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Beall DP, Bae HW, DePalma MJ, Amirdelfan K, Tavel E, Davis TT, Bainbridge JS, Weil A, Beckworth W, Kim K, Yuan P, Gupta PB, Wang E, Goodman BS, Reeves R, Furman MB, Mekhail N, Nunez D, DiMuro M, Shonnard MC, Rose E, Brown RD. Efficacy and safety of allogeneic mesenchymal precursor cells with and without hyaluronic acid for treatment of chronic low back pain: A prospective, randomized, double blind, concurrent-controlled 36-month study. Spine J 2025:S1529-9430(25)00164-0. [PMID: 40174800 DOI: 10.1016/j.spinee.2025.03.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/21/2024] [Revised: 01/30/2025] [Accepted: 03/22/2025] [Indexed: 04/04/2025]
Abstract
BACKGROUND CONTEXT Low back pain (LBP) associated with degenerative disc disease (DDD) is a serious condition resulting in significant morbidity, disability, and reduced quality of life for millions of people each year. Patients who fail to improve with conservative/noninvasive treatments including physical therapy and nonopioid analgesic medications have limited options, which include opioid analgesics with their associated significant risks; epidural steroid injections with limited supporting evidence; or surgical interventions such as spine fusion or artificial disc replacement. A safe, minimally invasive, nonopioid treatment that provides prolonged improvement in pain, function, and quality of life is needed for such patients. PURPOSE Evaluate the efficacy and safety of a single injection of mesenchymal precursor cells (MPCs) with or without hyaluronic acid (HA) compared to an intradiscal saline injection through 36 months follow-up in subjects with chronic low back pain (CLBP) associated with moderate DDD (mDDD). STUDY DESIGN/SETTING A prospective, multicenter, randomized, double-blind, concurrent-controlled study conducted at 49 clinical sites. SUBJECT SAMPLE A total of 404 subjects with CLBP associated with mDDD at one level from L1 to S1 received MPCs without HA (MPC), MPCs with HA (MPC+HA), or saline control (control) treatment. OUTCOME MEASURES Subjects were clinically and radiographically evaluated at 1, 3, 6, 12, 18, 24, and 36 months postinjection. Clinical evaluation included adverse events, neurologic evaluation, laboratory tests, LBP intensity measured by Visual Analog Scale (VAS), Oswestry Disability Index (ODI) and EQ-5D-5L Index. Radiographic assessments used Magnetic Resonance (MR) imaging and X-ray imaging studies. METHODS The primary efficacy endpoint was a composite responder analysis for overall treatment success at both 12 and 24 months that was comprised of:[1] at least a 50% reduction from baseline in low back pain VAS score (average pain over 24 h);[2] at least a 15-point decrease from baseline in ODI score; and[3] no adjudicated posttreatment interventions at the treated level. To assess superiority, a Bayesian analysis used a probability threshold of 0.9875. Additional analyses were performed on a prespecified subpopulation of subjects with CLBP duration at baseline less than the median baseline duration of 68 months (CLBPLTM). Statistical assessments included least squares (LS) mean, LS mean change from baseline (CFB) using the mixed model for repeated measures (MMRM) and categorical responder analyses using stratified Cochran Mantel Haenszel row means score test with p<.05 defined as statistically significant. This study was conducted under a US Food and Drug Administration (FDA) Investigational New Drug (IND) application sponsored and funded by Mesoblast. RESULTS All treatment groups showed substantial improvement from baseline in LS Mean LBP and ODI. The primary efficacy endpoint for the trial did not reach significance for either treatment group compared to control in all subjects. Furthermore, none of the secondary endpoints showed a significant difference between treatment and control in all subjects. While the primary and secondary responder efficacy endpoints were not reached, MPC+HA significantly reduced LS mean LBP compared to control at 12 and 24 months in all subjects. The results observed in all subjects were enhanced for MPC+HA and MPC in the prespecified CLBPLTM subgroup with MPC+HA having significantly greater reduction in LBP at all time points compared to control and MPC having significantly greater reduction in LBP at 6, 12 and 36 months. In the CLBPLTM subgroup, MPC+HA also showed significantly greater proportion of pain responders at 12, 24 and 36 compared to control. MPC+HA also showed significantly greater function improvement at 12 and 18 months compared to control in the CLBPLTM subgroup. Furthermore, MPC+HA subjects in the CLBPLTM subgroup showed significantly greater improvement in quality of life (QOL) compared to control at 12, 24 and 36 months. MPC+HA baseline opioid users had greater reduction in daily average morphine equivalent dose (MED) compared to control at 6 through 36 months. Furthermore, significantly more MPC+HA baseline opioid users (27.8%) were not taking opioids at 36 months compared to (7.8%) control. The injection procedure and MPC treatment were well tolerated with no appreciable differences in Treatment Emergent Adverse Events (TEAEs). No Serious Adverse Events (SAEs) were related to the treatment or procedure. The number of subjects that received posttreatment interventions (PTI) at the treated level were comparable among groups. CONCLUSIONS While the primary and secondary efficacy endpoints were not met in all subjects, MPC+HA treatment showed a significant reduction in pain compared to control that was enhanced in subjects with CLBP duration less than 68 months. Intra-discal injection of MPC+HA is a minimally invasive nonopioid therapy that appears to be safe and demonstrates reduction in pain through 24 months compared to control with enhanced results in subjects with mDDD that have had CLBP less than 68 months.
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Affiliation(s)
- Douglas P Beall
- Comprehensive Specialty Care, 1023 Waterwood Pkwy, Edmond, OK, USA.
| | - Hyun W Bae
- The Spine Institute, 2901 Wilshire Blvd. Suite 300, Santa Monica, CA, USA
| | - Michael J DePalma
- Virginia Spine Research Institute, Inc., 12874 Patterson Avenue, Suite A, Richmond, VA, USA
| | - Kasra Amirdelfan
- IPM Medical Group, Inc., 450 N. Wiget Lane, Walnut Creek, CA, USA
| | - Edward Tavel
- Clinical Trials of South Carolina, 2695 Elms Plantation Blvd. Suite D., Charleston, SC, USA
| | - Timothy T Davis
- Source Healthcare, 2801 Wilshire Blvd, Suite A, Santa Monica, CA, USA
| | - James Scott Bainbridge
- The Denver Spine & Pain Institute, Greenwood Village, 7730 E Belleview Ave, Ste A200, CO, USA
| | - Arnold Weil
- Nonsurgical Orthopedics, Coral Gables, 731 Almeria Ave., Coral Gables, USA
| | - William Beckworth
- Department of Orthopaedics, Emory University School of Medicine, 21 Ortho Lane, Atlanta, GA, USA
| | - Kee Kim
- University of California-Davis Neurological Surgery, Sacramento, 4860 Y Street, Suite 3740, CA, USA
| | - Philip Yuan
- Memorial Orthopaedic Surgical Group, Long Beach, 2760 Atlantic Ave., CA, USA
| | - Pragya B Gupta
- Otrimed Clinical Research, Edgewood, 162 Barnwood Drive, KY, USA
| | - Eugene Wang
- Summit Health, Garden City, 901 Franklin Ave, 2nd floor, NY, USA
| | | | - Ryan Reeves
- Spine Team Texas, Southlake, 1545 East Southlake Blvd, TX, USA
| | | | - Nagy Mekhail
- Cleveland Clinic, Cleveland, 9500 Euclid Ave, Ohio, USA
| | - David Nunez
- Mesoblast Inc., Bee Cave, 12912 Hill Country Blvd., Building F, Suite 230, TX, USA
| | - Michael DiMuro
- Mesoblast Inc., Bee Cave, 12912 Hill Country Blvd., Building F, Suite 230, TX, USA
| | | | - Eric Rose
- Mesoblast Inc., Bee Cave, 12912 Hill Country Blvd., Building F, Suite 230, TX, USA
| | - Roger D Brown
- Mesoblast Inc., Bee Cave, 12912 Hill Country Blvd., Building F, Suite 230, TX, USA
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Chen S, Liang B, Xu J. Unveiling heterogeneity in MSCs: exploring marker-based strategies for defining MSC subpopulations. J Transl Med 2024; 22:459. [PMID: 38750573 PMCID: PMC11094970 DOI: 10.1186/s12967-024-05294-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 05/11/2024] [Indexed: 05/19/2024] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) represent a heterogeneous cell population distributed throughout various tissues, demonstrating remarkable adaptability to microenvironmental cues and holding immense promise for disease treatment. However, the inherent diversity within MSCs often leads to variability in therapeutic outcomes, posing challenges for clinical applications. To address this heterogeneity, purification of MSC subpopulations through marker-based isolation has emerged as a promising approach to ensure consistent therapeutic efficacy. In this review, we discussed the reported markers of MSCs, encompassing those developed through candidate marker strategies and high-throughput approaches, with the aim of explore viable strategies for addressing the heterogeneity of MSCs and illuminate prospective research directions in this field.
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Affiliation(s)
- Si Chen
- Shenzhen University Medical School, Shenzhen University, Shenzhen, 518000, People's Republic of China
| | - Bowei Liang
- Shenzhen University Medical School, Shenzhen University, Shenzhen, 518000, People's Republic of China
| | - Jianyong Xu
- Shenzhen Key Laboratory of Reproductive Immunology for Peri-Implantation, Guangdong Engineering Technology Research Center of Reproductive Immunology for Peri-Implantation, Shenzhen Zhongshan Obstetrics & Gynecology Hospital (formerly Shenzhen Zhongshan Urology Hospital), Fuqiang Avenue 1001, Shenzhen, 518060, Guangdong, People's Republic of China.
- Guangdong Engineering Technology Research Center of Reproductive Immunology for Peri-Implantation, Shenzhen, 518000, People's Republic of China.
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Koroth J, Chitwood C, Kumar R, Lin WH, Reves BT, Boyce T, Reineke TM, Ellingson AM, Johnson CP, Stone LS, Chaffin KC, Simha NK, Ogle BM, Bradley EW. Identification of a novel, MSC-induced macrophage subtype via single-cell sequencing: implications for intervertebral disc degeneration therapy. Front Cell Dev Biol 2024; 11:1286011. [PMID: 38274272 PMCID: PMC10808728 DOI: 10.3389/fcell.2023.1286011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Accepted: 12/22/2023] [Indexed: 01/27/2024] Open
Abstract
Intervertebral disc (IVD) degeneration is a common pathological condition associated with low back pain. Recent evidence suggests that mesenchymal signaling cells (MSCs) promote IVD regeneration, but underlying mechanisms remain poorly defined. One postulated mechanism is via modulation of macrophage phenotypes. In this manuscript, we tested the hypothesis that MSCs produce trophic factors that alter macrophage subsets. To this end, we collected conditioned medium from human, bone marrow-derived STRO3+ MSCs. We then cultured human bone marrow-derived macrophages in MSC conditioned medium (CM) and performed single cell RNA-sequencing. Comparative analyses between macrophages cultured in hypoxic and normoxic MSC CM showed large overlap between macrophage subsets; however, we identified a unique hypoxic MSC CM-induced macrophage cluster. To determine if factors from MSC CM simulated effects of the anti-inflammatory cytokine IL-4, we integrated the data from macrophages cultured in hypoxic MSC CM with and without IL-4 addition. Integration of these data sets showed considerable overlap, demonstrating that hypoxic MSC CM simulates the effects of IL-4. Interestingly, macrophages cultured in normoxic MSC CM in the absence of IL-4 did not significantly contribute to the unique cluster within our comparison analyses and showed differential TGF-β signaling; thus, normoxic conditions did not approximate IL-4. In addition, TGF-β neutralization partially limited the effects of MSC CM. In conclusion, our study identified a unique macrophage subset induced by MSCs within hypoxic conditions and supports that MSCs alter macrophage phenotypes through TGF-β-dependent mechanisms.
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Affiliation(s)
- Jinsha Koroth
- Department of Orthopedic Surgery, Medical School, University of Minnesota, Minneapolis, MN, United States
| | - Casey Chitwood
- Department of Biomedical Engineering, College of Science and Engineering, University of Minnesota, Minneapolis, MN, United States
| | - Ramya Kumar
- Department of Chemical and Biological Engineering, Colorado School of Mines, Golden, CO, United States
- Department of Chemistry, College of Science and Engineering, University of Minnesota, Minneapolis, MN, United States
| | - Wei-Han Lin
- Department of Biomedical Engineering, College of Science and Engineering, University of Minnesota, Minneapolis, MN, United States
| | | | | | - Theresa M. Reineke
- Department of Chemistry, College of Science and Engineering, University of Minnesota, Minneapolis, MN, United States
- Stem Cell Institute, University of Minnesota, Minneapolis, MN, United States
| | - Arin M. Ellingson
- Department of Orthopedic Surgery, Medical School, University of Minnesota, Minneapolis, MN, United States
- Department of Rehabilitation Medicine, School of Medicine, University of Minnesota, Minneapolis, MN, United States
| | - Casey P. Johnson
- Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St. Paul, MN, United States
- Center for Magnetic Resonance Research, University of Minnesota, Minneapolis, MN, United States
| | - Laura S. Stone
- Department of Anesthesiology, School of Medicine, University of Minnesota, Minneapolis, MN, United States
| | | | | | - Brenda M. Ogle
- Department of Chemical and Biological Engineering, Colorado School of Mines, Golden, CO, United States
- Stem Cell Institute, University of Minnesota, Minneapolis, MN, United States
| | - Elizabeth W. Bradley
- Department of Orthopedic Surgery, Medical School, University of Minnesota, Minneapolis, MN, United States
- Stem Cell Institute, University of Minnesota, Minneapolis, MN, United States
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Soufi KH, Castillo JA, Rogdriguez FY, DeMesa CJ, Ebinu JO. Potential Role for Stem Cell Regenerative Therapy as a Treatment for Degenerative Disc Disease and Low Back Pain: A Systematic Review. Int J Mol Sci 2023; 24:ijms24108893. [PMID: 37240236 DOI: 10.3390/ijms24108893] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Revised: 05/09/2023] [Accepted: 05/15/2023] [Indexed: 05/28/2023] Open
Abstract
Back pain is the single leading cause of disability worldwide. Despite the prevalence and morbidity of lower back pain, we still lack a gold-standard treatment that restores the physiological function of degenerated intervertebral discs. Recently, stem cells have emerged as a promising strategy for regenerative therapy for degenerative disc disease. In this study, we review the etiology, pathogenesis, and developing treatment strategies for disc degeneration in low back pain with a focus on regenerative stem cell therapies. A systematic search of PubMed/MEDLINE/Embase/Clinical Trials.gov databases was conducted for all human subject abstracts or studies. There was a total of 10 abstracts and 11 clinical studies (1 RCT) that met the inclusion criteria. The molecular mechanism, approach, and progress of the different stem cell strategies in all studies are discussed, including allogenic bone marrow, allogenic discogenic cells, autologous bone marrow, adipose mesenchymal stem cells (MSCs), human umbilical cord MSC, adult juvenile chondrocytes, autologous disc derived chondrocytes, and withdrawn studies. Clinical success with animal model studies is promising; however, the clinical outcomes of stem cell regenerative therapy remain poorly understood. In this systematic review, we found no evidence to support its use in humans. Further studies on efficacy, safety, and optimal patient selection will establish whether this becomes a viable, non-invasive therapeutic option for back pain.
