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Peng BG, Li YC, Yang L. Role of neurogenic inflammation in intervertebral disc degeneration. World J Orthop 2025; 16:102120. [PMID: 39850033 PMCID: PMC11752484 DOI: 10.5312/wjo.v16.i1.102120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 11/29/2024] [Accepted: 12/20/2024] [Indexed: 01/13/2025] Open
Abstract
In healthy intervertebral discs (IVDs), nerves and blood vessels are present only in the outer annulus fibrosus, while in degenerative IVDs, a large amount of nerve and blood vessel tissue grows inward. Evidence supports that neurogenic inflammation produced by neuropeptides such as substance P and calcitonin gene related peptide released by the nociceptive nerve fibers innervating the IVDs plays a crucial role in the process of IVD degeneration. Recently, non-neuronal cells, including IVD cells and infiltrating immune cells, have emerged as important players in neurogenic inflammation. IVD cells and infiltrating immune cells express functional receptors for neuropeptides through which they receive signals from the nervous system. In return, IVD cells and immune cells produce neuropeptides and nerve growth factor, which stimulate nerve fibers. This communication generates a positive bidirectional feedback loop that can enhance the inflammatory response of the IVD. Recently emerging transient receptor potential channels have been recognized as contributors to neurogenic inflammation in the degenerative IVDs. These findings suggest that neurogenic inflammation involves complex pathophysiological interactions between sensory nerves and multiple cell types in the degenerative IVDs. Clarifying the mechanism of neurogenic inflammation in IVD degeneration may provide in-depth understanding of the pathology of discogenic low back pain.
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Affiliation(s)
- Bao-Gan Peng
- Department of Orthopaedics, The Third Medical Center, General Hospital of the Chinese People’s Liberation Army, Beijing 100039, China
| | - Yong-Chao Li
- Department of Orthopaedics, The Third Medical Center, General Hospital of the Chinese People’s Liberation Army, Beijing 100039, China
| | - Liang Yang
- Department of Orthopeadics, Featured Medical Center of Chinese People’s Armed Police Forces, Tianjin 300000, China
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Liu C, Ge X, Li Y. Repair of annulus fibrosus defects using decellularized annulus fibrosus matrix/chitosan hybrid hydrogels. J Orthop Surg Res 2024; 19:535. [PMID: 39223621 PMCID: PMC11370001 DOI: 10.1186/s13018-024-05017-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Accepted: 08/20/2024] [Indexed: 09/04/2024] Open
Abstract
Degenerative disc disease is the leading cause of lower back and leg pain, considerably impacting daily life and incurring substantial medical expenses for those affected. The development of annulus fibrosus tissue engineering offers hope for treating this condition. However, the current annulus fibrosus tissue engineering scaffolds fail to accurately mimic the natural biological environment of the annulus fibrosus, resulting in limited secretion of extracellular matrix produced by the seeded cells and poor biomechanical properties of the constructed biomimetic annulus fibrosus tissue. This inability to match the biomechanical performance of the natural annulus fibrosus hinders the successful treatment of annulus fibrosus defects. In this study, we fabricated decellularized annulus fibrosus matrix (DAFM)/chitosan hydrogel-1 (DAFM: Chitosan 6:2) and DAFM/chitosan hydrogel-2 (DAFM: Chitosan 4:4) by varying the ratio of DAFM to chitosan. Rat annulus fibrosus (AF)-derived stem cells were cultured on these hydrogel scaffolds, and the cell morphology, AF-related gene expression, and Interleukin-6 (IL-6) levels were investigated. Additionally, magnetic resonance imaging, Hematoxylin and eosin staining, and Safranine and Fast Green staining were performed to evaluate the repair effect of the DAFM/chitosan hydrogels in vivo. The gene expression results showed that the expression of Collagen type I (Col-I), Collagen type I (Col-II), and aggrecan by annulus fibrosus stem cells (AFSCs) cultured on the DAFM/chitosan-1 hydrogel was higher compared with the DAFM/chitosan-2 hydrogel. Conversely, the expression of metalloproteinase-9 (MMP-9) and IL-6 was lower on the DAFM/chitosan-1 hydrogel compared with the DAFM/chitosan-2 hydrogel. In vivo, both the DAFM/chitosan-1 and DAFM/chitosan-2 hydrogels could partially repair large defects of the annulus fibrosus in rat tail vertebrae. In conclusion, the DAFM/chitosan-1 hydrogel could be regarded as a candidate scaffold material for the repair of annulus fibrosus defects, offering the potential for improved treatment outcomes.
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Affiliation(s)
- Chen Liu
- Department of Spine Surgery, Yijishan Hospital of Wannan Medical College, No. 2 Zheshan West Road, Wuhu, Anhui, 241001, China
- Spine Research Center of Wannan Medical College, No.22 Wenchang West Road, Wuhu, Anhui, 241001, China
- Anhui Province Key Laboratory of Non-Coding RNA Basic and Clinical Transformation, No. 2 Zheshan West Road, Wuhu, Anhui, 241001, China
| | - Xin Ge
- Department of Joint Orthopaedics, Angqing First People's Hospital of Anhui Province, No.42 Xuxiao Road, Anqing, Anhui, 246000, China.
| | - Yifeng Li
- Department of Spine Surgery, Yijishan Hospital of Wannan Medical College, No. 2 Zheshan West Road, Wuhu, Anhui, 241001, China.
- Spine Research Center of Wannan Medical College, No.22 Wenchang West Road, Wuhu, Anhui, 241001, China.
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Chen X, Zhang A, Zhao K, Gao H, Shi P, Chen Y, Cheng Z, Zhou W, Zhang Y. The role of oxidative stress in intervertebral disc degeneration: Mechanisms and therapeutic implications. Ageing Res Rev 2024; 98:102323. [PMID: 38734147 DOI: 10.1016/j.arr.2024.102323] [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: 01/12/2024] [Revised: 04/19/2024] [Accepted: 05/03/2024] [Indexed: 05/13/2024]
Abstract
Oxidative stress is one of the main driving mechanisms of intervertebral disc degeneration(IDD). Oxidative stress has been associated with inflammation in the intervertebral disc, cellular senescence, autophagy, and epigenetics of intervertebral disc cells. It and the above pathological mechanisms are closely linked through the common hub reactive oxygen species(ROS), and promote each other in the process of disc degeneration and promote the development of the disease. This reveals the important role of oxidative stress in the process of IDD, and the importance and great potential of IDD therapy targeting oxidative stress. The efficacy of traditional therapy is unstable or cannot be maintained. In recent years, due to the rise of materials science, many bioactive functional materials have been applied in the treatment of IDD, and through the combination with traditional drugs, satisfactory efficacy has been achieved. At present, the research review of antioxidant bioactive materials in the treatment of IDD is not complete. Based on the existing studies, the mechanism of oxidative stress in IDD and the common antioxidant therapy were summarized in this paper, and the strategies based on emerging bioactive materials were reviewed.
