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Rajagopal K, Schaer TP, Meadows KD, Boyes M, Hilliard R, O'Donnell JC, Dodge GR, Petrov D, Elliott DM, Mauck RL, Smith LJ, Malhotra NR. In Vivo Measurements Reveal Increased Nucleus Pulposus Lactate and Oxygen Concentrations in a Goat Model of Intervertebral Disc Degeneration. JOR Spine 2025; 8:e70076. [PMID: 40438632 PMCID: PMC12116463 DOI: 10.1002/jsp2.70076] [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: 09/25/2024] [Revised: 04/20/2025] [Accepted: 04/22/2025] [Indexed: 06/01/2025] Open
Abstract
Introduction Intervertebral disc degeneration is strongly implicated as a cause of low back pain. Although the precise pathophysiological mechanisms remain elusive, perturbations in nutrition that adversely impact the cellular microenvironment of the central nucleus pulposus (NP) may be contributing factors. A comprehensive understanding of this microenvironment, including changes in nutrient availability as a function of degeneration, is critical for the development of effective cell-based treatments. The goal of this study was to adapt brain tissue oxygen probes and microdialysis catheters for in situ determination of relative NP oxygen, glucose, and lactate levels in a preclinical goat model of disc degeneration. Methods Following ex vivo technical refinement in bovine caudal discs, baseline metabolite measurements were performed in vivo in the lumbar discs of 3 large frame goats. Degeneration was then induced via injection of chondroitinase ABC (ChABC) into the NP, and measurements were repeated after 12 weeks. Degeneration severity was graded using magnetic resonance imaging (MRI) and histology, and vertebral endplate porosity was assessed using microcomputed tomography. Results Oxygen and lactate levels in goat NPs were significantly higher in degenerate compared to healthy discs, while glucose levels were not significantly different. ChABC-injected discs exhibited higher vertebral endplate porosity, worse histological and MRI grades, and a spectrum of cartilage endplate damage compared to healthy discs. There were significant positive correlations between MRI grade and both NP oxygen and lactate levels. Discussion We successfully adapted techniques including surgical placement, equilibration time, flow rate, and detection method for in situ measurement of oxygen, glucose, and lactate in a goat model of disc degeneration. Interestingly, while increased lactate with degeneration was expected, increased oxygen levels were unexpected. Our findings may, in part, be explained by associated alterations in disc and endplate structure, and motivate future studies to comprehensively establish the underlying mechanisms in this model.
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Affiliation(s)
- Karthikeyan Rajagopal
- Translational Musculoskeletal Research CenterCorporal Michael J. Crescenz VA Medical CenterPhiladelphiaPennsylvaniaUSA
- Department of Orthopaedic SurgeryPerelman School of Medicine, University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Thomas P. Schaer
- Translational Musculoskeletal Research CenterCorporal Michael J. Crescenz VA Medical CenterPhiladelphiaPennsylvaniaUSA
- Department of Clinical StudiesNew Bolton Center, School of Veterinary Medicine, University of PennsylvaniaKennett SquarePennsylvaniaUSA
| | - Kyle D. Meadows
- Department of Biomedical EngineeringUniversity of DelawareNewarkDelawareUSA
| | - Madeline Boyes
- Department of Clinical StudiesNew Bolton Center, School of Veterinary Medicine, University of PennsylvaniaKennett SquarePennsylvaniaUSA
| | - Rachel Hilliard
- Department of Clinical StudiesNew Bolton Center, School of Veterinary Medicine, University of PennsylvaniaKennett SquarePennsylvaniaUSA
| | - John C. O'Donnell
- Department of NeurosurgeryPerelman School of Medicine, University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Center for Neurotrauma, Neurodegeneration and RestorationCorporal Michael J. Crescenz VA Medical CenterPhiladelphiaPennsylvaniaUSA
| | - George R. Dodge
- Department of Orthopaedic SurgeryPerelman School of Medicine, University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Dmitriy Petrov
- Department of NeurosurgeryPerelman School of Medicine, University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Dawn M. Elliott
- Department of Biomedical EngineeringUniversity of DelawareNewarkDelawareUSA
| | - Robert L. Mauck
- Translational Musculoskeletal Research CenterCorporal Michael J. Crescenz VA Medical CenterPhiladelphiaPennsylvaniaUSA
- Department of Orthopaedic SurgeryPerelman School of Medicine, University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Lachlan J. Smith
- Translational Musculoskeletal Research CenterCorporal Michael J. Crescenz VA Medical CenterPhiladelphiaPennsylvaniaUSA
- Department of Orthopaedic SurgeryPerelman School of Medicine, University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Department of NeurosurgeryPerelman School of Medicine, University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
| | - Neil R. Malhotra
- Translational Musculoskeletal Research CenterCorporal Michael J. Crescenz VA Medical CenterPhiladelphiaPennsylvaniaUSA
- Department of Orthopaedic SurgeryPerelman School of Medicine, University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
- Department of NeurosurgeryPerelman School of Medicine, University of PennsylvaniaPhiladelphiaPennsylvaniaUSA
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Chen G, Bian C, Cheng X, Xu J, Zhou K, Zhang Y. Bio-engineered thermo-sensitive alginate/PNIA-g-CS co-polymeric injectable hydrogel laden with GDF-5 to stimulate nucleus pulposus for IVD regeneration. J Biol Eng 2025; 19:49. [PMID: 40405200 PMCID: PMC12100944 DOI: 10.1186/s13036-025-00520-0] [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] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Accepted: 05/05/2025] [Indexed: 05/24/2025] Open
Abstract
Chronic back pain and disability are primarily caused by intervertebral disc degeneration (IDD) that requires novel therapies to regenerate the nucleus pulposus (NP) and restore disc function. In this study, a bioengineered thermo-sensitive injectable hydrogel composed of co-polymeric poly-N-isopropyl acrylamide-grafted-chondroitin sulfate cross-linked with sodium alginate microspheres (PNIA-g-CS-NaA Ms: denote HMs) loaded with growth differentiation factor 5 (GDF-5), to stimulate Nucleus Pulposus cells (NPCs) activity and promote intervertebral disc (IVD) regeneration. The Low critical solution temperature (LCST) of PNIA-g-CS was 31.8 and 32.3 °C at 5% (w/v) and 15% (w/v), respectively. In the in vitro study, GDF-5-loaded hydrogel (1 mg/mL) marginally enhanced NPC proliferation and reduced inflammatory cytokines (TNF-α, IL-6, IL-1β) after 24 h. HMs-GDF-5 combined with Adipose-Derived Mesenchymal Stem Cells (ADMSCs) was delivered to NP tissue using a minimally invasive technique, promoting NP regeneration in rats. At 8 weeks, significant upregulation of COL-II and ACAN proteins and mRNA expressions was observed. X-ray imaging showed disc height recovery and increased water content, while histology revealed partial restoration of NPCs and matrix. The outcomes show that the biodegradable hydrogel could be used as a potential therapeutic agent for IVD repair.
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Affiliation(s)
- Guangnan Chen
- Department of Orthopedics Surgery, Minhang Hospital, Fudan University, NO.170, Xin Song Road, Shanghai, 201199, China
| | - Chong Bian
- Department of Orthopedics Surgery, Minhang Hospital, Fudan University, NO.170, Xin Song Road, Shanghai, 201199, China
| | - Xiangyang Cheng
- Department of Orthopedics Surgery, Minhang Hospital, Fudan University, NO.170, Xin Song Road, Shanghai, 201199, China
| | - Jun Xu
- Department of Orthopedics Surgery, Minhang Hospital, Fudan University, NO.170, Xin Song Road, Shanghai, 201199, China
| | - Kaifeng Zhou
- Department of Orthopedics Surgery, Minhang Hospital, Fudan University, NO.170, Xin Song Road, Shanghai, 201199, China
| | - Yiming Zhang
- Department of Orthopedics Surgery, Minhang Hospital, Fudan University, NO.170, Xin Song Road, Shanghai, 201199, China.
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Keshavarz S, Alavi CE, Aghayan H, Jafari-Shakib R, Vojoudi E. Advancements in Degenerative Disc Disease Treatment: A Regenerative Medicine Approach. Stem Cell Rev Rep 2025:10.1007/s12015-025-10882-z. [PMID: 40232618 DOI: 10.1007/s12015-025-10882-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/07/2025] [Indexed: 04/16/2025]
Abstract
Regenerative medicine represents a transformative approach to treating nucleus pulposus degeneration and offers hope for patients suffering from chronic low back pain due to disc degeneration. By focusing on restoring the natural structure and function of the nucleus pulposus rather than merely alleviating symptoms, these innovative therapies hold the potential to significantly improve patient outcomes. As research continues to advance in this field, we may soon witness a paradigm shift in how we approach spinal health and degenerative disc disease. The main purpose of this review is to provide an overview of the various regenerative approaches that target the restoration of the nucleus pulposus, a primary site for initiation of intervertebral disc degeneration.
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Affiliation(s)
- Samaneh Keshavarz
- School of Paramedicine, Guilan University of Medical Sciences, Rasht, Iran
| | - Cyrus Emir Alavi
- Department of Anesthesiology, Neuroscience Research Center, Avicenna University Hospital, Guilan University of Medical Sciences, Rasht, Iran
| | - Hamidreza Aghayan
- Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular- Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Jafari-Shakib
- Department of Immunology, School of Medicine, Guilan University of Medical Sciences, P.O.Box 41635 - 3363, Rasht, Iran.
| | - Elham Vojoudi
- Regenerative Medicine, Organ Procurement and Transplantation Multidisciplinary Center, School of Medicine, Razi Hospital, Guilan University of Medical Sciences, Rasht, Iran.
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Chen X, Li H, Huang B, Ruan J, Li X, Li Q. High impact works on stem cell transplantation in intervertebral disc degeneration. BMC Musculoskelet Disord 2024; 25:1029. [PMID: 39702055 DOI: 10.1186/s12891-024-08131-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2024] [Accepted: 11/29/2024] [Indexed: 12/21/2024] Open
Abstract
BACKGROUND Low back pain is a major disorder that causes disability and is strongly associated with intervertebral disc degeneration (IDD). Because of the limitations of contemporary interventions, stem cell transplantation (SCT) has been increasingly used to regenerate degenerative discs. Nevertheless, analyses of high-impact papers in this field are rare. This study aimed to determine and analyze the 100 highest-cited documents on SCT in IDD. METHODS The 100 highest-cited documents were retrieved from the Web of Science (WoS) database. Descriptive statistics were calculated and correlation analysis was conducted to determine the relationship between WoS citations, the Altmetric Attention Score (AAS), and Dimensions citations. RESULTS The citation counts of the top 100 most cited papers ranged from 13 to 372. These studies were conducted in 17 countries and were published in 48 journals between 2003 and 2021. The top three contributing countries were the China (31), United States (22), and Japan (14). Bone marrow-derived stem cells were the most common type of stem cells (70.00%), followed by adipose-derived stem cells (13.75%), and nucleus pulposus-derived stem cells (7.50). Rabbit was the most studied species (41.25%), followed by rat (21.25%), human (13.75%), sheep (8.75%), dog (8.75%), and pig (6.25%). Tokai University School of Medicine (11) had the largest number of documents, followed by The University of Hong Kong (8), and Southeast University (4). Sakai D (10) was the most fruitful author, followed by Cheung KMC (6), Melrose J (3), Pettine K (3), Lotz JC (3), and Murphy MB (3). We observed a very high correlation between the WoS and Dimensions citations (p < 0.001, r = 0.994). CONCLUSIONS This study highlights the highest impact works on SCT in IDD, thereby providing a deeper understanding of the historical works related to SCT in IDD, as well as benefits for future studies in this field.