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Affiliation(s)
- Khadija H Soufi
- Department of Neurological Surgery, University of California Davis, Sacramento, CA 95817, USA
| | - Jose A Castillo
- Department of Neurological Surgery, University of California Davis, Sacramento, CA 95817, USA
| | - Freddie Y Rogdriguez
- Department of Neurological Surgery, University of California Davis, Sacramento, CA 95817, USA
| | - Charles J DeMesa
- Department of Anesthesia and Pain Medicine, University of California Davis, Sacramento, CA 95817, USA
| | - Julius O Ebinu
- Department of Neurological Surgery, University of California Davis, Sacramento, CA 95817, USA
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Alini M, Diwan AD, Erwin WM, Little CB, Melrose J. An update on animal models of intervertebral disc degeneration and low back pain: Exploring the potential of artificial intelligence to improve research analysis and development of prospective therapeutics. JOR Spine 2023; 6:e1230. [PMID: 36994457 PMCID: PMC10041392 DOI: 10.1002/jsp2.1230] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2022] [Revised: 08/31/2022] [Accepted: 09/11/2022] [Indexed: 02/03/2023] Open
Abstract
Animal models have been invaluable in the identification of molecular events occurring in and contributing to intervertebral disc (IVD) degeneration and important therapeutic targets have been identified. Some outstanding animal models (murine, ovine, chondrodystrophoid canine) have been identified with their own strengths and weaknesses. The llama/alpaca, horse and kangaroo have emerged as new large species for IVD studies, and only time will tell if they will surpass the utility of existing models. The complexity of IVD degeneration poses difficulties in the selection of the most appropriate molecular target of many potential candidates, to focus on in the formulation of strategies to effect disc repair and regeneration. It may well be that many therapeutic objectives should be targeted simultaneously to effect a favorable outcome in human IVD degeneration. Use of animal models in isolation will not allow resolution of this complex issue and a paradigm shift and adoption of new methodologies is required to provide the next step forward in the determination of an effective repairative strategy for the IVD. AI has improved the accuracy and assessment of spinal imaging supporting clinical diagnostics and research efforts to better understand IVD degeneration and its treatment. Implementation of AI in the evaluation of histology data has improved the usefulness of a popular murine IVD model and could also be used in an ovine histopathological grading scheme that has been used to quantify degenerative IVD changes and stem cell mediated regeneration. These models are also attractive candidates for the evaluation of novel anti-oxidant compounds that counter inflammatory conditions in degenerate IVDs and promote IVD regeneration. Some of these compounds also have pain-relieving properties. AI has facilitated development of facial recognition pain assessment in animal IVD models offering the possibility of correlating the potential pain alleviating properties of some of these compounds with IVD regeneration.
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Affiliation(s)
| | - Ashish D. Diwan
- Spine Service, Department of Orthopedic Surgery, St. George & Sutherland Campus, Clinical SchoolUniversity of New South WalesSydneyNew South WalesAustralia
| | - W. Mark Erwin
- Department of SurgeryUniversity of TorontoOntarioCanada
| | - Chirstopher B. Little
- Raymond Purves Bone and Joint Research LaboratoryKolling Institute, Sydney University Faculty of Medicine and Health, Northern Sydney Area Health District, Royal North Shore HospitalSt. LeonardsNew South WalesAustralia
| | - James Melrose
- Raymond Purves Bone and Joint Research LaboratoryKolling Institute, Sydney University Faculty of Medicine and Health, Northern Sydney Area Health District, Royal North Shore HospitalSt. LeonardsNew South WalesAustralia
- Graduate School of Biomedical EngineeringThe University of New South WalesSydneyNew South WalesAustralia
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Qian H, He L, Ye Z, Wei Z, Ao J. Decellularized matrix for repairing intervertebral disc degeneration: Fabrication methods, applications and animal models. Mater Today Bio 2022; 18:100523. [PMID: 36590980 PMCID: PMC9800636 DOI: 10.1016/j.mtbio.2022.100523] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 12/14/2022] [Accepted: 12/16/2022] [Indexed: 12/23/2022] Open
Abstract
Intervertebral disc degeneration (IDD)-induced low back pain significantly influences the quality of life, placing a burden on public health systems worldwide. Currently available therapeutic strategies, such as conservative or operative treatment, cannot effectively restore intervertebral disc (IVD) function. Decellularized matrix (DCM) is a tissue-engineered biomaterial fabricated using physical, chemical, and enzymatic technologies to eliminate cells and antigens. By contrast, the extracellular matrix (ECM), including collagen and glycosaminoglycans, which are well retained, have been extensively studied in IVD regeneration. DCM inherits the native architecture and specific-differentiation induction ability of IVD and has demonstrated effectiveness in IVD regeneration in vitro and in vivo. Moreover, significant improvements have been achieved in the preparation process, mechanistic insights, and application of DCM for IDD repair. Herein, we comprehensively summarize and provide an overview of the roles and applications of DCM for IDD repair based on the existing evidence to shed a novel light on the clinical treatment of IDD.
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Key Words
- (3D), three-dimensional
- (AF), annular fibers
- (AFSC), AF stem cells
- (APNP), acellular hydrogel descendent from porcine NP
- (DAF-G), decellularized AF hydrogel
- (DAPI), 4,6-diamidino-2-phenylindole
- (DCM), decellularized matrix
- (DET), detergent-enzymatic treatment
- (DWJM), Wharton's jelly matrix
- (ECM), extracellular matrix
- (EVs), extracellular vesicles
- (Exos), exosome
- (IDD), intervertebral disc degeneration
- (IVD), intervertebral disc
- (LBP), Low back pain
- (NP), nucleus pulposus
- (NPCS), NP-based cell delivery system
- (PEGDA/DAFM), polyethylene glycol diacrylate/decellularized AF matrix
- (SD), sodium deoxycholate
- (SDS), sodium dodecyl sulfate
- (SIS), small intestinal submucosa
- (TGF), transforming growth factor
- (bFGF), basic fibroblast growth factor
- (hADSCs), human adipose-derived stem cells
- (hDF), human dermal fibroblast
- (iAF), inner annular fibers
- (oAF), outer annular fibers
- (sGAG), sulfated glycosaminoglycan
- Decellularized matrix
- Intervertebral disc degeneration
- Regenerative medicine
- Tissue engineering
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Affiliation(s)
- Hu Qian
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Li He
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Zhimin Ye
- Department of Pathology, School of Basic Medical Sciences, Central South University, Changsha, China
- Corresponding author. Department of Pathology, School of Basic Medical Sciences, Central South University, Changsha, 410000, China.
| | - Zairong Wei
- Department of Burns and Plastic Surgery, The Affiliated Hospital of Zunyi Medical College, Zunyi, China
| | - Jun Ao
- Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China
- Corresponding author. Department of Orthopaedic Surgery, Affiliated Hospital of Zunyi Medical University, 149 Dalian Road, Zunyi, 563000, China.
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Salzer E, Mouser VHM, Tryfonidou MA, Ito K. A bovine nucleus pulposus explant culture model. J Orthop Res 2022; 40:2089-2102. [PMID: 34812520 PMCID: PMC9542046 DOI: 10.1002/jor.25226] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 10/18/2021] [Accepted: 11/20/2021] [Indexed: 02/04/2023]
Abstract
Low back pain is a global health problem that is frequently caused by intervertebral disc degeneration (IVDD). Sulfated glycosaminoglycans (sGAGs) give the healthy nucleus pulposus (NP) a high fixed charge density (FCD), which creates an osmotic pressure that enables the disc to withstand high compressive forces. However, during IVDD sGAG reduction in the NP compromises biomechanical function. The aim of this study was to develop an ex vivo NP explant model with reduced sGAG content and subsequently investigate biomechanical restoration via injection of proteoglycan-containing notochordal cell-derived matrix (NCM). Bovine coccygeal NP explants were cultured in a bioreactor chamber and sGAG loss was induced by chondroitinase ABC (chABC) and cultured for up to 14 days. Afterwards, diurnal loading was studied, and explant restoration was investigated via injection of NCM. Explants were analyzed via histology, biochemistry, and biomechanical testing via stress relaxation tests and height measurements. ChABC injection induced dose-dependent sGAG reduction on Day 3, however, no dosing effects were detected after 7 and 14 days. Diurnal loading reduced sGAG loss after injection of chABC. NCM did not show an instant biomechanical (equilibrium pressure) or biochemical (FCD) restoration, as the injected fixed charges leached into the medium, however, NCM stimulated proliferation and increased Alcian blue staining intensity and matrix organization. NCM has biological repair potential and biomaterial/NCM combinations, which could better entrap NCM within the NP tissue, should be investigated in future studies. Concluding, chABC induced progressive, time-, dose- and loading-dependent sGAG reduction that led to a loss of biomechanical function. Keywords biomechanics | intervertebral disc | matrix degradation | low back pain | proteoglycans.
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Affiliation(s)
- Elias Salzer
- Orthopaedic Biomechanics, Department of Biomedical EngineeringEindhoven University of TechnologyEindhovenNoord‐BrabantThe Netherlands
| | - Vivian H. M. Mouser
- Orthopaedic Biomechanics, Department of Biomedical EngineeringEindhoven University of TechnologyEindhovenNoord‐BrabantThe Netherlands
| | - Marianna A. Tryfonidou
- Department of Clinical Sciences, Faculty of Veterinary MedicineUtrecht UniversityUtrechtThe Netherlands
| | - Keita Ito
- Orthopaedic Biomechanics, Department of Biomedical EngineeringEindhoven University of TechnologyEindhovenNoord‐BrabantThe Netherlands
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Constant C, Hom WW, Nehrbass D, Carmel E, Albers CE, Deml MC, Gehweiler D, Lee Y, Hecht A, Grad S, Iatridis JC, Zeiter S. Comparison and optimization of sheep in vivo intervertebral disc injury model. JOR Spine 2022; 5:e1198. [PMID: 35783908 PMCID: PMC9238284 DOI: 10.1002/jsp2.1198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 03/08/2022] [Accepted: 03/16/2022] [Indexed: 11/09/2022] Open
Abstract
Background The current standard of care for intervertebral disc (IVD) herniation, surgical discectomy, does not repair annulus fibrosus (AF) defects, which is partly due to the lack of effective methods to do so and is why new repair strategies are widely investigated and tested preclinically. There is a need to develop a standardized IVD injury model in large animals to enable comparison and interpretation across preclinical study results. The purpose of this study was to compare in vivo IVD injury models in sheep to determine which annulus fibrosus (AF) defect type combined with partial nucleus pulposus (NP) removal would better mimic degenerative human spinal pathologies. Methods Six skeletally mature sheep were randomly assigned to one of the two observation periods (1 and 3 months) and underwent creation of 3 different AF defect types (slit, cruciate, and box-cut AF defects) in conjunction with 0.1 g NP removal in three lumbar levels using a lateral retroperitoneal surgical approach. The spine was monitored by clinical CT scans pre- and postoperatively, at 2 weeks and euthanasia, and by magnetic resonance imaging (MRI) and histology after euthanasia to determine the severity of degeneration (disc height loss, Pfirrmann grading, semiquantitative histopathology grading). Results All AF defects led to significant degenerative changes detectable on CT and MR images, produced bulging of disc tissue without disc herniation and led to degenerative and inflammatory histopathological changes. However, AF defects were not equal in terms of disc height loss at 3 months postoperatively; the cruciate and box-cut AF defects showed significantly decreased disc height compared to their preoperative height, with the box-cut defect creating the greatest disc height loss, while the slit AF defect showed restoration of normal preoperative disc height. Conclusions The tested IVD injury models do not all generate comparable disc degeneration but can be considered suitable IVD injury models to investigate new treatments. Results of the current study clearly indicate that slit AF defect should be avoided if disc height is used as one of the main outcomes; additional confirmatory studies may be warranted to generalize this finding.
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Affiliation(s)
| | - Warren W. Hom
- Department of OrthopaedicsIcahn School of Medicine, Mount Sinai Health SystemNew YorkNew YorkUSA
| | | | - Eric‐Norman Carmel
- Département de sciences cliniques, Faculté de médecine vétérinaireUniversité de MontréalSaint‐HyacintheCanada
| | - Christoph E. Albers
- Department of Orthopaedic Surgery & TraumatologyInselspital, University Hospital BernBernSwitzerland
| | - Moritz C. Deml
- Department of Orthopaedic Surgery & TraumatologyInselspital, University Hospital BernBernSwitzerland
| | | | - Yunsoo Lee
- Department of OrthopaedicsIcahn School of Medicine, Mount Sinai Health SystemNew YorkNew YorkUSA
| | - Andrew Hecht
- Department of OrthopaedicsIcahn School of Medicine, Mount Sinai Health SystemNew YorkNew YorkUSA
| | | | - James C. Iatridis
- Department of OrthopaedicsIcahn School of Medicine, Mount Sinai Health SystemNew YorkNew YorkUSA
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Kirnaz S, Singh S, Capadona C, Lintz M, Goldberg JL, McGrath LB, Medary B, Sommer F, Bonassar LJ, Härtl R. Innovative Biological Treatment Methods for Degenerative Disc Disease. World Neurosurg 2021; 157:282-299. [PMID: 34929786 DOI: 10.1016/j.wneu.2021.09.068] [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: 09/13/2021] [Accepted: 09/14/2021] [Indexed: 10/19/2022]
Abstract
Low back pain is the leading cause of work absences and years lived with disability, and it is often associated with degenerative disc disease. In recent years, biological treatment approaches such as the use of growth factors, cell injections, annulus fibrosus (AF) repair, nucleus pulposus replacement, and tissue-engineered discs have been explored as means for preventing or reversing degenerative disc disease. Both animal and clinical studies have shown promising results for cell-based therapy on the grounds of its regenerative potential. Clinical data also indicate that stem cell injection is safe when appropriately performed, albeit its long-term safety and efficacy are yet to be explored. Numerous challenges also remain to be overcome, such as isolating, differentiating, and preconditioning the disc cells, as well as managing the nutrient-deficient and oxygen-deficient micromilieu of the intervertebral disc (IVD). AF repair methods including devices used in clinical trials have shown success in decreasing reherniation rates and improving overall clinical outcomes. In addition, recent studies that combined AF repair and nucleus pulposus replacement have shown improved biomechanical stability in IVDs after the combined treatment. Tissue-engineered IVDs for total disc replacement are still being developed, and future studies are necessary to overcome the challenges in their delivery, efficacy, and safety.
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Affiliation(s)
- Sertac Kirnaz
- Department of Neurological Surgery, Weill Cornell Medicine Brain and Spine Center, Weill Cornell Medicine, New York-Presbyterian Hospital, New York, New York, USA
| | - Sunidhi Singh
- Department of Neurological Surgery, Weill Cornell Medicine Brain and Spine Center, Weill Cornell Medicine, New York-Presbyterian Hospital, New York, New York, USA
| | - Charisse Capadona
- Department of Neurological Surgery, Weill Cornell Medicine Brain and Spine Center, Weill Cornell Medicine, New York-Presbyterian Hospital, New York, New York, USA
| | - Marianne Lintz
- Department of Neurological Surgery, Weill Cornell Medicine Brain and Spine Center, Weill Cornell Medicine, New York-Presbyterian Hospital, New York, New York, USA
| | - Jacob L Goldberg
- Department of Neurological Surgery, Weill Cornell Medicine Brain and Spine Center, Weill Cornell Medicine, New York-Presbyterian Hospital, New York, New York, USA
| | - Lynn B McGrath
- Department of Neurological Surgery, Weill Cornell Medicine Brain and Spine Center, Weill Cornell Medicine, New York-Presbyterian Hospital, New York, New York, USA
| | - Branden Medary
- Department of Neurological Surgery, Weill Cornell Medicine Brain and Spine Center, Weill Cornell Medicine, New York-Presbyterian Hospital, New York, New York, USA
| | - Fabian Sommer
- Department of Neurological Surgery, Weill Cornell Medicine Brain and Spine Center, Weill Cornell Medicine, New York-Presbyterian Hospital, New York, New York, USA
| | - Lawrence J Bonassar
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York, USA; Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, New York, USA
| | - Roger Härtl
- Department of Neurological Surgery, Weill Cornell Medicine Brain and Spine Center, Weill Cornell Medicine, New York-Presbyterian Hospital, New York, New York, USA.