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Affiliation(s)
- Xianglong Chen
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Anran Zhang
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Kangcheng Zhao
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Haiyang Gao
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Pengzhi Shi
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yuhang Chen
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Zhangrong Cheng
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Wenjuan Zhou
- Department of Operating Room, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
| | - Yukun Zhang
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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Li B, Wang T, Huang Y, Fan Y, Yu H, Li A, Qi D, Wang Q, Xue C, Wang Z, Zheng G, Wang Y. Correlation between Disc Imaging Observations and Clinical Efficacy after Percutaneous Endoscopic Lumbar Discectomy: A 1-Year Follow-up Study. Orthop Surg 2024; 16:851-863. [PMID: 38384172 PMCID: PMC10984810 DOI: 10.1111/os.14013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Revised: 01/14/2024] [Accepted: 01/18/2024] [Indexed: 02/23/2024] Open
Abstract
OBJECTIVE The connection between alterations in the disc structure following percutaneous endoscopic lumbar discectomy (PELD) and symptoms in patients postsurgery has not been reported yet. The purpose of the present study was to discuss the potential correlation between the changes in the morphological characteristics of various reference surfaces of the intervertebral disc after percutaneous endoscopic lumbar discectomy (PELD) and clinical outcomes, to identify the morphological parameters that affect efficacy and provide an evidence-based foundation for assessing postoperative efficacy. METHODS From October 2019 to October 2021, after percutaneous endoscopic lumbar discectomy (PELD), 98 individuals were enrolled. MRI DICOM data of the lumbar spine were obtained before and after surgery, specifically around 3 months. The morphological parameters of the operated and adjacent segments of the discs were measured using T2-weighted images from three reference planes. Outcomes were assessed using the Oswestry disability index (ODI), visual analogue pain scores for the back and leg (VAS-back/VAS-leg), Japanese Orthopaedic Association (JOA) scores, and recovery rates. Postoperative changes in disc parameters and outcomes were compared between patients with different severity and types of LDH based on the MSU staging. Patients completed the questionnaire during outpatient follow-up appointments 3, 6, and 12 months after the surgery. The follow-up period was 14.69 ± 4.21 months, ranging from 12 to 24 months. RESULTS Parameters such as area and circumference of intervertebral discs in the cross-section were not associated with the change in the efficacy index. Postoperatively, a negative correlation between the variation of the disc height, disc height index, and protrusion distance and the difference in VAS scores for low back pain at 3 and 6 months was observed among the two sagittal change parameters. Differences between changes in disc imaging parameters and postoperative efficacy were not statistically significant between various types of lumbar disc herniation. CONCLUSION For the patients after percutaneous endoscopic lumbar discectomy, the changes in parameters such as disc area and circumference in the cross-sectional plane are not associated with efficacy, and the changes in disc height and herniation distance in the sagittal plane provide a morphologic basis for the assessment of short-term postoperative efficacy. In addition, the changes in disc morphologic parameters and postoperative efficacy do not differ between various types of lumbar disc herniation.
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Affiliation(s)
- Bing Li
- Department of OrthopedicsMedical School of the Chinese People's Liberation Army (PLA)BeijingChina
- The First Medical Centre of the Chinese People's Liberation Army (PLA) General HospitalBeijingChina
| | - Tian‐hao Wang
- The First Medical Centre of the Chinese People's Liberation Army (PLA) General HospitalBeijingChina
- Department of OrthopedicsThe Fourth Medical Center of the Chinese People's Liberation Army (PLA) General HospitalBeijingChina
| | - Yi Huang
- Nankai University School of MedicineNankai UniversityTianjinChina
| | - Yi‐ming Fan
- Department of OrthopedicsMedical School of the Chinese People's Liberation Army (PLA)BeijingChina
- The First Medical Centre of the Chinese People's Liberation Army (PLA) General HospitalBeijingChina
| | - Han Yu
- Department of OrthopedicsMedical School of the Chinese People's Liberation Army (PLA)BeijingChina
- The First Medical Centre of the Chinese People's Liberation Army (PLA) General HospitalBeijingChina
| | - Ao‐qiong Li
- The First Medical Centre of the Chinese People's Liberation Army (PLA) General HospitalBeijingChina
- Department of OrthopedicsThe Fourth Medical Center of the Chinese People's Liberation Army (PLA) General HospitalBeijingChina
| | - Deng‐bin Qi
- The First Medical Centre of the Chinese People's Liberation Army (PLA) General HospitalBeijingChina
- Department of OrthopedicsThe Fourth Medical Center of the Chinese People's Liberation Army (PLA) General HospitalBeijingChina
| | - Qi Wang
- The First Medical Centre of the Chinese People's Liberation Army (PLA) General HospitalBeijingChina
- Department of OrthopedicsThe Fourth Medical Center of the Chinese People's Liberation Army (PLA) General HospitalBeijingChina
| | - Chao Xue
- The First Medical Centre of the Chinese People's Liberation Army (PLA) General HospitalBeijingChina
- Department of OrthopedicsThe Fourth Medical Center of the Chinese People's Liberation Army (PLA) General HospitalBeijingChina
| | - Ze Wang
- The First Medical Centre of the Chinese People's Liberation Army (PLA) General HospitalBeijingChina
| | - Guo‐quan Zheng
- The First Medical Centre of the Chinese People's Liberation Army (PLA) General HospitalBeijingChina
- Department of OrthopedicsThe Fourth Medical Center of the Chinese People's Liberation Army (PLA) General HospitalBeijingChina
| | - Yan Wang
- The First Medical Centre of the Chinese People's Liberation Army (PLA) General HospitalBeijingChina
- Department of OrthopedicsThe Fourth Medical Center of the Chinese People's Liberation Army (PLA) General HospitalBeijingChina