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Affiliation(s)
- Xiaofeng Chen
- Department of Orthopedics, Panyu Hospital of Chinese Medicine, Guangzhou, China
| | - Hao Li
- Department of Orthopedics, Panyu Hospital of Chinese Medicine, Guangzhou, China
| | - Baoci Huang
- Department of Ultrasound, Guangdong Second Provincial General Hospital Guangzhou City, Guangzhou, China
| | - Jiajian Ruan
- Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xi Li
- Department of Dermatology, Panyu Hospital of Chinese Medicine, Guangzhou, China.
| | - Qian Li
- Guangzhou University of Chinese Medicine, Guangzhou, China.
- Department of Dermatology, Panyu Hospital of Chinese Medicine, Guangzhou, China.
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Qian G, Yu Y, Dong Y, Hong Y, Wang M. Exosomes derived from human urine-derived stem cells ameliorate IL-1β-induced intervertebral disk degeneration. BMC Musculoskelet Disord 2024; 25:537. [PMID: 38997667 PMCID: PMC11241922 DOI: 10.1186/s12891-024-07636-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 06/27/2024] [Indexed: 07/14/2024] Open
Abstract
BACKGROUND Human intervertebral disk degeneration (IVDD) is a sophisticated degenerative pathological process. A key cause of IVDD progression is nucleus pulposus cell (NPC) degeneration, which contributes to excessive endoplasmic reticulum stress in the intervertebral disk. However, the mechanisms underlying IVDD and NPC degeneration remain unclear. METHODS We used interleukin (IL)-1β stimulation to establish an NPC-degenerated IVDD model and investigated whether human urine-derived stem cell (USC) exosomes could prevent IL-1β-induced NPC degeneration using western blotting, quantitative real-time polymerase chain reaction, flow cytometry, and transcriptome sequencing techniques. RESULTS We successfully extracted and identified USCs and exosomes from human urine. IL-1β substantially downregulated NPC viability and induced NPC degeneration while modulating the expression of SOX-9, collagen II, and aggrecan. Exosomes from USCs could rescue IL-1β-induced NPC degeneration and restore the expression levels of SOX-9, collagen II, and aggrecan. CONCLUSIONS USC-derived exosomes can prevent NPCs from degeneration following IL-1β stimulation. This finding can aid the development of a potential treatment strategy for IVDD.
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Grants
- 2020WYZT01 Scientific Research Project funded by Shanghai Fifth People 's Hospital, Fudan University
- 2020WYZT01 Scientific Research Project funded by Shanghai Fifth People 's Hospital, Fudan University
- 2020WYZT01 Scientific Research Project funded by Shanghai Fifth People 's Hospital, Fudan University
- 2020WYZT01 Scientific Research Project funded by Shanghai Fifth People 's Hospital, Fudan University
- 2020WYZT01 Scientific Research Project funded by Shanghai Fifth People 's Hospital, Fudan University
- 2022MHZ073 Natural Science Research Funds of Minhang District, Shanghai
- 2022MHZ073 Natural Science Research Funds of Minhang District, Shanghai
- 2022MHZ073 Natural Science Research Funds of Minhang District, Shanghai
- 2022MHZ073 Natural Science Research Funds of Minhang District, Shanghai
- 2022MHZ073 Natural Science Research Funds of Minhang District, Shanghai
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Affiliation(s)
- Guang Qian
- Department of Orthopedics, Shanghai Fifth People's Hospital, Fudan University, No. 801, Heqing Road, Minhang District, Shanghai, 200240, China
| | - Yueming Yu
- Department of Orthopedics, Shanghai Fifth People's Hospital, Fudan University, No. 801, Heqing Road, Minhang District, Shanghai, 200240, China
| | - Youhai Dong
- Department of Orthopedics, Shanghai Fifth People's Hospital, Fudan University, No. 801, Heqing Road, Minhang District, Shanghai, 200240, China
| | - Yang Hong
- Department of Orthopedics, Shanghai Fifth People's Hospital, Fudan University, No. 801, Heqing Road, Minhang District, Shanghai, 200240, China
| | - Minghai Wang
- Department of Orthopedics, Shanghai Fifth People's Hospital, Fudan University, No. 801, Heqing Road, Minhang District, Shanghai, 200240, China.
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de Oliveira CAA, Oliveira BS, Theodoro R, Wang J, Santos GS, Rodrigues BL, Rodrigues IJ, Jorge DDMF, Jeyaraman M, Everts PA, Navani A, Lana JF. Orthobiologic Management Options for Degenerative Disc Disease. Bioengineering (Basel) 2024; 11:591. [PMID: 38927827 PMCID: PMC11200769 DOI: 10.3390/bioengineering11060591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 05/20/2024] [Accepted: 05/22/2024] [Indexed: 06/28/2024] Open
Abstract
Degenerative disc disease (DDD) is a pervasive condition that limits quality of life and burdens economies worldwide. Conventional pharmacological treatments primarily aimed at slowing the progression of degeneration have demonstrated limited long-term efficacy and often do not address the underlying causes of the disease. On the other hand, orthobiologics are regenerative agents derived from the patient's own tissue and represent a promising emerging therapy for degenerative disc disease. This review comprehensively outlines the pathophysiology of DDD, highlighting the inadequacies of existing pharmacological therapies and detailing the potential of orthobiologic approaches. It explores advanced tools such as platelet-rich plasma and mesenchymal stem cells, providing a historical overview of their development within regenerative medicine, from foundational in vitro studies to preclinical animal models. Moreover, the manuscript delves into clinical trials that assess the effectiveness of these therapies in managing DDD. While the current clinical evidence is promising, it remains insufficient for routine clinical adoption due to limitations in study designs. The review emphasizes the need for further research to optimize these therapies for consistent and effective clinical outcomes, potentially revolutionizing the management of DDD and offering renewed hope for patients.
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Affiliation(s)
| | - Bernardo Scaldini Oliveira
- Orthopedics, ABCOliveira Medical Clinic, São Paulo 03310-000, SP, Brazil; (C.A.A.d.O.); (B.S.O.); (R.T.)
| | - Rafael Theodoro
- Orthopedics, ABCOliveira Medical Clinic, São Paulo 03310-000, SP, Brazil; (C.A.A.d.O.); (B.S.O.); (R.T.)
| | - Joshua Wang
- Learning and Teaching Unit, Queensland University of Technology, Brisbane, QLD 4059, Australia;
| | - Gabriel Silva Santos
- Department of Orthopedics, Brazilian Institute of Regenerative Medicine (BIRM), Indaiatuba 13334-170, SP, Brazil; (B.L.R.); (I.J.R.); (D.d.M.F.J.); (J.F.L.)
- Regenerative Medicine, Orthoregen International Course, Indaiatuba 13334-170, SP, Brazil; (M.J.); (P.A.E.); (A.N.)
| | - Bruno Lima Rodrigues
- Department of Orthopedics, Brazilian Institute of Regenerative Medicine (BIRM), Indaiatuba 13334-170, SP, Brazil; (B.L.R.); (I.J.R.); (D.d.M.F.J.); (J.F.L.)
- Regenerative Medicine, Orthoregen International Course, Indaiatuba 13334-170, SP, Brazil; (M.J.); (P.A.E.); (A.N.)
| | - Izair Jefthé Rodrigues
- Department of Orthopedics, Brazilian Institute of Regenerative Medicine (BIRM), Indaiatuba 13334-170, SP, Brazil; (B.L.R.); (I.J.R.); (D.d.M.F.J.); (J.F.L.)
| | - Daniel de Moraes Ferreira Jorge
- Department of Orthopedics, Brazilian Institute of Regenerative Medicine (BIRM), Indaiatuba 13334-170, SP, Brazil; (B.L.R.); (I.J.R.); (D.d.M.F.J.); (J.F.L.)
- Regenerative Medicine, Orthoregen International Course, Indaiatuba 13334-170, SP, Brazil; (M.J.); (P.A.E.); (A.N.)
| | - Madhan Jeyaraman
- Regenerative Medicine, Orthoregen International Course, Indaiatuba 13334-170, SP, Brazil; (M.J.); (P.A.E.); (A.N.)
- Department of Orthopaedics, ACS Medical College and Hospital, Dr MGR Educational and Research Institute, Chennai 600077, Tamil Nadu, India
| | - Peter Albert Everts
- Regenerative Medicine, Orthoregen International Course, Indaiatuba 13334-170, SP, Brazil; (M.J.); (P.A.E.); (A.N.)
- Medical School, Max Planck University Center (UniMAX), Indaiatuba 13343-060, SP, Brazil
| | - Annu Navani
- Regenerative Medicine, Orthoregen International Course, Indaiatuba 13334-170, SP, Brazil; (M.J.); (P.A.E.); (A.N.)
- Medical Director, Le Reve, San Jose, CA 95124, USA
- Chief Medical Officer, Boomerang Healthcare, Walnut Creek, CA 94598, USA
| | - José Fábio Lana
- Department of Orthopedics, Brazilian Institute of Regenerative Medicine (BIRM), Indaiatuba 13334-170, SP, Brazil; (B.L.R.); (I.J.R.); (D.d.M.F.J.); (J.F.L.)
- Regenerative Medicine, Orthoregen International Course, Indaiatuba 13334-170, SP, Brazil; (M.J.); (P.A.E.); (A.N.)
- Medical School, Max Planck University Center (UniMAX), Indaiatuba 13343-060, SP, Brazil
- Medical School, Jaguariúna University Center (UniFAJ), Jaguariúna 13918-110, SP, Brazil
- Clinical Research, Anna Vitória Lana Institute (IAVL), Indaiatuba 13334-170, SP, Brazil
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Ukeba D, Ishikawa Y, Yamada K, Ohnishi T, Tachi H, Tha KK, Iwasaki N, Sudo H. Bone Marrow Aspirate Concentrate Combined with Ultra-Purified Alginate Bioresorbable Gel Enhances Intervertebral Disc Repair in a Canine Model: A Preclinical Proof-of-Concept Study. Cells 2024; 13:987. [PMID: 38891119 PMCID: PMC11172114 DOI: 10.3390/cells13110987] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Revised: 06/03/2024] [Accepted: 06/04/2024] [Indexed: 06/21/2024] Open
Abstract
Although discectomy is commonly performed for lumbar intervertebral disc (IVD) herniation, the capacity for tissue repair after surgery is limited, resulting in residual lower back pain, recurrence of IVD herniation, and progression of IVD degeneration. Cell-based therapies, as one-step procedures, are desirable for enhancing IVD repair. This study aimed to investigate the therapeutic efficacy of a combination of newly developed ultra-purified alginate (UPAL) gel and bone marrow aspirate concentrate (BMAC) implantation for IVD repair after discectomy. Prior to an in vivo study, the cell concentration abilities of three commercially available preparation kits for creating the BMAC were compared by measuring the number of bone marrow mesenchymal stem cells harvested from the bone marrow of rabbits. Subsequently, canine-derived BMAC was tested in a canine model using a kit which had the highest concentration rate. At 24 weeks after implantation, we evaluated the changes in the magnetic resonance imaging (MRI) signals as well as histological degeneration grade and immunohistochemical analysis results for type II and type I collagen-positive cells in the treated IVDs. In all quantitative evaluations, such as MRI and histological and immunohistochemical analyses of IVD degeneration, BMAC-UPAL implantation significantly suppressed the progression of IVD degeneration compared to discectomy and UPAL alone. This preclinical proof-of-concept study demonstrated the potential efficacy of BMAC-UPAL gel as a therapeutic strategy for implementation after discectomy, which was superior to UPAL and discectomy alone in terms of tissue repair and regenerative potential.
