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Ambrosio L, Schol J, Ruiz-Fernández C, Tamagawa S, Joyce K, Nomura A, de Rinaldis E, Sakai D, Papalia R, Vadalà G, Denaro V. Getting to the Core: Exploring the Embryonic Development from Notochord to Nucleus Pulposus. J Dev Biol 2024; 12:18. [PMID: 39051200 PMCID: PMC11270426 DOI: 10.3390/jdb12030018] [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: 05/20/2024] [Revised: 06/12/2024] [Accepted: 07/02/2024] [Indexed: 07/27/2024] Open
Abstract
The intervertebral disc (IVD) is the largest avascular organ of the human body and plays a fundamental role in providing the spine with its unique structural and biomechanical functions. The inner part of the IVD contains the nucleus pulposus (NP), a gel-like tissue characterized by a high content of type II collagen and proteoglycans, which is crucial for the disc's load-bearing and shock-absorbing properties. With aging and IVD degeneration (IDD), the NP gradually loses its physiological characteristics, leading to low back pain and additional sequelae. In contrast to surrounding spinal tissues, the NP presents a distinctive embryonic development since it directly derives from the notochord. This review aims to explore the embryology of the NP, emphasizing the pivotal roles of key transcription factors, which guide the differentiation and maintenance of the NP cellular components from the notochord and surrounding sclerotome. Through an understanding of NP development, we sought to investigate the implications of the critical developmental aspects in IVD-related pathologies, such as IDD and the rare malignant chordomas. Moreover, this review discusses the therapeutic strategies targeting these pathways, including the novel regenerative approaches leveraging insights from NP development and embryology to potentially guide future treatments.
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Affiliation(s)
- Luca Ambrosio
- Operative Research Unit of Orthopaedic and Trauma Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, 00128 Rome, Italy; (L.A.); (R.P.); (V.D.)
- Research Unit of Orthopaedic and Trauma Surgery, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, 01128 Rome, Italy;
- Department of Orthopaedic Surgery, Tokai University School of Medicine, Isehara 259-1143, Japan; (J.S.); (C.R.-F.); (A.N.); (D.S.)
| | - Jordy Schol
- Department of Orthopaedic Surgery, Tokai University School of Medicine, Isehara 259-1143, Japan; (J.S.); (C.R.-F.); (A.N.); (D.S.)
| | - Clara Ruiz-Fernández
- Department of Orthopaedic Surgery, Tokai University School of Medicine, Isehara 259-1143, Japan; (J.S.); (C.R.-F.); (A.N.); (D.S.)
| | - Shota Tamagawa
- Department of Medicine for Orthopaedics and Motor Organ, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan;
| | - Kieran Joyce
- CÚRAM, SFI Research Centre for Medical Devices, University of Galway, H91 W2TY Galway, Ireland;
- School of Medicine, University of Galway, H91 W2TY Galway, Ireland
| | - Akira Nomura
- Department of Orthopaedic Surgery, Tokai University School of Medicine, Isehara 259-1143, Japan; (J.S.); (C.R.-F.); (A.N.); (D.S.)
| | - Elisabetta de Rinaldis
- Research Unit of Orthopaedic and Trauma Surgery, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, 01128 Rome, Italy;
| | - Daisuke Sakai
- Department of Orthopaedic Surgery, Tokai University School of Medicine, Isehara 259-1143, Japan; (J.S.); (C.R.-F.); (A.N.); (D.S.)
| | - Rocco Papalia
- Operative Research Unit of Orthopaedic and Trauma Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, 00128 Rome, Italy; (L.A.); (R.P.); (V.D.)
- Research Unit of Orthopaedic and Trauma Surgery, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, 01128 Rome, Italy;
| | - Gianluca Vadalà
- Operative Research Unit of Orthopaedic and Trauma Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, 00128 Rome, Italy; (L.A.); (R.P.); (V.D.)
- Research Unit of Orthopaedic and Trauma Surgery, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, 01128 Rome, Italy;
| | - Vincenzo Denaro
- Operative Research Unit of Orthopaedic and Trauma Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, 00128 Rome, Italy; (L.A.); (R.P.); (V.D.)
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Farag M, Rezk R, Hutchinson H, Zankevich A, Lucke‐Wold B. Intervertebral disc degeneration and regenerative medicine. CLINICAL AND TRANSLATIONAL DISCOVERY 2024; 4. [DOI: 10.1002/ctd2.289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Accepted: 03/15/2024] [Indexed: 01/08/2025]
Abstract
AbstractIntervertebral disc (IVD) degeneration is a common phenomenon that affects patients with increasing prevalence with increasing age. Both conservative treatments, such as the use of pain medication or physical therapy, and surgical treatments, such as fusion or disc replacement therapies, are offered to patients. Both non‐invasive and invasive treatments have been shown to improve pain and quality of life for patients. This review explores the role of regenerative medicine techniques as a promising therapeutic intervention that can be used before or in combination with conservative therapy and surgery to enhance the treatment process in patients with IVD degeneration or disc pathology. Currently, there are four major modules of regenerative medicine: genetic therapy, platelet‐rich plasma therapy, stem cell transplantation and tissue engineering. Several research studies have shown promising outcomes of stem cell transplantation and tissue engineering when combined with either surgical or conservative treatment, resulting in improved pain outcomes. The additional benefit of regenerative medicine techniques, specifically stem cell transplantation, is the potential for treating the root pathology of degeneration. Regenerative medicine techniques also have the potential to either halt or reverse degeneration as opposed to current standards of care for managing symptoms. There is a plethora of current research highlighting the benefits of regenerative medicine techniques; however, there remains clinical concerns and ethical concerns regarding the use of regenerative therapy techniques such as stem cell transplantation in the context of IVD degeneration.
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Affiliation(s)
| | - Rogina Rezk
- University of Florida Gainesville Florida USA
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Tilotta V, Vadalà G, Ambrosio L, Di Giacomo G, Cicione C, Russo F, Darinskas A, Papalia R, Denaro V. Wharton's Jelly mesenchymal stromal cell-derived extracellular vesicles promote nucleus pulposus cell anabolism in an in vitro 3D alginate-bead culture model. JOR Spine 2024; 7:e1274. [PMID: 38222813 PMCID: PMC10782051 DOI: 10.1002/jsp2.1274] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 06/29/2023] [Accepted: 07/02/2023] [Indexed: 01/16/2024] Open
Abstract
Background Intradiscal transplantation of mesenchymal stromal cells (MSCs) has emerged as a promising therapy for intervertebral disc degeneration (IDD). However, the hostile microenvironment of the intervertebral disc (IVD) may compromise the survival of implanted cells. Interestingly, studies reported that paracrine factors, such as extracellular vesicles (EVs) released by MSCs, may regenerate the IVD. The aim of this study was to investigate the therapeutic effects of Wharton's Jelly MSC (WJ-MSC)-derived EVs on human nucleus pulposus cells (hNPCs) using an in vitro 3D alginate-bead culture model. Methods After EV isolation and characterization, hNPCs isolated from surgical specimens were encapsulated in alginate beads and treated with 10, 50, and 100 μg/mL WJ-MSC-EVs. Cell proliferation and viability were assessed by flow cytometry and live/dead staining. Nitrite and glycosaminoglycan (GAG) content was evaluated through Griess and 1,9-dimethylmethylene blue assays. hNPCs in alginate beads were paraffin-embedded and stained for histological analysis (hematoxylin-eosin and Alcian blue) to assess extracellular matrix (ECM) composition. Gene expression levels of catabolic (MMP1, MMP13, ADAMTS5, IL6, NOS2), anabolic (ACAN), and hNPC marker (SOX9, KRT19) genes were analyzed through qPCR. Collagen type I and type II content was assessed with Western blot analysis. Results Treatment with WJ-MSC-EVs resulted in an increase in cell content and a decrease in cell death in degenerated hNPCs. Nitrite production was drastically reduced by EV treatment compared to the control. Furthermore, proteoglycan content was enhanced and confirmed by Alcian blue histological staining. EV stimulation attenuated ECM degradation and inflammation by suppressing catabolic and inflammatory gene expression levels. Additionally, NPC phenotypic marker genes were also maintained by the EV treatment. Conclusions WJ-MSC-derived EVs ameliorated hNPC growth and viability, and attenuated ECM degradation and oxidative stress, offering new opportunities for IVD regeneration as an attractive alternative strategy to cell therapy, which may be jeopardized by the harsh microenvironment of the IVD.
