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Barakat AH, Elwell VA, Lam KS. Stem cell therapy in discogenic back pain. JOURNAL OF SPINE SURGERY (HONG KONG) 2019; 5:561-583. [PMID: 32043007 PMCID: PMC6989932 DOI: 10.21037/jss.2019.09.22] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Accepted: 09/09/2019] [Indexed: 04/23/2023]
Abstract
Chronic low back pain has both substantial social and economic impacts on patients and healthcare budgets. Adding to the magnitude of the problem is the difficulty in identifying the exact causes of disc degeneration with modern day diagnostic and imaging techniques. With that said, current non-operative and surgical treatment modalities for discogenic low back pain fails to meet the expectations in many patients and hence the challenge. The objective for newly emerging stem cell regenerative therapy is to treat degenerative disc disease (DDD) by restoring the disc's cellularity and modulating the inflammatory response. Appropriate patient selection is crucial for the success of stem cell therapy. Regenerative modalities for discogenic pain currently focus on the use of either primary cells harvested from the intervertebral discs or stem cells from other sources whether autogenic or allogenic. The microenvironment in which stem cells are being cultured has been recognized to play a crucial role in directing or maintaining the production of the desired phenotypes and may enhance their regenerative potential. This has led to a more specific focus on innovating more effective culturing techniques, delivery vehicles and scaffolds for stem cell application. Although stem cell therapy might offer an attractive alternative treatment option, more clinical studies are still needed to establish on the safety and feasibility of such therapy. In this literature review, we aim to present the most recent in vivo and in vitro studies related to the use of stem cell therapy in the treatment of discogenic low back pain.
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Affiliation(s)
- Ahmed H. Barakat
- Brighton and Sussex University Hospitals NHS Trust, Brighton, UK
| | - Vivian A. Elwell
- Brighton and Sussex University Hospitals NHS Trust, Brighton, UK
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Thakar H, Sebastian SM, Mandal S, Pople A, Agarwal G, Srivastava A. Biomolecule-Conjugated Macroporous Hydrogels for Biomedical Applications. ACS Biomater Sci Eng 2019; 5:6320-6341. [DOI: 10.1021/acsbiomaterials.9b00778] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Fernandez-Moure J, Moore CA, Kim K, Karim A, Smith K, Barbosa Z, Van Eps J, Rameshwar P, Weiner B. Novel therapeutic strategies for degenerative disc disease: Review of cell biology and intervertebral disc cell therapy. SAGE Open Med 2018; 6:2050312118761674. [PMID: 29568524 PMCID: PMC5858682 DOI: 10.1177/2050312118761674] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2017] [Accepted: 02/05/2018] [Indexed: 12/17/2022] Open
Abstract
Intervertebral disc degeneration is a disease of the discs connecting adjoining vertebrae in which structural damage leads to loss of disc integrity. Degeneration of the disc can be a normal process of ageing, but can also be precipitated by other factors. Literature has made substantial progress in understanding the biological basis of intervertebral disc, which is reviewed here. Current medical and surgical management strategies have shortcomings that do not lend promise to be effective solutions in the coming years. With advances in understanding the cell biology and characteristics of the intervertebral disc at the molecular and cellular level that have been made, alternative strategies for addressing disc pathology can be discovered. A brief overview of the anatomic, cellular, and molecular structure of the intervertebral disc is provided as well as cellular and molecular pathophysiology surrounding intervertebral disc degeneration. Potential therapeutic strategies involving stem cell, protein, and genetic therapy for intervertebral disc degeneration are further discussed.