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Affiliation(s)
- Daisuke Ukeba
- Department of Orthopedic Surgery, Hokkaido University Hospital, N14W5, Sapporo, Hokkaido 060-8638, Japan; (D.U.); (Y.I.); (K.Y.); (T.O.); (H.T.); (N.I.)
| | - Yoko Ishikawa
- Department of Orthopedic Surgery, Hokkaido University Hospital, N14W5, Sapporo, Hokkaido 060-8638, Japan; (D.U.); (Y.I.); (K.Y.); (T.O.); (H.T.); (N.I.)
| | - Katsuhisa Yamada
- Department of Orthopedic Surgery, Hokkaido University Hospital, N14W5, Sapporo, Hokkaido 060-8638, Japan; (D.U.); (Y.I.); (K.Y.); (T.O.); (H.T.); (N.I.)
| | - Takashi Ohnishi
- Department of Orthopedic Surgery, Hokkaido University Hospital, N14W5, Sapporo, Hokkaido 060-8638, Japan; (D.U.); (Y.I.); (K.Y.); (T.O.); (H.T.); (N.I.)
| | - Hiroyuki Tachi
- Department of Orthopedic Surgery, Hokkaido University Hospital, N14W5, Sapporo, Hokkaido 060-8638, Japan; (D.U.); (Y.I.); (K.Y.); (T.O.); (H.T.); (N.I.)
| | - Khin Khin Tha
- Laboratory for Biomarker Imaging Science, Graduate School of Biomedical Science and Engineering, Hokkaido University, N15 W7, Kita-ku, Sapporo 060-8638, Japan;
| | - Norimasa Iwasaki
- Department of Orthopedic Surgery, Hokkaido University Hospital, N14W5, Sapporo, Hokkaido 060-8638, Japan; (D.U.); (Y.I.); (K.Y.); (T.O.); (H.T.); (N.I.)
| | - Hideki Sudo
- Department of Orthopedic Surgery, Hokkaido University Hospital, N14W5, Sapporo, Hokkaido 060-8638, Japan; (D.U.); (Y.I.); (K.Y.); (T.O.); (H.T.); (N.I.)
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Farag M, Rezk R, Hutchinson H, Zankevich A, Lucke‐Wold B. Intervertebral disc degeneration and regenerative medicine. CLINICAL AND TRANSLATIONAL DISCOVERY 2024; 4. [DOI: 10.1002/ctd2.289] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/28/2023] [Accepted: 03/15/2024] [Indexed: 01/08/2025]
Abstract
AbstractIntervertebral disc (IVD) degeneration is a common phenomenon that affects patients with increasing prevalence with increasing age. Both conservative treatments, such as the use of pain medication or physical therapy, and surgical treatments, such as fusion or disc replacement therapies, are offered to patients. Both non‐invasive and invasive treatments have been shown to improve pain and quality of life for patients. This review explores the role of regenerative medicine techniques as a promising therapeutic intervention that can be used before or in combination with conservative therapy and surgery to enhance the treatment process in patients with IVD degeneration or disc pathology. Currently, there are four major modules of regenerative medicine: genetic therapy, platelet‐rich plasma therapy, stem cell transplantation and tissue engineering. Several research studies have shown promising outcomes of stem cell transplantation and tissue engineering when combined with either surgical or conservative treatment, resulting in improved pain outcomes. The additional benefit of regenerative medicine techniques, specifically stem cell transplantation, is the potential for treating the root pathology of degeneration. Regenerative medicine techniques also have the potential to either halt or reverse degeneration as opposed to current standards of care for managing symptoms. There is a plethora of current research highlighting the benefits of regenerative medicine techniques; however, there remains clinical concerns and ethical concerns regarding the use of regenerative therapy techniques such as stem cell transplantation in the context of IVD degeneration.
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Affiliation(s)
| | - Rogina Rezk
- University of Florida Gainesville Florida USA
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Mizuno S, Vadala G, Kang JD. Biological Therapeutic Modalities for Intervertebral Disc Diseases: An Orthoregeneration Network (ON) Foundation Review. Arthroscopy 2024; 40:1019-1030. [PMID: 37918699 DOI: 10.1016/j.arthro.2023.10.032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Revised: 10/17/2023] [Accepted: 10/20/2023] [Indexed: 11/04/2023]
Abstract
Orthoregeneration is defined as a solution for orthopaedic conditions that harnesses the benefits of biology to improve healing, reduce pain, improve function, and, optimally, provide an environment for tissue regeneration. Options include drugs, surgical intervention, scaffolds, biologics as a product of cells, and physical and electromagnetic stimuli. The goal of regenerative medicine is to enhance the healing of tissue after musculoskeletal injuries as both isolated treatment and adjunct to surgical management, using novel therapies to improve recovery and outcomes. Various orthopaedic biologics (orthobiologics) have been investigated for the treatment of pathology involving the spine, including lower back pain, with or without numbness and/or dysfunction in the lower extremities, disc herniation, spinal stenosis, and spondylolisthesis. Promising and established treatment modalities include repair of the annulus fibrosis, injection of expanded or nonexpanded autologous or allogenic cells that are chondrogenic or from a stem cell lineage used to promote matrix tissue regeneration of the intervertebral disc, including nucleus pulpous cells and mesenchymal stem cells isolated from bone marrow, umbilical cord blood, or adipose tissue; and injection of platelet-rich plasma, platelet-rich fibrin, or fibrin sealant. Early clinical studies show promise for pain reduction and functional recovery. LEVEL OF EVIDENCE: Level V, expert opinion.
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Affiliation(s)
- Shuichi Mizuno
- Department of Orthopaedic Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, U.S.A
| | - Gianluca Vadala
- Laboratory for Regenerative Orthopaedics, Research Unit of Orthopaedic and Trauma Surgery, Department of Medicine and Surgery, Università Campus Bio-Medico di Roma, Rome, Italy; Operative Research Unit of Orthopaedic and Trauma Surgery, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
| | - James D Kang
- Department of Orthopaedic Surgery, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, U.S.A..
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10
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Soydan Z, Bayramoglu E, Urut DU, Iplikcioglu AC, Sen C. Tracing the disc: The novel qualitative morphometric MRI based disc degeneration classification system. JOR Spine 2024; 7:e1321. [PMID: 38500784 PMCID: PMC10945309 DOI: 10.1002/jsp2.1321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 01/20/2024] [Accepted: 02/25/2024] [Indexed: 03/20/2024] Open
Abstract
Background This study aimed to develop a classification system for lumbar disc degeneration using routine magnetic resonance images (MRIs) that is easily applicable and unaffected by existing classifications' limitations, and to compare its reliability, reproducibility, and discriminative power to the widely used Pfirrmann classification. Methods Five features were graded. This new classification system has eight grades, with at least one of these five features altering each grade. The T2-weighted sagittal images were acquired using a rapid spin-echo sequence with a repetition time of 2680 to 4900 milliseconds, an echo time of 100 to 109 milliseconds, and an echo train length of 17. Slice thick was 4 mm and the display field of view was 32 × 32 cm. The new classification system used five features: signal intensity, disc height, disc boundary regularity, and nucleus annulus separation. Increased signal intensity, decreased height, decreased regularity, and decreased nucleus-annulus separation indicated degeneration. Four raters classified 400 discs from 80 patients using the Pfirrmann and Novel systems. Statistical analyses were conducted to investigate reliability and correlation. Results The overall ICC and kappa values were found to be higher in the novel classification. (0.988 indicating excellent agreement for ICC and 0.76/0.94 indicating good-very good agreement for kappa). The Kendall tau c value, which shows the correlation between the two classifications and indicates the validity of the new classification, was 0.872, which is very strong. Through the use of cross-tabulations, the discriminatory power of the two newly added classification criteria was determined. Conclusions This study demonstrates the intra-rater and inter-rater reliability of an easy-to-use, discriminative novel morphometric MRI based classification system for lumbar disc degeneration. The differentiation of grades based on five distinct criteria may generate novel hypotheses regarding treatment selection and response monitoring, as well as new insights into the study of disc degeneration.
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Affiliation(s)
- Zafer Soydan
- BHT Clinic İstanbul Tema Hospital, Department of Orthopedics and TraumatologyNisantası UniversityIstanbulTurkey
| | - Emru Bayramoglu
- Department of Orthopedics and TraumatologyBursa City HospitalBursaTurkey
| | - Devrim Ulas Urut
- BHT Clinic İstanbul Tema HospitalDepartment of RadiologyIstanbulTurkey
| | | | - Cengiz Sen
- İstanbul UniversityDepartment of Orthopedics And TraumatologyIstanbulTurkey
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11
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Ye S, Chen R, Shi J, Wu Y. The most influential articles on stem cells in intervertebral disc degeneration. BMC Musculoskelet Disord 2024; 25:116. [PMID: 38331829 PMCID: PMC10851499 DOI: 10.1186/s12891-024-07253-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 02/02/2024] [Indexed: 02/10/2024] Open
Abstract
BACKGROUND Stem cell-related studies have been increasingly conducted to facilitate the regeneration of degenerative discs. However, analyses of high-impact articles focused on this topic are rare. This study aimed to determine and summarize the most-cited studies examining stem cells in the context of intervertebral disc degeneration (IDD). METHODS We searched the Web of Science (WoS) database for stem cell-related articles in IDD, and the 50 highest-cited papers were summarized. A correlation analysis was conducted to determine the relationship among WoS citations, Altmetric Attention Score (AAS), and Dimensions. RESULTS The number of citations of the top 50 manuscripts ranged from 92 to 370. The top three countries were the United States (14), China (10), and Japan (9). Spine (12) was the most prevalent journal, and this was followed by Biomaterials (6). Bone marrow-derived stem cells were the most common subject (38), and they were followed by nucleus pulposus-derived stem cells (4) and annulus fibrosus-derived stem cells (4). Humans were the most studied species (31), and the next most studied were rabbits (9) and rats (7). There was a very high correlation between WoS and Dimension citations (p < 0.001, r = 0.937). CONCLUSIONS For the first time, the highest impact articles examining stem cells in the context of IDD were assessed together. The current study provides a deepened understanding of historical studies focused on stem cells in IDD and is beneficial for future studies in this field.
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Affiliation(s)
- Shuxi Ye
- Department of Spine Surgery, Ganzhou People's Hospital, No 16, Meiguan Road, Ganzhou, 341099, China
| | - Rongchun Chen
- Department of Spine Surgery, Ganzhou People's Hospital, No 16, Meiguan Road, Ganzhou, 341099, China
| | - Jiangyou Shi
- Department of Spine Surgery, Ganzhou People's Hospital, No 16, Meiguan Road, Ganzhou, 341099, China.
| | - Yaohong Wu
- Department of Spine Surgery, Ganzhou People's Hospital, No 16, Meiguan Road, Ganzhou, 341099, China.
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12
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Li Y, Zhang K, Ai X, Zhang Q, Jiang L, Long J, Xu H, Feng C, Zhang Y, Tang G, Chong F, Wang L, Huang B. A Biomimetic Peptide Functions as Specific Extracellular Matrix for Quiescence of Stem Cells against Intervertebral Disc Degeneration. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2023; 19:e2300578. [PMID: 37423970 DOI: 10.1002/smll.202300578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 05/03/2023] [Indexed: 07/11/2023]
Abstract
Maintaining quiescence of stem cells is a potential way to decrease cell nutrition demand for restoring the organization. Herein, a biomimetic peptide to maintain quiescence of stem cells through C-X-C motif chemokine ligand 8 (CXCL8)-C-X-C motif chemokine receptor 1 (CXCR1) pathway against intervertebral disc degeneration (IVDD) is developed. First, it is confirmed that quiescence can be induced via inhibiting phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway in nucleus pulposus stem cells (NPSCs). Meanwhile, it is well known that CXCR1, a chemokine receptor, can be targeted by CXCL8, resulting in cell proliferation via activating PI3K/Akt/mTOR pathway. Second, a biomimetic peptide (OAFF) that can bind to CXCR1 and form fibrous networks on NPSCs, mimicking extracellular matrix formation is developed. The multivalent effect and long-term binding to CXCR1 on NPSCs of OAFF fibers offer forcefully competitive inhibition with natural CXCL8, which induces NPSCs quiescence and ultimately overcomes obstacle in intradiscal injection therapy. In rat caudal disc puncture model, OAFF nanofibers still maintain at 5 weeks after operation and inhibit degeneration process of intervertebral disc in terms of histopathology and imageology. In situ fibrillogenesis of biomimetic peptide on NPSCs provides promising stem cells for intradiscal injection therapy against IVDD.