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Affiliation(s)
- Veronica Tilotta
- Laboratory for Regenerative Orthopaedics, Research Unit of Orthopaedic and Trauma Surgery, Department of Medicine and SurgeryUniversità Campus Bio‐Medico di RomaRomeItaly
| | - Gianluca Vadalà
- Laboratory for Regenerative Orthopaedics, Research Unit of Orthopaedic and Trauma Surgery, Department of Medicine and SurgeryUniversità Campus Bio‐Medico di RomaRomeItaly
- Operative Research Unit of Orthopaedic and Trauma SurgeryFondazione Policlinico Universitario Campus Bio‐MedicoRomeItaly
| | - Luca Ambrosio
- Laboratory for Regenerative Orthopaedics, Research Unit of Orthopaedic and Trauma Surgery, Department of Medicine and SurgeryUniversità Campus Bio‐Medico di RomaRomeItaly
- Operative Research Unit of Orthopaedic and Trauma SurgeryFondazione Policlinico Universitario Campus Bio‐MedicoRomeItaly
| | - Giuseppina Di Giacomo
- Laboratory for Regenerative Orthopaedics, Research Unit of Orthopaedic and Trauma Surgery, Department of Medicine and SurgeryUniversità Campus Bio‐Medico di RomaRomeItaly
| | - Claudia Cicione
- Laboratory for Regenerative Orthopaedics, Research Unit of Orthopaedic and Trauma Surgery, Department of Medicine and SurgeryUniversità Campus Bio‐Medico di RomaRomeItaly
| | - Fabrizio Russo
- Laboratory for Regenerative Orthopaedics, Research Unit of Orthopaedic and Trauma Surgery, Department of Medicine and SurgeryUniversità Campus Bio‐Medico di RomaRomeItaly
- Operative Research Unit of Orthopaedic and Trauma SurgeryFondazione Policlinico Universitario Campus Bio‐MedicoRomeItaly
| | - Adas Darinskas
- Laboratory of Immunology, National Cancer InstituteVilniusLithuania
- JSC Innovita Research, Tissue BankVilniusLithuania
| | - Rocco Papalia
- Laboratory for Regenerative Orthopaedics, Research Unit of Orthopaedic and Trauma Surgery, Department of Medicine and SurgeryUniversità Campus Bio‐Medico di RomaRomeItaly
- Operative Research Unit of Orthopaedic and Trauma SurgeryFondazione Policlinico Universitario Campus Bio‐MedicoRomeItaly
| | - Vincenzo Denaro
- Operative Research Unit of Orthopaedic and Trauma SurgeryFondazione Policlinico Universitario Campus Bio‐MedicoRomeItaly
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Jiang W, Glaeser JD, Kaneda G, Sheyn J, Wechsler JT, Stephan S, Salehi K, Chan JL, Tawackoli W, Avalos P, Johnson C, Castaneda C, Kanim LE, Tanasansomboon T, Burda JE, Shelest O, Yameen H, Perry TG, Kropf M, Cuellar JM, Seliktar D, Bae HW, Stone LS, Sheyn D. Intervertebral disc human nucleus pulposus cells associated with back pain trigger neurite outgrowth in vitro and pain behaviors in rats. Sci Transl Med 2023; 15:eadg7020. [PMID: 38055799 PMCID: PMC12083434 DOI: 10.1126/scitranslmed.adg7020] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 10/06/2023] [Indexed: 12/08/2023]
Abstract
Low back pain (LBP) is often associated with the degeneration of human intervertebral discs (IVDs). However, the pain-inducing mechanism in degenerating discs remains to be elucidated. Here, we identified a subtype of locally residing human nucleus pulposus cells (NPCs), generated by certain conditions in degenerating discs, that was associated with the onset of discogenic back pain. Single-cell transcriptomic analysis of human tissues showed a strong correlation between a specific cell subtype and the pain condition associated with the human degenerated disc, suggesting that they are pain-triggering. The application of IVD degeneration-associated exogenous stimuli to healthy NPCs in vitro recreated a pain-associated phenotype. These stimulated NPCs activated functional human iPSC-derived sensory neuron responses in an in vitro organ-chip model. Injection of stimulated NPCs into the healthy rat IVD induced local inflammatory responses and increased cold sensitivity and mechanical hypersensitivity. Our findings reveal a previously uncharacterized pain-inducing mechanism mediated by NPCs in degenerating IVDs. These findings could aid in the development of NPC-targeted therapeutic strategies for the clinically unmet need to attenuate discogenic LBP.
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Affiliation(s)
- Wensen Jiang
- Orthopaedic Stem Cell Research Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Juliane D. Glaeser
- Orthopaedic Stem Cell Research Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Giselle Kaneda
- Orthopaedic Stem Cell Research Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Julia Sheyn
- Orthopaedic Stem Cell Research Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Jacob T. Wechsler
- Orthopaedic Stem Cell Research Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Stephen Stephan
- Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Khosrowdad Salehi
- Orthopaedic Stem Cell Research Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Julie L. Chan
- Orthopaedic Stem Cell Research Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Wafa Tawackoli
- Orthopaedic Stem Cell Research Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Biomedical Imaging Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Pablo Avalos
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Christopher Johnson
- Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Chloe Castaneda
- Orthopaedic Stem Cell Research Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Linda E.A. Kanim
- Orthopaedic Stem Cell Research Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Teerachat Tanasansomboon
- Orthopaedic Stem Cell Research Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Center of Excellence in Biomechanics and Innovative Spine Surgery, Department of Orthopedics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand
| | - Joshua E. Burda
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Oksana Shelest
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Haneen Yameen
- Department of Biomedical Engineering, Israeli Institute of Technology Technion, Haifa 3200003, Israel
| | - Tiffany G. Perry
- Department of Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Michael Kropf
- Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Jason M. Cuellar
- Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Dror Seliktar
- Department of Biomedical Engineering, Israeli Institute of Technology Technion, Haifa 3200003, Israel
| | - Hyun W. Bae
- Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Laura S. Stone
- Department of Biomedical Engineering, Israeli Institute of Technology Technion, Haifa 3200003, Israel
| | - Dmitriy Sheyn
- Orthopaedic Stem Cell Research Laboratory, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
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Cicione C, Vadalà G, Di Giacomo G, Tilotta V, Ambrosio L, Russo F, Zampogna B, Cannata F, Papalia R, Denaro V. Micro-fragmented and nanofat adipose tissue derivatives: In vitro qualitative and quantitative analysis. Front Bioeng Biotechnol 2023; 11:911600. [PMID: 36733959 PMCID: PMC9887143 DOI: 10.3389/fbioe.2023.911600] [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: 04/02/2022] [Accepted: 01/06/2023] [Indexed: 01/18/2023] Open
Abstract
Introduction: Adipose tissue is widely exploited in regenerative medicine thanks to its trophic properties, mainly based on the presence of adipose-derived stromal cells. Numerous devices have been developed to promote its clinical use, leading to the introduction of one-step surgical procedures to obtain minimally manipulated adipose tissue derivatives. However, only a few studies compared their biological properties. This study aimed to characterize micro-fragmented (MAT) and nanofat adipose tissue (NAT) obtained with two different techniques. Methods: MAT, NAT and unprocessed lipoaspirate were collected from surgical specimens. RNA extraction and collagenase isolation of stromal vascular fraction (SVF) were performed. Tissue sections were analysed by histological and immunohistochemical (collagen type I, CD31, CD34 and PCNA) staining to assess tissue morphology and cell content. qPCR was performed to evaluate the expression of stemness-related (SOX2, NANOG and OCT3/4), extracellular matrix (COL1A1) and inflammatory genes (IL1β, IL6 and iNOS). Furthermore, multilineage differentiation was assessed following culture in adipogenic and osteogenic media and staining with Oil Red O and Alizarin red. ASC immunophenotype was assessed by flow cytometric analysis of CD90, CD105, CD73 and CD45. Results: Histological and immunohistochemical results showed an increased amount of stroma and a reduction of adipocytes in MAT and NAT, with the latter displaying the highest content of collagen type I, CD31, CD34 and PCNA. From LA to MAT and NAT, an increasing expression of NANOG, SOX2, OCT3/4, COL1A1 and IL6 was noted, while no significant differences in terms of IL1β and iNOS emerged. No statistically significant differences were noted between NAT and SVF in terms of stemness-related genes, while the latter demonstrated a significantly higher expression of stress-related markers. SVF cells derived from all three samples (LA, MAT, and NAT) showed a similar ASC immunoprofile as well as osteogenic and adipogenic differentiation. Discussion: Our results showed that both MAT and NAT techniques allowed the rapid isolation of ASC-rich grafts with a high anabolic and proliferative potential. However, NAT showed the highest levels of extracellular matrix content, replicating cells, and stemness gene expression. These results may provide precious clues for the use of adipose tissue derivatives in the clinical setting.