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10
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Ekram S, Khalid S, Bashir I, Salim A, Khan I. Human umbilical cord-derived mesenchymal stem cells and their chondroprogenitor derivatives reduced pain and inflammation signaling and promote regeneration in a rat intervertebral disc degeneration model. Mol Cell Biochem 2021; 476:3191-3205. [PMID: 33864569 DOI: 10.1007/s11010-021-04155-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2020] [Accepted: 04/02/2021] [Indexed: 12/21/2022]
Abstract
Intervertebral disc (IVD) degeneration is an asymptomatic pathophysiological condition and a strong causative factor of low back pain. There is no cure available except spinal fusion and pain management. Stem cell-based regenerative medicine is being considered as an alternative approach to treat disc diseases. The current study aimed to differentiate human umbilical cord-mesenchymal stem cells (hUC-MSCs) into chondrocyte-like cells and to elucidate their feasibility and efficacy in the degenerated IVD rat model. Chondrogenic induction medium was used to differentiate hUC-MSCs into chondroprogenitors. Rat tail IVD model was established with three consecutive coccygeal discs. qPCR was performed to quantify the molecular markers of pain and inflammation. Histological staining was performed to evaluate the degree of regeneration. Induced chondroprogenitors showed the expression of chondrogenic genes, SOX9, TGF-β1, ACAN, BMP2, and GDF5. Immunocytochemical staining showed positive expression of chondrogenic proteins SOX9, TGF-β1, TGF-β2, and Collagen 2. In in vivo study, transplanted chondroprogenitors showed better survival, homing, and distribution in IVD as compared to normal MSCs. Expression of pain and inflammatory genes at day 5 of cell transplantation modulated immune response significantly. The transplanted labeled MSCs and induced chondroprogenitors differentiated into functional nucleus pulposus (NP) cells as evident from co-localization of red (DiI) and green fluorescence for SOX9, TGF-β1, and TGF-β2. Alcian blue and H & E staining showed standard histological features, indicating better preservation of the NP structure and cellularity than degenerated discs. hUC-MSCs-derived chondroprogenitors showed better regeneration potential as compared to normal MSCs. The pain and inflammation genes were downregulated in the treated group as compared to the degenerated IVD.
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Affiliation(s)
- Sobia Ekram
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Shumaila Khalid
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Imtiaz Bashir
- Zainab Panjwani Memorial Hospital, Mohammadali Habib Road, Numaish Karachi, 74800, Pakistan
| | - Asmat Salim
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan
| | - Irfan Khan
- Dr. Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, 75270, Pakistan.
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11
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Amirdelfan K, Bae H, McJunkin T, DePalma M, Kim K, Beckworth WJ, Ghiselli G, Bainbridge JS, Dryer R, Deer TR, Brown RD. Allogeneic mesenchymal precursor cells treatment for chronic low back pain associated with degenerative disc disease: a prospective randomized, placebo-controlled 36-month study of safety and efficacy. Spine J 2021; 21:212-230. [PMID: 33045417 DOI: 10.1016/j.spinee.2020.10.004] [Citation(s) in RCA: 52] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2019] [Revised: 10/01/2020] [Accepted: 10/02/2020] [Indexed: 02/03/2023]
Abstract
BACKGROUND CONTEXT PURPOSE Evaluate the safety and efficacy of a single intradiscal injection of STRO-3+ adult allogeneic mesenchymal precursor cells (MPCs) combined with hyaluronic acid (HA) in subjects with chronic low back pain (CLBP) associated with degenerative disc disease (DDD) through 36-month follow-up. STUDY DESIGN/SETTING A multicenter, randomized, controlled study conducted at 13 clinical sites (12 in the United States and 1 in Australia). SUBJECT SAMPLE A total of 100 subjects with chronic low back pain associated with moderate DDD (modified Pfirrmann score of 3-6) at one level from L1 to S1 for at least 6 months and failing 3 months of conservative treatment, including physical therapy were randomized in a 3:3:2:2 ratio to receive 6 million MPCs with HA, 18 million MPCs with HA, HA vehicle control, or saline control (placebo) treatment. OUTCOME MEASURES Subjects were clinically and radiographically evaluated at 1, 3, 6, 12, 24, and 36 months postinjection. Subject-reported outcomes including adverse events, LBP on a Visual Analog Scale (VAS), Oswestry Disability Index (ODI), SF-36 and Work Productivity and Activity Index were collected. METHODS Clinical and radiographic measures were collected at each visit. All randomized subjects were included in the safety assessments and analyzed based on the treatment received. Safety assessments included assessments of AEs, physical and radiographic examinations and laboratory testing. Efficacy assessments evaluated changes in VAS, ODI, and modified Pfirrmann (MP) scores between all active and control groups, respectively. Assessments included least squares mean (Mean), LS mean change from baseline (Mean Change) and responder analyses in order to assess the clinical significance of observed changes from baseline. The population for efficacy assessments was adjusted for the confounding effects of post-treatment interventions (PTIs). This study was conducted under an FDA Investigational New Drug application sponsored and funded by Mesoblast. RESULTS There were significant differences between the control and MPC groups for improvement in VAS and ODI. The PTI-corrected VAS and ODI Means and Mean Change analyses; the proportion of subjects with VAS ≥30% and ≥50% improvement from baseline; absolute VAS score ≤20; and ODI reduction ≥10 and ≥15 points from baseline showed MPC therapy superior to controls at various time points through 36 months. Additionally, the proportion of subjects achieving the minimally important change and clinically significant change composite endpoints for the MPC groups was also superior compared with controls at various time points from baseline to 36 months. There were no significant differences in change in MP score from baseline across the groups. There were also no statistically significant differences in change in modified MP score at the level above or below the level treated between study arms. Both the procedure and treatment were well tolerated and there were no clinical symptoms of immune reaction to allogeneic MPCs. There was a low rate of Treatment Emergent Adverse Events (TEAEs) and Serious Adverse Events, and the rates of these events in the MPC groups were not significantly different from the control groups. One TEAE of severe back pain was possibly related to study agent and one TEAE of implantation site infection was considered to be related to the study procedure. CONCLUSIONS Results provide evidence that intradiscal injection of MPCs could be a safe, effective, durable, and minimally invasive therapy for subjects who have CLBP associated with moderate DDD.
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Affiliation(s)
- Kasra Amirdelfan
- IPM Medical Group, Inc., 450 Wiget Lane, Walnut Creek, CA 94598, USA.
| | - Hyun Bae
- The Spine Institute, 2811 Wilshire Blvd, Suite 850, Santa Monica, CA 90403, USA
| | - Tory McJunkin
- Arizona Pain Specialists, 9787 N. 91st St, Suite 101, Scottsdale, AZ 85258, USA
| | - Michael DePalma
- Virginia Spine Research Institute, Inc., 9020 Stony Point Parkway, Suite 140, Richmond, VA 23235, USA
| | - Kee Kim
- UC Davis Spine Center, 3301 C St, Suite 1500, Sacramento, CA 95816, USA
| | - William J Beckworth
- Department of Orthopaedics, Emory University School of Medicine, 59 Executive Park South, Suite 3000, Atlanta, GA 30329, USA
| | - Gary Ghiselli
- Denver Spine, 7800 E. Orchard Rd, Suite 100, Greenwood Village, CO 80111, USA
| | | | - Randall Dryer
- Central Texas Spine Institute, 6818 Austin Center Blvd, Suite 200, Austin, TX 78731, USA
| | - Timothy R Deer
- The Center for Pain Relief, Inc., 400 Court St, Suite 100, Charleston, WV 25301, USA
| | - Roger D Brown
- Mesoblast Inc., 12912 Hill Country Blvd, Building F, Suite 230, Bee Cave, TX 78738, USA
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12
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Borem R, Walters J, Madeline A, Madeline L, Gill S, Easley J, Mercuri J. Characterization of chondroitinase-induced lumbar intervertebral disc degeneration in a sheep model intended for assessing biomaterials. J Biomed Mater Res A 2020; 109:1232-1246. [PMID: 33040470 DOI: 10.1002/jbm.a.37117] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Revised: 10/04/2020] [Accepted: 10/09/2020] [Indexed: 02/06/2023]
Abstract
Intervertebral disc (IVD) degeneration (IVDD) leads to structural and functional changes. Biomaterials for restoring IVD function and promoting regeneration are currently being investigated; however, such approaches require validation using animal models that recapitulate clinical, biochemical, and biomechanical hallmarks of the human pathology. Herein, we comprehensively characterized a sheep model of chondroitinase-ABC (ChABC) induced IVDD. Briefly, ChABC (1 U) was injected into the L1/2 , L2/3 , and L3/4 IVDs. Degeneration was assessed via longitudinal magnetic resonance (MR) and radiographic imaging. Additionally, kinematic, biochemical, and histological analyses were performed on explanted functional spinal units (FSUs). At 17-weeks, ChABC treated IVDs demonstrated significant reductions in MR index (p = 0.030) and disc height (p = 0.009) compared with pre-operative values. Additionally, ChABC treated IVDs exhibited significantly increased creep displacement (p = 0.004) and axial range of motion (p = 0.007) concomitant with significant decreases in tensile (p = 0.034) and torsional (p = 0.021) stiffnesses and long-term viscoelastic properties (p = 0.016). ChABC treated IVDs also exhibited a significant decrease in NP glycosaminoglycan: hydroxyproline ratio (p = 0.002) and changes in microarchitecture, particularly in the NP and endplates, compared with uninjured IVDs. Taken together, this study demonstrated that intradiscal injection of ChABC induces significant degeneration in sheep lumbar IVDs and the potential for using this model in evaluating biomaterials for IVD repair, regeneration, or fusion.
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Affiliation(s)
- Ryan Borem
- The Laboratory of Orthopaedic Tissue Regeneration & Orthobiologics, Department of Bioengineering, Clemson University, Clemson, South Carolina, USA
| | - Joshua Walters
- The Laboratory of Orthopaedic Tissue Regeneration & Orthobiologics, Department of Bioengineering, Clemson University, Clemson, South Carolina, USA
| | - Allison Madeline
- The Laboratory of Orthopaedic Tissue Regeneration & Orthobiologics, Department of Bioengineering, Clemson University, Clemson, South Carolina, USA
| | - Lee Madeline
- Department of Radiology, Greenville Health System, Greenville, South Carolina, USA
| | - Sanjitpal Gill
- The Laboratory of Orthopaedic Tissue Regeneration & Orthobiologics, Department of Bioengineering, Clemson University, Clemson, South Carolina, USA.,Department of Orthopaedic Surgery, Medical Group of the Carolinas-Pelham, Spartanburg Regional Healthcare System, Greer, South Carolina, USA
| | - Jeremiah Easley
- Preclinical Surgical Research Laboratory, Colorado State University, Fort Collins, Colorado, USA
| | - Jeremy Mercuri
- The Laboratory of Orthopaedic Tissue Regeneration & Orthobiologics, Department of Bioengineering, Clemson University, Clemson, South Carolina, USA
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13
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Kim MJ, Lee JH, Kim JS, Kim HY, Lee HC, Byun JH, Lee JH, Kim NH, Oh SH. Intervertebral Disc Regeneration Using Stem Cell/Growth Factor-Loaded Porous Particles with a Leaf-Stacked Structure. Biomacromolecules 2020; 21:4795-4805. [PMID: 32955865 DOI: 10.1021/acs.biomac.0c00992] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Although biological therapies based on growth factors and transplanted cells have demonstrated some positive outcomes for intervertebral disc (IVD) regeneration, repeated injection of growth factors and cell leakage from the injection site remain considerable challenges for human therapeutic use. Herein, we prepare human bone marrow-derived mesenchymal stem cells (hBMSCs) and transforming growth factor-β3 (TGF-β3)-loaded porous particles with a unique leaf-stack structural morphology (LSS particles) as a combination bioactive delivery matrix for degenerated IVD. The LSS particles are fabricated with clinically acceptable biomaterials (polycaprolactone and tetraglycol) and procedures (simple heating and cooling). The LSS particles allow sustained release of TGF-β3 for 18 days and stable cell adhesiveness without additional modifications of the particles. On the basis of in vitro and in vivo studies, it was observed that the hBMSCs/TGF-β3-loaded LSS particles can provide a suitable milieu for chondrogenic differentiation of hBMSCs and effectively induce IVD regeneration in a beagle dog model. Thus, therapeutically loaded LSS particles offer the promise of an effective bioactive delivery system for regeneration of various tissues including IVD.
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Affiliation(s)
- Min Ji Kim
- Department of Nanobiomedical Science, Dankook University, Cheonan 31116, Republic of Korea
| | - Jin Ho Lee
- Department of Advanced Materials, Hannam University, Daejeon 34054, Republic of Korea
| | - Jun-Soo Kim
- Institute of Animal Medicine, College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea
| | - Ho Yong Kim
- Department of Nanobiomedical Science, Dankook University, Cheonan 31116, Republic of Korea
| | - Hee-Chun Lee
- Department of Veterinary Medical Imaging, College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea
| | - June-Ho Byun
- Department of Oral and Maxillofacial Surgery, Gyeongsang National University School of Medicine, Gyeongsang National University Hospital, Institute of Health Sciences, Gyeongsang National University, Jinju 52727, Republic of Korea
| | - Jae-Hoon Lee
- Institute of Animal Medicine, College of Veterinary Medicine, Gyeongsang National University, Jinju 52828, Republic of Korea
| | - Na-Hyun Kim
- Gyeongnam Department of Environment & Toxicology, Korea Institute of Toxicology, Jinju 52834, Republic of Korea
| | - Se Heang Oh
- Department of Nanobiomedical Science, Dankook University, Cheonan 31116, Republic of Korea
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14
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Hussain I, Sloan SR, Wipplinger C, Navarro-Ramirez R, Zubkov M, Kim E, Kirnaz S, Bonassar LJ, Härtl R. Mesenchymal Stem Cell-Seeded High-Density Collagen Gel for Annular Repair: 6-Week Results From In Vivo Sheep Models. Neurosurgery 2020; 85:E350-E359. [PMID: 30476218 DOI: 10.1093/neuros/nyy523] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2018] [Accepted: 10/04/2018] [Indexed: 12/27/2022] Open
Abstract
BACKGROUND Our group has previously demonstrated in vivo annulus fibrosus repair in animal models using an acellular, riboflavin crosslinked, high-density collagen (HDC) gel. OBJECTIVE To assess if seeding allogenic mesenchymal stem cells (MSCs) into this gel yields improved histological and radiographic benefits in an in vivo sheep model of annular injury. METHODS Fifteen lumbar intervertebral discs (IVDs) were randomized into 4 groups: intact, injury only, injury + acellular gel treatment, or injury + MSC-seeded gel treatment. Sheep were sacrificed at 6 wk. Disc height index (DHI), Pfirrmann grade, nucleus pulposus area, and T2 relaxation time (T2-RT) were calculated for each IVD and standardized to healthy controls from the same sheep. Quantitative histological assessment was also performed using the Han scoring system. RESULTS All treated IVDs retained gel plugs on gross assessment and there were no adverse perioperative complications. The MSC-seeded gel treatment group demonstrated statistically significant improvement over other experimental groups in DHI (P = .002), Pfirrmann grade (P < .001), and T2-RT (P = .015). There was a trend for greater Han scores in the MSC-seeded gel-treated discs compared with injury only and acellular gel-treated IVDs (P = .246). CONCLUSION MSC-seeded HDC gel can be delivered into injured IVDs and maintained safely in live sheep to 6 wk. Compared with no treatment and acellular HDC gel, our data show that MSC-seeded HDC gel improves outcomes in DHI, Pfirrmann grade, and T2-RT. Histological analysis shows improved annulus fibrosus and nucleus pulposus reconstitution and organization over other experimental groups as well.