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Affiliation(s)
- Yuan Li
- Department of Orthopedics, Xinqiao Hospital, Army Medical University, Chongqing, 400037, P. R. China
| | - Kuo Zhang
- CAS Center for Excellence in Nanoscience, CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), Beijing, 100190, P. R. China
| | - Xuezheng Ai
- Department of Orthopedics, Xinqiao Hospital, Army Medical University, Chongqing, 400037, P. R. China
| | - Qingshi Zhang
- CAS Center for Excellence in Nanoscience, CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), Beijing, 100190, P. R. China
| | - Lu Jiang
- Clinical Medicine Research Center, Xinqiao Hospital, Army Medical University, Chongqing, 400037, P. R. China
| | - Jiang Long
- Department of Orthopedics, Xinqiao Hospital, Army Medical University, Chongqing, 400037, P. R. China
| | - Huange Xu
- CAS Center for Excellence in Nanoscience, CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), Beijing, 100190, P. R. China
| | - Chencheng Feng
- Department of Orthopedics, Xinqiao Hospital, Army Medical University, Chongqing, 400037, P. R. China
| | - Yaqing Zhang
- Department of Orthopedics, Xinqiao Hospital, Army Medical University, Chongqing, 400037, P. R. China
| | - Guoke Tang
- Department of Orthopedics, Shanghai General Hospital, Shanghai Jiaotong University, Shanghai, 200080, P. R. China
| | - Fanli Chong
- Department of Orthopedics, Xinqiao Hospital, Army Medical University, Chongqing, 400037, P. R. China
| | - Lei Wang
- CAS Center for Excellence in Nanoscience, CAS Key Laboratory for Biological Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology (NCNST), Beijing, 100190, P. R. China
| | - Bo Huang
- Department of Orthopedics, Xinqiao Hospital, Army Medical University, Chongqing, 400037, P. R. China
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13
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Tang S, Gantt C, Salazar Puerta A, Bodine L, Khan S, Higuita‐Castro N, Purmessur D. Nonviral overexpression of Scleraxis or Mohawk drives reprogramming of degenerate human annulus fibrosus cells from a diseased to a healthy phenotype. JOR Spine 2023; 6:e1270. [PMID: 37780832 PMCID: PMC10540831 DOI: 10.1002/jsp2.1270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 05/17/2023] [Accepted: 06/06/2023] [Indexed: 10/03/2023] Open
Abstract
Background Intervertebral disc (IVD) degeneration is a major contributor to low back pain (LBP), yet there are no clinical therapies targeting the underlying pathology. The annulus fibrosus (AF) plays a critical role in maintaining IVD structure/function and undergoes degenerative changes such as matrix catabolism and inflammation. Thus, therapies targeting the AF are crucial to fully restore IVD function. Previously, we have shown nonviral delivery of transcription factors to push diseased nucleus pulposus cells to a healthy phenotype. As a next step in a proof-of-concept study, we report the use of Scleraxis (SCX) and Mohawk (MKX), which are critical for the development, maintenance, and regeneration of the AF and may have therapeutic potential to induce a healthy, pro-anabolic phenotype in diseased AF cells. Methods MKX and SCX plasmids were delivered via electroporation into diseased human AF cells from autopsy specimens and patients undergoing surgery for LBP. Transfected cells were cultured over 14 days and assessed for cell morphology, viability, density, gene expression of key phenotypic, inflammatory, matrix, pain markers, and collagen accumulation. Results AF cells demonstrated a fibroblastic phenotype posttreatment. Moreover, transfection of SCX and MKX resulted in significant upregulation of the respective genes, as well as SOX9. Transfected autopsy cells demonstrated upregulation of core extracellular matrix markers; however, this was observed to a lesser effect in surgical cells. Matrix-degrading enzymes and inflammatory cytokines were downregulated, suggesting a push toward a pro-anabolic, anti-inflammatory phenotype. Similarly, pain markers were downregulated over time in autopsy cells. At the protein level, collagen content was increased in both MKX and SCX transfected cells compared to controls. Conclusions This exploratory study demonstrates the potential of MKX or SCX to drive reprogramming in mild to moderately degenerate AF cells from autopsy and severely degenerate AF cells from surgical patients toward a healthy phenotype and may be a potential nonviral gene therapy for LBP.
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Affiliation(s)
- Shirley Tang
- Department of Biomedical EngineeringThe Ohio State UniversityColumbusOhioUSA
| | - Connor Gantt
- Department of Biomedical EngineeringThe Ohio State UniversityColumbusOhioUSA
| | - Ana Salazar Puerta
- Department of Biomedical EngineeringThe Ohio State UniversityColumbusOhioUSA
| | - Lucy Bodine
- Department of Mechanical EngineeringThe Ohio State UniversityColumbusOhioUSA
| | - Safdar Khan
- Department of OrthopedicsThe Ohio State University Wexner Medical CenterColumbusOhioUSA
| | | | - Devina Purmessur
- Department of Biomedical EngineeringThe Ohio State UniversityColumbusOhioUSA
- Department of OrthopedicsThe Ohio State University Wexner Medical CenterColumbusOhioUSA
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14
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Miranda L, Quaranta M, Oliva F, Maffulli N. Stem cells and discogenic back pain. Br Med Bull 2023; 146:73-87. [PMID: 37164906 PMCID: PMC10788843 DOI: 10.1093/bmb/ldad008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/25/2023] [Indexed: 05/12/2023]
Abstract
BACKGROUND Chronic low back pain, common from the sixth decade, negatively impacts the quality of life of patients and health care systems. Recently, mesenchymal stem cells (MSCs) have been introduced in the management of degenerative discogenic pain. The present study summarizes the current knowledge on the effectiveness of MSCs in patients with discogenic back pain. SOURCES OF DATA We performed a systematic review of the literature following the PRISMA guidelines. We searched PubMed and Google Scholar database, and identified 14 articles about management of chronic low back pain with MSCs injection therapy. We recorded information on type of stem cells employed, culture medium, clinical scores and MRI outcomes. AREAS OF AGREEMENT We identified a total of 303 patients. Ten studies used bone marrow stem cells. In the other four studies, different stem cells were used (of adipose, umbilical, or chondrocytic origin and a pre-packaged product). The most commonly used scores were Visual Analogue Scale and Oswestry Disability Index. AREAS OF CONTROVERSY There are few studies with many missing data. GROWING POINTS The studies analysed demonstrate that intradiscal injections of MSCs are effective on discogenic low-back pain. This effect may result from inhibition of nociceptors, reduction of catabolism and repair of injured or degenerated tissues. AREAS TIMELY FOR DEVELOPING RESEARCH Further research should define the most effective procedure, trying to standardize a single method.
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Affiliation(s)
- Luca Miranda
- Department of Musculoskeletal Disorders, Faculty of Medicine and Surgery, University of Salerno, Via Salvador Allende, 43, Baronissi SA 84081, Italy
- Clinica Ortopedica, Ospedale San Giovanni di Dio e Ruggi D’Aragona, Via San Leonardo, Salerno 84131, Italy
| | - Marco Quaranta
- Department of Musculoskeletal Disorders, Faculty of Medicine and Surgery, University of Salerno, Via Salvador Allende, 43, Baronissi SA 84081, Italy
- Clinica Ortopedica, Ospedale San Giovanni di Dio e Ruggi D’Aragona, Via San Leonardo, Salerno 84131, Italy
| | - Francesco Oliva
- Department of Musculoskeletal Disorders, Faculty of Medicine and Surgery, University of Salerno, Via Salvador Allende, 43, Baronissi SA 84081, Italy
- Clinica Ortopedica, Ospedale San Giovanni di Dio e Ruggi D’Aragona, Via San Leonardo, Salerno 84131, Italy
| | - Nicola Maffulli
- Department of Musculoskeletal Disorders, Faculty of Medicine and Surgery, University of Salerno, Via Salvador Allende, 43, Baronissi SA 84081, Italy
- Clinica Ortopedica, Ospedale San Giovanni di Dio e Ruggi D’Aragona, Via San Leonardo, Salerno 84131, Italy
- Centre for Sports and Exercise Medicine, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Mile End Hospital, 275 Bancroft Road, London E1 4DG, England
- Guy Hilton Research Centre, Faculty of Medicine, School of Pharmacy and Bioengineering, Keele University, Thornburrow Drive, Hartshill, Stoke-on-Trent ST4 7QB, England
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15
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Yang J, Liu L, Oda Y, Wada K, Ago M, Matsuda S, Hattori M, Goto T, Ishibashi S, Kawashima-Sonoyama Y, Matsuzaki Y, Taketani T. Extracellular Vesicles and Cx43-Gap Junction Channels Are the Main Routes for Mitochondrial Transfer from Ultra-Purified Mesenchymal Stem Cells, RECs. Int J Mol Sci 2023; 24:10294. [PMID: 37373439 DOI: 10.3390/ijms241210294] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 06/10/2023] [Accepted: 06/16/2023] [Indexed: 06/29/2023] Open
Abstract
Mitochondria are essential organelles for maintaining intracellular homeostasis. Their dysfunction can directly or indirectly affect cell functioning and is linked to multiple diseases. Donation of exogenous mitochondria is potentially a viable therapeutic strategy. For this, selecting appropriate donors of exogenous mitochondria is critical. We previously demonstrated that ultra-purified bone marrow-derived mesenchymal stem cells (RECs) have better stem cell properties and homogeneity than conventionally cultured bone marrow-derived mesenchymal stem cells. Here, we explored the effect of contact and noncontact systems on three possible mitochondrial transfer mechanisms involving tunneling nanotubes, connexin 43 (Cx43)-mediated gap junction channels (GJCs), and extracellular vesicles (Evs). We show that Evs and Cx43-GJCs provide the main mechanism for mitochondrial transfer from RECs. Through these two critical mitochondrial transfer pathways, RECs could transfer a greater number of mitochondria into mitochondria-deficient (ρ0) cells and could significantly restore mitochondrial functional parameters. Furthermore, we analyzed the effect of exosomes (EXO) on the rate of mitochondrial transfer from RECs and recovery of mitochondrial function. REC-derived EXO appeared to promote mitochondrial transfer and slightly improve the recovery of mtDNA content and oxidative phosphorylation in ρ0 cells. Thus, ultrapure, homogenous, and safe stem cell RECs could provide a potential therapeutic tool for diseases associated with mitochondrial dysfunction.
