orthopedics, University Hospital of Larisa, 41110, Larissa, Greece
| | - Dimitrios L Arvanitis
- Department of Anatomy, School of Medicine, University of Thessaly, Panepistimiou 3 (Biopolis), 41110, Larissa, Greece
| | - Apostolos H Karantanas
- Department of Radiology, School of Medicine, University of Crete, 71110, Heraklion, Greece
| | | | - Michael Hantes
- Department of Orthopedics, University Hospital of Larisa, 41110, Larissa, Greece
| | - Aristeidis H Zibis
- Department of Anatomy, School of Medicine, University of Thessaly, Panepistimiou 3 (Biopolis), 41110, Larissa, Greece.
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