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Affiliation(s)
- Ibrahim Hussain
- Department of Neurological Surgery, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, New York
| | - Stephen R Sloan
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York
| | - Christoph Wipplinger
- Department of Neurological Surgery, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, New York
| | - Rodrigo Navarro-Ramirez
- Department of Neurological Surgery, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, New York
| | - Micaella Zubkov
- Department of Neurological Surgery, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, New York
| | - Eliana Kim
- Department of Neurological Surgery, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, New York
| | - Sertac Kirnaz
- Department of Neurological Surgery, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, New York
| | - Lawrence J Bonassar
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, New York.,Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, New York
| | - Roger Härtl
- Department of Neurological Surgery, Weill Cornell Medical College, New York-Presbyterian Hospital, New York, New York
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15
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Stem Cells for the Treatment of Intervertebral Disk Degeneration. Tech Orthop 2019. [DOI: 10.1097/bto.0000000000000346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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16
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Borem R, Madeline A, Bowman M, Gill S, Tokish J, Mercuri J. Differential Effector Response of Amnion- and Adipose-Derived Mesenchymal Stem Cells to Inflammation; Implications for Intradiscal Therapy. J Orthop Res 2019; 37:2445-2456. [PMID: 31287173 DOI: 10.1002/jor.24412] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 06/25/2019] [Indexed: 02/04/2023]
Abstract
Intervertebral disc degeneration (IVDD) is a progressive condition marked by tissue destruction and inflammation. The therapeutic effector functions of mesenchymal stem cells (MSCs) makes them an attractive therapy for patients with IVDD. While several sources of MSCs exist, the optimal choice for use in the inflamed IVD remains a significant question. Adipose (AD)- and amnion (AM)-derived MSCs have several advantages compared with other sources, however, no study has directly compared the impact of IVDD inflammation on their effector functions. Human MSCs were cultured in media with or without supplementation of interleukin-1β (IL-1β) and tumor necrosis factor-α at concentrations reportedly produced by IVDD cells. MSC proliferation and production of pro- and anti-inflammatory cytokines were quantified following 24 and 48 h of culture. Additionally, the osteogenic and chondrogenic potential of AD- and AM-MSCs was characterized via histology and biochemical analysis following 28 days of culture. In inflammatory culture, AM-MSCs produced significantly more anti-inflammatory IL-10 (14.47 ± 2.39 pg/ml; p = 0.004) and larger chondrogenic pellets (5.67 ± 0.26 mm2 ; p = 0.04) with greater percent area staining positively for glycosaminoglycan (82.03 ± 3.26%; p < 0.001) compared with AD-MSCs (0.00 ± 0.00 pg/ml; 2.76 ± 0.18 mm2 ; 34.75 ± 2.49%; respectively). Conversely, AD-MSCs proliferated more resulting in higher cell numbers (221,000 ± 8,021 cells; p = 0.048) and produced higher concentrations of pro-inflammatory cytokines prostaglandin E2 (1,118.30 ± 115.56 pg/ml; p = 0.030) and IL-1β (185.40 ± 7.63 pg/ml; p = 0.010) compared with AM-MSCs (109,667 ± 5,696 cells; 1,291.40 ± 78.47 pg/ml; 144.10 ± 4.57 pg/ml; respectively). AD-MSCs produced more mineralized extracellular matrix (3.34 ± 0.05 relative absorbance units [RAU]; p < 0.001) compared with AM-MSCs (1.08 ± 0.06 RAU). Under identical inflammatory conditions, a different effector response was observed with AM-MSCs producing more anti-inflammatories and demonstrating enhanced chondrogenesis compared with AD-MSCs, which produced more pro-inflammatory cytokines and demonstrated enhanced osteogenesis. These findings may begin to help inform researchers which MSC source may be optimal for IVD regeneration. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:2445-2456, 2019.
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Affiliation(s)
- Ryan Borem
- Department of Bioengineering, Laboratory of Orthopaedic Tissue Regeneration & Orthobiologics, Clemson University, Clemson, South Carolina, 29634
| | - Allison Madeline
- Department of Bioengineering, Laboratory of Orthopaedic Tissue Regeneration & Orthobiologics, Clemson University, Clemson, South Carolina, 29634
| | - Mackenzie Bowman
- Department of Bioengineering, Laboratory of Orthopaedic Tissue Regeneration & Orthobiologics, Clemson University, Clemson, South Carolina, 29634
| | - Sanjitpal Gill
- Department of Bioengineering, Laboratory of Orthopaedic Tissue Regeneration & Orthobiologics, Clemson University, Clemson, South Carolina, 29634.,Department of Orthopaedic Surgery, Medical Group of the Carolinas-Pelham, Spartanburg Regional Healthcare System, Greer, South Carolina, 29651
| | - John Tokish
- Department of Bioengineering, Laboratory of Orthopaedic Tissue Regeneration & Orthobiologics, Clemson University, Clemson, South Carolina, 29634.,Department of Orthopaedic Surgery, Mayo Clinic, Phoenix, Arizona, 85054
| | - Jeremy Mercuri
- Department of Bioengineering, Laboratory of Orthopaedic Tissue Regeneration & Orthobiologics, Clemson University, Clemson, South Carolina, 29634
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17
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Clouet J, Fusellier M, Camus A, Le Visage C, Guicheux J. Intervertebral disc regeneration: From cell therapy to the development of novel bioinspired endogenous repair strategies. Adv Drug Deliv Rev 2019; 146:306-324. [PMID: 29705378 DOI: 10.1016/j.addr.2018.04.017] [Citation(s) in RCA: 144] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2017] [Revised: 03/29/2018] [Accepted: 04/24/2018] [Indexed: 12/15/2022]
Abstract
Low back pain (LBP), frequently associated with intervertebral disc (IVD) degeneration, is a major public health concern. LBP is currently managed by pharmacological treatments and, if unsuccessful, by invasive surgical procedures, which do not counteract the degenerative process. Considering that IVD cell depletion is critical in the degenerative process, the supplementation of IVD with reparative cells, associated or not with biomaterials, has been contemplated. Recently, the discovery of reparative stem/progenitor cells in the IVD has led to increased interest in the potential of endogenous repair strategies. Recruitment of these cells by specific signals might constitute an alternative strategy to cell transplantation. Here, we review the status of cell-based therapies for treating IVD degeneration and emphasize the current concept of endogenous repair as well as future perspectives. This review also highlights the challenges of the mobilization/differentiation of reparative progenitor cells through the delivery of biologics factors to stimulate IVD regeneration.
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Affiliation(s)
- Johann Clouet
- INSERM, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, Nantes F-44042, France; CHU Nantes, Pharmacie Centrale, PHU 11, Nantes F-44093, France; Université de Nantes, UFR Sciences Biologiques et Pharmaceutiques, Nantes F-44035, France; Université de Nantes, UFR Odontologie, Nantes F-44042, France
| | - Marion Fusellier
- INSERM, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, Nantes F-44042, France; Department of Diagnostic Imaging, CRIP, National Veterinary School (ONIRIS), Nantes F-44307, France
| | - Anne Camus
- INSERM, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, Nantes F-44042, France; Université de Nantes, UFR Odontologie, Nantes F-44042, France
| | - Catherine Le Visage
- INSERM, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, Nantes F-44042, France; Université de Nantes, UFR Odontologie, Nantes F-44042, France
| | - Jérôme Guicheux
- INSERM, UMR 1229, RMeS, Regenerative Medicine and Skeleton, Université de Nantes, ONIRIS, Nantes F-44042, France; Université de Nantes, UFR Odontologie, Nantes F-44042, France; CHU Nantes, PHU4 OTONN, Nantes, F-44093, France.
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18
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Hamidian Jahromi S, Davies JE. Concise Review: Skeletal Muscle as a Delivery Route for Mesenchymal Stromal Cells. Stem Cells Transl Med 2019; 8:456-465. [PMID: 30720934 PMCID: PMC6477141 DOI: 10.1002/sctm.18-0208] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Accepted: 01/02/2019] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) have demonstrated extensive capacity to modulate a catabolic microenvironment toward tissue repair. The fate, biodistribution, and dwell time of the in vivo delivered MSCs largely depend on the choice of the cell delivery route. Intramuscular (IM) delivery of MSCs is clinically safe and has been used for the effective treatment of local pathologies. Recent findings have shown that the secretome of the IM‐delivered MSCs enters the circulation and provides systemic effects on distant organs. In addition, muscle tissue provides a safe residence for the delivered MSCs and an extended secretorily active dwell time compared with other delivery routes. There are, however, controversies concerning the fate of MSCs post IM‐delivery and, specifically, into an injured site with proinflammatory cues. This review seeks to provide a brief overview of the fate and efficacy of IM‐delivered MSCs and to identify the gaps that require further assessment for adoption of this promising route in the treatment of systemic disease. stem cells translational medicine2019;8:456–465
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Affiliation(s)
- Shiva Hamidian Jahromi
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Canada.,Faculty of Dentistry, University of Toronto, Toronto, Canada
| | - John E Davies
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, Canada.,Faculty of Dentistry, University of Toronto, Toronto, Canada
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Goodman RR, Jong MK, Davies JE. Concise review: The challenges and opportunities of employing mesenchymal stromal cells in the treatment of acute pancreatitis. Biotechnol Adv 2019; 42:107338. [PMID: 30639517 DOI: 10.1016/j.biotechadv.2019.01.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2018] [Revised: 01/02/2019] [Accepted: 01/07/2019] [Indexed: 02/08/2023]
Abstract
To date only small animal models have been employed to assess the effect of mesenchymal stromal cell (MSC) therapy on acute pancreatitis (AP), the most common cause of hospitalization for gastrointestinal diseases worldwide. We outline the challenges inherent in the small animal models of AP. We also point to specific benefits afforded by the adoption of larger animal models. The potential for MSC therapeutics in the treatment of AP was recognized over a decade ago. With sharper focus on the form of AP and development of new MSC delivery routes in larger animals, we believe the challenge can be engaged.
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Affiliation(s)
- Robbie R Goodman
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto M5S 3G9, Canada
| | - Madelaine K Jong
- Faculty of Dentistry, University of Toronto, Toronto M5G 1G6, Canada
| | - John E Davies
- Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto M5S 3G9, Canada; Faculty of Dentistry, University of Toronto, Toronto M5G 1G6, Canada.
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20
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Perez-Cruet M, Beeravolu N, McKee C, Brougham J, Khan I, Bakshi S, Chaudhry GR. Potential of Human Nucleus Pulposus-Like Cells Derived From Umbilical Cord to Treat Degenerative Disc Disease. Neurosurgery 2019; 84:272-283. [PMID: 29490072 PMCID: PMC6292795 DOI: 10.1093/neuros/nyy012] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Accepted: 01/09/2018] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Degenerative disc disease (DDD) is a common spinal disorder that manifests with neck and lower back pain caused by the degeneration of intervertebral discs (IVDs). Currently, there is no treatment to cure this debilitating ailment. OBJECTIVE To investigate the potential of nucleus pulposus (NP)-like cells (NPCs) derived from human umbilical cord mesenchymal stem cells (MSCs) to restore degenerated IVDs using a rabbit DDD model. METHODS NPCs differentiated from MSCs were characterized using quantitative real-time reverse transcription polymerase chain reaction and immunocytochemical analysis. MSCs and NPCs were labeled with fluorescent dye, PKH26, and transplanted into degenerated IVDs of a rabbit model of DDD (n = 9 each). Magnetic resonance imaging of the IVDs was performed before and after IVD degeneration, and following cell transplantation. IVDs were extracted 8 wk post-transplantation and analyzed by various biochemical, immunohistological, and molecular techniques. RESULTS NPC derivatives of MSCs expressed known NP-specific genes, SOX9, ACAN, COL2, FOXF1, and KRT19. Transplanted cells survived, dispersed, and integrated into the degenerated IVDs. IVDs augmented with NPCs showed significant improvement in the histology, cellularity, sulfated glycosaminoglycan and water contents of the NP. In addition, expression of human genes, SOX9, ACAN, COL2, FOXF1, KRT19, PAX6, CA12, and COMP, as well as proteins, SOX9, ACAN, COL2, and FOXF1, suggest NP biosynthesis due to transplantation of NPCs. Based on these results, a molecular mechanism for NP regeneration was proposed. CONCLUSION The findings of this study demonstrating feasibility and efficacy of NPCs to regenerate NP should spur interest for clinical studies to treat DDD using cell therapy.
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Affiliation(s)
- Mick Perez-Cruet
- Department of Neurosurgery, Beaumont Health System, Royal Oak, Michigan
- OUWB School of Medicine, Oakland University, Rochester, Michigan
- OU-WB Institute for Stem Cell and Regenerative Medicine, Rochester, Michigan
- Michigan Head and Spine Institute, Southfield, Michigan
| | - Naimisha Beeravolu
- OU-WB Institute for Stem Cell and Regenerative Medicine, Rochester, Michigan
- Department of Biological Sciences, Oakland University, Rochester, Michigan
| | - Christina McKee
- OU-WB Institute for Stem Cell and Regenerative Medicine, Rochester, Michigan
- Department of Biological Sciences, Oakland University, Rochester, Michigan
| | - Jared Brougham
- OUWB School of Medicine, Oakland University, Rochester, Michigan
| | - Irfan Khan
- OU-WB Institute for Stem Cell and Regenerative Medicine, Rochester, Michigan
- Department of Biological Sciences, Oakland University, Rochester, Michigan
- Dr Panjwani Center for Molecular Medicine and Drug Research, International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan
| | - Shreeya Bakshi
- OU-WB Institute for Stem Cell and Regenerative Medicine, Rochester, Michigan
- Department of Biological Sciences, Oakland University, Rochester, Michigan
| | - G Rasul Chaudhry
- OU-WB Institute for Stem Cell and Regenerative Medicine, Rochester, Michigan
- Department of Biological Sciences, Oakland University, Rochester, Michigan
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21
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Smith LJ, Silverman L, Sakai D, Le Maitre CL, Mauck RL, Malhotra NR, Lotz JC, Buckley CT. Advancing cell therapies for intervertebral disc regeneration from the lab to the clinic: Recommendations of the ORS spine section. JOR Spine 2018; 1:e1036. [PMID: 30895277 PMCID: PMC6419951 DOI: 10.1002/jsp2.1036] [Citation(s) in RCA: 73] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Revised: 09/09/2018] [Accepted: 09/10/2018] [Indexed: 12/28/2022] Open
Abstract
Intervertebral disc degeneration is strongly associated with chronic low back pain, a leading cause of disability worldwide. Current back pain treatment approaches (both surgical and conservative) are limited to addressing symptoms, not necessarily the root cause. Not surprisingly therefore, long-term efficacy of most approaches is poor. Cell-based disc regeneration strategies have shown promise in preclinical studies, and represent a relatively low-risk, low-cost, and durable therapeutic approach suitable for a potentially large patient population, thus making them attractive from both clinical and commercial standpoints. Despite such promise, no such therapies have been broadly adopted clinically. In this perspective we highlight primary obstacles and provide recommendations to help accelerate successful clinical translation of cell-based disc regeneration therapies. The key areas addressed include: (a) Optimizing cell sources and delivery techniques; (b) Minimizing potential risks to patients; (c) Selecting physiologically and clinically relevant efficacy metrics; (d) Maximizing commercial potential; and (e) Recognizing the importance of multidisciplinary collaborations and engaging with clinicians from inception through to clinical trials.