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Affiliation(s)
- Jiahao Yang
- Department of Pediatrics, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo 693-8501, Japan
| | - Lu Liu
- Department of Pediatrics, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo 693-8501, Japan
| | - Yasuaki Oda
- Department of Pediatrics, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo 693-8501, Japan
| | - Keisuke Wada
- Department of Pediatrics, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo 693-8501, Japan
| | - Mako Ago
- Department of Pediatrics, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo 693-8501, Japan
| | - Shinichiro Matsuda
- Department of Medical Oncology, Shimane University Hospital, 89-1 Enya-cho, Izumo 693-8501, Japan
| | - Miho Hattori
- Department of Pediatrics, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo 693-8501, Japan
| | - Tsukimi Goto
- Department of Pediatrics, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo 693-8501, Japan
| | - Shuichi Ishibashi
- Department of Digestive and General Surgery, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo 693-8501, Japan
| | - Yuki Kawashima-Sonoyama
- Department of Pediatrics, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo 693-8501, Japan
| | - Yumi Matsuzaki
- Department of Life Science, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo 693-8501, Japan
| | - Takeshi Taketani
- Department of Pediatrics, Faculty of Medicine, Shimane University, 89-1 Enya-cho, Izumo 693-8501, Japan
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16
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Schol J, Sakai D. Comprehensive narrative review on the analysis of outcomes from cell transplantation clinical trials for discogenic low back pain. NORTH AMERICAN SPINE SOCIETY JOURNAL 2023; 13:100195. [PMID: 36655116 PMCID: PMC9841054 DOI: 10.1016/j.xnsj.2022.100195] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 11/24/2022] [Accepted: 12/15/2022] [Indexed: 12/24/2022]
Abstract
Background Intervertebral disc (IVD) degeneration is one of the primary causes of low back pain (LBP) and despite a prominent prevalence, present treatment options remain inadequate for a large portion of LBP patients. New developments in regenerative therapeutics offer potentially powerful medical tools to modify this pathology, with specific focus on (stem) cell transplantations. Multiple clinical trials have since reported overall beneficial outcomes favoring cell therapy. Nonetheless, the significance of these improvements is often not (clearly) discussed. As such, this narrative review aims to summarize the significance of the reported improvements from human clinical trials on IVD-targeted cell therapy. Methods Through a comprehensive narrative review we discuss the improvements in pain, disability, quality of life, and imaging modalities and reported adverse events following cell therapy for discogenic pain. Results Most clinical trials were able to report clear and significant improvements in pain and disability outcomes. Imaging and quality of life improvements however were not as clearly reported but did present some enhancements for a select number of patients. Finally, whether cell therapy can outperform placebo treatment remains intangible. Conclusions Our review highlights the clinical significance of observed trends in pain and disability improvement. Nevertheless, reporting quality was found unsatisfactory and large-scale randomized controlled studies remain small in number. Future studies and articles should put more emphasis on improvements in imaging modalities and compare outcomes to (placebo) control groups to fully elucidate the efficacy and safety of cellular therapeutics against LBP.
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Affiliation(s)
- Jordy Schol
- Tokai University School of Medicine, Department of Orthopedic Surgery, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan
| | - Daisuke Sakai
- Tokai University School of Medicine, Department of Orthopedic Surgery, 143 Shimokasuya, Isehara, Kanagawa 259-1193, Japan
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17
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Suzuki H, Ura K, Ukeba D, Suyama T, Iwasaki N, Watanabe M, Matsuzaki Y, Yamada K, Sudo H. Injection of Ultra-Purified Stem Cells with Sodium Alginate Reduces Discogenic Pain in a Rat Model. Cells 2023; 12:cells12030505. [PMID: 36766847 PMCID: PMC9914726 DOI: 10.3390/cells12030505] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 01/21/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023] Open
Abstract
Intervertebral disc (IVD) degeneration is a major cause of low back pain. However, treatments directly approaching the etiology of IVD degeneration and discogenic pain are not yet established. We previously demonstrated that intradiscal implantation of cell-free bioresorbable ultra-purified alginate (UPAL) gel promotes tissue repair and reduces discogenic pain, and a combination of ultra-purified, Good Manufacturing Practice (GMP)-compliant, human bone marrow mesenchymal stem cells (rapidly expanding clones; RECs), and the UPAL gel increasingly enhanced IVD regeneration in animal models. This study investigated the therapeutic efficacy of injecting a mixture of REC and UPAL non-gelling solution for discogenic pain and IVD regeneration in a rat caudal nucleus pulposus punch model. REC and UPAL mixture and UPAL alone suppressed not only the expression of TNF-α, IL-6, and TrkA (p < 0.01, respectively), but also IVD degeneration and nociceptive behavior compared to punching alone (p < 0.01, respectively). Furthermore, REC and UPAL mixture suppressed these expression levels and nociceptive behavior compared to UPAL alone (p < 0.01, respectively). These results suggest that this minimally invasive treatment strategy with a single injection may be applied to treat discogenic pain and as a regenerative therapy.
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Affiliation(s)
- Hisataka Suzuki
- Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, N15W7, Sapporo 060-8638, Japan
| | - Katsuro Ura
- Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, N15W7, Sapporo 060-8638, Japan
| | - Daisuke Ukeba
- Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, N15W7, Sapporo 060-8638, Japan
| | - Takashi Suyama
- PuREC/Bio-Venture, Shimane University, Izumo 693-8501, Japan
| | - Norimasa Iwasaki
- Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, N15W7, Sapporo 060-8638, Japan
| | - Masatoki Watanabe
- Japan Tissue Engineering Co., Ltd. (J-TEC), Gamagori 443-0022, Japan
| | - Yumi Matsuzaki
- PuREC/Bio-Venture, Shimane University, Izumo 693-8501, Japan
| | - Katsuhisa Yamada
- Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, N15W7, Sapporo 060-8638, Japan
- Correspondence: (K.Y.); (H.S.)
| | - Hideki Sudo
- Department of Orthopedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, N15W7, Sapporo 060-8638, Japan
- Department of Advanced Medicine for Spine and Spinal Cord Disorders, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, N15W7, Sapporo 060-8638, Japan
- Correspondence: (K.Y.); (H.S.)
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18
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Calodney A, Vest AT. Discography. Regen Med 2023. [DOI: 10.1007/978-3-030-75517-1_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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19
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Chu G, Zhang W, Han F, Li K, Liu C, Wei Q, Wang H, Liu Y, Han F, Li B. The role of microenvironment in stem cell-based regeneration of intervertebral disc. Front Bioeng Biotechnol 2022; 10:968862. [PMID: 36017350 PMCID: PMC9395990 DOI: 10.3389/fbioe.2022.968862] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2022] [Accepted: 07/18/2022] [Indexed: 01/07/2023] Open
Abstract
Regenerative medicine for intervertebral disc (IVD) disease, by utilizing chondrocytes, IVD cells, and stem cells, has progressed to clinical trials in the treatment of back pain, and has been studied in various animal models of disc degeneration in the past decade. Stem cells exist in their natural microenvironment, which provides vital dynamic physical and chemical signals for their survival, proliferation and function. Long-term survival, function and fate of mesenchymal stem cells (MSCs) depend on the microenvironment in which they are transplanted. However, the transplanted MSCs and the endogenous disc cells were influenced by the complicated microenvironment in the degenerating disc with the changes of biochemical and biophysical components. It is important to understand how the MSCs and endogenous disc cells survive and thrive in the harsh microenvironment of the degenerative disc. Furthermore, materials containing stem cells and their natural microenvironment have good clinical effects. However, the implantation of tissue engineering IVD (TE-IVD) cannot provide a complete and dynamic microenvironment for MSCs. IVD graft substitutes may need further improvement to provide the best engineered MSC microenvironment. Additionally, the IVD progenitor cells inside the stem cell niches have been regarded as popular graft cells for IVD regeneration. However, it is still unclear whether actual IVD progenitor cells exist in degenerative spinal conditions. Therefore, the purpose of this review is fourfold: to discuss the presence of endogenous stem cells; to review and summarize the effects of the microenvironment in biological characteristics of MSC, especially those from IVD; to explore the feasibility and prospects of IVD graft substitutes and to elaborate state of the art in the use of MSC transplantation for IVD degeneration in vivo as well as their clinical application.
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Affiliation(s)
- Genglei Chu
- Orthopaedic Institute, Department of Orthopaedic Surgery, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, China
| | - Weidong Zhang
- Department of Orthopaedic Surgery, Affiliated Hospital of Nantong University, Nantong, China
| | - Feng Han
- Orthopaedic Institute, Department of Orthopaedic Surgery, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, China
| | - Kexin Li
- Orthopaedic Institute, Department of Orthopaedic Surgery, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, China
| | - Chengyuan Liu
- Orthopaedic Institute, Department of Orthopaedic Surgery, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, China
| | - Qiang Wei
- Orthopaedic Institute, Department of Orthopaedic Surgery, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, China
| | - Huan Wang
- Orthopaedic Institute, Department of Orthopaedic Surgery, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, China
| | - Yijie Liu
- Orthopaedic Institute, Department of Orthopaedic Surgery, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, China
| | - Fengxuan Han
- Orthopaedic Institute, Department of Orthopaedic Surgery, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, China
| | - Bin Li
- Orthopaedic Institute, Department of Orthopaedic Surgery, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, China
- Collaborative Innovation Center of Hematology, Suzhou Medical College, Soochow University, Suzhou, China
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20
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Bhujel B, Shin HE, Choi DJ, Han I. Mesenchymal Stem Cell-Derived Exosomes and Intervertebral Disc Regeneration: Review. Int J Mol Sci 2022; 23:7306. [PMID: 35806304 PMCID: PMC9267028 DOI: 10.3390/ijms23137306] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 06/27/2022] [Accepted: 06/28/2022] [Indexed: 02/07/2023] Open
Abstract
Intervertebral disc degeneration (IVDD) is a common cause of lower back pain (LBP), which burdens individuals and society as a whole. IVDD occurs as a result of aging, mechanical trauma, lifestyle factors, and certain genetic abnormalities, leads to loss of nucleus pulposus, alteration in the composition of the extracellular matrix, excessive oxidative stress, and inflammation in the intervertebral disc. Pharmacological and surgical interventions are considered a boon for the treatment of IVDD, but the effectiveness of those strategies is limited. Mesenchymal stem cells (MSCs) have recently emerged as a possible promising regenerative therapy for IVDD due to their paracrine effect, restoration of the degenerated cells, and capacity for differentiation into disc cells. Recent investigations have shown that the pleiotropic effect of MSCs is not related to differentiation capacity but is mediated by the secretion of soluble paracrine factors. Early studies have demonstrated that MSC-derived exosomes have therapeutic potential for treating IVDD by promoting cell proliferation, tissue regeneration, modulation of the inflammatory response, and reduced apoptosis. This paper highlights the current state of MSC-derived exosomes in the field of treatment of IVDD with further possible future developments, applications, and challenges.
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Affiliation(s)
- Basanta Bhujel
- Department of Biomedical Science, College of Life Sciences, CHA University, Seongnam-si 13496, Korea; (B.B.); (H.-E.S.)
| | - Hae-Eun Shin
- Department of Biomedical Science, College of Life Sciences, CHA University, Seongnam-si 13496, Korea; (B.B.); (H.-E.S.)
| | - Dong-Jun Choi
- Department of Medicine, CHA Univerity School of Medicine, Seongnam-si 13496, Korea;
| | - Inbo Han
- Department of Neurosurgery, CHA University School of Medicine, CHA Bundang Medical Center, Seongnam-si 13496, Korea
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21
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Zehra U, Tryfonidou M, Iatridis JC, Illien-Jünger S, Mwale F, Samartzis D. Mechanisms and clinical implications of intervertebral disc calcification. Nat Rev Rheumatol 2022; 18:352-362. [PMID: 35534553 PMCID: PMC9210932 DOI: 10.1038/s41584-022-00783-7] [Citation(s) in RCA: 72] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/06/2022] [Indexed: 12/19/2022]
Abstract
Low back pain is a leading cause of disability worldwide. Intervertebral disc (IVD) degeneration is often associated with low back pain but is sometimes asymptomatic. IVD calcification is an often overlooked disc phenotype that might have considerable clinical impact. IVD calcification is not a rare finding in ageing or in degenerative and scoliotic spinal conditions, but is often ignored and under-reported. IVD calcification may lead to stiffer IVDs and altered segmental biomechanics, more severe IVD degeneration, inflammation and low back pain. Calcification is not restricted to the IVD but is also observed in the degeneration of other cartilaginous tissues, such as joint cartilage, and is involved in the tissue inflammatory process. Furthermore, IVD calcification may also affect the vertebral endplate, leading to Modic changes (non-neoplastic subchondral vertebral bone marrow lesions) and the generation of pain. Such effects in the spine might develop in similar ways to the development of subchondral marrow lesions of the knee, which are associated with osteoarthritis-related pain. We propose that IVD calcification is a phenotypic biomarker of clinically relevant disc degeneration and endplate changes. As IVD calcification has implications for the management and prognosis of degenerative spinal changes and could affect targeted therapeutics and regenerative approaches for the spine, awareness of IVD calcification should be raised in the spine community.