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Affiliation(s)
- Claudia Cicione
- Laboratory for Regenerative Orthopaedics, Research Unit of Orthopaedic and Trauma Surgery, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy
| | - Gianluca Vadalà
- Laboratory for Regenerative Orthopaedics, Research Unit of Orthopaedic and Trauma Surgery, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy,Operative Research Unit of Orthopaedic and Trauma Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy,*Correspondence: Gianluca Vadalà,
| | - Giuseppina Di Giacomo
- Laboratory for Regenerative Orthopaedics, Research Unit of Orthopaedic and Trauma Surgery, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy
| | - Veronica Tilotta
- Laboratory for Regenerative Orthopaedics, Research Unit of Orthopaedic and Trauma Surgery, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy
| | - Luca Ambrosio
- Laboratory for Regenerative Orthopaedics, Research Unit of Orthopaedic and Trauma Surgery, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy,Operative Research Unit of Orthopaedic and Trauma Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
| | - Fabrizio Russo
- Laboratory for Regenerative Orthopaedics, Research Unit of Orthopaedic and Trauma Surgery, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy,Operative Research Unit of Orthopaedic and Trauma Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
| | - Biagio Zampogna
- Laboratory for Regenerative Orthopaedics, Research Unit of Orthopaedic and Trauma Surgery, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy,Operative Research Unit of Orthopaedic and Trauma Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
| | - Francesca Cannata
- Operative Research Unit of Endocrinology and Diabetes, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
| | - Rocco Papalia
- Laboratory for Regenerative Orthopaedics, Research Unit of Orthopaedic and Trauma Surgery, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy,Operative Research Unit of Orthopaedic and Trauma Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
| | - Vincenzo Denaro
- Operative Research Unit of Orthopaedic and Trauma Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
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A Soft Zwitterionic Hydrogel as Potential Coating on a Polyimide Surface to Reduce Foreign Body Reaction to Intraneural Electrodes. Molecules 2022; 27:molecules27103126. [PMID: 35630604 PMCID: PMC9147366 DOI: 10.3390/molecules27103126] [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: 04/04/2022] [Revised: 05/08/2022] [Accepted: 05/10/2022] [Indexed: 12/04/2022] Open
Abstract
Invasive intraneural electrodes can control advanced neural-interfaced prostheses in human amputees. Nevertheless, in chronic implants, the progressive formation of a fibrotic capsule can gradually isolate the electrode surface from the surrounding tissue leading to loss of functionality. This is due to a nonspecific inflammatory response called foreign-body reaction (FBR). The commonly used poly(ethylene glycol) (PEG)-based low-fouling coatings of implantable devices can be easily encapsulated and are susceptible to oxidative damage in long-term in vivo applications. Recently, sulfobetaine-based zwitterionic hydrogels have emerged as an important class of robust ultra-low fouling biomaterials, holding great potential to mitigate FBR. The aim of this proof-of-principle in vitro work was to assess whether the organic zwitterionic—poly(sulfobetaine methacrylate) [poly(SBMA)]—hydrogel could be a suitable coating for Polyimide (PI)-based intraneural electrodes to reduce FBR. We first synthesized and analyzed the hydrogel through a mechanical characterization (i.e., Young’s modulus). Then, we demonstrated reduced adhesion and activation of fibrogenic and pro-inflammatory cells (i.e., human myofibroblasts and macrophages) on the hydrogel compared with PEG-coated and polystyrene surfaces using cell viability assays, confocal fluorescence microscopy and high-content analysis of oxidative stress production. Interestingly, we successfully coated PI surfaces with a thin film of the hydrogel through covalent bond and demonstrated its high hydrophilicity via water contact angle measurement. Importantly, we showed the long-term release of an anti-fibrotic drug (i.e., Everolimus) from the hydrogel. Because of the low stiffness, biocompatibility, high hydration and ultra-low fouling characteristics, our zwitterionic hydrogel could be envisioned as long-term diffusion-based delivery system for slow and controlled anti-inflammatory and anti-fibrotic drug release in vivo.
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Kim JH, Ham CH, Kwon WK. Current Knowledge and Future Therapeutic Prospects in Symptomatic Intervertebral Disc Degeneration. Yonsei Med J 2022; 63:199-210. [PMID: 35184422 PMCID: PMC8860939 DOI: 10.3349/ymj.2022.63.3.199] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 11/29/2021] [Accepted: 12/01/2021] [Indexed: 11/27/2022] Open
Abstract
Intervertebral disc (IVD) degeneration is the main source of intractable lower back pain, and symptomatic IVD degeneration could be due to different degeneration mechanisms. In this article, we describe the molecular basis of symptomatic IVD degenerative disc diseases (DDDs), emphasizing the role of degeneration, inflammation, angiogenesis, and extracellular matrix (ECM) regulation during this process. In symptomatic DDD, pro-inflammatory mediators modulate catabolic reactions, resulting in changes in ECM homeostasis and, finally, neural/vascular ingrowth-related chronic intractable discogenic pain. In ECM homeostasis, anabolic protein-regulating genes show reduced expression and changes in ECM production, while matrix metalloproteinase gene expression increases and results in aggressive ECM degradation. The resultant loss of normal IVD viscoelasticity and a concomitant change in ECM composition are key mechanisms in DDDs. During inflammation, a macrophage-related cascade is represented by the secretion of high levels of pro-inflammatory cytokines, which induce inflammation. Aberrant angiogenesis is considered a key initiative pathologic step in symptomatic DDD. In reflection of angiogenesis, vascular endothelial growth factor expression is regulated by hypoxia-inducible factor-1 in the hypoxic conditions of IVDs. Furthermore, IVD cells undergoing degeneration potentially enhance neovascularization by secreting large amounts of angiogenic cytokines, which penetrate the IVD from the outer annulus fibrosus, extending deep into the outer part of the nucleus pulposus. Based on current knowledge, a multi-disciplinary approach is needed in all aspects of spinal research, starting from basic research to clinical applications, as this will provide information regarding treatments for DDDs and discogenic pain.
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Affiliation(s)
- Joo Han Kim
- Department of Neurosurgery, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Chang Hwa Ham
- Department of Neurosurgery, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea
| | - Woo-Keun Kwon
- Department of Neurosurgery, Korea University Guro Hospital, Korea University College of Medicine, Seoul, Korea.
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Ashraf S, Chatoor K, Chong J, Pilliar R, Santerre P, Kandel R. Transforming Growth Factor β Enhances Tissue Formation by Passaged Nucleus Pulposus Cells In Vitro. J Orthop Res 2020; 38:438-449. [PMID: 31529713 DOI: 10.1002/jor.24476] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 09/10/2019] [Indexed: 02/04/2023]
Abstract
The nucleus pulposus (NP) is composed of NP and notochord cell. It is a paucicellular tissue and if it is to be used as a source of cells for tissue engineering the cell number will have to be expanded by cell passaging. The hypothesis of this study is that passaged NP and notochordal cells grown in three-dimensional (3D) culture in the presence of transforming growth factor β (TGFβ) will show enhanced NP tissue formation compared with cells grown in the absence of this growth factor. Bovine NP cells isolated by sequential enzymatic digestion from caudal intervertebral discs were either placed directly in 3D culture (P0) or serially passaged up to passage 3 (P3) prior to placement in 3D culture. Serial cell passage in monolayer culture led to de-differentiation, increased senescence and oxidative stress and decreases in the gene expression of NP and notochordal associated markers and increases in de-differentiation markers. The NP tissue regeneration capacity of cells in 3D culture decreases with passaging as indicated by diminished tissue thickness and total collagen content when compared with tissues formed by P0 cells. Immunohistochemical studies showed that type II collagen accumulation appeared to decrease. TGFβ1 or TGFβ3 treatment enhanced the ability of cells at each passage to form tissue, in part by decreasing cell death. However, neither TGFβ1 nor TGFβ3 were able to restore the notochordal phenotype. Although TGFβ1/3 recovered NP tissue formation by passaged cells, to generate NP in vitro that resembles the native tissue will require identification of conditions facilitating retention of notochordal cell differentiation. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:438-449, 2020.