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Affiliation(s)
- Lachlan J. Smith
- Department of NeurosurgeryUniversity of PennsylvaniaPhiladelphiaPennsylvania
- Department of Orthopaedic SurgeryUniversity of PennsylvaniaPhiladelphiaPennsylvania
- Translational Musculoskeletal Research CenterCorporal Michael J. Crescenz VA Medical CenterPhiladelphiaPennsylvania
| | - Lara Silverman
- DiscGenics Inc.Salt Lake CityUtah
- Department of NeurosurgeryUniversity of Tennessee Health Science CenterMemphisTennessee
| | - Daisuke Sakai
- Department of Orthopaedic Surgery, Surgical ScienceTokai University School of MedicineIseharaJapan
| | | | - Robert L. Mauck
- Department of Orthopaedic SurgeryUniversity of PennsylvaniaPhiladelphiaPennsylvania
- Translational Musculoskeletal Research CenterCorporal Michael J. Crescenz VA Medical CenterPhiladelphiaPennsylvania
- Department of BioengineeringUniversity of PennsylvaniaPhiladelphiaPennsylvania
| | - Neil R. Malhotra
- Department of NeurosurgeryUniversity of PennsylvaniaPhiladelphiaPennsylvania
| | - Jeffrey C. Lotz
- Department of Orthopaedic SurgeryUniversity of CaliforniaSan FranciscoCalifornia
| | - Conor T. Buckley
- Trinity Centre for BioengineeringTrinity Biomedical Sciences Institute, Trinity College Dublin, The University of DublinDublinIreland
- School of EngineeringTrinity College Dublin, The University of DublinDublinIreland
- Advanced Materials and Bioengineering Research (AMBER) CentreRoyal College of Surgeons in Ireland & Trinity College Dublin, The University of DublinDublinIreland
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22
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Washington EA, Barber SR, Murray CM, Davies HMS, Kimpton WG, Yen HH. Lymphatic cannulation models in sheep: Recent advances for immunological and biomedical research. J Immunol Methods 2018; 457:6-14. [PMID: 29625076 DOI: 10.1016/j.jim.2018.03.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Revised: 02/22/2018] [Accepted: 03/27/2018] [Indexed: 10/17/2022]
Abstract
Lymphatic cannulation models are useful tools for studying the immunobiology of the lymphatic system and the immunopathology of specific tissues in diseases. Sheep cannulations have been used extensively, as models for human physiology, fetal and neonatal development, human diseases, and for studies of ruminant pathobiology. The development of new and improved cannulation techniques in recent years has meant that difficult to access sites, such as mucosal associated tissues, are now more readily available to researchers. This review highlights the new approaches to cannulation and how these, in combination with advanced omics technologies, will direct future research using the sheep model.
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Affiliation(s)
- Elizabeth A Washington
- Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia
| | - Stuart R Barber
- Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia
| | - Christina M Murray
- Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia
| | - Helen M S Davies
- Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia
| | - Wayne G Kimpton
- Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia
| | - Hung-Hsun Yen
- Faculty of Veterinary and Agricultural Sciences, The University of Melbourne, Parkville, Victoria 3010, Australia..
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23
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Daly CD, Ghosh P, Zannettino ACW, Badal T, Shimmon R, Jenkin G, Oehme D, Jain K, Sher I, Vais A, Cohen C, Chandra RV, Goldschlager T. Mesenchymal progenitor cells primed with pentosan polysulfate promote lumbar intervertebral disc regeneration in an ovine model of microdiscectomy. Spine J 2018; 18:491-506. [PMID: 29055739 DOI: 10.1016/j.spinee.2017.10.008] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2017] [Revised: 09/12/2017] [Accepted: 10/05/2017] [Indexed: 02/03/2023]
Abstract
BACKGROUND CONTEXT Neural compression associated with lumbar disc herniation is usually managed surgically by microdiscectomy. However, 10%-20% of patients re-present with debilitating back pain, and approximately 15% require further surgery. PURPOSE Using an ovine model of microdiscectomy, the present study investigated the relative potential of pentosan polysulfate-primed mesenchymal progenitor cells (pMPCs) or MPC alone implanted into the lesion site to facilitate disc recovery. STUDY DESIGN An ovine model of lumbar microdiscectomy was used to compare the relative outcomes of administering MPCs or pMPCs to the injury site postsurgery. METHODS At baseline 3T magnetic resonance imaging (MRI) of 18 adult ewes was undertaken followed by annular microdiscectomy at two lumbar disc levels. Sheep were randomized into three groups (n=6). The injured controls received no further treatment. Defects of the treated groups were implanted with a collagen sponge and MPC (5×105 cells) or pMPC (5×105 cells). After 6 months, 3T MRI and standard radiography were performed. Spinal columns were dissected, individual lumbar discs were sectioned horizontally, and nucleus pulposus (NP) and annulus fibrosus (AF) regions were assessed morphologically and histologically. The NP and AF tissues were dissected into six regions and analyzed biochemically for their proteoglycans (PGs), collagen, and DNA content. RESULTS Both the MPC- and pMPC-injected groups exhibited less reduction in disc height (p<.05) and lower Pfirrmann grades (p≤.001) compared with the untreated injury controls, but morphologic scores for the pMPC-injected discs were lower (p<.05). The PG content of the AF injury site region (AF1) of pMPC discs was higher than MPC and injury control AF1 (p<.05). At the AF1 and contralateral AF2 regions, the DNA content of pMPC discs was significantly lower than injured control discs and MPC-injected discs. Histologic and birefringent microscopy revealed increased structural organization and reduced degeneration in pMPC discs compared with MPC and the injured controls. CONCLUSIONS In an ovine model 6 months after administration of pMPCs to the injury site disc PG content and matrix organization were improved relative to controls, suggesting pMPCs' potential as a postsurgical adjunct for limiting progression of disc degeneration after microdiscectomy.
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Affiliation(s)
- Chris D Daly
- Department of Surgery, Monash University, 246 Clayton Rd, Clayton, VIC 3168, Australia; Department of Neurosurgery, Monash Medical Centre, 246 Clayton Rd, Clayton, VIC 3168, Australia; The Ritchie Centre, Hudson Institute of Medical Research, Monash University, 246 Clayton Rd, Clayton, VIC 3168, Australia.
| | - Peter Ghosh
- The Ritchie Centre, Hudson Institute of Medical Research, Monash University, 246 Clayton Rd, Clayton, VIC 3168, Australia; Proteobioactives Pty Ltd, PO Box 174, Balgowlah, NSW 2093, Australia
| | - Andrew C W Zannettino
- Myeloma Research Laboratory, Adelaide Medical School, Faculty of Health and Medical Sciences, University of Adelaide, Adelaide, SA 5000, Australia; Cancer Theme, South Australia Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, SA 5000, Australia
| | - Tanya Badal
- Chemical Technology Unit, Faculty of Science, University of Technology, 15 Broadway, Ultimo, Sydney, NSW 2007, Australia
| | - Ronald Shimmon
- Chemical Technology Unit, Faculty of Science, University of Technology, 15 Broadway, Ultimo, Sydney, NSW 2007, Australia
| | - Graham Jenkin
- The Ritchie Centre, Hudson Institute of Medical Research, Monash University, 246 Clayton Rd, Clayton, VIC 3168, Australia; Department of Obstetrics and Gynaecology, Monash University, 246 Clayton Rd, Clayton, VIC 3168, Australia
| | - David Oehme
- Department of Neurosurgery, St Vincent's Hospital, 41 Victoria Pde, Fitzroy, VIC 3065, Australia
| | - Kanika Jain
- The Ritchie Centre, Hudson Institute of Medical Research, Monash University, 246 Clayton Rd, Clayton, VIC 3168, Australia
| | - Idrees Sher
- Department of Surgery, Monash University, 246 Clayton Rd, Clayton, VIC 3168, Australia; Department of Neurosurgery, Monash Medical Centre, 246 Clayton Rd, Clayton, VIC 3168, Australia
| | - Angela Vais
- Monash Histology Platform, Monash University, Wellington Rd, Clayton, VIC, 3168, Australia
| | - Camilla Cohen
- Monash Histology Platform, Monash University, Wellington Rd, Clayton, VIC, 3168, Australia
| | - Ronil V Chandra
- Department of Surgery, Monash University, 246 Clayton Rd, Clayton, VIC 3168, Australia; Monash Department of Radiology, Monash Medical Centre, 246 Clayton Rd, Clayton, VIC 3168, Australia
| | - Tony Goldschlager
- Department of Surgery, Monash University, 246 Clayton Rd, Clayton, VIC 3168, Australia; Department of Neurosurgery, Monash Medical Centre, 246 Clayton Rd, Clayton, VIC 3168, Australia; The Ritchie Centre, Hudson Institute of Medical Research, Monash University, 246 Clayton Rd, Clayton, VIC 3168, Australia
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24
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Tam V, Chan WCW, Leung VYL, Cheah KSE, Cheung KMC, Sakai D, McCann MR, Bedore J, Séguin CA, Chan D. Histological and reference system for the analysis of mouse intervertebral disc. J Orthop Res 2018. [PMID: 28636254 DOI: 10.1002/jor.23637] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
A new scoring system based on histo-morphology of mouse intervertebral disc (IVD) was established to assess changes in different mouse models of IVD degeneration and repair. IVDs from mouse strains of different ages, transgenic mice, or models of artificially induced IVD degeneration were assessed. Morphological features consistently observed in normal, and early/later stages of degeneration were categorized into a scoring system focused on nucleus pulposus (NP) and annulus fibrosus (AF) changes. "Normal NP" exhibited a highly cellularized cell mass that decreased with natural ageing and in disc degeneration. "Normal AF" consisted of distinct concentric lamellar structures, which was disrupted in severe degeneration. NP/AF clefts indicated more severe changes. Consistent scores were obtained between experienced and new users. Altogether, our scoring system effectively differentiated IVD changes in various strains of wild-type and genetically modified mice and in induced models of IVD degeneration, and is applicable from the post-natal stage to the aged mouse. This scoring tool and reference resource addresses a pressing need in the field for studying IVD changes and cross-study comparisons in mice, and facilitates a means to normalize mouse IVD assessment between different laboratories. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:233-243, 2018.
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Affiliation(s)
- Vivian Tam
- School of Biomedical Sciences, The University of Hong Kong, 3/F, Laboratory Block, Faculty of Medicine Building, 21 Sassoon Road, Pokfulam, Hong Kong, China.,The University of Hong Kong-Shenzhen Institute of Research and Innovation (HKU-SIRI), Hi-Tech Industrial Park, Nanshan, Shenzhen, China
| | - Wilson C W Chan
- School of Biomedical Sciences, The University of Hong Kong, 3/F, Laboratory Block, Faculty of Medicine Building, 21 Sassoon Road, Pokfulam, Hong Kong, China.,The University of Hong Kong-Shenzhen Institute of Research and Innovation (HKU-SIRI), Hi-Tech Industrial Park, Nanshan, Shenzhen, China
| | - Victor Y L Leung
- Department of Orthopaedics and Traumatology, The University of Hong Kong, Pokfulam, Hong Kong
| | - Kathryn S E Cheah
- School of Biomedical Sciences, The University of Hong Kong, 3/F, Laboratory Block, Faculty of Medicine Building, 21 Sassoon Road, Pokfulam, Hong Kong, China
| | - Kenneth M C Cheung
- Department of Orthopaedics and Traumatology, The University of Hong Kong, Pokfulam, Hong Kong
| | - Daisuke Sakai
- Department of Orthopaedic Surgery, Surgical Science, Tokai University School of Medicine, Hiratsuka, Japan
| | - Matthew R McCann
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The Bone and Joint Institute, The University of Western Ontario, London, Canada
| | - Jake Bedore
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The Bone and Joint Institute, The University of Western Ontario, London, Canada
| | - Cheryle A Séguin
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, The Bone and Joint Institute, The University of Western Ontario, London, Canada
| | - Danny Chan
- School of Biomedical Sciences, The University of Hong Kong, 3/F, Laboratory Block, Faculty of Medicine Building, 21 Sassoon Road, Pokfulam, Hong Kong, China.,The University of Hong Kong-Shenzhen Institute of Research and Innovation (HKU-SIRI), Hi-Tech Industrial Park, Nanshan, Shenzhen, China
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25
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Moriguchi Y, Mojica-Santiago J, Grunert P, Pennicooke B, Berlin C, Khair T, Navarro-Ramirez R, Ricart Arbona RJ, Nguyen J, Härtl R, Bonassar LJ. Total disc replacement using tissue-engineered intervertebral discs in the canine cervical spine. PLoS One 2017; 12:e0185716. [PMID: 29053719 PMCID: PMC5650136 DOI: 10.1371/journal.pone.0185716] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2017] [Accepted: 09/18/2017] [Indexed: 01/07/2023] Open
Abstract
The most common reason that adults in the United States see their physician is lower back or neck pain secondary to degenerative disc disease. To date, approaches to treat degenerative disc disease are confined to purely mechanical devices designed to either eliminate or enable flexibility of the diseased motion segment. Tissue engineered intervertebral discs (TE-IVDs) have been proposed as an alternative approach and have shown promise in replacing native IVD in the rodent tail spine. Here we demonstrate the efficacy of our TE-IVDs in the canine cervical spine. TE-IVD components were constructed using adult canine annulus fibrosis and nucleus pulposus cells seeded into collagen and alginate hydrogels, respectively. Seeded gels were formed into a single disc unit using molds designed from the geometry of the canine spine. Skeletally mature beagles underwent discectomy with whole IVD resection at levels between C3/4 and C6/7, and were then divided into two groups that received only discectomy or discectomy followed by implantation of TE-IVD. Stably implanted TE-IVDs demonstrated significant retention of disc height and physiological hydration compared to discectomy control. Both 4-week and 16-week histological assessments demonstrated chondrocytic cells surrounded by proteoglycan-rich matrices in the NP and by fibrocartilaginous matrices in the AF portions of implanted TE-IVDs. Integration into host tissue was confirmed over 16 weeks without any signs of immune reaction. Despite the significant biomechanical demands of the beagle cervical spine, our stably implanted TE-IVDs maintained their position, structure and hydration as well as disc height over 16 weeks in vivo.
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Affiliation(s)
- Yu Moriguchi
- Department of Neurological Surgery, Weill Cornell Medical College, New York, NY, United States of America
| | - Jorge Mojica-Santiago
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, United States of America
| | - Peter Grunert
- Department of Neurological Surgery, Weill Cornell Medical College, New York, NY, United States of America
| | - Brenton Pennicooke
- Department of Neurological Surgery, Weill Cornell Medical College, New York, NY, United States of America
| | - Connor Berlin
- Department of Neurological Surgery, Weill Cornell Medical College, New York, NY, United States of America
| | - Thamina Khair
- Department of Neurological Surgery, Weill Cornell Medical College, New York, NY, United States of America
| | - Rodrigo Navarro-Ramirez
- Department of Neurological Surgery, Weill Cornell Medical College, New York, NY, United States of America
| | - Rodolfo J. Ricart Arbona
- Center of Comparative Medicine and Pathology, Memorial Sloan Kettering Cancer Center & Weill Cornell Medicine, New York, NY, United States of America
| | - Joseph Nguyen
- Healthcare Research Institute, Hospital for Special Surgery, Hospital for Special Surgery, New York, NY, United States of America
| | - Roger Härtl
- Department of Neurological Surgery, Weill Cornell Medical College, New York, NY, United States of America
| | - Lawrence J. Bonassar
- Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY, United States of America
- * E-mail:
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26
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Ludtka C, Schwan S, Friedmann A, Brehm W, Wiesner I, Goehre F. Micro-CT evaluation of asymmetrical ovine intervertebral disc height loss from surgical approach. 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; 26:2031-2037. [PMID: 28289843 DOI: 10.1007/s00586-017-5024-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Revised: 01/16/2017] [Accepted: 02/28/2017] [Indexed: 12/12/2022]
Abstract
PURPOSE The primary goal of this study is to clearly define and evaluate new intervertebral disc height parameters in analysing the morphological pathology of disc degeneration for application in damage model and regeneration therapy development, as well as applying traditional variables to 3-D characterization methods. METHODS A posterolateral surgical approach was used to induce disc degeneration in an ovine model. At 12-months post-operation, sheep vertebral segments were removed and characterized using micro-CT to evaluate disc height parameters in regard to injury localization. RESULTS Statistically significant differences between the disc height loss of the left and right side of the disc, consistent with the lateral surgical approach used were seen using the modified average disc height method by Dabbs et al. However, convexity index and the newly proposed Cross Tilt Index did not conclusively demonstrate a difference. CONCLUSION Two-dimensional morphological evaluations can be applied in 3-D to provide a more complete picture of disc height loss for injury models. New 3-D parameters that are tailored to the type of surgical approach used should be investigated, with the 9-point system described herein providing a useful basis for derived values. Additionally, the surgical approach chosen when artificially injuring the disc can result in asymmetrical degeneration, as indicated by uneven disc height loss.