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Affiliation(s)
- Uruj Zehra
- Department of Anatomy, University of Health Sciences, Lahore, Pakistan
| | - Marianna Tryfonidou
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - James C Iatridis
- Leni & Peter W. May Department of Orthopaedics, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | | | - Fackson Mwale
- Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital and Department of Surgery, McGill University, Montreal, QC, Canada
| | - Dino Samartzis
- Department of Orthopaedic Surgery, Rush University Medical Center, Chicago, IL, USA.
- International Spine Research and Innovation Initiative, Rush University Medical Center, Chicago, IL, USA.
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22
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Low-dose mesenchymal stem cell therapy for discogenic pain: safety and efficacy results from a 1-year feasibility study. Future Sci OA 2022; 8:FSO794. [PMID: 35662742 PMCID: PMC9136638 DOI: 10.2144/fsoa-2021-0155] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Accepted: 03/22/2022] [Indexed: 11/23/2022] Open
Abstract
Aim: To evaluate safety and efficacy of low dose autologous adipose-derived mesenchymal stem cells (ADMSCs) for treatment of disc degeneration resulting in low back pain (LBP). Methods: Nine participants with chronic LBP originating from single-level lumbar disc disease underwent intradiscal injection of 10 million ADMSCs with optional repetition after 6 months. Results: No unexpected or serious adverse events were recorded. Seven (78%) of participants reported reductions in pain 12 months after treatment. Five (56%) reported increased work capacity. Three (33%) reduced analgesic medication. Improvements in EQ-5D and Oswestry disability index results were observed. MRI demonstrated no further disc degeneration and improvements to annular fissures and disc protrusions. Conclusion: This study provides initial evidence of safety and efficacy of ADMSCs for discogenic LBP.
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23
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Seki S, Iwasaki M, Makino H, Yahara Y, Miyazaki Y, Kamei K, Futakawa H, Nogami M, Tran Canh Tung N, Hirokawa T, Tsuji M, Kawaguchi Y. Direct Reprogramming and Induction of Human Dermal Fibroblasts to Differentiate into iPS-Derived Nucleus Pulposus-like Cells in 3D Culture. Int J Mol Sci 2022; 23:4059. [PMID: 35409417 PMCID: PMC8999916 DOI: 10.3390/ijms23074059] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 04/02/2022] [Accepted: 04/04/2022] [Indexed: 12/14/2022] Open
Abstract
Intervertebral disc (IVD) diseases are common spinal disorders that cause neck or back pain in the presence or absence of an underlying neurological disorder. IVD diseases develop on the basis of degeneration, and there are no established treatments for degeneration. IVD diseases may therefore represent a candidate for the application of regenerative medicine, potentially employing normal human dermal fibroblasts (NHDFs) induced to differentiate into nucleus pulposus (NP) cells. Here, we used a three-dimensional culture system to demonstrate that ectopic expression of MYC, KLF4, NOTO, SOX5, SOX6, and SOX9 in NHDFs generated NP-like cells, detected using Safranin-O staining. Quantitative PCR, microarray analysis, and fluorescence-activated cell sorting revealed that the induced NP cells exhibited a fully differentiated phenotype. These findings may significantly contribute to the development of effective strategies for treating IVD diseases.
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Affiliation(s)
- Shoji Seki
- Department of Orthopaedic Surgery, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan; (M.I.); (H.M.); (K.K.); (H.F.); (M.N.); (N.T.C.T.); (T.H.); (M.T.); (Y.K.)
| | - Mami Iwasaki
- Department of Orthopaedic Surgery, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan; (M.I.); (H.M.); (K.K.); (H.F.); (M.N.); (N.T.C.T.); (T.H.); (M.T.); (Y.K.)
| | - Hiroto Makino
- Department of Orthopaedic Surgery, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan; (M.I.); (H.M.); (K.K.); (H.F.); (M.N.); (N.T.C.T.); (T.H.); (M.T.); (Y.K.)
| | - Yasuhito Yahara
- Department of Molecular and Medical Pharmacology, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan;
| | | | - Katsuhiko Kamei
- Department of Orthopaedic Surgery, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan; (M.I.); (H.M.); (K.K.); (H.F.); (M.N.); (N.T.C.T.); (T.H.); (M.T.); (Y.K.)
| | - Hayato Futakawa
- Department of Orthopaedic Surgery, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan; (M.I.); (H.M.); (K.K.); (H.F.); (M.N.); (N.T.C.T.); (T.H.); (M.T.); (Y.K.)
| | - Makiko Nogami
- Department of Orthopaedic Surgery, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan; (M.I.); (H.M.); (K.K.); (H.F.); (M.N.); (N.T.C.T.); (T.H.); (M.T.); (Y.K.)
| | - Nguyen Tran Canh Tung
- Department of Orthopaedic Surgery, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan; (M.I.); (H.M.); (K.K.); (H.F.); (M.N.); (N.T.C.T.); (T.H.); (M.T.); (Y.K.)
- Department of Trauma and Orthopaedic Surgery, Vietnam Military Medical University, Hanoi 100000, Vietnam
| | - Tatsuro Hirokawa
- Department of Orthopaedic Surgery, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan; (M.I.); (H.M.); (K.K.); (H.F.); (M.N.); (N.T.C.T.); (T.H.); (M.T.); (Y.K.)
| | - Mamiko Tsuji
- Department of Orthopaedic Surgery, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan; (M.I.); (H.M.); (K.K.); (H.F.); (M.N.); (N.T.C.T.); (T.H.); (M.T.); (Y.K.)
| | - Yoshiharu Kawaguchi
- Department of Orthopaedic Surgery, Faculty of Medicine, University of Toyama, Toyama 930-0194, Japan; (M.I.); (H.M.); (K.K.); (H.F.); (M.N.); (N.T.C.T.); (T.H.); (M.T.); (Y.K.)
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24
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Sakai D, Schol J, Watanabe M. Clinical Development of Regenerative Medicine Targeted for Intervertebral Disc Disease. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:267. [PMID: 35208590 PMCID: PMC8878570 DOI: 10.3390/medicina58020267] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/31/2021] [Revised: 01/31/2022] [Accepted: 02/08/2022] [Indexed: 02/06/2023]
Abstract
Low back pain is critical health, social, and economic issue in modern societies. This disease is often associated with intervertebral disc degeneration; however, contemporary treatments are unable to target this underlying pathology to alleviate the pain symptoms. Cell therapy offers a promising novel therapeutic that, in theory, should be able to reduce low back pain through mitigating the degenerative disc environment. With the clinical development of cell therapeutics ongoing, this review aims to summarize reporting on the different clinical trials and assess the different regenerative strategies being undertaken to collectively obtain an impression on the potential safety and effectiveness of cell therapeutics against intervertebral disc-related diseases.
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Affiliation(s)
- Daisuke Sakai
- Department of Orthopaedic Surgery, Surgical Science, School of Medicine, Tokai University, Isehara 259-1193, Japan; (J.S.); (M.W.)
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25
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Yamada K, Iwasaki N, Sudo H. Biomaterials and Cell-Based Regenerative Therapies for Intervertebral Disc Degeneration with a Focus on Biological and Biomechanical Functional Repair: Targeting Treatments for Disc Herniation. Cells 2022; 11:602. [PMID: 35203253 PMCID: PMC8870062 DOI: 10.3390/cells11040602] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2021] [Revised: 01/22/2022] [Accepted: 02/07/2022] [Indexed: 12/11/2022] Open
Abstract
Intervertebral disc (IVD) degeneration is a common cause of low back pain and most spinal disorders. As IVD degeneration is a major obstacle to the healthy life of so many individuals, it is a major issue that needs to be overcome. Currently, there is no clinical treatment for the regeneration of degenerated IVDs. However, recent advances in regenerative medicine and tissue engineering suggest the potential of cell-based and/or biomaterial-based IVD regeneration therapies. These treatments may be indicated for patients with IVDs in the intermediate degenerative stage, a point where the number of viable cells decreases, and the structural integrity of the disc begins to collapse. However, there are many biological, biomechanical, and clinical challenges that must be overcome before the clinical application of these IVD regeneration therapies can be realized. This review summarizes the basic research and clinical trials literature on cell-based and biomaterial-based IVD regenerative therapies and outlines the important role of these strategies in regenerative treatment for IVD degenerative diseases, especially disc herniation.
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Affiliation(s)
- Katsuhisa Yamada
- Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan; (K.Y.); (N.I.)
- Department of Advanced Medicine for Spine and Spinal Cord Disorders, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Norimasa Iwasaki
- Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan; (K.Y.); (N.I.)
| | - Hideki Sudo
- Department of Advanced Medicine for Spine and Spinal Cord Disorders, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
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26
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Xuan A, Ruan D, Wang C, He Q, Wang D, Hou L, Zhang C, Li C, Ji W, Wen T, Xu C, Zhu Z. OUP accepted manuscript. Stem Cells Transl Med 2022; 11:490-503. [PMID: 35427416 PMCID: PMC9154349 DOI: 10.1093/stcltm/szac013] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Accepted: 02/04/2022] [Indexed: 11/13/2022] Open
Abstract
The treatment of intervertebral disc degeneration (IVDD) is still a huge challenge for clinical updated surgical techniques and basic strategies of intervertebral disc regeneration. Few studies have ever tried to combine surgery and cell therapy to bridge the gap between clinical and basic research. A prospective clinical study with a 72-month follow-up was conducted to assess the safety and feasibility of autologous discogenic cells transplantation combined with discectomy in the treatment of lumbar disc herniation (LDH) and to evaluate the regenerative ability of discogenic cells in IVDD. Forty patients with LDH who were scheduled to have discectomy enrolled in our study and were divided into the observed group (transplantation of autologous discogenic cells after discectomy) and control group (only-discectomy). Serial MRI and X-ray were used to evaluate the degenerative extent of index discs, and clinical scores were used to determine the symptomatic improvement. No adverse events were observed in the observed group, and seven patients in the control group underwent revisions. Both groups had significant improvement of all functional scores post-operatively, with the observed group improving more considerably at 36-month and 72-month follow-up. The height and water content of discs in both groups decreased significantly since 36 months post-op with the control group decreased more obviously. Discectomy combined with autologous discogenic cells transplantation is safe and feasible in the treatment of LDH. Radiological analysis demonstrated that discogenic cells transplantation could slow down the further degeneration of index discs and decrease the complications of discectomy.