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Affiliation(s)
- Sajjad Ashraf
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada
| | - Kenny Chatoor
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.,Institute of Biomaterials and Biomedical Engineering, University of Toronto, Ontario, Canada
| | - Jasmine Chong
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.,Institute of Biomaterials and Biomedical Engineering, University of Toronto, Ontario, Canada
| | - Robert Pilliar
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Ontario, Canada
| | - Paul Santerre
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Ontario, Canada
| | - Rita Kandel
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.,Pathology and Laboratory Medicine, Sinai Health System and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
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9
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Sheyn D, Ben-David S, Tawackoli W, Zhou Z, Salehi K, Bez M, De Mel S, Chan V, Roth J, Avalos P, Giaconi JC, Yameen H, Hazanov L, Seliktar D, Li D, Gazit D, Gazit Z. Human iPSCs can be differentiated into notochordal cells that reduce intervertebral disc degeneration in a porcine model. Theranostics 2019; 9:7506-7524. [PMID: 31695783 PMCID: PMC6831475 DOI: 10.7150/thno.34898] [Citation(s) in RCA: 55] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Accepted: 06/12/2019] [Indexed: 12/12/2022] Open
Abstract
Introduction: As many as 80% of the adult population experience back pain at some point in their lifetimes. Previous studies have indicated a link between back pain and intervertebral disc (IVD) degeneration. Despite decades of research, there is an urgent need for robust stem cell therapy targeting underlying causes rather than symptoms. It has been proposed that notochordal cells (NCs) appear to be the ideal cell type to regenerate the IVD: these cells disappear in humans as they mature, are replaced by nucleus pulposus (NP) cells, and their disappearance correlates with the initiation of degeneration of the disc. Human NCs are in short supply, thus here aimed for generation of notochordal-like cells from induced pluripotent cells (iPSCs). Methods: Human iPSCs were generated from normal dermal fibroblasts by transfecting plasmids encoding for six factors: OCT4, SOX2, KLF4, L-MYC, LIN28, and p53 shRNA. Then the iPSCs were treated with GSK3i to induce differentiation towards Primitive Streak Mesoderm (PSM). The differentiation was confirmed by qRT-PCR and immunofluorescence. PSM cells were transfected with Brachyury (Br)-encoding plasmid and the cells were encapsulated in Tetronic-tetraacrylate-fibrinogen (TF) hydrogel that mimics the NP environment (G'=1kPa), cultured in hypoxic conditions (2% O2) and with specifically defined growth media. The cells were also tested in vivo in a large animal model. IVD degeneration was induced after an annular puncture in pigs, 4 weeks later the cells were injected and IVDs were analyzed at 12 weeks after the injury using MRI, gene expression analysis and histology. Results: After short-term exposure of iPSCs to GSK3i there was a significant change in cell morphology, Primitive Streak Mesoderm (PSM) markers (Brachyury, MIXL1, FOXF1) were upregulated and markers of pluripotency (Nanog, Oct4, Sox2) were downregulated, both compared to the control group. PSM cells nucleofected with Br (PSM-Br) cultured in TF hydrogels retained the NC phenotype consistently for up to 8 weeks, as seen in the gene expression analysis. PSM-Br cells were co-cultured with bone marrow (BM)-derived mesenchymal stem cells (MSCs) which, with time, expressed the NC markers in higher levels, however the levels of expression in BM-MSCs alone did not change. Higher expression of NC and NP marker genes in human BM-MSCs was found to be induced by iNC-condition media (iNC-CM) than porcine NC-CM. The annular puncture induced IVD degeneration as early as 2 weeks after the procedure. The injected iNCs were detected in the degenerated discs after 8 weeks in vivo. The iNC-treated discs were found protected from degeneration. This was evident in histological analysis and changes in the pH levels, indicative of degeneration state of the discs, observed using qCEST MRI. Immunofluorescence stains show that their phenotype was consistent with the in vitro study, namely they still expressed the notochordal markers Keratin 18, Keratin 19, Noto and Brachyury. Conclusion: In the present study, we report a stepwise differentiation method to generate notochordal cells from human iPSCs. These cells not only demonstrate a sustainable notochordal cell phenotype in vitro and in vivo, but also show the functionality of notochordal cells and have protective effect in case of induced disc degeneration and prevent the change in the pH level of the injected IVDs. The mechanism of this effect could be suggested via the paracrine effect on resident cells, as it was shown in the in vitro studies with MSCs.
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Affiliation(s)
- Dmitriy Sheyn
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, 90048, CA
- Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, 90048, CA
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, 90048, CA
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, 90048, CA
| | - Shiran Ben-David
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, 90048, CA
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, 90048, CA
| | - Wafa Tawackoli
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, 90048, CA
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, 90048, CA
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, 90048, CA
- Biomedical Research Imaging Institute, Cedars-Sinai Medical Center, Los Angeles, 90048, CA
| | - Zhengwei Zhou
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, 90048, CA
- Biomedical Research Imaging Institute, Cedars-Sinai Medical Center, Los Angeles, 90048, CA
| | - Khosrawdad Salehi
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, 90048, CA
- Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, 90048, CA
| | - Maxim Bez
- Skeletal Biotech Laboratory, Hebrew University of Jerusalem, 91120, Israel
| | - Sandra De Mel
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, 90048, CA
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, 90048, CA
| | - Virginia Chan
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, 90048, CA
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, 90048, CA
| | - Joseph Roth
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, 90048, CA
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, 90048, CA
| | - Pablo Avalos
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, 90048, CA
| | - Joseph C Giaconi
- Biomedical Research Imaging Institute, Cedars-Sinai Medical Center, Los Angeles, 90048, CA
| | - Haneen Yameen
- Faculty of Biomedical Engineering, Technion, Haifa, 32003, Israel
| | - Lena Hazanov
- Faculty of Biomedical Engineering, Technion, Haifa, 32003, Israel
| | - Dror Seliktar
- Faculty of Biomedical Engineering, Technion, Haifa, 32003, Israel
| | - Debiao Li
- Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, 90048, CA
- Biomedical Research Imaging Institute, Cedars-Sinai Medical Center, Los Angeles, 90048, CA
| | - Dan Gazit
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, 90048, CA
- Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, 90048, CA
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, 90048, CA
- Skeletal Biotech Laboratory, Hebrew University of Jerusalem, 91120, Israel
| | - Zulma Gazit
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, 90048, CA
- Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, 90048, CA
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, 90048, CA
- Skeletal Biotech Laboratory, Hebrew University of Jerusalem, 91120, Israel
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Togao O, Hiwatashi A, Wada T, Yamashita K, Kikuchi K, Tokunaga C, Keupp J, Yoneyama M, Honda H. A Qualitative and Quantitative Correlation Study of Lumbar Intervertebral Disc Degeneration Using Glycosaminoglycan Chemical Exchange Saturation Transfer, Pfirrmann Grade, and T1-ρ. AJNR Am J Neuroradiol 2018; 39:1369-1375. [PMID: 29748204 DOI: 10.3174/ajnr.a5657] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2018] [Accepted: 03/09/2018] [Indexed: 11/07/2022]
Abstract
BACKGROUND AND PURPOSE Glycosaminoglycan chemical exchange saturation transfer (gagCEST) imaging allows the direct measurement and mapping of glycosaminoglycans. In this study, we aimed to evaluate the usefulness of gagCEST imaging in the quantitative assessment of intervertebral disc degeneration in a comparison with Pfirrmann grade and T1-ρ measurements. MATERIALS AND METHODS Ninety-six lumbar intervertebral discs in 24 volunteers (36.0 ± 8.5 years of age, 21 men and 3 women) were examined with both gagCEST imaging and T1-ρ measurements. The gagCEST imaging was performed at 3T with a saturation pulse with 1.0-second duration and the B1 amplitude of 0.8 μT followed by imaging by a 2D fast spin-echo sequence. The Z-spectra were obtained at 25 frequency offsets from -3 to +3 ppm (step, 0.25 ppm). A point-by-point B0 correction was performed with a B0 map. The gagCEST signal and T1-ρ values were measured in the nucleus pulposus in each intervertebral disc. The Pfirrmann grades were assessed on T2-weighted images. RESULTS The gagCEST signal at grade I (5.36% ± 2.79%) was significantly higher than those at Pfirrmann grade II (3.15% ± 1.40%, P = .0006), grade III (0.14% ± 1.03%, P < .0001), grade IV (-1.75% ± 2.82%, P < .0001), and grade V (-1.47% ± 0.36%, P < .0001). The gagCEST signal at grade II was significantly higher than those of grade III (P < .0001), grade IV (P < .0001), and grade V (P < .0001). The gagCEST signal was significantly correlated negatively with Pfirrmann grade (P < .0001) and positively correlated with T1-ρ (P < .0001). CONCLUSIONS GagCEST imaging could be a reliable and quantitative technique for assessing intervertebral disc degeneration.