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Affiliation(s)
- Christopher Ludtka
- Fraunhofer Institute for Microstructure of Materials and Systems IMWS, Halle (Saale), Germany.,Department of Chemical and Biomolecular Engineering, University of Tennessee Knoxville, Knoxville, TN, USA
| | - Stefan Schwan
- Fraunhofer Institute for Microstructure of Materials and Systems IMWS, Halle (Saale), Germany. .,Translational Center for Regenerative Medicine, University of Leipzig, Leipzig, Germany.
| | - Andrea Friedmann
- Fraunhofer Institute for Microstructure of Materials and Systems IMWS, Halle (Saale), Germany.,Translational Center for Regenerative Medicine, University of Leipzig, Leipzig, Germany
| | - Walther Brehm
- Translational Center for Regenerative Medicine, University of Leipzig, Leipzig, Germany.,Department of Veterinary Medicine, University of Leipzig, Leipzig, Germany
| | - Ingo Wiesner
- Department of General Surgery, BG Bergmannstrost Clinic, Halle, Germany
| | - Felix Goehre
- Department of General Surgery, BG Bergmannstrost Clinic, Halle, Germany.,Department of Neurosurgery, University of Helsinki, Helsinki, Finland
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27
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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: 65] [Impact Index Per Article: 8.1] [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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Sakai D, Schol J. Cell therapy for intervertebral disc repair: Clinical perspective. J Orthop Translat 2017; 9:8-18. [PMID: 29662795 PMCID: PMC5822958 DOI: 10.1016/j.jot.2017.02.002] [Citation(s) in RCA: 86] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2016] [Revised: 01/24/2017] [Accepted: 02/02/2017] [Indexed: 12/22/2022] Open
Abstract
Low back pain is the main cause of disability and is associated with intervertebral disc degeneration. Contemporary treatments are limited to palliative therapeutics or aggressive surgical interventions; however, current advancements in cell therapy offer to fill this breach. Clinical data suggest that cell transplantation can accomplish pain relief without any observed adverse effects. Despite a large variety of preclinical studies and preliminary clinical investigations, controversy remains on the optimal cell type and transplantation strategies. The translational potential of this article lies in the aim to update on the current state of intervertebral disc cell therapy and to identify current obstacles.
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Affiliation(s)
- Daisuke Sakai
- Department of Orthopaedic Surgery, Surgical Science, Tokai University School of Medicine, Isehara, Japan
| | - Jordy Schol
- Department of Orthopaedic Surgery, Surgical Science, Tokai University School of Medicine, Isehara, Japan
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Abdalmula A, Dooley LM, Kaufman C, Washington EA, House JV, Blacklaws BA, Ghosh P, Itescu S, Bailey SR, Kimpton WG. Immunoselected STRO-3 + mesenchymal precursor cells reduce inflammation and improve clinical outcomes in a large animal model of monoarthritis. Stem Cell Res Ther 2017; 8:22. [PMID: 28173831 PMCID: PMC5297153 DOI: 10.1186/s13287-016-0460-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2016] [Revised: 12/04/2016] [Accepted: 12/16/2016] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The purpose of this study was to investigate the therapeutic efficacy of intravenously administered immunoselected STRO-3 + mesenchymal precursor cells (MPCs) on clinical scores, joint pathology and cytokine production in an ovine model of monoarthritis. METHODS Monoarthritis was established in 16 adult merino sheep by administration of bovine type II collagen into the left hock joint following initial sensitization to this antigen. After 24 h, sheep were administered either 150 million allogeneic ovine MPCs (n = 8) or saline (n = 8) intravenously (IV). Lameness, joint swelling and pain were monitored and blood samples for leukocytes and cytokine levels were collected at intervals following arthritis induction. Animals were necropsied 14 days after arthritis induction and gross and histopathological evaluations were undertaken on tissues from the arthritic (left) and contralateral (right) joints. RESULTS MPC-treated sheep demonstrated significantly reduced clinical signs of lameness, joint pain and swelling compared with saline controls. They also showed decreased cartilage erosions, synovial stromal cell activation and angiogenesis. This was accompanied by decreased infiltration of the synovial tissues by CD4+ lymphocytes and CD14+ monocytes/macrophages. Over the 3 days following joint arthropathy induction, the numbers of neutrophils circulating in the blood and plasma concentrations of activin A were significantly reduced in animals administered MPCs. CONCLUSIONS The results of this study have demonstrated the capacity of IV-administered MPCs to mitigate the clinical signs and some of the inflammatory mediators responsible for joint tissue destruction in a large animal model of monoarthritis.
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MESH Headings
- Activins/blood
- Animals
- Antigens, Surface/genetics
- Antigens, Surface/immunology
- Arthritis, Experimental/chemically induced
- Arthritis, Experimental/genetics
- Arthritis, Experimental/pathology
- Arthritis, Experimental/therapy
- Arthritis, Rheumatoid/genetics
- Arthritis, Rheumatoid/immunology
- Arthritis, Rheumatoid/pathology
- CD4-Positive T-Lymphocytes/immunology
- CD4-Positive T-Lymphocytes/pathology
- Cell Differentiation
- Cell Movement
- Collagen Type II/administration & dosage
- Disease Models, Animal
- Female
- Gene Expression
- Interferon-gamma/biosynthesis
- Interferon-gamma/immunology
- Interleukin-10/biosynthesis
- Interleukin-10/immunology
- Interleukin-17/biosynthesis
- Interleukin-17/immunology
- Joints/immunology
- Joints/pathology
- Macrophages/immunology
- Macrophages/pathology
- Mesenchymal Stem Cell Transplantation
- Mesenchymal Stem Cells/cytology
- Mesenchymal Stem Cells/immunology
- Monocytes/immunology
- Monocytes/pathology
- Neutrophils/immunology
- Neutrophils/pathology
- Sheep, Domestic
- Synovial Fluid/chemistry
- Synovial Fluid/cytology
- Synovial Fluid/immunology
- Treatment Outcome
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Affiliation(s)
- Anwar Abdalmula
- Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, VIC 5010 Australia
| | - Laura M. Dooley
- Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, VIC 5010 Australia
| | - Claire Kaufman
- Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, VIC 5010 Australia
| | - Elizabeth A. Washington
- Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, VIC 5010 Australia
| | - Jacqueline V. House
- Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3010 Australia
| | - Barbara A. Blacklaws
- Department of Veterinary Medicine, University of Cambridge, Cambridge, CB3 0ES UK
| | - Peter Ghosh
- Mesoblast Ltd, 55 Collins Street, Melbourne, VIC 3000 Australia
| | - Silviu Itescu
- Mesoblast Ltd, 55 Collins Street, Melbourne, VIC 3000 Australia
| | - Simon R. Bailey
- Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, VIC 5010 Australia
| | - Wayne G. Kimpton
- Faculty of Veterinary and Agricultural Sciences, University of Melbourne, Parkville, VIC 5010 Australia
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Fitter S, Gronthos S, Ooi SS, Zannettino AC. The Mesenchymal Precursor Cell Marker Antibody STRO-1 Binds to Cell Surface Heat Shock Cognate 70. Stem Cells 2017; 35:940-951. [DOI: 10.1002/stem.2560] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Revised: 11/25/2016] [Accepted: 12/02/2016] [Indexed: 01/07/2023]
Affiliation(s)
- Stephen Fitter
- Myeloma Research Laboratory, Faculty of Health and Medical Science, Adelaide Medical School
- Cancer Theme, South Australian Health and Medical Research Institute; Adelaide South Australia Australia
| | - Stan Gronthos
- Mesenchymal Stem Cell Laboratory, Faculty of Health and Medical Sciences, Adelaide Medical School, University of Adelaide; Adelaide South Australia Australia
- Cancer Theme, South Australian Health and Medical Research Institute; Adelaide South Australia Australia
| | - Soo Siang Ooi
- Myeloma Research Laboratory, Faculty of Health and Medical Science, Adelaide Medical School
- Cancer Theme, South Australian Health and Medical Research Institute; Adelaide South Australia Australia
| | - Andrew C.W. Zannettino
- Myeloma Research Laboratory, Faculty of Health and Medical Science, Adelaide Medical School
- Cancer Theme, South Australian Health and Medical Research Institute; Adelaide South Australia Australia
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Fávaro RC, Arruda ADO, Vialle LRG, Vialle EN. Influence of mononuclear cell therapy on disc degeneration in rabbits. Rev Bras Ortop 2017; 51:707-715. [PMID: 28050544 PMCID: PMC5198066 DOI: 10.1016/j.rboe.2016.10.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2016] [Accepted: 03/18/2016] [Indexed: 01/07/2023] Open
Abstract
OBJECTIVE The objective of this research was to evaluate the influence of autologous mononuclear stem cells injections on histological changes of collagen in the fibrous annulus of the intervertebral disk after experimental injury. METHODS 32 New Zealand rabbits were submitted to intervertebral disk puncture, followed by intradiscal injection of mononuclear cells from the iliac crest versus saline injection in the following time periods: two months after the injury (SC2M and SS2M), two weeks (SC2W and SS2W) immediately after injury (SCCP and SSCP), and without inducing degeneration (SCSP and SSSP). Two months after cell therapy, the animals were euthanized and collagen changes in the intervertebral discs were histologically evaluated. RESULTS There were significant differences in ELAF between SS2W and SS2S groups (p = 0.018). This difference was due to an increase in type I collagen in SS2W group (56.7%) compared to SC2S (13.28%). CONCLUSION Treatment with mononuclear mesenchymal stem cells reduced changes in the type I and III collagen distribution in rabbits AF degenerated discs up to two weeks after the induction of degeneration.
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Affiliation(s)
- Rodrigo Caldonazzo Fávaro
- Pontifícia Universidade Católica do Paraná, Hospital Universitário Cajuru, Serviço de Ortopedia e Traumatologia, Curitiba, PR, Brazil
| | - André de Oliveira Arruda
- Pontifícia Universidade Católica do Paraná, Hospital Universitário Cajuru, Serviço de Ortopedia e Traumatologia, Curitiba, PR, Brazil
| | - Luiz Roberto Gomes Vialle
- Pontifícia Universidade Católica do Paraná, Hospital Universitário Cajuru, Serviço de Ortopedia e Traumatologia, Curitiba, PR, Brazil
| | - Emiliano Neves Vialle
- Pontifícia Universidade Católica do Paraná, Hospital Universitário Cajuru, Serviço de Ortopedia e Traumatologia, Curitiba, PR, Brazil
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Fávaro RC, Arruda ADO, Vialle LRG, Vialle EN. Influência da terapia celular mononuclear sobre a degeneração discal em coelhos. Rev Bras Ortop 2016. [DOI: 10.1016/j.rbo.2016.03.007] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
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Use of FGF-2 and FGF-18 to direct bone marrow stromal stem cells to chondrogenic and osteogenic lineages. Future Sci OA 2016; 2:FSO142. [PMID: 28116125 PMCID: PMC5242207 DOI: 10.4155/fsoa-2016-0034] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2016] [Accepted: 07/29/2016] [Indexed: 02/07/2023] Open
Abstract
Aim: Intervertebral disc degeneration/low back pain is the number one global musculoskeletal condition in terms of disability and socioeconomic impact. Materials & methods Multipotent mesenchymal stem cells (MSCs) were cultured in micromass pellets ± FGF-2 or -18 up to 41 days, matrix components were immunolocalized and gene expression monitored by quantitative-reverse transcription PCR. Results: Chondrogenesis occurred earlier in FGF-18 than FGF-2 cultures. Lower COL2A1, COL10A1 and ACAN expression by day 41 indicated a downregulation in chondrocyte hypertrophy. MEF2c, ALPL, were upregulated; calcium, decorin and biglycan, and 4C3 and 7D4 chondroitin sulphate sulfation motifs were evident in FGF-18 but not FGF-2 pellets. Conclusion: FGF-2 and -18 preconditioned MSCs produced cell lineages which promoted chondrogenesis and osteogenesis and may be useful in the production of MSC lineages suitable for repair of cartilaginous tissue defects. Intervertebral disc degeneration and low back pain is the number one global musculoskeletal disorder effecting 80% of the general population. A remedy for this condition is being eagerly sought as part of a WHO research priority. Stem cells are one potential therapy that shows promise in animal models, laboratory studies, and preclinical and early clinical trials. Conditioning of stem cells in the laboratory before injection may improve their efficacy for the alleviation of low back pain. In the present study we have developed a means of improving how stem cells form cartilage and bone, which should be of application in the repair of spinal defects.
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Allogeneic Mesenchymal Precursor Cells Promote Healing in Postero-lateral Annular Lesions and Improve Indices of Lumbar Intervertebral Disc Degeneration in an Ovine Model. Spine (Phila Pa 1976) 2016; 41:1331-1339. [PMID: 26913464 DOI: 10.1097/brs.0000000000001528] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN In-vivo ovine model of intervertebral disc degeneration (IVD) to evaluate treatment with stem cells. OBJECTIVE To determine if stem cells delivered to the nucleus pulposus (NP) or the annulus fibrosus (AF) of degenerated lumbar IVDs leads to improved indices of disc health. SUMMARY OF BACKGROUND DATA Previous studies assessing the efficacy of stem cell injections into degenerated IVDs have reported positive findings. However, studies have been limited to small animals, targeting solely the NP, with short term follow-up. METHODS Mesenchymal precursor cells (MSC) were obtained from the iliac crest of 8-week-old sheep. IVD degeneration was induced by postero-lateral annulotomy at three lumbar levels in eight 2-year-old sheep. Six months later, each degenerated IVD was randomized to one of three treatments: Injection of MSC into (i) previously incised AF (AFI), (ii) NP (NPI), or (iii) no injection (negative control, NC). The adjacent IVD received injection of phosphate buffered saline into NP (positive control, PC). Radiographs and magnetic resonance imaging scans were obtained at baseline, 6, 9, and 12 months. Discs were harvested at 12 months for biochemical and histological analyses. RESULTS IVD degeneration was consistently observed postannulotomy, and characterized by reduced disc height index (DHI), disc height (DH), glycosaminoglycan (GAG) content, and increased grade of disc degeneration.Six months after stem cell injection, DHI and DH had recovered in AFI and NPI groups when compared with NC group (P < 0.01). Mean Pfirrmann grade improved from 3.25 to 2.67 (AFI group) and from 2.96 to 2.43 (NPI group). Mean histopathological grade improved for both AFI (P < 0.002) and NPI (P < 0.02) groups. Both AFI and NPI groups demonstrated spontaneous repair of the postero-lateral annular lesion. CONCLUSION In this large animal model, injection of MSCs into the annulus fibrosus or the nucleus pulposus of degenerated IVD resulted in significant improvements in disc health. LEVEL OF EVIDENCE N/A.