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Peredo AP, Tsinman TK, Bonnevie ED, Jiang X, Smith HE, Gullbrand SE, Dyment NA, Mauck RL. Developmental morphogens direct human induced pluripotent stem cells toward an annulus fibrosus-like cell phenotype. JOR Spine 2024; 7:e1313. [PMID: 38283179 PMCID: PMC10810760 DOI: 10.1002/jsp2.1313] [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: 04/26/2023] [Revised: 12/08/2023] [Accepted: 12/11/2023] [Indexed: 01/30/2024] Open
Abstract
Introduction Therapeutic interventions for intervertebral disc herniation remain scarce due to the inability of endogenous annulus fibrosus (AF) cells to respond to injury and drive tissue regeneration. Unlike other orthopedic tissues, such as cartilage, delivery of exogenous cells to the site of annular injury remains underdeveloped, largely due to a lack of an ideal cell source and the invasive nature of cell isolation. Human induced pluripotent stem cells (iPSCs) can be differentiated to specific cell fates using biochemical factors and are, therefore, an invaluable tool for cell therapy approaches. While differentiation protocols have been developed for cartilage and fibrous connective tissues (e.g., tendon), the signals that regulate the induction and differentiation of human iPSCs toward the AF fate remain unknown. Methods iPSC-derived sclerotome cells were treated with various combinations of developmental signals including transforming growth factor beta 3 (TGF-β3), connective tissue growth factor (CTGF), platelet derived growth factor BB (PDGF-BB), insulin-like growth factor 1 (IGF-1), or the Hedgehog pathway activator, Purmorphamine, and gene expression changes in major AF-associated ECM genes were assessed. The top performing combination treatments were further validated by using three distinct iPSC lines and by assessing the production of upregulated ECM proteins of interest. To conduct a broader analysis of the transcriptomic shifts elicited by each factor combination, and to compare genetic profiles of treated cells to mature human AF cells, a 96.96 Fluidigm gene expression array was applied, and principal component analysis was employed to identify the transcriptional signatures of each cell population and treatment group in comparison to native AF cells. Results TGF-β3, in combination with PDGF-BB, CTGF, or IGF-1, induced an upregulation of key AF ECM genes in iPSC-derived sclerotome cells. In particular, treatment with a combination of TGF-β3 with PDGF-BB for 14 days significantly increased gene expression of collagen II and aggrecan and increased protein deposition of collagen I and elastin compared to other treatment groups. Assessment of genes uniquely highly expressed by AF cells or SCL cells, respectively, revealed a shift toward the genetic profile of AF cells with the addition of TGF-β3 and PDGF-BB for 14 days. Discussion These findings represent an initial approach to guide human induced pluripotent stem cells toward an AF-like fate for cellular delivery strategies.
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Affiliation(s)
- Ana P. Peredo
- Department of BioengineeringUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Department of Orthopaedic SurgeryUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Corporal Michael J. Crescenz VA Medical Center, Translational Musculoskeletal Research CenterPhiladelphiaPennsylvaniaUSA
| | - Tonia K. Tsinman
- Department of BioengineeringUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Department of Orthopaedic SurgeryUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Corporal Michael J. Crescenz VA Medical Center, Translational Musculoskeletal Research CenterPhiladelphiaPennsylvaniaUSA
| | - Edward D. Bonnevie
- Department of Orthopaedic SurgeryUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Corporal Michael J. Crescenz VA Medical Center, Translational Musculoskeletal Research CenterPhiladelphiaPennsylvaniaUSA
| | - Xi Jiang
- Department of Orthopaedic SurgeryUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Harvey E. Smith
- Department of Orthopaedic SurgeryUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Corporal Michael J. Crescenz VA Medical Center, Translational Musculoskeletal Research CenterPhiladelphiaPennsylvaniaUSA
| | - Sarah E. Gullbrand
- Department of Orthopaedic SurgeryUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Corporal Michael J. Crescenz VA Medical Center, Translational Musculoskeletal Research CenterPhiladelphiaPennsylvaniaUSA
| | - Nathaniel A. Dyment
- Department of BioengineeringUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Department of Orthopaedic SurgeryUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Robert L. Mauck
- Department of BioengineeringUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Department of Orthopaedic SurgeryUniversity of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Corporal Michael J. Crescenz VA Medical Center, Translational Musculoskeletal Research CenterPhiladelphiaPennsylvaniaUSA
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Song H, Guo C, Wu Y, Liu Y, Kong Q, Wang Y. Therapeutic factors and biomaterial-based delivery tools for degenerative intervertebral disc repair. Front Cell Dev Biol 2024; 12:1286222. [PMID: 38374895 PMCID: PMC10875104 DOI: 10.3389/fcell.2024.1286222] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2023] [Accepted: 01/15/2024] [Indexed: 02/21/2024] Open
Abstract
Intervertebral disc degeneration (IDD) is the main cause of low back pain (LBP), which significantly impacts global wellbeing and contributes to global productivity declines. Conventional treatment approaches, encompassing conservative and surgical interventions, merely serve to postpone the advancement of IDD without offering a fundamental reversal. Consequently, there is an urgent demand for an effective approach to prevent the progression of IDD. Recent investigations focusing on the treatment of IDD utilizing diverse bioactive substances integrated within various biomaterials have exhibited promising outcomes. Various bioactive substances, encompassing conventional small molecule drugs, small molecule nucleic acids, and cell therapies, exhibit distinct capacities for repairing IDD. Additionally, various biological material delivery systems, such as nano micelles, microspheres, and hydrogels, possess diverse biological and release characteristics. Consequently, these diverse materials and drugs hold promise for advancing the treatment of IDD. This article aims to provide a concise overview of the IDD process and investigate the research advancements in biomaterials and bioactive substances for IDD treatment, delving into their mechanisms.