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Affiliation(s)
- O Togao
- From the Department of Clinical Radiology (O.T., A.H., K.Y., K.K., H.H.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - A Hiwatashi
- From the Department of Clinical Radiology (O.T., A.H., K.Y., K.K., H.H.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - T Wada
- Division of Radiology (T.W., C.T.), Department of Medical Technology, Kyushu University Hospital, Fukuoka, Japan
| | - K Yamashita
- From the Department of Clinical Radiology (O.T., A.H., K.Y., K.K., H.H.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - K Kikuchi
- From the Department of Clinical Radiology (O.T., A.H., K.Y., K.K., H.H.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - C Tokunaga
- Division of Radiology (T.W., C.T.), Department of Medical Technology, Kyushu University Hospital, Fukuoka, Japan
| | - J Keupp
- Philips Research (J.K.), Hamburg, Germany
| | | | - H Honda
- From the Department of Clinical Radiology (O.T., A.H., K.Y., K.K., H.H.), Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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11
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Prolactin inhibits the progression of intervertebral disc degeneration through inactivation of the NF-κB pathway in rats. Cell Death Dis 2018; 9:98. [PMID: 29367664 PMCID: PMC5833353 DOI: 10.1038/s41419-017-0151-z] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Revised: 10/20/2017] [Accepted: 11/10/2017] [Indexed: 02/06/2023]
Abstract
Intervertebral disc degeneration (IVDD) is one of the key predisposing factors for low back pain. Although the exact mechanism remains unclear, inflammatory response and nucleus pulposus (NP) apoptosis are known to play important roles in this process. Prolactin protects against inflammation-associated chondrocyte apoptosis in arthritis. Based on prior studies, we hypothesized that prolactin might have therapeutic effects on IVDD by inhibiting the apoptosis of degenerative human disc NP cells. An experimental model of IVDD was established in 3-month-old Sprague-Dawley rats by submitting them to percutaneous disc puncture with a 20-gauge needle on levels 7–8 and 8–9 of the coccygeal vertebrae. Then the rats were injected with 20 or 200 ng prolactin on a weekly basis. Radiologic and histologic analyses were performed on days 4, 7, 14, and 28. The expression of prolactin and its receptor was analyzed in human tissue obtained from symptomatic patients undergoing microencoscopy discectomy, or from scoliosis patients undergoing deformity correction surgery. The results showed that intradiscal injection of prolactin maintained disc height and the mean signal intensity of the punctured disc. Histological analysis indicated that prolactin treatment significantly retained the complete structure of the NP and annulus fibrosus compared with the vehicle group. In addition, more collagen II, but fewer collagen I-containing tissues were detected in the prolactin treatment groups compared to the vehicle group. Moreover, low levels of tumor necrosis factor-α, interleukin-1β, cleaved-caspase 3, and TUNEL staining were observed in the prolactin treatment groups. We also demonstrated that prolactin impaired puncture-induced inflammation and cell apoptosis by downregulating activation of the NF-κB pathway. The degenerated NP tissues from patients had decreased expression of prolactin and its receptor, whereas expression was increased in the NP tissues removed from scoliosis patients. These results suggest that prolactin may be a novel therapeutic target for the treatment of IVDD.
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12
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Rigal J, Léglise A, Barnetche T, Cogniet A, Aunoble S, Le Huec JC. Meta-analysis of the effects of genetic polymorphisms on intervertebral disc degeneration. EUROPEAN SPINE JOURNAL : OFFICIAL PUBLICATION OF THE EUROPEAN SPINE SOCIETY, THE EUROPEAN SPINAL DEFORMITY SOCIETY, AND THE EUROPEAN SECTION OF THE CERVICAL SPINE RESEARCH SOCIETY 2017; 26:2045-2052. [PMID: 28551829 DOI: 10.1007/s00586-017-5146-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Revised: 04/24/2017] [Accepted: 05/16/2017] [Indexed: 01/07/2023]
Abstract
INTRODUCTION Chronic low back pain is a significant public health issue. Both its direct and indirect cost represents tens of billions of US dollars. Although chronic low back pain can be the result of many factors, the predominant cause is disc degeneration. Recent studies have shown genetic involvement in up to 74% of cases. This study aimed to evaluate genetic risk factors of disc degeneration by performing a systematic analysis of association studies. The objective is to provide a guide for practice by assessing the clinical relevance of current information. METHODS AND MATERIALS We performed a meta-analysis of 3122 items collected from 6 databases. 74 articles were selected according to our inclusion criteria. 18 (24%) could be grouped into 16 meta-analyses of 16 mutations in 12 genes. The statistics of the meta-analysis were conducted through Revman 5.1 software. RESULTS The items included are 10,250 cases and 14,136 controls. The GOLD range from 3.42 to 0.38. Two alleles were significantly associated with disc degeneration: IL-6 rs1800797 and MMP-9 rs17576 and one proved to be protective: IL-6 rs1800795. 13 meta-analyses did not yield significant results and methodological heterogeneity. DISCUSSION The results highlight the lack of methodological rigor in most of the studies. The absence of international clinical and radiological classification of early disc degeneration, limits the homogeneity of studies. Understanding which populations are predisposed to this significant public health problem may change our approach to diagnostic and therapeutic methods. This work opens up enormous opportunities to provide a genetic solution and consider new diagnostic and therapeutic means to this public health problem.
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Affiliation(s)
- J Rigal
- Spine Unit 2, Orthopaedic Department, University of Bordeaux, Bordeaux, France
| | - A Léglise
- Spine Unit 2, Orthopaedic Department, University of Bordeaux, Bordeaux, France
| | - T Barnetche
- Spine Unit 2, Orthopaedic Department, University of Bordeaux, Bordeaux, France
| | - A Cogniet
- Spine Unit 2, Orthopaedic Department, University of Bordeaux, Bordeaux, France
| | - S Aunoble
- Spine Unit 2, Orthopaedic Department, University of Bordeaux, Bordeaux, France
| | - J C Le Huec
- Spine Unit 2, Orthopaedic Department, University of Bordeaux, Bordeaux, France.
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13
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Vadalà G, Russo F, Ambrosio L, Loppini M, Denaro V. Stem cells sources for intervertebral disc regeneration. World J Stem Cells 2016; 8:185-201. [PMID: 27247704 PMCID: PMC4877563 DOI: 10.4252/wjsc.v8.i5.185] [Citation(s) in RCA: 73] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2015] [Revised: 12/18/2015] [Accepted: 02/16/2016] [Indexed: 02/06/2023] Open
Abstract
Intervertebral disc regeneration field is rapidly growing since disc disorders represent a major health problem in industrialized countries with very few possible treatments. Indeed, current available therapies are symptomatic, and surgical procedures consist in disc removal and spinal fusion, which is not immune to regardable concerns about possible comorbidities, cost-effectiveness, secondary risks and long-lasting outcomes. This review paper aims to share recent advances in stem cell therapy for the treatment of intervertebral disc degeneration. In literature the potential use of different adult stem cells for intervertebral disc regeneration has already been reported. Bone marrow mesenchymal stromal/stem cells, adipose tissue derived stem cells, synovial stem cells, muscle-derived stem cells, olfactory neural stem cells, induced pluripotent stem cells, hematopoietic stem cells, disc stem cells, and embryonic stem cells have been studied for this purpose either in vitro or in vivo. Moreover, several engineered carriers (e.g., hydrogels), characterized by full biocompatibility and prompt biodegradation, have been designed and combined with different stem cell types in order to optimize the local and controlled delivery of cellular substrates in situ. The paper overviews the literature discussing the current status of our knowledge of the different stem cells types used as a cell-based therapy for disc regeneration.
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14
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Mok GSP, Zhang D, Chen SZ, Yuan J, Griffith JF, Wang YXJ. Comparison of three approaches for defining nucleus pulposus and annulus fibrosus on sagittal magnetic resonance images of the lumbar spine. J Orthop Translat 2016; 6:34-41. [PMID: 30035081 PMCID: PMC5987025 DOI: 10.1016/j.jot.2016.02.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2015] [Revised: 02/08/2016] [Accepted: 02/22/2016] [Indexed: 12/14/2022] Open
Abstract
Objective To compare three methods commonly used in the literature to define intervertebral disc nucleus pulposus (NP) and annulus fibrosus (AF) on magnetic resonance (MR) images. Methods Fifty-two patients (26 males and 26 females; age range, 23-76 years) were recruited for this study; they underwent standard T1/T2-weighted MR imaging, and T2 and T1rho mapping acquisitions. The corresponding midsagittal images were analysed and a total of 256 discs were evaluated, using three different region-of-interest (ROI) drawing methods: (1) radiologist-guided manual ROI (M-ROI); (2) five square ROIs where each measured 20% of the midline disc diameter (5-ROI); and (3) seven square ROIs placed horizontally from anterior to posterior (7-ROI) to define NP and AF. The agreement between the three ROI methods was assessed using intraclass correlation coefficient values and Bland-Altman plots. Results Inner AF and NP could not be differentiated on T1/T2-weighted MR imaging, T2 maps, or T1rho maps. The intraclass correlation coefficient values were all > 0.75 when comparing the 5-/7-ROI methods with the M-ROI methods for NP, and 0.167-0.488 for AF when comparing the 7-ROI method with the M-ROI method. The intraclass correlation coefficient values for AF increased to 0.378-0.582 for the M-ROI method compared with the 5-ROI method. Comparable results were obtained with Bland-Altman plots. Conclusion The 5-/7-ROI methods agreed with the M-ROI approach for NP selection, while the agreement with AF was moderate to poor, with the 5-ROI method showing slight advantage over the 7-ROI method. Cautions should be taken to interpret the MR relaxometry findings when 5-/7-ROI methods are used to select AF.