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Affiliation(s)
- Joseph Fernandez-Moure
- Department of Surgery, Houston Methodist Hospital, Houston, TX, USA.,Department of Regenerative and Biomimetic Medicine, Houston Methodist Research Institute, Houston, TX, USA
| | - Caitlyn A Moore
- Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
| | | | - Azim Karim
- Department of Surgery, Houston Methodist Hospital, Houston, TX, USA
| | - Kevin Smith
- Department of Orthopedic Surgery, Houston Methodist Hospital, Houston, TX, USA
| | - Zonia Barbosa
- Department of Regenerative and Biomimetic Medicine, Houston Methodist Research Institute, Houston, TX, USA
| | - Jeffrey Van Eps
- Department of Surgery, Houston Methodist Hospital, Houston, TX, USA.,Department of Regenerative and Biomimetic Medicine, Houston Methodist Research Institute, Houston, TX, USA
| | - Pranela Rameshwar
- Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
| | - Bradley Weiner
- Department of Regenerative and Biomimetic Medicine, Houston Methodist Research Institute, Houston, TX, USA.,Department of Orthopedic Surgery, Houston Methodist Hospital, Houston, TX, USA
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Knezevic NN, Mandalia S, Raasch J, Knezevic I, Candido KD. Treatment of chronic low back pain - new approaches on the horizon. J Pain Res 2017; 10:1111-1123. [PMID: 28546769 PMCID: PMC5436786 DOI: 10.2147/jpr.s132769] [Citation(s) in RCA: 70] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Back pain is the second leading cause of disability among American adults and is currently treated either with conservative therapy or interventional pain procedures. However, the question that remains is whether we, as physicians, have adequate therapeutic options to offer to the patients who suffer from chronic low back pain but fail both conservative therapy and interventional pain procedures before they consider surgical options such as discectomy, disc arthroplasty, or spinal fusion. The purpose of this article is to review the potential novel therapies that are on the horizon for the treatment of chronic low back pain. We discuss medications that are currently in use through different phases of clinical trials (I–III) for the treatment of low back pain. In this review, we discuss revisiting the concept of chemonucleolysis using chymopapain, as the first drug in an intradiscal injection to reduce herniated disc size, and newer intradiscal therapies, including collagenase, chondroitinase, matrix metalloproteinases, and ethanol gel. We also review an intravenous glial cell-derived neurotrophic growth factor called artemin, which may repair sensory nerves compressed by herniated discs. Another new drug in development for low back pain without radiculopathy is a subcutaneous monoclonal antibody acting as nerve growth factor called tanezumab. Finally, we discuss how platelet-rich plasma and stem cells are being studied for the treatment of low back pain. We believe that with these new therapeutic options, we can bridge the current gap between conservative/interventional procedures and surgeries in patients with chronic back pain.
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Affiliation(s)
- Nebojsa Nick Knezevic
- Department of Anesthesiology, Advocate Illinois Masonic Medical Center.,Department of Anesthesiology.,Department of Surgery, University of Illinois, Chicago, IL, USA
| | - Shane Mandalia
- Department of Anesthesiology, Advocate Illinois Masonic Medical Center
| | - Jennifer Raasch
- Department of Anesthesiology, Advocate Illinois Masonic Medical Center
| | - Ivana Knezevic
- Department of Anesthesiology, Advocate Illinois Masonic Medical Center
| | - Kenneth D Candido
- Department of Anesthesiology, Advocate Illinois Masonic Medical Center.,Department of Anesthesiology.,Department of Surgery, University of Illinois, Chicago, IL, USA
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Tong W, Lu Z, Qin L, Mauck RL, Smith HE, Smith LJ, Malhotra NR, Heyworth MF, Caldera F, Enomoto-Iwamoto M, Zhang Y. Cell therapy for the degenerating intervertebral disc. Transl Res 2017; 181:49-58. [PMID: 27986604 PMCID: PMC5776755 DOI: 10.1016/j.trsl.2016.11.008] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2016] [Revised: 11/17/2016] [Accepted: 11/22/2016] [Indexed: 01/03/2023]
Abstract
Spinal conditions related to intervertebral disc (IVD) degeneration cost billions of dollars in the US annually. Despite the prevalence and soaring cost, there is no specific treatment that restores the physiological function of the diseased IVD. Thus, it is vital to develop new treatment strategies to repair the degenerating IVD. Persons with IVD degeneration without back pain or radicular leg pain often do not require any intervention. Only patients with severe back pain related to the IVD degeneration or biomechanical instability are likely candidates for cell therapy. The IVD progressively degenerates with age in humans, and strategies to repair the IVD depend on the stage of degeneration. Cell therapy and cell-based gene therapy aim to address moderate disc degeneration; advanced stage disease may require surgery. Studies involving autologous, allogeneic, and xenogeneic cells have all shown good survival