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Affiliation(s)
| | | | | | | | - Qingquan Kong
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Yu Wang
- Department of Orthopedic Surgery and Orthopedic Research Institute, West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Xu H, Zhang Y, Zhang Y, Yu C, Xia K, Cheng F, Shi K, Huang X, Li Y, Chen J, Shu J, Zhou X, Tao Y, Liang C, Li F, Chen Q. A novel rat model of annulus fibrosus injury for intervertebral disc degeneration. Spine J 2024; 24:373-386. [PMID: 37797841 DOI: 10.1016/j.spinee.2023.09.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2023] [Revised: 09/19/2023] [Accepted: 09/20/2023] [Indexed: 10/07/2023]
Abstract
BACKGROUND CONTEXT In clinical practice, acute trauma and chronic degeneration of the annulus fibrosus (AF) can promote further degeneration of the intervertebral disc (IVD). Therefore, it is critical to understand the AF repair process and its consequences on IVD. However, the lack of cost-effective and reproducible in vivo animal models of AF injury has limited research development in this field. PURPOSES The purpose of this study was to establish and evaluate the utility of a novel animal model for full-thickness AF injury. Three foci were proposed: (1) whether this new modeling method can cause full-layer AF damage; (2) the repair processes and pathological changes in the damaged area after AF injury, and (3) the morphological and histological changes in the IVD are after AF injury. STUDY DESIGN/SETTING In vivo rat AF injury model with characterization of AF damage repair, IVD degeneration. METHODS A total of 72,300 g male rats were randomly assigned to one of the two groups: experimental or sham. Annulus fibrosus was separated layer by layer under the microscope with a #11 blade up to the AF- nucleus pulpous (NP) junction. The repair process of the horizontal AF and morphological changes in the sagittal IVD were evaluated with HE staining. Sirius red staining under polarized light. Immunofluorescence was conducted to analyze changes in the expression of COL1 and COL3 in the AF injury area and 8-OHdg, IL-6, MMP13, FSP1, and ACAN in the IVD. The disc height and structural changes after AF injury were measured using X-ray and contrast-enhanced micro-CT. Additionally, the resistance of the AF to stretching was analyzed using three-point bending. RESULTS Annulus fibrosus-nucleus pulpous border was identified to stably induce the full-thickness AF injury without causing immediate NP injury. The AF repair process after injury was slow and expressed inflammation factors continuously, with abundant amounts of type III collagen appearing in the inner part of the AF. The scar at the AF lesion had decreased resistance to small molecule penetration and weakened tensile strength. Full-thickness AF injury induced disc degeneration with loss of disc height, progressive unilateral vertebral collapse, and ossification of the subchondral bone. Inflammatory-induced degeneration and extracellular matrix catabolism gradually appeared in the NP and cartilage endplate (CEP). CONCLUSIONS We established a low-cost and reproducible small animal model of AF injury which accurately replicated the pathological state of the limited AF self-repair ability and demonstrated that injury to the AF alone could cause further degeneration of the IVD. CLINICAL RELEVANCE This in vivo rat model can be used to study the repair process of the AF defect and pathological changes in the gradual degeneration of IVD after AF damage. In addition, the model provides an experimental platform for in vivo experimental research of potential clinical therapeutics.
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Affiliation(s)
- Haibin Xu
- Department of Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, P. R. China; Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, P.R. China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, P.R. China; Clinical Research Center of Motor System Disease of Zhejiang Province, P.R. China
| | - Yuang Zhang
- Department of Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, P. R. China; Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, P.R. China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, P.R. China; Clinical Research Center of Motor System Disease of Zhejiang Province, P.R. China
| | - Yujie Zhang
- Department of Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, P. R. China; Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, P.R. China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, P.R. China; Clinical Research Center of Motor System Disease of Zhejiang Province, P.R. China
| | - Chao Yu
- Department of Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, P. R. China; Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, P.R. China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, P.R. China; Clinical Research Center of Motor System Disease of Zhejiang Province, P.R. China
| | - Kaishun Xia
- Department of Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, P. R. China; Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, P.R. China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, P.R. China; Clinical Research Center of Motor System Disease of Zhejiang Province, P.R. China
| | - Feng Cheng
- Department of Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, P. R. China; Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, P.R. China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, P.R. China; Clinical Research Center of Motor System Disease of Zhejiang Province, P.R. China
| | - Kesi Shi
- Department of Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, P. R. China; Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, P.R. China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, P.R. China; Clinical Research Center of Motor System Disease of Zhejiang Province, P.R. China
| | - Xianpeng Huang
- Department of Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, P. R. China; Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, P.R. China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, P.R. China; Clinical Research Center of Motor System Disease of Zhejiang Province, P.R. China
| | - Yi Li
- Department of Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, P. R. China; Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, P.R. China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, P.R. China; Clinical Research Center of Motor System Disease of Zhejiang Province, P.R. China
| | - Jiangjie Chen
- Department of Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, P. R. China; Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, P.R. China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, P.R. China; Clinical Research Center of Motor System Disease of Zhejiang Province, P.R. China
| | - Jiawei Shu
- Department of Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, P. R. China; Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, P.R. China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, P.R. China; Clinical Research Center of Motor System Disease of Zhejiang Province, P.R. China
| | - Xiaopeng Zhou
- Department of Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, P. R. China; Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, P.R. China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, P.R. China; Clinical Research Center of Motor System Disease of Zhejiang Province, P.R. China
| | - Yiqing Tao
- Department of Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, P. R. China; Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, P.R. China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, P.R. China; Clinical Research Center of Motor System Disease of Zhejiang Province, P.R. China
| | - Chengzhen Liang
- Department of Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, P. R. China; Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, P.R. China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, P.R. China; Clinical Research Center of Motor System Disease of Zhejiang Province, P.R. China.
| | - Fangcai Li
- Department of Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, P. R. China; Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, P.R. China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, P.R. China; Clinical Research Center of Motor System Disease of Zhejiang Province, P.R. China.
| | - Qixin Chen
- Department of Orthopedic Surgery, the Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou City, Zhejiang Province, P. R. China; Orthopedics Research Institute of Zhejiang University, Hangzhou City, Zhejiang Province, P.R. China; Key Laboratory of Motor System Disease Research and Precision Therapy of Zhejiang Province, Hangzhou City, Zhejiang Province, P.R. China; Clinical Research Center of Motor System Disease of Zhejiang Province, P.R. China.