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Affiliation(s)
- Greta S P Mok
- Biomedical Imaging Laboratory, Department of Electrical and Computer Engineering, University of Macau, Macau Special Administrative Region
| | - Duo Zhang
- Biomedical Imaging Laboratory, Department of Electrical and Computer Engineering, University of Macau, Macau Special Administrative Region
| | - Shu-Zhong Chen
- Department of Imaging and Interventional Radiology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong Special Administrative Region
| | - Jing Yuan
- Medical Physics and Research Department, Hong Kong Sanatorium and Hospital, Happy Valley, Hong Kong Special Administrative Region
| | - James F Griffith
- Department of Imaging and Interventional Radiology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong Special Administrative Region
| | - Yi Xiang J Wang
- Department of Imaging and Interventional Radiology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong Special Administrative Region
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15
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Byvaltsev VA, Stepanov IA, Bardonova LA, Belykh EG. [The Use of Stem Cells in the Treatment of Intervertebral Disc Degeneration]. ACTA ACUST UNITED AC 2016; 71:359-66. [PMID: 29297665 DOI: 10.15690/vramn729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
The paper presents a review of current data on the use of stem cells in the treatment of intervertebral disc degeneration. Acute spinal pain is often a consequence of the pathology affecting the intervertebral disc. Many applied therapeutic techniques do not provide effective results as expected because most of them address symptoms, but do not treat the underlying disease. We have outlined current findings on the molecular mechanisms of intervertebral disc degeneration, analyzed international experimental studies demonstrating the feasibility of a stem cell therapy for intervertebral disc degeneration. The conducted studies reported on the clinical application of mesenchymal stem cells or stem cells derived from adipose, synovium, and bone marrow tissue. The most pressing and undetermined issues that require further experimental and clinical studies are indicated and defined in the article.
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16
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Molinos M, Almeida CR, Caldeira J, Cunha C, Gonçalves RM, Barbosa MA. Inflammation in intervertebral disc degeneration and regeneration. J R Soc Interface 2015; 12:20141191. [PMID: 25673296 DOI: 10.1098/rsif.2014.1191] [Citation(s) in RCA: 247] [Impact Index Per Article: 24.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Intervertebral disc (IVD) degeneration is one of the major causes of low back pain, a problem with a heavy economic burden, which has been increasing in prevalence as populations age. Deeper knowledge of the complex spatial and temporal orchestration of cellular interactions and extracellular matrix remodelling is critical to improve current IVD therapies, which have so far proved unsatisfactory. Inflammation has been correlated with degenerative disc disease but its role in discogenic pain and hernia regression remains controversial. The inflammatory response may be involved in the onset of disease, but it is also crucial in maintaining tissue homeostasis. Furthermore, if properly balanced it may contribute to tissue repair/regeneration as has already been demonstrated in other tissues. In this review, we focus on how inflammation has been associated with IVD degeneration by describing observational and in vitro studies as well as in vivo animal models. Finally, we provide an overview of IVD regenerative therapies that target key inflammatory players.
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Affiliation(s)
- Maria Molinos
- Instituto de Engenharia Biomédica-INEB, Universidade do Porto, Porto, Portugal Instituto de Ciências Biomédicas Abel Salazar-ICBAS, Universidade do Porto, Porto, Portugal
| | - Catarina R Almeida
- Instituto de Engenharia Biomédica-INEB, Universidade do Porto, Porto, Portugal
| | - Joana Caldeira
- Instituto de Engenharia Biomédica-INEB, Universidade do Porto, Porto, Portugal Instituto de Patologia e Imunologia-IPATIMUP, Universidade do Porto, Porto, Portugal
| | - Carla Cunha
- Instituto de Engenharia Biomédica-INEB, Universidade do Porto, Porto, Portugal
| | - Raquel M Gonçalves
- Instituto de Engenharia Biomédica-INEB, Universidade do Porto, Porto, Portugal
| | - Mário A Barbosa
- Instituto de Engenharia Biomédica-INEB, Universidade do Porto, Porto, Portugal Instituto de Ciências Biomédicas Abel Salazar-ICBAS, Universidade do Porto, Porto, Portugal
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Tsaryk R, Gloria A, Russo T, Anspach L, De Santis R, Ghanaati S, Unger RE, Ambrosio L, Kirkpatrick CJ. Collagen-low molecular weight hyaluronic acid semi-interpenetrating network loaded with gelatin microspheres for cell and growth factor delivery for nucleus pulposus regeneration. Acta Biomater 2015; 20:10-21. [PMID: 25861947 DOI: 10.1016/j.actbio.2015.03.041] [Citation(s) in RCA: 86] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2014] [Revised: 03/07/2015] [Accepted: 03/18/2015] [Indexed: 12/19/2022]
Abstract
Intervertebral disc (IVD) degeneration is one of the main causes of low back pain. Current surgical treatments are complex and generally do not fully restore spine mobility. Development of injectable extracellular matrix-based hydrogels offers an opportunity for minimally invasive treatment of IVD degeneration. Here we analyze a specific formulation of collagen-low molecular weight hyaluronic acid (LMW HA) semi-interpenetrating network (semi-IPN) loaded with gelatin microspheres as a potential material for tissue engineering of the inner part of the IVD, the nucleus pulposus (NP). The material displayed a gel-like behavior, it was easily injectable as demonstrated by suitable tests and did not induce cytotoxicity or inflammation. Importantly, it supported the growth and chondrogenic differentiation potential of mesenchymal stem cells (MSC) and nasal chondrocytes (NC) in vitro and in vivo. These properties of the hydrogel were successfully combined with TGF-β3 delivery by gelatin microspheres, which promoted the chondrogenic phenotype. Altogether, collagen-LMW HA loaded with gelatin microspheres represents a good candidate material for NP tissue engineering as it combines important rheological, functional and biological features.
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Current trends in biologics delivery to restore intervertebral disc anabolism. Adv Drug Deliv Rev 2015; 84:146-58. [PMID: 25174310 DOI: 10.1016/j.addr.2014.08.008] [Citation(s) in RCA: 122] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2014] [Revised: 07/31/2014] [Accepted: 08/20/2014] [Indexed: 12/30/2022]
Abstract
Low back pain is generally attributed to intervertebral disc (IVD) degeneration. This is a multifactorial disease induced by genetic and environmental factors and that progresses with aging. Disc degeneration is characterized by a limited ability of IVD cells to produce functional matrix while producing abnormal amounts of matrix-degrading enzymes. The prolonged imbalance between anabolism and catabolism in degenerative discs alters their composition and hydration. In turn, this results in increased angiogenesis and the loss of the disc's ability to maintain its aneural condition. Inflammation in the IVD, in particular the presence of pro-inflammatory cytokines, was found to favor innervation and also sensitization of the nociceptive pathways, thereby exacerbating degenerative symptoms. In this review, we discuss anti-inflammatory approaches to encounter disc catabolism, potential treatments to lower discogenic pain and pro-anabolic approaches in the form of protein delivery, gene therapy and cell delivery, to trigger regeneration in the IVD.
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Early intervertebral disc degeneration changes in asymptomatic weightlifters assessed by t1ρ-magnetic resonance imaging. Spine (Phila Pa 1976) 2014; 39:1881-6. [PMID: 25099319 PMCID: PMC5585866 DOI: 10.1097/brs.0000000000000554] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN Case-control study. OBJECTIVE To evaluate early intervertebral disc degeneration quantified by T1ρ- and T2-weighted magnetic resonance imaging (MRI) in asymptomatic weightlifters compared with a healthy control group matched for sex and age. SUMMARY OF BACKGROUND DATA Athletes consistently recruit or transfer high levels of repetitive forces through the spine, and MRI has documented a higher rate of intervertebral disc degeneration in athletes compared with matched controls. This study aims to analyze the potential role of T1ρ-MRI in the assessment of early degenerative changes occurring in intervertebral discs of young asymptomatic weightlifters compared with healthy controls. METHODS Twenty-six asymptomatic young male weightlifters versus a sedentary control group matched for age and sex, both having no lower back pain nor any spinal symptoms, underwent MRI (1.5 T). Degenerative grade was assessed using T2-weighted images, according to the Pfirrmann scale. T1ρ mapping and values in the nucleus pulposus (n=130) were obtained. Differences in T1ρ value between among the groups and linear regression analyses with degenerative grade were determined. RESULTS Pfirrmann degenerative grade did not show significant differences among groups. Instead, T1ρ values were significantly lower in the lumbar spine of weightlifters compared with controls (P<0.05). T1ρ values decreased linearly with degenerative grade. CONCLUSION T1ρ values were significantly lower in athletes compared with a sedentary matched control group showing differences in intervertebral disc degeneration onset among individuals with lifestyle and environmental factors leading to back pain. T1ρ can be potentially used as a valid clinical tool to identify early changes in intervertebral disc on the verge of new emerging intervertebral discs regenerative strategies and treatments. LEVEL OF EVIDENCE 4.