of these cells in the IVD, confirming that the disc niche is an immunologically privileged site, permitting long-term survival of transplanted cells. All of the animal studies reviewed here reported some improvement in disc structure, and 2 studies showed attenuation of local inflammation. Among the 50 studies reviewed, 25 used some type of scaffold, and cell leakage is a consistently noted problem, though some studies showed reduced cell leakage. Hydrogel scaffolds may prevent cell leakage and provide biomechanical support until cells can become established matrix producers. However, these gels need to be optimized to prevent this leakage. Many animal models have been leveraged in this research space. Rabbit is the most frequently used model (28 of 50), followed by rat, pig, and dog. Sheep and goat IVDs resemble those of humans in size and in the absence of notochordal cells. Despite this advantage, there were only 2 sheep and 1 goat studies of 50 studies in this cohort. It is also unclear if a study in large animals is needed before clinical trials since some of the clinical trials proceeded without a study in large animals. No animal studies or clinical trials completely restored IVD structure. However, results suggest cause for optimism. In light of the fact that patients primarily seek medical care for back pain, attenuating local inflammation should be a priority in benchmarks for success. Clinicians generally agree that short-term back pain should be treated conservatively. When interventions are considered, the ideal therapy should also be minimally invasive and concurrent with other procedures such as discography or discectomy. Restoration of tissue structure and preservation of spinal motion are desirable.
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Affiliation(s)
- Wei Tong
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa; Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R.China
| | - Zhouyu Lu
- Department of Physical Medicine & Rehabilitation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa
| | - Ling Qin
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa
| | - Robert L Mauck
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa; Department of Physical Medicine & Rehabilitation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa; Translational Musculoskeletal Research Center (TMRC), Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, Pa
| | - Harvey E Smith
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa; Translational Musculoskeletal Research Center (TMRC), Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, Pa
| | - Lachlan J Smith
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa; Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa
| | - Neil R Malhotra
- Department of Neurosurgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa
| | - Martin F Heyworth
- Research Service, Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, Pa; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa
| | - Franklin Caldera
- Department of Physical Medicine & Rehabilitation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa
| | - Motomi Enomoto-Iwamoto
- Department of Surgery, Division of Orthopedic Surgery, Children's Hospital of Philadelphia, Philadelphia, Pa
| | - Yejia Zhang
- Department of Orthopaedic Surgery, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa; Department of Physical Medicine & Rehabilitation, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa; Translational Musculoskeletal Research Center (TMRC), Corporal Michael J. Crescenz Veterans Affairs Medical Center, Philadelphia, Pa.
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Tao H, Lin Y, Zhang G, Gu R, Chen B. Experimental observation of human bone marrow mesenchymal stem cell transplantation into rabbit intervertebral discs. Biomed Rep 2016; 5:357-360. [PMID: 27588177 DOI: 10.3892/br.2016.731] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Accepted: 07/13/2016] [Indexed: 11/06/2022] Open
Abstract
Allogeneic bone marrow mesenchymal stem cell (BMSC) transplantation has been investigated worldwide. However, few reports have addressed the survival status of human BMSCs in the intervertebral discs (IVDs) in vivo following transplantation. The current study aimed to observe the survival status of human BMSCs in rabbit IVDs. The IVDs of 15 New Zealand white rabbits were divided into three groups: Punctured blank control group (L1-2); punctured physiological saline control group (L2-3); and punctured human BMSCs transfected with green fluorescent protein (GFP) group (L3-4, L4-5 and L5-6). One, 2, 4, 6 and 8 weeks after transplantation the IVDs were removed and a fluorescence microscope was used to observe the density of GFP-positive human BMSCs. The results indicated that in the sections of specimens removed at 1, 2, 4, 6 and 8 weeks post-transplantation, no GFP-positive cells were observed in the control groups, whereas GFP-positive cells were apparent in the nucleus pulposus at all periods in the GFP-labeled human BMSCs group, and the cell density at 6 and 8 weeks was significantly less than that at 1, 2 and 4 weeks post-transplantation (P<0.001). Thus, it was identified that human BMSCs were able to survive in the rabbit IVDs for 8 weeks.