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8
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Yang S, Zhang Y, Peng Q, Meng B, Wang J, Sun H, Chen L, Dai R, Zhang L. Regulating pyroptosis by mesenchymal stem cells and extracellular vesicles: A promising strategy to alleviate intervertebral disc degeneration. Biomed Pharmacother 2024; 170:116001. [PMID: 38128182 DOI: 10.1016/j.biopha.2023.116001] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 12/06/2023] [Accepted: 12/06/2023] [Indexed: 12/23/2023] Open
Abstract
Intervertebral disc degeneration (IVDD) is a main cause of low back pain (LBP), which can lead to disability and thus generate a heavy burden on society. IVDD is characterized by a decrease in nucleus pulposus cells (NPCs) and endogenous mesenchymal stem cells (MSCs), degradation of the extracellular matrix, macrophage infiltration, and blood vessel and nerve ingrowth. To date, the therapeutic approaches regarding IVDD mainly include conservative treatment and surgical intervention. However, both can only relieve symptoms rather than stop or revert the progression of IVDD, since the pathogenesis of IVDD is not yet clear. Pyroptosis, which is characterized by Caspase family dependence and conducted by the Gasdermin family, is a newly discovered mode of programmed cell death. Pyroptosis has been observed in NPCs, annulus fibrosus cells (AFCs), chondrocytes, MSCs, macrophages, vascular endothelial cells and neurons and may contribute to IVDD. MSCs are a kind of pluripotent stem cell that can be found in almost all tissues. MSCs have a strong ability to secrete extracellular vesicles (EVs), which contain exosomes, microvesicles and apoptotic bodies. EVs derived from MSCs play an important role in pyroptosis regulation and could be beneficial for alleviating IVDD. This review focuses on clarifying the regulation of pyroptosis to improve IVDD by MSCs and EVs derived from MSCs.
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Affiliation(s)
- Sheng Yang
- Department of Orthopedics, Graduate School of Dalian Medical University, Dalian 116044, China
| | - Yongbo Zhang
- Department of Orthopedics, Graduate School of Dalian Medical University, Dalian 116044, China
| | - Qing Peng
- Department of Orthopedics, Clinical Medical College, Yangzhou University, Yangzhou 225001, China
| | - Bo Meng
- Department of Orthopedics, Graduate School of Dalian Medical University, Dalian 116044, China
| | - Jiabo Wang
- Department of Orthopedics, Huai'an 82 Hospital, Huai'an 223003, China
| | - Hua Sun
- Department of Orthopedics, Clinical Medical College, Yangzhou University, Yangzhou 225001, China
| | - Liuyang Chen
- Department of Orthopedics, Clinical Medical College, Yangzhou University, Yangzhou 225001, China
| | - Rui Dai
- Department of Orthopedics, Clinical Medical College, Yangzhou University, Yangzhou 225001, China
| | - Liang Zhang
- Department of Orthopedics, Clinical Medical College, Yangzhou University, Yangzhou 225001, China.
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Zhu S, Wang J, Suo M, Huang H, Liu X, Wang J, Li Z. Can extracellular vesicles be considered as a potential frontier in the treatment of intervertebral disc disease? Ageing Res Rev 2023; 92:102094. [PMID: 37863436 DOI: 10.1016/j.arr.2023.102094] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Revised: 10/04/2023] [Accepted: 10/16/2023] [Indexed: 10/22/2023]
Abstract
As a global public health problem, low back pain (LBP) caused by intervertebral disc degeneration (IDD) seriously affects patients' quality of life. In addition, the prevalence of IDD tends to be younger, which brings a huge burden to individuals and society economically. Current treatments do not delay or reverse the progression of IDD. The emergence of biologic therapies has brought new hope for the treatment of IDD. Among them, extracellular vesicles (EVs), as nanoscale bioactive substances that mediate cellular communication, have now produced many surprising results in the research of the treatment of IDD. This article reviews the mechanisms and roles of EVs in delaying IDD and describes the prospects and challenges of EVs.
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Affiliation(s)
- Shengxu Zhu
- Department of Orthopedics, First Affiliated Hospital of Dalian Medical University, Dalian, the People's Republic of China; Key Laboratory of Molecular Mechanism for Repair and Remodeling of Orthopedic Diseases, Liaoning Province, the People's Republic of China
| | - Junlin Wang
- Department of Orthopedics, First Affiliated Hospital of Dalian Medical University, Dalian, the People's Republic of China
| | - Moran Suo
- Department of Orthopedics, First Affiliated Hospital of Dalian Medical University, Dalian, the People's Republic of China; Key Laboratory of Molecular Mechanism for Repair and Remodeling of Orthopedic Diseases, Liaoning Province, the People's Republic of China
| | - Huagui Huang
- Department of Orthopedics, First Affiliated Hospital of Dalian Medical University, Dalian, the People's Republic of China; Key Laboratory of Molecular Mechanism for Repair and Remodeling of Orthopedic Diseases, Liaoning Province, the People's Republic of China
| | - Xin Liu
- Department of Orthopedics, First Affiliated Hospital of Dalian Medical University, Dalian, the People's Republic of China; Key Laboratory of Molecular Mechanism for Repair and Remodeling of Orthopedic Diseases, Liaoning Province, the People's Republic of China
| | - Jinzuo Wang
- Department of Orthopedics, First Affiliated Hospital of Dalian Medical University, Dalian, the People's Republic of China; Key Laboratory of Molecular Mechanism for Repair and Remodeling of Orthopedic Diseases, Liaoning Province, the People's Republic of China
| | - Zhonghai Li
- Department of Orthopedics, First Affiliated Hospital of Dalian Medical University, Dalian, the People's Republic of China; Key Laboratory of Molecular Mechanism for Repair and Remodeling of Orthopedic Diseases, Liaoning Province, the People's Republic of China.
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10
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Zhang A, Cheng Z, Chen Y, Shi P, Gan W, Zhang Y. Emerging tissue engineering strategies for annulus fibrosus therapy. Acta Biomater 2023:S1742-7061(23)00337-9. [PMID: 37330029 DOI: 10.1016/j.actbio.2023.06.012] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 05/31/2023] [Accepted: 06/12/2023] [Indexed: 06/19/2023]
Abstract
Low back pain is a major public health concern experienced by 80% of the world's population during their lifetime, which is closely associated with intervertebral disc (IVD) herniation. IVD herniation manifests as the nucleus pulposus (NP) protruding beyond the boundaries of the intervertebral disc due to disruption of the annulus fibrosus (AF). With a deepening understanding of the importance of the AF structure in the pathogenesis of intervertebral disc degeneration, numerous advanced therapeutic strategies for AF based on tissue engineering, cellular regeneration, and gene therapy have emerged. However, there is still no consensus concerning the optimal approach for AF regeneration. In this review, we summarized strategies in the field of AF repair and highlighted ideal cell types and pro-differentiation targeting approaches for AF repair, and discussed the prospects and difficulties of implant systems combining cells and biomaterials to guide future research directions. STATEMENT OF SIGNIFICANCE: Low back pain is a major public health concern experienced by 80% of the world's population during their lifetime, which is closely associated with intervertebral disc (IVD) herniation. However, there is still no consensus concerning the optimal approach for annulus fibrosus (AF) regeneration. In this review, we summarized strategies in the field of AF repair and highlighted ideal cell types and pro-differentiation targeting approaches for AF repair, and discussed the prospects and difficulties of implant systems combining cells and biomaterials to guide future research directions.