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Bach FC, Willems N, Penning LC, Ito K, Meij BP, Tryfonidou MA. Potential regenerative treatment strategies for intervertebral disc degeneration in dogs. BMC Vet Res 2014; 10:3. [PMID: 24387033 PMCID: PMC3914844 DOI: 10.1186/1746-6148-10-3] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2013] [Accepted: 12/31/2013] [Indexed: 01/07/2023] Open
Abstract
Pain due to spontaneous intervertebral disc (IVD) disease is common in dogs. In chondrodystrophic (CD) dogs, IVD disease typically develops in the cervical or thoracolumbar spine at about 3–7 years of age, whereas in non-chondrodystrophic (NCD) dogs, it usually develops in the caudal cervical or lumbosacral spine at about 6–8 years of age. IVD degeneration is characterized by changes in the biochemical composition and mechanical integrity of the IVD. In the degenerated IVD, the content of glycosaminoglycan (GAG, a proteoglycan side chain) decreases and that of denatured collagen increases. Dehydration leads to tearing of the annulus fibrosus (AF) and/or disc herniation, which is clinically characterized by pain and/or neurological signs. Current treatments (physiotherapy, anti-inflammatory/analgesic medication, surgery) for IVD disease may resolve neurological deficits and reduce pain (although in many cases insufficient), but do not lead to repair of the degenerated disc. For this reason, there is interest in new regenerative therapies that can repair the degenerated disc matrix, resulting in restoration of the biomechanical function of the IVD. CD dogs are considered a suitable animal model for human IVD degeneration because of their spontaneous IVD degeneration, and therefore studies investigating cell-, growth factor-, and/or gene therapy-based regenerative therapies with this model provide information relevant to both human and canine patients. The aim of this article is to review potential regenerative treatment strategies for canine IVD degeneration, with specific emphasis on cell-based strategies.
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Affiliation(s)
- Frances C Bach
- Department of Clinical Sciences of Companion Animals, Faculty of Veterinary Medicine, Utrecht University, Utrecht, Netherlands.
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Vadalà G, Russo F, Di Martino A, Denaro V. Intervertebral disc regeneration: from the degenerative cascade to molecular therapy and tissue engineering. J Tissue Eng Regen Med 2013; 9:679-90. [PMID: 23512973 DOI: 10.1002/term.1719] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2012] [Revised: 12/21/2012] [Accepted: 01/05/2013] [Indexed: 12/21/2022]
Abstract
Low back pain is one of the major health problems in industrialized countries, as a leading source of disability in the working population. Intervertebral disc degeneration has been identified as its main cause, being a progressive process mainly characterized by alteration of extracellular matrix composition and water content. Many factors are involved in the degenerative cascade, such as anabolism/catabolism imbalance, reduction of nutrition supply and progressive cell loss. Currently available treatments are symptomatic, and surgical procedures consisting of disc removal are often necessary. Recent advances in our understanding of intervertebral disc biology led to an increased interest in the development of novel biological treatments aimed at disc regeneration. Growth factors, gene therapy, stem cell transplantation and biomaterials-based tissue engineering might support intervertebral disc regeneration by overcoming the limitation of the self-renewal mechanism. The aim of this paper is to overview the literature discussing the current status of our knowledge from the degenerative cascade of the intervertebral disc to the latest molecular, cell-based therapies and tissue-engineering strategies for disc regeneration.
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Affiliation(s)
- Gianluca Vadalà
- Department of Orthopaedics and Trauma Surgery, Campus Bio-Medico University of Rome, Italy
| | - Fabrizio Russo
- Department of Orthopaedics and Trauma Surgery, Campus Bio-Medico University of Rome, Italy
| | - Alberto Di Martino
- Department of Orthopaedics and Trauma Surgery, Campus Bio-Medico University of Rome, Italy
| | - Vincenzo Denaro
- Department of Orthopaedics and Trauma Surgery, Campus Bio-Medico University of Rome, Italy
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Cuellar JM, Golish SR, Leroux EJ, Reuter MW, Carragee EJ, Hanna LS, Scuderi GJ. Does a fibronectin and aggrecan complex play a role in painful vertebral disks? PM R 2013; 5:297-302; quiz 302. [PMID: 23490723 DOI: 10.1016/j.pmrj.2013.01.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2012] [Revised: 12/13/2012] [Accepted: 01/02/2013] [Indexed: 11/19/2022]
Abstract
OBJECTIVE To determine the presence of a fibronectin-aggrecan complex (FAC) in the disk space of persons with chronic low back pain as relates to provocative diskography. DESIGN A single-center prospective consecutive case series. SETTING A single private practice setting. PATIENTS Thirty-seven patients with symptomatic degenerative disk disease of the cervical, thoracic, or lumbar spine undergoing provocative diskography to identify a source of pain. METHODS Diskographic lavage for analysis was simultaneously performed at each disk level injected during diskography. MAIN OUTCOME MEASURES Visual analog scale (VAS) pain scores, Pfirrmann magnetic resonance imaging grade, and biochemical analysis of disk material were statistically analyzed. RESULTS A total of 105 levels in 37 patients had a complete set of data (mean age 43.2 ± 11.9 years; 15 male/22 female). The FAC was present in 43 of 108 levels and in at least one level in 25 of 37 patients. The Pfirrmann magnetic resonance imaging grade did not differ between complex-positive and negative levels (P = .125), nor did the intraoperative VAS (IO-VAS) score for pain by level (P = .206). A significant but loose correlation was found between Pfirrmann grade and IO-VAS (R(2) = 0.4, P < .001), but no significant correlation was found between VAS or IO-VAS and complex concentration (R(2) = 0.08, P = .11 and R(2) = 0.003, P = .5). CONCLUSIONS The FAC was identified in some painful disks by diskography. There was no significant correlation between the Pfirrmann grade or pre/intraoperative pain scores during diskography and complex concentrations within the disk measured by disk lavage.
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Affiliation(s)
- Jason M Cuellar
- Department of Orthopaedic Surgery, NYU Hospital for Joint Diseases, New York, NY, USA
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Anisimov SV. Cell therapy for age-related intervertebral disc pathologies. ADVANCES IN GERONTOLOGY 2012. [DOI: 10.1134/s2079057012040029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Wang YXJ, Zhao F, Griffith JF, Mok GSP, Leung JCS, Ahuja AT, Yuan J. T1rho and T2 relaxation times for lumbar disc degeneration: an in vivo comparative study at 3.0-Tesla MRI. Eur Radiol 2012; 23:228-34. [PMID: 22865227 DOI: 10.1007/s00330-012-2591-2] [Citation(s) in RCA: 68] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2012] [Revised: 06/15/2012] [Accepted: 06/29/2012] [Indexed: 12/20/2022]
Abstract
OBJECTIVE To determine the relative performance of T1rho and T2 relaxation times in disc degeneration assessment. METHODS Lumbar sagittal MRI was performed at 3 T in 52 subjects. With a spin-lock frequency of 500 Hz, T1rho was measured using a rotary echo spin-lock pulse embedded in a three-dimensional (3D) balanced fast field echo sequence. A multi-echo TSE sequence was used for T2 mapping. Regions of interest (ROIs) were drawn over the T1rho and T2 maps, including nucleus pulposus (NP) and annulus fibrosus (AF). Eight- and five-level disc degeneration semi-quantitative grading was performed. RESULTS For NP, T1rho and T2 decreased quadratically with disc degeneration grades and had no significant trend difference (P = 0.40). For AF, T1rho decreased linearly as the disc degenerated and had a slope of -3.02 and -4.56 for eight- and five-level gradings respectively; while the slopes for T2 values were -1.43 and -1.84 respectively, being significantly flatter than those of T1rho (P < 0.001). There was no significant difference in T1rho and T2 values for both NP and AF among discs of grade 5/8 to 8/8 degeneration. CONCLUSION T1rho is better suited for evaluating AF in degenerated disc than T2. In NP, T1rho and T2 decrease in a similar pattern following disc degeneration.