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Moriguchi Y, Alimi M, Khair T, Manolarakis G, Berlin C, Bonassar LJ, Härtl R. Biological Treatment Approaches for Degenerative Disk Disease: A Literature Review of In Vivo Animal and Clinical Data. Global Spine J 2016; 6:497-518. [PMID: 27433434 PMCID: PMC4947401 DOI: 10.1055/s-0036-1571955] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2015] [Accepted: 09/24/2015] [Indexed: 12/11/2022] Open
Abstract
STUDY DESIGN Literature review. OBJECTIVE Degenerative disk disease (DDD) has a negative impact on quality of life and is a major cause of morbidity worldwide. There has been a growing interest in the biological repair of DDD by both researchers and clinicians alike. To generate an overview of the recent progress in reparative strategies for the treatment of DDD highlighting their promises and limitations, a comprehensive review of the current literature was performed elucidating data from in vivo animal and clinical studies. METHODS Articles and abstracts available in electronic databases of PubMed, Web of Science, and Google Scholar as of December 2014 were reviewed. Additionally, data from unpublished, ongoing clinical trials was retrieved from clinicaltrials.gov and available abstracts from research forums. Data was extracted from the most recent in vivo animal or clinical studies involving any of the following: (1) treatment with biomolecules, cells, or tissue-engineered constructs and (2) annulus fibrosus repair. RESULTS Seventy-five articles met the inclusion criteria for review. Among these, 17 studies involved humans; 37, small quadrupeds; and 21, large quadrupeds. Findings from all treatments employed demonstrated improvement either in regenerative capacity or in pain attenuation, with the exception of one clinical study. CONCLUSION Published clinical studies on cell therapy have reported encouraging results in the treatment of DDD and resultant back pain. We expect new data to emerge in the near future as treatments for DDD continue to evolve in parallel to our greater understanding of disk health and pathology.
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Affiliation(s)
- Yu Moriguchi
- Weill Cornell Brain and Spine Center, Department of Neurological Surgery, Weill Cornell Medicine, New York-Presbyterian Hospital, New York, New York, United States
| | - Marjan Alimi
- Weill Cornell Brain and Spine Center, Department of Neurological Surgery, Weill Cornell Medicine, New York-Presbyterian Hospital, New York, New York, United States
| | - Thamina Khair
- Weill Cornell Brain and Spine Center, Department of Neurological Surgery, Weill Cornell Medicine, New York-Presbyterian Hospital, New York, New York, United States
| | - George Manolarakis
- Weill Cornell Brain and Spine Center, Department of Neurological Surgery, Weill Cornell Medicine, New York-Presbyterian Hospital, New York, New York, United States
| | - Connor Berlin
- Weill Cornell Brain and Spine Center, Department of Neurological Surgery, Weill Cornell Medicine, New York-Presbyterian Hospital, New York, New York, United States
| | - Lawrence J. Bonassar
- Department of Biomedical Engineering, Cornell University, Ithaca, New York, United States
| | - Roger Härtl
- Weill Cornell Brain and Spine Center, Department of Neurological Surgery, Weill Cornell Medicine, New York-Presbyterian Hospital, New York, New York, United States
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A Review of Animal Models of Intervertebral Disc Degeneration: Pathophysiology, Regeneration, and Translation to the Clinic. BIOMED RESEARCH INTERNATIONAL 2016; 2016:5952165. [PMID: 27314030 PMCID: PMC4893450 DOI: 10.1155/2016/5952165] [Citation(s) in RCA: 195] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/18/2016] [Accepted: 05/03/2016] [Indexed: 12/19/2022]
Abstract
Lower back pain is the leading cause of disability worldwide. Discogenic pain secondary to intervertebral disc degeneration is a significant cause of low back pain. Disc degeneration is a complex multifactorial process. Animal models are essential to furthering understanding of the degenerative process and testing potential therapies. The adult human lumbar intervertebral disc is characterized by the loss of notochordal cells, relatively large size, essentially avascular nature, and exposure to biomechanical stresses influenced by bipedalism. Animal models are compared with regard to the above characteristics. Numerous methods of inducing disc degeneration are reported. Broadly these can be considered under the categories of spontaneous degeneration, mechanical and structural models. The purpose of such animal models is to further our understanding and, ultimately, improve treatment of disc degeneration. The role of animal models of disc degeneration in translational research leading to clinical trials of novel cellular therapies is explored.
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Abstract
Numerous health care resources are utilized to treat low back pain (LBP) resulting from degenerative disc disease (DDD). Most patients with disc degeneration remain asymptomatic, and the degree of disc degeneration does not correlate with pain severity, making diagnosis and effective treatment challenging.
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Oehme D, Ghosh P, Goldschlager T, Itescu S, Shimon S, Wu J, McDonald C, Troupis JM, Rosenfeld JV, Jenkin G. Reconstitution of degenerated ovine lumbar discs by STRO-3-positive allogeneic mesenchymal precursor cells combined with pentosan polysulfate. J Neurosurg Spine 2016; 24:715-26. [PMID: 26799116 DOI: 10.3171/2015.8.spine141097] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
OBJECTIVE Disc degeneration and associated low-back pain are major causes of suffering and disability. The authors examined the potential of mesenchymal precursor cells (MPCs), when formulated with pentosan polysulfate (PPS), to ameliorate disc degeneration in an ovine model. METHODS Twenty-four sheep had annular incisions made at L2-3, L3-4, and L4-5 to induce degeneration. Twelve weeks after injury, the nucleus pulposus of a degenerated disc in each animal was injected with ProFreeze and PPS formulated with either a low dose (0.1 million MPCs) or a high dose (0.5 million MPCs) of cells. The 2 adjacent injured discs in each spine were either injected with PPS and ProFreeze (PPS control) or not injected (nil-injected control). The adjacent noninjured L1-2 and L5-6 discs served as noninjured control discs. Disc height indices (DHIs) were obtained at baseline, before injection, and at planned death. After necropsy, 24 weeks after injection, the spines were subjected to MRI and morphological, histological, and biochemical analyses. RESULTS Twelve weeks after the annular injury, all the injured discs exhibited a significant reduction in mean DHI (low-dose group 17.19%; high-dose group 18.01% [p < 0.01]). Twenty-four weeks after injections, the discs injected with the low-dose MPC+PPS formulation recovered disc height, and their mean DHI was significantly greater than the DHI of PPS- and nil-injected discs (p < 0.001). Although the mean Pfirrmann MRI disc degeneration score for the low-dose MPC+PPS-injected discs was lower than that for the nil- and PPS-injected discs, the differences were not significant. The disc morphology scores for the nil- and PPS-injected discs were significantly higher than the normal control disc scores (p < 0.005), whereas the low-dose MPC+PPS-injected disc scores were not significantly different from those of the normal controls. The mean glycosaminoglycan content of the nuclei pulposus of the low-dose MPC+PPS-injected discs was significantly higher than that of the PPS-injected controls (p < 0.05) but was not significantly different from the normal control disc glycosaminoglycan levels. Histopathology degeneration frequency scores for the low-dose MPC+PPS-injected discs were lower than those for the PPS- and Nil-injected discs. The corresponding high-dose MPC+PPS-injected discs failed to show significant improvements in any outcome measure relative to the controls. CONCLUSIONS Intradiscal injections of a formulation composed of 0.1 million MPCs combined with PPS resulted in positive effects in reducing the progression of disc degeneration in an ovine model, as assessed by improvements in DHI and morphological, biochemical, and histopathological scores.
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Affiliation(s)
- David Oehme
- The Ritchie Centre, MIMR-PHI Institute, Monash University, Clayton, Victoria
| | - Peter Ghosh
- The Ritchie Centre, MIMR-PHI Institute, Monash University, Clayton, Victoria;,Proteobioactives, Pty Ltd, Brookvale, New South Wales;,Mesoblast Ltd, Melbourne
| | - Tony Goldschlager
- The Ritchie Centre, MIMR-PHI Institute, Monash University, Clayton, Victoria;,Mesoblast Ltd, Melbourne
| | | | - Susan Shimon
- Proteobioactives, Pty Ltd, Brookvale, New South Wales
| | - Jiehua Wu
- Proteobioactives, Pty Ltd, Brookvale, New South Wales
| | - Courtney McDonald
- The Ritchie Centre, MIMR-PHI Institute, Monash University, Clayton, Victoria
| | | | - Jeffrey V Rosenfeld
- Department of Surgery, Monash University, Clayton; and.,Department of Neurosurgery, Alfred Hospital, Melbourne, Victoria, Australia
| | - Graham Jenkin
- The Ritchie Centre, MIMR-PHI Institute, Monash University, Clayton, Victoria
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Multipotent Mesenchymal Stem Cell Treatment for Discogenic Low Back Pain and Disc Degeneration. Stem Cells Int 2016; 2016:3908389. [PMID: 26880958 PMCID: PMC4737050 DOI: 10.1155/2016/3908389] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2015] [Accepted: 10/18/2015] [Indexed: 01/07/2023] Open
Abstract
Low back pain with resultant loss of function, decreased productivity, and high economic costs is burdensome for both the individual and the society. Evidence suggests that intervertebral disc pathology is a major contributor to spine-related pain and degeneration. When commonly used conservative therapies fail, traditional percutaneous or surgical options may be beneficial for pain relief but are suboptimal because of their inability to alter disc microenvironment catabolism, restore disc tissue, and/or preserve native spine biomechanics. Percutaneously injected Multipotent Mesenchymal Stem Cell (MSC) therapy has recently gained clinical interest for its potential to revolutionarily treat disc-generated (discogenic) pain and associated disc degeneration. Unlike previous therapies to date, MSCs may uniquely offer the ability to improve discogenic pain and provide more sustained improvement by reducing disc microenvironment catabolism and regenerating disc tissue. Consistent treatment success has the potential to create a paradigm shift with regards to the treatment of discogenic pain and disc degeneration.
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O'Connell GD, Leach JK, Klineberg EO. Tissue Engineering a Biological Repair Strategy for Lumbar Disc Herniation. Biores Open Access 2015; 4:431-45. [PMID: 26634189 PMCID: PMC4652242 DOI: 10.1089/biores.2015.0034] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
The intervertebral disc is a critical part of the intersegmental soft tissue of the spinal column, providing flexibility and mobility, while absorbing large complex loads. Spinal disease, including disc herniation and degeneration, may be a significant contributor to low back pain. Clinically, disc herniations are treated with both nonoperative and operative methods. Operative treatment for disc herniation includes removal of the herniated material when neural compression occurs. While this strategy may have short-term advantages over nonoperative methods, the remaining disc material is not addressed and surgery for mild degeneration may have limited long-term advantage over nonoperative methods. Furthermore, disc herniation and surgery significantly alter the mechanical function of the disc joint, which may contribute to progression of degeneration in surrounding tissues. We reviewed recent advances in tissue engineering and regenerative medicine strategies that may have a significant impact on disc herniation repair. Our review on tissue engineering strategies focuses on cell-based and inductive methods, each commonly combined with material-based approaches. An ideal clinically relevant biological repair strategy will significantly reduce pain and repair and restore flexibility and motion of the spine.
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Affiliation(s)
- Grace D. O'Connell
- Department of Mechanical Engineering, University of California, Berkeley, Berkeley, California
| | - J. Kent Leach
- Department of Biomedical Engineering, University of California, Davis, Davis, California
- Department of Orthopedic Surgery, University of California, Davis Medical Center, Davis, California
| | - Eric O. Klineberg
- Department of Orthopedic Surgery, University of California, Davis Medical Center, Davis, California
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Ahn J, Park EM, Kim BJ, Kim JS, Choi B, Lee SH, Han I. Transplantation of human Wharton's jelly-derived mesenchymal stem cells highly expressing TGFβ receptors in a rabbit model of disc degeneration. Stem Cell Res Ther 2015; 6:190. [PMID: 26432097 PMCID: PMC4592544 DOI: 10.1186/s13287-015-0183-1] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2015] [Revised: 03/17/2015] [Accepted: 09/11/2015] [Indexed: 12/17/2022] Open
Abstract
Introduction Mesenchymal stem cells (MSCs) are widely considered to hold promise for the treatment of intervertebral disc (IVD) degeneration. However, variation in the therapeutic efficacy of MSCs is a major problem and the derivation of MSCs for use in IVD regeneration has not been optimized. Additionally, no data are available on the efficacy of Wharton’s Jelly-derived MSC (WJ-MSC) transplantation in an animal model of IVD degeneration. Methods This study evaluated the effectiveness of a cross-linked hyaluronic acid (XHA) scaffold loaded with human WJ-MSCs, according to their expression levels of transforming growth factor-β receptor I/activin-like kinase receptor 5 (TβRI/ALK5) and TβRII, for IVD regeneration in a rabbit model. We compared the degree of IVD regeneration between rabbits transplanted with a XHA scaffold loaded with WJ-MSCs highly and lowly expressing TβRI/ALK5 and TβRII (MSC-highTR and MSC-lowTR, respectively) using magnetic resonance imaging (MRI) and histological analysis. Results At 12 weeks after transplantation, T2-weighted MRI analysis showed significant restoration of the disc water content in rabbits treated with a MSC-highTR-loaded XHA scaffold in comparison to rabbits treated with the scaffold alone or a MSC-lowTR-loaded XHA scaffold. In addition, morphological and histological analyses revealed that IVD regeneration was highest in rabbits transplanted with a MSC-highTR-loaded XHA scaffold. Conclusion Taken together, our results suggest that a MSC-highTR-loaded XHA scaffold supports IVD regeneration more effectively than a MSC-lowTR-loaded XHA scaffold. This study supports the potential clinical use of MSC-highTR-loaded XHA scaffolds to halt IVD degeneration or to enhance IVD regeneration. Electronic supplementary material The online version of this article (doi:10.1186/s13287-015-0183-1) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Jongchan Ahn
- Department of Biomedical Science, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400, South Korea.
| | - Eun-Mi Park
- Department of Biomedical Science, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400, South Korea.
| | - Byeong Ju Kim
- Department of Biomedical Science, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400, South Korea.
| | - Jin-Soo Kim
- Department of Biomedical Science, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400, South Korea.
| | - Bogyu Choi
- Department of Biomedical Science, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400, South Korea.
| | - Soo-Hong Lee
- Department of Biomedical Science, CHA University, 335 Pangyo-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 463-400, South Korea.
| | - Inbo Han
- Department of Neurosurgery, CHA University, CHA Bundang Medical Center, 59 Yatap-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13496, South Korea.
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Potier E, Ito K. Can notochordal cells promote bone marrow stromal cell potential for nucleus pulposus enrichment? A simplified in vitro system. Tissue Eng Part A 2015; 20:3241-51. [PMID: 24873993 DOI: 10.1089/ten.tea.2013.0703] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Bone marrow stromal cells (BMSCs) have shown promising potential to stop intervertebral disc degeneration in several animal models. In order to restore a healthy state, though, this potential should be further stimulated. Notochordal cells (NCs), influential in disc development, have been shown to stimulate BMSC differentiation, but it is unclear how this effect will translate in an environment where resident disc cells (nucleus pulposus cells [NPCs]) could also influence BMSCs. The goal of this study was, therefore, to evaluate the effects of NCs on BMSCs when cocultured with NPCs, in a simplified 3D in vitro system. Bovine BMSCs and NPCs were mixed (Mix) and seeded into alginate beads. Using culture inserts, the Mix was then cocultured with porcine NCs (alginate beads) and compared to coculture with empty beads or porcine skin fibroblasts (SFs, alginate beads). NPCs alone were also cocultured with NCs, and BMSCs alone cultured under chondrogenic conditions. The effects of coculture conditions on cell viability, matrix production (proteoglycan and collagen), and gene expression of disc markers (aggrecan, type II collagen, and SOX9) were assessed after 4 weeks of culture. The NC phenotype and gene expression profile were also analyzed. Coculture with NCs did not significantly influence cell viability, proteoglycan production, or disc marker gene expression of the Mix. When compared to NPCs, the Mix produced the same amount of proteoglycan and displayed a higher expression of disc marker, indicating a stimulation of the BMSCs (and/or NPCs) in the Mix. Additionally, during the 4 weeks of culture, the NC phenotype changed drastically (morphology, gene expression profile). These results show that NCs might not be as stimulatory for BMSCs in an NPC-rich environment, as believed from individual cultures. This absence of effects could be explained by a mild stimulation provided by (de)differentiating NCs and the costimulation of BMSCs and NPCs by each other.