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Affiliation(s)
- Anran Zhang
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Zhangrong Cheng
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yuhang Chen
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Pengzhi Shi
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Weikang Gan
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yukun Zhang
- Department of Orthopedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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Core-shell oxygen-releasing fibers for annulus fibrosus repair in the intervertebral disc of rats. Mater Today Bio 2023; 18:100535. [PMID: 36654965 PMCID: PMC9841168 DOI: 10.1016/j.mtbio.2022.100535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2022] [Revised: 12/15/2022] [Accepted: 12/26/2022] [Indexed: 01/05/2023] Open
Abstract
The repair of annulus fibrosus (AF) defect after discectomy in the intervertebral disc (IVD) has presented a challenge over the past decade. Hostile microenvironments in the IVD, including, compression and hypoxia, are critical issues that require special attention. Till date, little information is available on potential strategies to cope with the hypoxia dilemma in AF defect sites. In this study, perfluorotributylamine (PFTBA) core-shell fibers were fabricated by coaxial electrospinning to construct oxygen-releasing scaffold for promoting endogenous repair in the AF after discectomy. We demonstrated that PFTBA fibers (10% chitosan, chitosan: PCL, 1:6) could release oxygen for up to 144 h. The oxygen released from PFTBA fibers was found to protect annulus fibrosus stem cells (AFSCs) from hypoxia-induced apoptosis. In addition, the PFTBA fibers were able to promote proliferation, migration and extracellular matrix (ECM) production in AFSCs under hypoxia, highlighting their therapeutic potential in AF defect repair. Subsequent in vivo studies demonstrated that oxygen-supplying fibers were capable of ameliorating disc degeneration after discectomy, which was evidenced by improved disc height and morphological integrity in rats with the oxygen-releasing scaffolds. Further transcriptome analysis indicated that differential expression genes (DEGs) were enriched in "oxygen transport" and "angiogenesis", which likely contributed to their beneficial effect on endogenous AF regeneration. In summary, the oxygen-releasing scaffold provides novel insights into the oxygen regulation by bioactive materials and raises the therapeutic possibility of oxygen supply strategies for defect repair in AF, as well as other aerobic tissues.
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Wei Q, Liu D, Chu G, Yu Q, Liu Z, Li J, Meng Q, Wang W, Han F, Li B. TGF-β1-supplemented decellularized annulus fibrosus matrix hydrogels promote annulus fibrosus repair. Bioact Mater 2023; 19:581-593. [PMID: 35600980 PMCID: PMC9108517 DOI: 10.1016/j.bioactmat.2022.04.025] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2022] [Revised: 04/06/2022] [Accepted: 04/23/2022] [Indexed: 12/19/2022] Open
Abstract
Annulus fibrosus (AF) repair remains a challenge because of its limited self-healing ability. Endogenous repair strategies combining scaffolds and growth factors show great promise in AF repair. Although the unique and beneficial characteristics of decellularized extracellular matrix (ECM) in tissue repair have been demonstrated, the poor mechanical property of ECM hydrogels largely hinders their applications in tissue regeneration. In the present study, we combined polyethylene glycol diacrylate (PEGDA) and decellularized annulus fibrosus matrix (DAFM) to develop an injectable, photocurable hydrogel for AF repair. We found that the addition of PEGDA markedly improved the mechanical strength of DAFM hydrogels while maintaining their porous structure. Transforming growth factor-β1 (TGF-β1) was further incorporated into PEGDA/DAFM hydrogels, and it could be continuously released from the hydrogel. The in vitro experiments showed that TGF-β1 facilitated the migration of AF cells. Furthermore, PEGDA/DAFM/TGF-β1 hydrogels supported the adhesion, proliferation, and increased ECM production of AF cells. In vivo repair performance of the hydrogels was assessed using a rat AF defect model. The results showed that the implantation of PEGDA/DAFM/TGF-β1 hydrogels effectively sealed the AF defect, prevented nucleus pulposus atrophy, retained disc height, and partially restored the biomechanical properties of disc. In addition, the implanted hydrogel was infiltrated by cells resembling AF cells and well integrated with adjacent AF tissue. In summary, findings from this study indicate that TGF-β1-supplemented DAFM hydrogels hold promise for AF repair.
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Affiliation(s)
- Qiang Wei
- Department of Orthopaedic Surgery, Orthopaedic Institute, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China
| | - Dachuan Liu
- Department of Orthopaedic Surgery, Orthopaedic Institute, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China
| | - Genglei Chu
- Department of Orthopaedic Surgery, Orthopaedic Institute, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China
| | - Qifan Yu
- Department of Orthopaedic Surgery, Orthopaedic Institute, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China
| | - Zhao Liu
- Department of Orthopaedic Surgery, Orthopaedic Institute, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China
| | - Jiaying Li
- Department of Orthopaedic Surgery, Orthopaedic Institute, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China
| | - Qingchen Meng
- Department of Orthopaedic Surgery, Orthopaedic Institute, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China
| | - Weishan Wang
- Department of Orthopaedic Surgery, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, China
| | - Fengxuan Han
- Department of Orthopaedic Surgery, Orthopaedic Institute, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China
| | - Bin Li
- Department of Orthopaedic Surgery, Orthopaedic Institute, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China
- Department of Orthopaedic Surgery, The First Affiliated Hospital, Shihezi University School of Medicine, Shihezi, Xinjiang, China
- Collaborative Innovation Center of Hematology, Soochow University, Suzhou, Jiangsu, China
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Peng BG, Yan XJ. Barriers to mesenchymal stromal cells for low back pain. World J Stem Cells 2022; 14:815-821. [PMID: 36619693 PMCID: PMC9813839 DOI: 10.4252/wjsc.v14.i12.815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 10/30/2022] [Accepted: 11/30/2022] [Indexed: 12/21/2022] Open
Abstract
Intervertebral disc degeneration is the main cause of low back pain. In the past 20 years, the injection of mesenchymal stromal cells (MSCs) into the nucleus pulposus of the degenerative disc has become the main approach for the treatment of low back pain. Despite the progress made in this field, there are still many barriers to overcome. First, intervertebral disc is a highly complex load-bearing composite tissue composed of annulus fibrosus, nucleus pulposus and cartilaginous endplates. Any structural damage will change its overall biomechanical function, thereby causing progressive degeneration of the entire intervertebral disc. Therefore, MSC-based treatment strategies should not only target the degenerated nucleus pulposus but also include degenerated annulus fibrosus or cartilaginous endplates. Second, to date, there has been relatively little research on the basic biology of annulus fibrosus and cartilaginous endplates, although their pathological changes such as annular tears or fissures, Modic changes, or Schmorl's nodes are more commonly associated with low back pain. Given the high complexity of the structure and composition of the annulus fibrosus and cartilaginous endplates, it remains an open question whether any regeneration techniques are available to achieve their restorative regeneration. Finally, due to the harsh microenvironment of the degenerated intervertebral disc, the delivered MSCs die quickly. Taken together, current MSC-based regenerative medicine therapies to regenerate the entire disc complex by targeting the degenerated nucleus pulposus alone are unlikely to be successful.