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Affiliation(s)
- Yi-Xiang J Wang
- Department of Imaging and Interventional Radiology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong SAR, China.
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Zobel BB, Vadalà G, Del Vescovo R, Battisti S, Martina FM, Stellato L, Leoncini E, Borthakur A, Denaro V. T1ρ magnetic resonance imaging quantification of early lumbar intervertebral disc degeneration in healthy young adults. Spine (Phila Pa 1976) 2012; 37:1224-30. [PMID: 22281486 PMCID: PMC5583725 DOI: 10.1097/brs.0b013e31824b2450] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN Cross-sectional study using T1ρ magnetic resonance imaging (MRI) of lumbar spine in healthy young adults. OBJECTIVE To evaluate early intervertebral disc degeneration (IDD) quantified by T1ρ- and T2-weighted MRI in asymptomatic young adults and to correlate T1ρ value with Pfirrmann degenerative grade, sex, and body mass index (BMI). SUMMARY OF BACKGROUND DATA Intervertebral disc starts early to degenerate losing proteoglycan content in the nucleus pulposus (NP). A potential tool for the study of early stage of IDD is T1ρ MRI. T1ρ relaxation time of human discs has been correlated to proteoglycan content in previous studies. METHODS T1ρ- and T2-weighted images of the lumbar spine were obtained for 63 asymptomatic young subjects (34 men and 29 women; mean age, 22.95 ± 1.8 yr), with a 1.5-T MRI scanner. T1ρ mapping and values in the NP and anulus fibrosus (n = 315) were obtained. Degenerative grade was assessed using T2-weighted images, according to the Pfirrmann scale. Differences in T1ρ value between sexes, BMI, and linear regression analyses with degenerative grade were determined. RESULTS T1ρ values of NPs were significantly higher than those of anulus fibrosus at all levels. T1ρ values were significantly lower in women at L3-L4 and L4-L5 discs (P < 0.05). T1ρ values decreased linearly with degenerative grade. However, nondegenerated discs (Pfirrmann grades 1 and 2) showed a wide range of T1ρ relaxation time. No significant correlation was observed between T1ρ value and BMI. CONCLUSION The data of this study showed a significant difference in IDD onset between sexes. T1ρ values correlate with Pfirrmann degenerative grade in young adults. However, the wide distribution of T1ρ values in healthy intervertebral disc highlights the low sensitivity of Pfirrmann grade to detect the early IDD changes. T1ρ can be potentially used as a clinical tool to identify early IDD and to create a reliable quantitative scale.
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Affiliation(s)
- Bruno Beomonte Zobel
- Department of Radiology, Campus Bio-Medico University Hospital of Rome, Italy, Rome, Rome, Italy
| | - Gianluca Vadalà
- Department of Orthopaedic and Trauma Surgery, Campus Bio-Medico University Hospital of Rome, Italy, Rome, Rome, Italy
| | - Riccardo Del Vescovo
- Department of Radiology, Campus Bio-Medico University Hospital of Rome, Italy, Rome, Rome, Italy
| | - Sofia Battisti
- Department of Orthopaedic and Trauma Surgery, Campus Bio-Medico University Hospital of Rome, Italy, Rome, Rome, Italy
| | - Francesca Maria Martina
- Department of Radiology, Campus Bio-Medico University Hospital of Rome, Italy, Rome, Rome, Italy
| | - Luigi Stellato
- Department of Radiology, Campus Bio-Medico University Hospital of Rome, Italy, Rome, Rome, Italy
| | | | - Arijitt Borthakur
- CMROI, Department of Radiology, University of Pennsylvania School of Medicine, Philadelphia, PA
| | - Vincenzo Denaro
- Department of Orthopaedic and Trauma Surgery, Campus Bio-Medico University Hospital of Rome, Italy, Rome, Rome, Italy
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Outcome of lumbar epidural steroid injection is predicted by assay of a complex of fibronectin and aggrecan from epidural lavage. Spine (Phila Pa 1976) 2011; 36:1464-9. [PMID: 21224775 DOI: 10.1097/brs.0b013e3181f40e88] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN A single-center, prospective, consecutive case series of patients undergoing epidural lavage before the treatment of radiculopathy due to lumbar disc herniation. OBJECTIVE To determine whether a novel complex of fibronectin and aggrecan predicts clinical response to epidural steroid injection (ESI) for the indication of radiculopathy from lumbar herniated nucleus pulposus (HNP). SUMMARY OF BACKGROUND DATA ESI for lumbar radiculopathy due to HNP is widely used despite variable effectiveness for this indication. With increased attention aimed at cost containment, it would be beneficial to identify those in whom ESI may be helpful. There are currently no accurate diagnostic tests to predict response to ESI in back pain and sciatica syndromes. We have previously investigated biomarkers of disc degeneration associated with radiculopathy. METHODS We embarked to determine whether a molecular complex of fibronectin and aggrecan predicts clinical response to ESI for the indication of radiculopathy from HNP. This prospective study was conducted at a single center and included 26 patients with radiculopathic pain and magnetic resonance imaging positive for HNP, who elected ESI. Epidural lavage with physiologic saline was performed immediately before ESI. The lavage fluid was assayed for the fibronectin-aggrecan complex (FAC) by using a heterogeneous sandwich enzyme-linked immunosorbent assay. The results were compared with the interval improvement in the physical component summary (PCS) score of the Medical Outcomes Study Short Form-36 instrument (SF-36) after injection compared with baseline. RESULTS The mean improvement from baseline PCS in patients with the FAC was 22.9 (SD, 12.4) and without the complex was 0.64 (SD, 3.97; P < 0.001). Differences in total SF-36 improvement were also highly significant (P < 0.001). The presence of the FAC predicts a clinically significant increase in PCS after lumbar ESI by receiver-operating-characteristic analysis (area under the curve = 0.97; P < 0.001). There was no significant difference in age (P = 0.25), sex (P = 0.84), laterality (P = 0.06), lumbar spinal level (P = 0.75), or payer type (worker's compensation vs. private insurance; P = 0.90) between groups with and without the marker. CONCLUSION A molecular complex of fibronectin and aggrecan predicts response to lumbar ESI for radiculopathy with HNP. The biomarker is accurate, objective, and not affected by demographic or psychosocial variables in this series.
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Sowa G, Vadalà G, Studer R, Kompel J, Iucu C, Georgescu H, Gilbertson L, Kang J. Characterization of intervertebral disc aging: longitudinal analysis of a rabbit model by magnetic resonance imaging, histology, and gene expression. Spine (Phila Pa 1976) 2008; 33:1821-8. [PMID: 18670334 DOI: 10.1097/brs.0b013e31817e2ce3] [Citation(s) in RCA: 79] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN A cohort of young, healthy New Zealand White rabbits was followed longitudinally with serial magnetic resonance imaging (MRI) analysis and terminal analysis of histologic changes and gene expression. OBJECTIVE To examine the changes observed during normal aging in the intervertebral disc. SUMMARY OF BACKGROUND DATA Although there is a correlation between aging and the onset of intervertebral disc degeneration (IDD), evidence suggests that distinct pathways are involved in these processes. Our group has characterized a reproducible rabbit model of IDD by MRI, radiograph, histology, and mRNA expression. However, no similar analysis has been performed longitudinally for intervertebral disc aging to allow comparison of these 2 important processes. METHODS Four skeletally mature female NZW rabbits were housed for 122 weeks, and lumbar spine MRIs were characterized serially. Histologic and quantitative gene expression analysis of the nucleus pulposus of these aging animals was performed, and compared with adult and young rabbits. RESULTS Mean MRI index decreased by <25% through 120 weeks. The histologic analysis showed changes in cell composition, with abundant notochordal cells in the young, chondrocyte-like cells and notochordal cells in the adult, and clusters of hypertrophic chondrocytes in the aging discs. The PCR analysis of the nucleus pulposus showed that gene expression of collagen decreased, whereas that for proteoglycans increased with aging. BMP-2, TIMP-1, and SOX-9 expression was significantly lower in the young compared with adult discs and TGF-beta1 demonstrated lower gene expression in young and aging animals. CONCLUSION Although dramatic cellular changes were observed, age-related MRI changes occurred in this rabbit model of normal aging at a much slower rate than in a previous injury model of degeneration. In addition, the gene expression analysis of the nucleus pulposus demonstrated remarkable differences between aging and injury induced degeneration. These results suggest that aging and injury contribute uniquely to the process of IDD.
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Affiliation(s)
- Gwendolyn Sowa
- Departments of Orthopaedic Surgery and daggerPhysical Medicine and Rehabilitation, Ferguson Laboratory for Orthopaedic Research, University of Pittsburgh, Pittsburgh, PA 15213, USA
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