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Affiliation(s)
- Anwu Xuan
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, People’s Republic of China
- Department of Orthopedics, The Sixth Medical Center of PLA General Hospital, Beijing, People’s Republic of China
| | - Dike Ruan
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, People’s Republic of China
- Department of Orthopedics, The Sixth Medical Center of PLA General Hospital, Beijing, People’s Republic of China
- Corresponding author: Dike Ruan, MD, The Second School of Clinical Medicine, Southern Medical University, No. 1023, South Shatai Road, Baiyun District, Guangzhou 510515, People’s Republic of China, and the Department of Orthopedics, The Sixth Medical Center of PLA General Hospital, 6 Fucheng Road, Haidian District, Beijing 100048, People’s Republic of China.
| | - Chaofeng Wang
- Department of Orthopedics, Xi’an Honghui Hospital, Xi’an, People’s Republic of China
| | - Qing He
- Department of Orthopedics, The Sixth Medical Center of PLA General Hospital, Beijing, People’s Republic of China
| | - Deli Wang
- Department of Orthopedics, Peking University Shenzhen Hospital, Shenzhen, People’s Republic of China
| | - Lisheng Hou
- Department of Orthopedics, The Sixth Medical Center of PLA General Hospital, Beijing, People’s Republic of China
| | - Chao Zhang
- Department of Orthopedics, The Sixth Medical Center of PLA General Hospital, Beijing, People’s Republic of China
| | - Chao Li
- Department of Orthopedics, The Sixth Medical Center of PLA General Hospital, Beijing, People’s Republic of China
| | - Wei Ji
- Department of Orthopedics, The Sixth Medical Center of PLA General Hospital, Beijing, People’s Republic of China
| | - Tianyong Wen
- Department of Orthopedics, The Sixth Medical Center of PLA General Hospital, Beijing, People’s Republic of China
| | - Cheng Xu
- Department of Orthopedics, The Sixth Medical Center of PLA General Hospital, Beijing, People’s Republic of China
| | - Zhenbiao Zhu
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, People’s Republic of China
- Department of Orthopedics, The Sixth Medical Center of PLA General Hospital, Beijing, People’s Republic of China
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27
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Peng Y, Li J, Lin H, Tian S, Liu S, Pu F, Zhao L, Ma K, Qing X, Shao Z. Endogenous repair theory enriches construction strategies for orthopaedic biomaterials: a narrative review. BIOMATERIALS TRANSLATIONAL 2021; 2:343-360. [PMID: 35837417 PMCID: PMC9255795 DOI: 10.12336/biomatertransl.2021.04.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Accepted: 11/19/2021] [Indexed: 02/06/2023]
Abstract
The development of tissue engineering has led to new strategies for mitigating clinical problems; however, the design of the tissue engineering materials remains a challenge. The limited sources and inadequate function, potential risk of microbial or pathogen contamination, and high cost of cell expansion impair the efficacy and limit the application of exogenous cells in tissue engineering. However, endogenous cells in native tissues have been reported to be capable of spontaneous repair of the damaged tissue. These cells exhibit remarkable plasticity, and thus can differentiate or be reprogrammed to alter their phenotype and function after stimulation. After a comprehensive review, we found that the plasticity of these cells plays a major role in establishing the cell source in the mechanism involved in tissue regeneration. Tissue engineering materials that focus on assisting and promoting the natural self-repair function of endogenous cells may break through the limitations of exogenous seed cells and further expand the applications of tissue engineering materials in tissue repair. This review discusses the effects of endogenous cells, especially stem cells, on injured tissue repairing, and highlights the potential utilisation of endogenous repair in orthopaedic biomaterial constructions for bone, cartilage, and intervertebral disc regeneration.
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Affiliation(s)
- Yizhong Peng
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Jinye Li
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Hui Lin
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Shuo Tian
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Sheng Liu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Feifei Pu
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Lei Zhao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Kaige Ma
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Xiangcheng Qing
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
| | - Zengwu Shao
- Department of Orthopaedics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei Province, China
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28
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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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29
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Regenerative Medicine Modalities for the Treatment of Degenerative Disk Disease. Clin Spine Surg 2021; 34:363-368. [PMID: 33264128 DOI: 10.1097/bsd.0000000000001114] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Accepted: 11/07/2020] [Indexed: 11/26/2022]
Abstract
Degenerative disk disease is a pathologic state associated with axial skeletal pain, radiculopathy, and myelopathy, and will inevitably increase in prevalence in parallel with an aging population. The objective of regenerative medicine is to convert the inflammatory, catabolic microenvironment of degenerative disease into an anti-inflammatory, anabolic environment. This comprehensive review discusses and outlines both in vitro and in vivo efficacy of regenerative treatment modalities for degenerative disk disease, such as; mesenchymal stem cells, gene therapy, tissue engineering, and biologic treatments. To date, clinical applications have been limited secondary to a lack of standardized high quality clinical data. Additional research should focus on determining the optimal cellular makeup and concentration for each of these interventions. Nevertheless, modern medicine provides a new avenue of confronting disease, with methods surpassing traditional methods of removing the pathology in question, as regenerative medicine provides the opportunity to recover from the diseased state.
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30
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Williams RJ, Tryfonidou MA, Snuggs JW, Le Maitre CL. Cell sources proposed for nucleus pulposus regeneration. JOR Spine 2021; 4:e1175. [PMID: 35005441 PMCID: PMC8717099 DOI: 10.1002/jsp2.1175] [Citation(s) in RCA: 45] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 10/01/2021] [Accepted: 10/20/2021] [Indexed: 12/13/2022] Open
Abstract
Lower back pain (LBP) occurs in 80% of adults in their lifetime; resulting in LBP being one of the biggest causes of disability worldwide. Chronic LBP has been linked to the degeneration of the intervertebral disc (IVD). The current treatments for chronic back pain only provide alleviation of symptoms through pain relief, tissue removal, or spinal fusion; none of which target regenerating the degenerate IVD. As nucleus pulposus (NP) degeneration is thought to represent a key initiation site of IVD degeneration, cell therapy that specifically targets the restoration of the NP has been reviewed here. A literature search to quantitatively assess all cell types used in NP regeneration was undertaken. With key cell sources: NP cells; annulus fibrosus cells; notochordal cells; chondrocytes; bone marrow mesenchymal stromal cells; adipose-derived stromal cells; and induced pluripotent stem cells extensively analyzed for their regenerative potential of the NP. This review highlights: accessibility; expansion capability in vitro; cell survival in an IVD environment; regenerative potential; and safety for these key potential cell sources. In conclusion, while several potential cell sources have been proposed, iPSC may provide the most promising regenerative potential.
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Affiliation(s)
- Rebecca J. Williams
- Biomedical Research Centre, BiosciencesSheffield Hallam UniversitySheffieldUK
| | - Marianna A. Tryfonidou
- Department of Clinical Sciences, Faculty of Veterinary MedicineUtrecht UniversityUtrechtThe Netherlands
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Shalash W, Ahrens SR, Bardonova LA, Byvaltsev VA, Giers MB. Patient-specific apparent diffusion maps used to model nutrient availability in degenerated intervertebral discs. JOR Spine 2021; 4:e1179. [PMID: 35005445 PMCID: PMC8717112 DOI: 10.1002/jsp2.1179] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 09/29/2021] [Accepted: 10/25/2021] [Indexed: 01/07/2023] Open
Abstract
INTRODUCTION In this study, magnetic resonance imaging data was used to (1) model IVD-specific gradients of glucose, oxygen, lactate, and pH; and (2) investigate possible effects of covariate factors (i.e., disc geometry, and mean apparent diffusion coefficient values) on the IVD's microenvironment. Mathematical modeling of the patient's specific IVD microenvironment could be important when selecting patients for stem cell therapy due to the increased nutrient demand created by that treatment. MATERIALS AND METHODS Disc geometry and water diffusion coefficients were extracted from MRIs of 37 patients using sagittal T1-weighted images, T2-weighted images, and ADC Maps. A 2-D steady state finite element mathematical model was developed in COMSOL Multiphysics® 5.4 to compute concentration maps of glucose, oxygen, lactate and pH. RESULTS Concentration of nutrients (i.e., glucose, and oxygen) dropped with increasing distance from the cartilaginous endplates (CEP), whereas acidity levels increased. Most discs experienced poor nutrient levels along with high acidity values in the inner annulus fibrosus (AF). The disc's physiological microenvironment became more deficient as degeneration progressed. For example, minimum glucose concentration in grade 4 dropped by 31.1% compared to grade 3 (p < 0.0001). The model further suggested a strong effect of the following parameters: disc size, AF and CEP diffusivities, metabolic reactions, and cell density on solute concentrations in the disc (p < 0.05). CONCLUSION The significance of this work implies that the individual morphology and physiological conditions of each disc, even among discs of the same Pfirrmann grade, should be evaluated when modeling IVD solute concentrations.
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Affiliation(s)
- Ward Shalash
- School of Chemical, Biological and Environmental EngineeringOregon State UniversityCorvallisOregonUSA
| | - Sonia R. Ahrens
- School of Chemical, Biological and Environmental EngineeringOregon State UniversityCorvallisOregonUSA
| | - Liudmila A. Bardonova
- School of Chemical, Biological and Environmental EngineeringOregon State UniversityCorvallisOregonUSA
- Irkutsk State Medical UniversityIrkutskRussia
| | - Vadim A. Byvaltsev
- Irkutsk State Medical UniversityIrkutskRussia
- Railway Clinical Hospital at the Irkutsk‐Passazhirsky StationIrkutskRussia
| | - Morgan B. Giers
- School of Chemical, Biological and Environmental EngineeringOregon State UniversityCorvallisOregonUSA
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Dieterle MP, Husari A, Rolauffs B, Steinberg T, Tomakidi P. Integrins, cadherins and channels in cartilage mechanotransduction: perspectives for future regeneration strategies. Expert Rev Mol Med 2021; 23:e14. [PMID: 34702419 PMCID: PMC8724267 DOI: 10.1017/erm.2021.16] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Revised: 09/16/2021] [Accepted: 09/20/2021] [Indexed: 02/07/2023]
Abstract
Articular cartilage consists of hyaline cartilage, is a major constituent of the human musculoskeletal system and has critical functions in frictionless joint movement and articular homoeostasis. Osteoarthritis (OA) is an inflammatory disease of articular cartilage, which promotes joint degeneration. Although it affects millions of people, there are no satisfying therapies that address this disease at the molecular level. Therefore, tissue regeneration approaches aim at modifying chondrocyte biology to mitigate the consequences of OA. This requires appropriate biochemical and biophysical stimulation of cells. Regarding the latter, mechanotransduction of chondrocytes and their precursor cells has become increasingly important over the last few decades. Mechanotransduction is the transformation of external biophysical stimuli into intracellular biochemical signals, involving sensor molecules at the cell surface and intracellular signalling molecules, so-called mechano-sensors and -transducers. These signalling events determine cell behaviour. Mechanotransducing ion channels and gap junctions additionally govern chondrocyte physiology. It is of great scientific and medical interest to induce a specific cell behaviour by controlling these mechanotransduction pathways and to translate this knowledge into regenerative clinical therapies. This review therefore focuses on the mechanotransduction properties of integrins, cadherins and ion channels in cartilaginous tissues to provide perspectives for cartilage regeneration.
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Affiliation(s)
- Martin Philipp Dieterle
- Division of Oral Biotechnology, Center for Dental Medicine, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, 79106Freiburg, Germany
| | - Ayman Husari
- Division of Oral Biotechnology, Center for Dental Medicine, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, 79106Freiburg, Germany
- Department of Orthodontics, Center for Dental Medicine, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, 79106Freiburg, Germany
| | - Bernd Rolauffs
- Department of Orthopedics and Trauma Surgery, G.E.R.N. Research Center for Tissue Replacement, Regeneration & Neogenesis, Medical Center – Albert-Ludwigs-University of Freiburg, Faculty of Medicine, Albert-Ludwigs-University of Freiburg, 79085Freiburg im Breisgau, Germany
| | - Thorsten Steinberg
- Division of Oral Biotechnology, Center for Dental Medicine, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, 79106Freiburg, Germany
| | - Pascal Tomakidi
- Division of Oral Biotechnology, Center for Dental Medicine, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Hugstetter Str. 55, 79106Freiburg, Germany
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Stem Cell Therapy and Exercise for Treatment of Intervertebral Disc Degeneration. Stem Cells Int 2021; 2021:7982333. [PMID: 34691192 PMCID: PMC8528633 DOI: 10.1155/2021/7982333] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2021] [Accepted: 09/13/2021] [Indexed: 02/07/2023] Open
Abstract
As part of the motor system, intervertebral disc (IVD) is a complicated tissue with multiple components. The degeneration of IVD may result in low back pain (LBP), which strongly impairs quality of life. Various causes are related to the degeneration of IVD, including cell senescence, hydration lost, and inflammation. Stem cells founded in different tissues have attracted the interest of the researchers and clinicians to study the implication of these cells in the treatment for tissue injury and degeneration. In this report, we will review the study of stem cells in the treatment for IVD degeneration. On the other hand, the effect of exercise on IVD degeneration and the relationship between IVD degeneration and musculoskeletal disorders like sarcopenia are discussed.