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Affiliation(s)
- Bao-Gan Peng
- Department of Orthopaedics, The Third Medical Center, General Hospital of the Chinese People’s Liberation Army, Beijing 100039, China
| | - Xiu-Jie Yan
- Department of Orthopaedics, The Third Medical Center, General Hospital of the Chinese People’s Liberation Army, Beijing 100039, China
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14
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Xia Y, Yang R, Hou Y, Wang H, Li Y, Zhu J, Fu C. Application of mesenchymal stem cell-derived exosomes from different sources in intervertebral disc degeneration. Front Bioeng Biotechnol 2022; 10:1019437. [PMID: 36277386 PMCID: PMC9585200 DOI: 10.3389/fbioe.2022.1019437] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 09/26/2022] [Indexed: 12/12/2022] Open
Abstract
Intervertebral disc degeneration (IVDD) is a main cause of lower back pain, leading to psychological and economic burdens to patients. Physical therapy only delays pain in patients but cannot eliminate the cause of IVDD. Surgery is required when the patient cannot tolerate pain or has severe neurological symptoms. Although surgical resection of IVD or decompression of the laminae eliminates the diseased segment, it damages adjacent normal IVD. There is also a risk of re-protrusion after IVD removal. Cell therapy has played a crucial role in the development of regenerative medicine. Cell transplantation promotes regeneration of degenerative tissue. However, owing to the lack of vascular structure in IVD, sufficient nutrients cannot be provided for transplanted mesenchymal stem cells (MSCs). In addition, dead cells release harmful substances that aggravate IVDD. Extracellular vesicles (EVs) have been extensively studied as an emerging therapeutic approach. EVs generated by paracrine MSCs retain the potential of MSCs and serve as carriers to deliver their contents to target cells to regulate target cell activity. Owing to their double-layered membrane structure, EVs have a low immunogenicity and no immune rejection. Therefore, EVs are considered an emerging therapeutic modality in IVDD. However, they are limited by mass production and low loading rates. In this review, the structure of IVD and advantages of EVs are introduced, and the application of MSC-EVs in IVDD is discussed. The current limitations of EVs and future applications are described.
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Affiliation(s)
- Yuanliang Xia
- Department of Spine Surgery, The First Hospital of Jilin University, Changchun, China
| | - Ruohan Yang
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Yulin Hou
- Department of Cardiology, Guangyuan Central Hospital, Guangyuan, China
| | - Hengyi Wang
- Department of Spine Surgery, The First Hospital of Jilin University, Changchun, China
| | - Yuehong Li
- Department of Spine Surgery, The First Hospital of Jilin University, Changchun, China
| | - Jianshu Zhu
- Department of Spine Surgery, The First Hospital of Jilin University, Changchun, China
| | - Changfeng Fu
- Department of Spine Surgery, The First Hospital of Jilin University, Changchun, China
- *Correspondence: Changfeng Fu,
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15
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Li C, Bai Q, Lai Y, Tian J, Li J, Sun X, Zhao Y. Advances and Prospects in Biomaterials for Intervertebral Disk Regeneration. Front Bioeng Biotechnol 2021; 9:766087. [PMID: 34746112 PMCID: PMC8569141 DOI: 10.3389/fbioe.2021.766087] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Accepted: 10/08/2021] [Indexed: 12/12/2022] Open
Abstract
Low-back and neck-shoulder pains caused by intervertebral disk degeneration are highly prevalent among middle-aged and elderly people globally. The main therapy method for intervertebral disk degeneration is surgical intervention, including interbody fusion, disk replacement, and diskectomy. However, the stress changes caused by traditional fusion surgery are prone to degeneration of adjacent segments, while non-fusion surgery has problems, such as ossification of artificial intervertebral disks. To overcome these drawbacks, biomaterials that could endogenously regenerate the intervertebral disk and restore the biomechanical function of the intervertebral disk is imperative. Intervertebral disk is a fibrocartilaginous tissue, primarily comprising nucleus pulposus and annulus fibrosus. Nucleus pulposus (NP) contains high water and proteoglycan, and its main function is absorbing compressive forces and dispersing loads from physical activities to other body parts. Annulus fibrosus (AF) is a multilamellar structure that encloses the NP, comprises water and collagen, and supports compressive and shear stress during complex motion. Therefore, different biomaterials and tissue engineering strategies are required for the functional recovery of NP and AF based on their structures and function. Recently, great progress has been achieved on biomaterials for NP and AF made of functional polymers, such as chitosan, collagen, polylactic acid, and polycaprolactone. However, scaffolds regenerating intervertebral disk remain unexplored. Hence, several tissue engineering strategies based on cell transplantation and growth factors have been extensively researched. In this review, we summarized the functional polymers and tissue engineering strategies of NP and AF to endogenously regenerate degenerative intervertebral disk. The perspective and challenges of tissue engineering strategies using functional polymers, cell transplantation, and growth factor for generating degenerative intervertebral disks were also discussed.