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Affiliation(s)
- Hao Tao
- Department of Orthopedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Yazhou Lin
- Department of Orthopedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Guoqing Zhang
- Department of Orthopedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
| | - Rui Gu
- Department of Spinal and Neural Function Reconstruction, China Rehabilitation Research Center, Beijing 100068, P.R. China
| | - Bohua Chen
- Department of Orthopedic Surgery, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266003, P.R. China
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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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Chai JW, Kang HS, Lee JW, Kim SJ, Hong SH. Quantitative Analysis of Disc Degeneration Using Axial T2 Mapping in a Percutaneous Annular Puncture Model in Rabbits. Korean J Radiol 2016; 17:103-10. [PMID: 26798222 PMCID: PMC4720797 DOI: 10.3348/kjr.2016.17.1.103] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Accepted: 10/23/2015] [Indexed: 11/15/2022] Open
Abstract
Objective To evaluate T2 relaxation time change using axial T2 mapping in a rabbit degenerated disc model and determine the most correlated variable with histologic score among T2 relaxation time, disc height index, and Pfirrmann grade. Materials and Methods Degenerated disc model was made in 4 lumbar discs of 11 rabbits (n = 44) by percutaneous annular puncture with various severities of an injury. Lumbar spine lateral radiograph, MR T2 sagittal scan and MR axial T2 mapping were obtained at baseline and 2 weeks and 4 weeks after the injury in 7 rabbits and at baseline and 2 weeks, 4 weeks, and 6 weeks after the injury in 4 rabbits. Generalized estimating equations were used for a longitudinal analysis of changes in T2 relaxation time in degenerated disc model. T2 relaxation time, disc height index and Pfirrmann grade were correlated with the histologic scoring of disc degeneration using Spearman's rho test. Results There was a significant difference in T2 relaxation time between uninjured and injured discs after annular puncture. Progressive decrease in T2 relaxation time was observed in injured discs throughout the study period. Lower T2 relaxation time was observed in the more severely injured discs. T2 relaxation time showed the strongest inverse correlation with the histologic score among the variables investigated (r = -0.811, p < 0.001). Conclusion T2 relaxation time measured with axial T2 mapping in degenerated discs is a potential method to assess disc degeneration.
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Affiliation(s)
- Jee Won Chai
- Department of Radiology, SMG-SNU Boramae Medical Center, Seoul 07061, Korea
| | - Heung Sik Kang
- Department of Radiology, Seoul National University Bundang Hospital, Seongnam 13620, Korea
| | - Joon Woo Lee
- Department of Radiology, Seoul National University Bundang Hospital, Seongnam 13620, Korea
| | - Su-Jin Kim
- Department of Radiology, SMG-SNU Boramae Medical Center, Seoul 07061, Korea
| | - Sung Hwan Hong
- Department of Radiology, Seoul National University Hospital, Seoul 03080, Korea
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Sakai D, Andersson GBJ. Stem cell therapy for intervertebral disc regeneration: obstacles and solutions. Nat Rev Rheumatol 2015; 11:243-56. [PMID: 25708497 DOI: 10.1038/nrrheum.2015.13] [Citation(s) in RCA: 332] [Impact Index Per Article: 33.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Intervertebral disc (IVD) degeneration is frequently associated with low back and neck pain, which accounts for disability worldwide. Despite the known outcomes of the IVD degeneration cascade, the treatment of IVD degeneration is limited in that available conservative and surgical treatments do not reverse the pathology or restore the IVD tissue. Regenerative medicine for IVD degeneration, by injection of IVD cells, chondrocytes or stem cells, has been extensively studied in the past decade in various animal models of induced IVD degeneration, and has progressed to clinical trials in the treatment of various spinal conditions. Despite preliminary results showing positive effects of cell-injection strategies for IVD regeneration, detailed basic research on IVD cells and their niche indicates that transplanted cells are unable to survive and adapt in the avascular niche of the IVD. For this therapeutic strategy to succeed, the indications for its use and the patients who would benefit need to be better defined. To surmount these obstacles, the solution will be identified only by focused research, both in the laboratory and in the clinic.
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Affiliation(s)
- Daisuke Sakai
- Department of Orthopaedic Surgery, Tokai University School of Medicine, Isehara, Kanagawa, 259-1193, Japan
| | - Gunnar B J Andersson
- Department of Orthopedic Surgery, Rush University Medical Center, Chicago, IL 60612, USA
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