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Affiliation(s)
- Esther Potier
- 1 Orthopaedic Biomechanics, Department of Biomedical Engineering, Eindhoven University of Technology , Eindhoven, The Netherlands
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43
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McDonald CA, Oehme D, Pham Y, Kelly K, Itescu S, Gibbon A, Jenkin G. Evaluation of the safety and tolerability of a high-dose intravenous infusion of allogeneic mesenchymal precursor cells. Cytotherapy 2015; 17:1178-87. [DOI: 10.1016/j.jcyt.2015.05.007] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2014] [Revised: 04/23/2015] [Accepted: 05/14/2015] [Indexed: 12/13/2022]
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Veizi E, Hayek S. Interventional therapies for chronic low back pain. Neuromodulation 2015; 17 Suppl 2:31-45. [PMID: 25395115 DOI: 10.1111/ner.12250] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2014] [Revised: 08/28/2014] [Accepted: 08/31/2014] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Low back pain (LBP) is a highly prevalent condition and one of the leading causes of lost productivity and health-care costs. The objective of this review is to discuss the role of interventional pain procedures and evidence of their effectiveness in treatment of chronic LBP. METHODS This is a narrative review examining published studies on interventional procedures for LBP. The rationales, indications, technique, evidence, and complications for the interventional procedures are discussed. RESULTS Interventional pain procedures are used extensively in diagnosis and treatment of chronic pain. LBP is multifactorial, and while significant progress has been made in understanding its pathophysiology, this has not resulted in a proportional improvement of functional outcomes. For certain procedures, such as spinal cord stimulation, medical branch blocks and radiofrequency ablations, and epidural steroid injections for radiculopathy, safety, efficacy, and cost-effectiveness in treating LBP have been well studied. For others, such as interventions for discogenic pain, treatment successes have been modest at best. CONCLUSIONS Implementation of interventional pain procedures in the treatment framework of LBP has resulted in improvement of pain intensity in at least the short and medium terms, but equivocal results have been observed in functional improvement.
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Affiliation(s)
- Elias Veizi
- Department of Anesthesiology, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH, USA; Pain Medicine & Spine Care, Louis Stokes Cleveland Veterans Affairs Medical Center, Cleveland, OH, USA
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Cell-Based Therapies Used to Treat Lumbar Degenerative Disc Disease: A Systematic Review of Animal Studies and Human Clinical Trials. Stem Cells Int 2015; 2015:946031. [PMID: 26074979 PMCID: PMC4446495 DOI: 10.1155/2015/946031] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2015] [Revised: 04/08/2015] [Accepted: 04/15/2015] [Indexed: 01/07/2023] Open
Abstract
Low back pain and degenerative disc disease are a significant cause of pain and disability worldwide. Advances in regenerative medicine and cell-based therapies, particularly the transplantation of mesenchymal stem cells and intervertebral disc chondrocytes, have led to the publication of numerous studies and clinical trials utilising these biological therapies to treat degenerative spinal conditions, often reporting favourable outcomes. Stem cell mediated disc regeneration may bridge the gap between the two current alternatives for patients with low back pain, often inadequate pain management at one end and invasive surgery at the other. Through cartilage formation and disc regeneration or via modification of pain pathways stem cells are well suited to enhance spinal surgery practice. This paper will systematically review the current status of basic science studies, preclinical and clinical trials utilising cell-based therapies to repair the degenerate intervertebral disc. The mechanism of action of transplanted cells, as well as the limitations of published studies, will be discussed.
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46
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Dooley LM, Abdalmula A, Washington EA, Kaufman C, Tudor EM, Ghosh P, Itescu S, Kimpton WG, Bailey SR. Effect of mesenchymal precursor cells on the systemic inflammatory response and endothelial dysfunction in an ovine model of collagen-induced arthritis. PLoS One 2015; 10:e0124144. [PMID: 25950840 PMCID: PMC4423911 DOI: 10.1371/journal.pone.0124144] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2014] [Accepted: 03/10/2015] [Indexed: 02/07/2023] Open
Abstract
Background and Aim Mesenchymal precursor cells (MPC) are reported to possess immunomodulatory properties that may prove beneficial in autoimmune and other inflammatory conditions. However, their mechanism of action is poorly understood. A collagen-induced arthritis model has been previously developed which demonstrates local joint inflammation and systemic inflammatory changes. These include not only increased levels of inflammatory markers, but also vascular endothelial cell dysfunction, characterised by reduced endothelium-dependent vasodilation. This study aimed to characterise the changes in systemic inflammatory markers and endothelial function following the intravenous administration of MPC, in the ovine model. Methods Arthritis was induced in sixteen adult sheep by administration of bovine type II collagen into the hock joint following initial sensitisation. After 24h, sheep were administered either 150 million allogeneic ovine MPCs intravenously, or saline only. Fibrinogen and serum amyloid-A were measured in plasma to assess systemic inflammation, along with pro-inflammatory and anti-inflammatory cytokines. Animals were necropsied two weeks following arthritis induction. Coronary and digital arterial segments were mounted in a Mulvaney-Halpern wire myograph. The relaxant response to endothelium-dependent and endothelium-independent vasodilators was used to assess endothelial dysfunction. Results and Conclusion Arthritic sheep treated with MPC demonstrated a marked spike in plasma IL-10, 24h following MPC administration. They also showed significantly reduced plasma levels of the inflammatory markers, fibrinogen and serum amyloid A, and increased HDL. Coronary arteries from RA sheep treated with MPCs demonstrated a significantly greater maximal relaxation to bradykinin when compared to untreated RA sheep (253.6 ± 17.1% of pre-contracted tone vs. 182.3 ± 27.3% in controls), and digital arteries also demonstrated greater endothelium-dependent vasodilation. This study demonstrated that MPCs given intravenously are able to attenuate systemic inflammatory changes associated with a monoarthritis, including the development of endothelial dysfunction.
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Affiliation(s)
- Laura M. Dooley
- Faculty of Veterinary Science, The University of Melbourne, Parkville, Victoria, Australia
| | - Anwar Abdalmula
- Faculty of Veterinary Science, The University of Melbourne, Parkville, Victoria, Australia
| | | | - Claire Kaufman
- Faculty of Veterinary Science, The University of Melbourne, Parkville, Victoria, Australia
| | - Elizabeth M. Tudor
- Faculty of Veterinary Science, The University of Melbourne, Parkville, Victoria, Australia
| | - Peter Ghosh
- Mesoblast Ltd, Melbourne, Victoria, Australia
| | | | - Wayne G. Kimpton
- Faculty of Veterinary Science, The University of Melbourne, Parkville, Victoria, Australia
| | - Simon R. Bailey
- Faculty of Veterinary Science, The University of Melbourne, Parkville, Victoria, Australia
- * E-mail:
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Wang Z, Perez-Terzic CM, Smith J, Mauck WD, Shelerud RA, Maus TP, Yang TH, Murad MH, Gou S, Terry MJ, Dauffenbach JP, Pingree MJ, Eldrige JS, Mohammed K, Benkhadra K, van Wijnen AJ, Qu W. Efficacy of intervertebral disc regeneration with stem cells - a systematic review and meta-analysis of animal controlled trials. Gene 2015; 564:1-8. [PMID: 25796605 DOI: 10.1016/j.gene.2015.03.022] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Accepted: 03/13/2015] [Indexed: 12/25/2022]
Abstract
Management of intervertebral disc (IVD) degenerative disease is challenging, as it is accompanied by irreversible loss of IVD cells. Stem cell transplantation to the disc has shown promise in decelerating or arresting the degenerative process. Multiple pre-clinical animal trials have been conducted, but with conflicting outcomes. To assess the effect of stem cell transplantation, a systematic review and meta-analysis was performed. A comprehensive literature search was conducted through Week 3, 2015. Inclusion criteria consisted of controlled animal trials. Two reviewers screened abstracts and full texts. Disagreements were resolved by a third reviewer. Random effects models were constructed to pool standardized mean difference (SMD). Twenty two studies were included; nine of which were randomized. Statistically significant differences were found with the stem cell group exhibiting increased disc height index (SMD=3.64, 95% confidence interval (CI): 2.49, 4.78; p<0.001), increased MRI T2 signal intensity (SMD=2.28, 95% CI: 1.48, 3.08; p<0.001), increased Type II collagen mRNA expression (SMD=3.68, 95% CI: 1.66, 5.70; p<0.001), and decreased histologic disc degeneration grade (SMD=-2.97, 95% CI: -3.97, -1.97; p<0.001). There was statistical heterogeneity between studies that could not be explained with pre-planned subgroup analyses based on animal species, study designs, and transplanted cell types. Stem cells transplanted to the IVD in quadruped animals decelerate or arrest the IVD degenerative process. Further studies in human clinical trials will be needed to understand if such benefit can be translated to bipedal humans.
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Affiliation(s)
- Zhen Wang
- Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN 55905, USA
| | - Carman M Perez-Terzic
- Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN 55905, USA; Rehabilitation Medicine Research Center, Mayo Clinic, Rochester, MN 55905, USA
| | - Jay Smith
- Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN 55905, USA
| | - William D Mauck
- Department of Anesthesiology Pain Division, Mayo Clinic, Rochester, MN 55905, USA
| | - Randy A Shelerud
- Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN 55905, USA; Spine Center, Mayo Clinic, Rochester, MN 55905, USA
| | - Timothy P Maus
- Department of Radiology, Mayo Clinic, Rochester, MN 55905, USA
| | - Tai-Hua Yang
- Department of Biomedical Engineering, National Cheng Kung University, Taiwan; Biomechanics Laboratory and Tendon and Soft Tissue Biology Laboratory, Division of Orthopedic Research, Mayo Clinic, Rochester, MN 55905, USA
| | - Mohammad Hassan Murad
- Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN 55905, USA
| | - Shanmiao Gou
- Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN 55905, USA; Department of Anesthesiology Pain Division, Mayo Clinic, Rochester, MN 55905, USA
| | - Marisa J Terry
- Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN 55905, USA
| | - Jason P Dauffenbach
- Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN 55905, USA
| | - Mathew J Pingree
- Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN 55905, USA; Department of Anesthesiology Pain Division, Mayo Clinic, Rochester, MN 55905, USA
| | - Jason S Eldrige
- Department of Anesthesiology Pain Division, Mayo Clinic, Rochester, MN 55905, USA
| | - Khaled Mohammed
- Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN 55905, USA
| | - Khalid Benkhadra
- Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN 55905, USA
| | | | - Wenchun Qu
- Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN 55905, USA; Department of Anesthesiology Pain Division, Mayo Clinic, Rochester, MN 55905, USA; Spine Center, Mayo Clinic, Rochester, MN 55905, USA.
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Oehme D, Goldschlager T, Rosenfeld JV, Ghosh P, Jenkin G. The role of stem cell therapies in degenerative lumbar spine disease: a review. Neurosurg Rev 2015; 38:429-45. [PMID: 25749802 DOI: 10.1007/s10143-015-0621-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2013] [Revised: 06/23/2014] [Accepted: 01/18/2015] [Indexed: 02/06/2023]
Abstract
Degenerative conditions of the lumbar spine are extremely common. Ninety percent of people over the age of 60 years have degenerative change on imaging; however, only a small minority of people will require spine surgery (Hicks et al. Spine (Phila Pa 1976) 34(12):1301-1306, 2009). This minority, however, constitutes a core element of spinal surgery practice. Whilst the patient outcomes from spinal surgeries have improved in recent years, some patients will remain with pain and disability despite technically successful surgery. Advances in regenerative medicine and stem cell therapies, particularly the use of mesenchymal stem cells and allogeneic mesenchymal precursor cells, have led to numerous clinical trials utilising these cell-based therapies to treat degenerative spinal conditions. Through cartilage formation and disc regeneration, fusion enhancement or via modification of pain pathways, stem cells are well suited to enhance spinal surgery practice. This review will focus on the outcomes of lumbar spinal procedures and the role of stem cells in the treatment of degenerative lumbar conditions to enhance clinical practice. The current status of clinical trials utilising stem cell therapies will be discussed, providing clinicians with an overview of the various cell-based treatments likely to be available to patients in the near future.
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Affiliation(s)
- David Oehme
- The Ritchie Centre, MIM-PHI Institute of Medical Research, Monash University Clayton Victoria, PO Box 6178, Clayton, VIC, 3141, Australia,
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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: 335] [Impact Index Per Article: 33.5] [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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Chen HJ, Chen CH, Chang MY, Tsai DC, Baum EZ, Hariri R, Herzberg U, Hsieh PCH. Human placenta-derived adherent cells improve cardiac performance in mice with chronic heart failure. Stem Cells Transl Med 2015; 4:269-75. [PMID: 25673767 DOI: 10.5966/sctm.2014-0135] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Human placenta-derived adherent cells (PDACs) are a culture-expanded, undifferentiated mesenchymal-like population derived from full-term placental tissue, with immunomodulatory, anti-inflammatory, angiogenic, and neuroprotective properties. PDA-001 (cenplacel-L), an intravenous formulation of PDAC cells, is in clinical development for the treatment of autoimmune and inflammatory diseases. We tested the therapeutic effects of PDA-001 in mice with chronic heart failure (CHF). Three weeks after transaortic constriction surgery to induce CHF, the mice underwent direct intramyocardial (IM) or i.v. injection of PDA-001 at a high (0.5 × 10(6) cells per mouse), medium (0.5 × 10(5) cells per mouse), or low (0.5 × 10(4) cells per mouse) dose. The mice were sacrificed 4 weeks after treatment. Echocardiography and ventricular catheterization showed that IM injection of PDA-001 significantly improved left ventricular systolic and diastolic function compared with injection of vehicle or i.v. injection of PDA-001. IM injection of PDA-001 also decreased cardiac fibrosis, shown by trichrome staining in the vicinity of the injection sites. Low-dose treatment showed the best improvement in cardiac performance compared with the medium- and high-dose groups. In another independent study to determine the mechanism of action with bromodeoxyuridine labeling, the proliferation rates of endothelial cells and cardiomyocytes were significantly increased by low or medium IM dose PDA-001. However, no surviving PDA-001 cells were detected in the heart 1 month after injection. In vivo real-time imaging consistently revealed that the PDA-001 cells were detectable only within 2 days after IM injection of luciferase-expressing PDA-001. Together, these results have demonstrated the cardiac therapeutic potential of PDA-001, likely through a paracrine effect.
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Affiliation(s)
- Hong-Jung Chen
- Celgene Cellular Therapeutics, Warren, New Jersey, USA; Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China
| | - Chien-Hsi Chen
- Celgene Cellular Therapeutics, Warren, New Jersey, USA; Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China
| | - Ming-Yao Chang
- Celgene Cellular Therapeutics, Warren, New Jersey, USA; Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China
| | - Da-Ching Tsai
- Celgene Cellular Therapeutics, Warren, New Jersey, USA; Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China
| | - Ellen Z Baum
- Celgene Cellular Therapeutics, Warren, New Jersey, USA; Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China
| | - Robert Hariri
- Celgene Cellular Therapeutics, Warren, New Jersey, USA; Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China
| | - Uri Herzberg
- Celgene Cellular Therapeutics, Warren, New Jersey, USA; Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China
| | - Patrick C H Hsieh
- Celgene Cellular Therapeutics, Warren, New Jersey, USA; Institute of Clinical Medicine, National Cheng Kung University, Tainan, Taiwan, Republic of China; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, Republic of China
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