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Affiliation(s)
- Chunxu Li
- Department of Orthopaedics, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Qiushi Bai
- Department of Orthopaedics, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Yuxiao Lai
- Centre for Translational Medicine Research and Development, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Jingjing Tian
- Medical Science Research Center, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Jiahao Li
- Department of Orthopaedics, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Xiaodan Sun
- State Key Laboratory of New Ceramics and Fine Processing, School of Materials Science and Engineering, Tsinghua University, Beijing, China
| | - Yu Zhao
- Department of Orthopaedics, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
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Peng Y, Qing X, Shu H, Tian S, Yang W, Chen S, Lin H, Lv X, Zhao L, Chen X, Pu F, Huang D, Cao X, Shao Z, Yp, Zs, Xc, Yp, Yp, Xq, Hs, St, Wy, Yp, Xq, Hs, St, Hl, Xl, Lz, Xc, Fp, Sc, Yp, Xq, Hs, St, Yp, Xq, Wy, Hl, Xl, Lz, Xc, Fp, Sc, Hdh, Wy, Hl, Xl, Lz, Xc, Fp, Sc, Hdh, Zs, Xc. Proper animal experimental designs for preclinical research of biomaterials for intervertebral disc regeneration. BIOMATERIALS TRANSLATIONAL 2021; 2:91-142. [PMID: 35836965 PMCID: PMC9255780 DOI: 10.12336/biomatertransl.2021.02.003] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 06/09/2021] [Indexed: 01/17/2023]
Abstract
Low back pain is a vital musculoskeletal disease that impairs life quality, leads to disability and imposes heavy economic burden on the society, while it is greatly attributed to intervertebral disc degeneration (IDD). However, the existing treatments, such as medicines, chiropractic adjustments and surgery, cannot achieve ideal disc regeneration. Therefore, advanced bioactive therapies are implemented, including stem cells delivery, bioreagents administration, and implantation of biomaterials etc. Among these researches, few reported unsatisfying regenerative outcomes. However, these advanced therapies have barely achieved successful clinical translation. The main reason for the inconsistency between satisfying preclinical results and poor clinical translation may largely rely on the animal models that cannot actually simulate the human disc degeneration. The inappropriate animal model also leads to difficulties in comparing the efficacies among biomaterials in different reaches. Therefore, animal models that better simulate the clinical charateristics of human IDD should be acknowledged. In addition, in vivo regenerative outcomes should be carefully evaluated to obtain robust results. Nevertheless, many researches neglect certain critical characteristics, such as adhesive properties for biomaterials blocking annulus fibrosus defects and hyperalgesia that is closely related to the clinical manifestations, e.g., low back pain. Herein, in this review, we summarized the animal models established for IDD, and highlighted the proper models and parameters that may result in acknowledged IDD models. Then, we discussed the existing biomaterials for disc regeneration and the characteristics that should be considered for regenerating different parts of discs. Finally, well-established assays and parameters for in vivo disc regeneration are explored.
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Affiliation(s)
- Yizhong Peng
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Xiangcheng Qing
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Hongyang Shu
- Division of Cardiology, Department of Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China,Hubei Key Laboratory of Genetics and Molecular Mechanism of Cardiologic Disorders, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Shuo Tian
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Wenbo Yang
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Songfeng Chen
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Hui Lin
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Xiao Lv
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Lei Zhao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Xi Chen
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Feifei Pu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Donghua Huang
- Department of Orthopaedic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
| | - Xu Cao
- Department of Orthopaedic Surgery, Institute for Cell Engineering, Johns Hopkins University, Baltimore, MD, USA,Corresponding authors: Zengwu Shao, ; Xu Cao,
| | - Zengwu Shao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China,Corresponding authors: Zengwu Shao, ; Xu Cao,
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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: 22] [Impact Index Per Article: 5.5] [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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Peredo AP, Gullbrand SE, Mauck RL, Smith HE. A challenging playing field: Identifying the endogenous impediments to annulus fibrosus repair. JOR Spine 2021; 4:e1133. [PMID: 33778407 PMCID: PMC7984000 DOI: 10.1002/jsp2.1133] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2020] [Revised: 11/10/2020] [Accepted: 11/11/2020] [Indexed: 12/31/2022] Open
Abstract
Intervertebral disc (IVD) herniations, caused by annulus fibrosus (AF) tears that enable disc tissue extrusion beyond the disc space, are very prevalent, especially among adults in the third to fifth decade of life. Symptomatic herniations, in which the extruded tissue compresses surrounding nerves, are characterized by back pain, numbness, and tingling and can cause extreme physical disability. Patients whose symptoms persist after nonoperative intervention may undergo surgical removal of the herniated tissue via microdiscectomy surgery. The AF, however, which has a poor endogenous healing ability, is left unrepaired increasing the risk for re-herniation and pre-disposing the IVD to degenerative disc disease. The lack of understanding of the mechanisms involved in native AF repair limits the design of repair systems that overcome the impediments to successful AF restoration. Moreover, the complexity of the AF structure and the challenging anatomy of the repair environment represents a significant challenge for the design of new repair devices. While progress has been made towards the development of an effective AF repair technique, these methods have yet to demonstrate long-term repair and recovery of IVD biomechanics. In this review, the limitations of endogenous AF healing are discussed and key cellular events and factors involved are highlighted to identify potential therapeutic targets that can be integrated into AF repair methods. Clinical repair strategies and their limitations are described to further guide the design of repair approaches that effectively restore native tissue structure and function.
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Affiliation(s)
- Ana P. Peredo
- Department of BioengineeringSchool of Engineering and Applied Science, University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- McKay Orthopaedic Research Laboratory, Department of Orthopaedic SurgeryPerelman School of Medicine, University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Translational Musculoskeletal Research CenterCorporal Michael J. Crescenz Veterans Affairs Medical CenterPhiladelphiaPennsylvaniaUSA
| | - Sarah E. Gullbrand
- McKay Orthopaedic Research Laboratory, Department of Orthopaedic SurgeryPerelman School of Medicine, University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Translational Musculoskeletal Research CenterCorporal Michael J. Crescenz Veterans Affairs Medical CenterPhiladelphiaPennsylvaniaUSA
| | - Robert L. Mauck
- Department of BioengineeringSchool of Engineering and Applied Science, University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- McKay Orthopaedic Research Laboratory, Department of Orthopaedic SurgeryPerelman School of Medicine, University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Translational Musculoskeletal Research CenterCorporal Michael J. Crescenz Veterans Affairs Medical CenterPhiladelphiaPennsylvaniaUSA
| | - Harvey E. Smith
- McKay Orthopaedic Research Laboratory, Department of Orthopaedic SurgeryPerelman School of Medicine, University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Translational Musculoskeletal Research CenterCorporal Michael J. Crescenz Veterans Affairs Medical CenterPhiladelphiaPennsylvaniaUSA
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