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Krut Z, Pelled G, Gazit D, Gazit Z. Stem Cells and Exosomes: New Therapies for Intervertebral Disc Degeneration. Cells 2021; 10:cells10092241. [PMID: 34571890 PMCID: PMC8471333 DOI: 10.3390/cells10092241] [Citation(s) in RCA: 105] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/23/2021] [Accepted: 08/25/2021] [Indexed: 12/12/2022] Open
Abstract
Intervertebral disc degeneration (IVDD) occurs as a result of an imbalance of the anabolic and catabolic processes in the intervertebral disc, leading to an alteration in the composition of the extracellular matrix (ECM), loss of nucleus pulposus (NP) cells, excessive oxidative stress and inflammation. Degeneration of the IVD occurs naturally with age, but mechanical trauma, lifestyle factors and certain genetic abnormalities can increase the likelihood of symptomatic disease progression. IVDD, often referred to as degenerative disc disease (DDD), poses an increasingly substantial financial burden due to the aging population and increasing incidence of obesity in the United States. Current treatments for IVDD include pharmacological and surgical interventions, but these lack the ability to stop the progression of disease and restore the functionality of the IVD. Biological therapies have been evaluated but show varying degrees of efficacy in reversing disc degeneration long-term. Stem cell-based therapies have shown promising results in the regeneration of the IVD, but face both biological and ethical limitations. Exosomes play an important role in intercellular communication, and stem cell-derived exosomes have been shown to maintain the therapeutic benefit of their origin cells without the associated risks. This review highlights the current state of research on the use of stem-cell derived exosomes in the treatment of IVDD.
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Affiliation(s)
- Zoe Krut
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (Z.K.); (G.P.); (D.G.)
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Gadi Pelled
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (Z.K.); (G.P.); (D.G.)
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Dan Gazit
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (Z.K.); (G.P.); (D.G.)
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Faculty of Dental Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel
| | - Zulma Gazit
- Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; (Z.K.); (G.P.); (D.G.)
- Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Department of Orthopedics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
- Correspondence:
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Baroncini A, Eschweiler J, Kobbe P, Quack V, Smajic S, Trobisch P, Hildebrand F, Migliorini F. Mesenchymal Stem Cell Applications in Spine Disorders: A Comprehensive Review. APPLIED SCIENCES 2021; 11:7966. [DOI: 10.3390/app11177966] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Abstract
Mesenchymal stem cells (MSCs) are increasingly being employed in a number of orthopedic settings, in particular in the treatment of hip and knee osteoarthritis. Recently, the use MSCs has been investigated for different spine settings. However, the use of these cells is not yet widespread in the clinical practice. The aim of this review was to investigate the current literature regarding the use of MSCs in different spine conditions and discuss possible future applications. In particular, degenerative disc disease is the most studied field for MSC application, and is the only one that has already reached the clinical practice, albeit not routinely. Spinal cord injuries are another extensively investigated use of MSCs: despite encouraging preliminary results, a consensus on the efficacy of stem cell therapy for spinal cord injuries has not yet been reached, and their use is still only experimental.
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Affiliation(s)
- Alice Baroncini
- Department of Orthopaedics, Trauma and Reconstructive Surgery, RWTH Aachen University, 52074 Aachen, Germany
- Department of Spine Surgery, Eifelklinik St. Brigida, 52152 Simmerath, Germany
| | - Jörg Eschweiler
- Department of Orthopaedics, Trauma and Reconstructive Surgery, RWTH Aachen University, 52074 Aachen, Germany
| | - Philipp Kobbe
- Department of Orthopaedics, Trauma and Reconstructive Surgery, RWTH Aachen University, 52074 Aachen, Germany
| | - Valentin Quack
- Department of Orthopaedics, Trauma and Reconstructive Surgery, RWTH Aachen University, 52074 Aachen, Germany
| | - Samir Smajic
- Department of Orthopaedic and Trauma Surgery, St-Josef-Krankenhaus, 52441 Linnich, Germany
| | - Per Trobisch
- Department of Spine Surgery, Eifelklinik St. Brigida, 52152 Simmerath, Germany
| | - Frank Hildebrand
- Department of Orthopaedics, Trauma and Reconstructive Surgery, RWTH Aachen University, 52074 Aachen, Germany
| | - Filippo Migliorini
- Department of Orthopaedics, Trauma and Reconstructive Surgery, RWTH Aachen University, 52074 Aachen, Germany
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Selective Retention of Bone Marrow Stromal Cells with Gelatin Sponge for Repair of Intervertebral Disc Defects after Microendoscopic Discectomy: A Prospective Controlled Study and 2-Year Follow-Up. BIOMED RESEARCH INTERNATIONAL 2021; 2021:4822383. [PMID: 34337012 PMCID: PMC8294975 DOI: 10.1155/2021/4822383] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/17/2021] [Accepted: 06/29/2021] [Indexed: 01/08/2023]
Abstract
Objective Discectomy remains the classic procedure for treating lumbar intervertebral disc (IVD) herniation, but the occurrence of defects after discectomy is thought to be an important cause generating recurrent and accelerated IVD degeneration. Previous studies attempted suture of the annulus fissure, but the validity of this technique on restraining the degenerative process is controversial. On the other hand, cell therapies have been shown in multiple clinical and basic studies. Our purpose was to investigate the effectiveness of selective retention of autologous Bone Marrow Stromal Cells (BMSCs) with gelatin sponge in combination with annulus fibrosus suture (AFS) for the repair of IVD defects following mobile microendoscopic discectomy (MMED). Methods This prospective, two-armed, and controlled clinical study was conducted from December 2016 to December 2018. Written informed consent was obtained from each patient. Forty-five patients with typical symptoms, positive signs of radiculopathy, and obvious lumbar disc herniation observed by MRI were enrolled. Patients were divided into 3 groups with different treating methods: MMED (n = 15), MMED+AFS (n = 15), and MMED+AFS+BMSCs (n = 15). A postoperative 2-year follow-up was performed to evaluate the patient-reported outcomes of VAS, ODI, and SF-36. The improvement rate of VAS and ODI was calculated as [(latest‐preoperative)/preoperative] to evaluate the therapeutic effect of the three groups. Assessment parameters included Pfirrmann grade, intervertebral disc height (IDH), and disc protrusion size (DPS), as measured by MRI to evaluate the morphological changes. Results All patients enrolled had a postoperative follow-up at 3, 6, 12, and 24 months. VAS and ODI scores were significantly improved compared to the preoperative status in all three groups with a mean DPS reduction rate over 50%. At the final follow-up, the improvement rate of the VAS score in the MMED+AFS+BMSCs group was significantly higher than the MMED+AFS and MMED groups (80.1% ± 7.6% vs. 71.3% ± 7.0% vs. 70.1% ± 7.8%), while ODI improvement showed a significant change (65.6% ± 8.8% vs. 59.9% ± 5.5% vs. 57.8% ± 8.1%). All participants showed significant improvement in SF-36 PCS and MCS; the differences between each group were not significant. The mean IDH loss rate of the MMED+AFS+BMSCs group was also significantly lower than other groups (−17.2% ± 1.3% vs. −27.6% ± 0.7% vs. −29.3% ± 2.2%). The Pfirrmann grade was aggravated in the MMED and MMED+AFS groups while maintained at the preoperative grade in the MMED+AFS+BMSCs group. No adverse events of cell transplantation or recurrence were found in all patients during the postoperative follow-up period. Conclusions It is feasible and effective to repair lumbar IVD defects using SCR-enriched BMSCs with gelatin sponges, which warrants further study and development as a cell-based therapy for IVD repair.
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Kim S, Kwon OJ, Lee J, Kim J, Kim TH, Kim K. A Brief Overview of Recent Engineering Approaches for Intervertebral Disc Regeneration Using Adipose Derived Mesenchymal Stem Cell Administration. BIOTECHNOL BIOPROC E 2021. [DOI: 10.1007/s12257-019-0346-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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The Application of Mesenchymal Stromal Cells and Their Homing Capabilities to Regenerate the Intervertebral Disc. Int J Mol Sci 2021; 22:ijms22073519. [PMID: 33805356 PMCID: PMC8036861 DOI: 10.3390/ijms22073519] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2021] [Revised: 03/25/2021] [Accepted: 03/26/2021] [Indexed: 12/12/2022] Open
Abstract
Chronic low back pain (LBP) remains a challenging condition to treat, and especially to cure. If conservative treatment approaches fail, the current “gold standard” for intervertebral disc degeneration (IDD)-provoked back pain is spinal fusion. However, due to its invasive and destructive nature, the focus of orthopedic research related to the intervertebral disc (IVD) has shifted more towards cell-based therapeutic approaches. They aim to reduce or even reverse the degenerative cascade by mimicking the human body’s physiological healing system. The implementation of progenitor and/or stem cells and, in particular, the delivery of mesenchymal stromal cells (MSCs) has revealed significant potential to cure the degenerated/injured IVD. Over the past decade, many research groups have invested efforts to find ways to utilize these cells as efficiently and sustainably as possible. This narrative literature review presents a summary of achievements made with the application of MSCs for the regeneration of the IVD in recent years, including their preclinical and clinical applications. Moreover, this review presents state-of-the-art strategies on how the homing capabilities of MSCs can be utilized to repair damaged or degenerated IVDs, as well as their current limitations and future perspectives.
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Yin Y, Li Y, Wang S, Dong Z, Liang C, Sun J, Wang C, Chai R, Fei W, Zhang J, Qi M, Feng L, Zhang Q. MSCs-engineered biomimetic PMAA nanomedicines for multiple bioimaging-guided and photothermal-enhanced radiotherapy of NSCLC. J Nanobiotechnology 2021; 19:80. [PMID: 33743720 PMCID: PMC7981797 DOI: 10.1186/s12951-021-00823-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 03/05/2021] [Indexed: 01/09/2023] Open
Abstract
Background The recently developed biomimetic strategy is one of the mostly effective strategies for improving the theranostic efficacy of diverse nanomedicines, because nanoparticles coated with cell membranes can disguise as “self”, evade the surveillance of the immune system, and accumulate to the tumor sites actively. Results Herein, we utilized mesenchymal stem cell memabranes (MSCs) to coat polymethacrylic acid (PMAA) nanoparticles loaded with Fe(III) and cypate—an derivative of indocyanine green to fabricate Cyp-PMAA-Fe@MSCs, which featured high stability, desirable tumor-accumulation and intriguing photothermal conversion efficiency both in vitro and in vivo for the treatment of lung cancer. After intravenous administration of Cyp-PMAA-Fe@MSCs and Cyp-PMAA-Fe@RBCs (RBCs, red blood cell membranes) separately into tumor-bearing mice, the fluorescence signal in the MSCs group was 21% stronger than that in the RBCs group at the tumor sites in an in vivo fluorescence imaging system. Correspondingly, the T1-weighted magnetic resonance imaging (MRI) signal at the tumor site decreased 30% after intravenous injection of Cyp-PMAA-Fe@MSCs. Importantly, the constructed Cyp-PMAA-Fe@MSCs exhibited strong photothermal hyperthermia effect both in vitro and in vivo when exposed to 808 nm laser irradiation, thus it could be used for photothermal therapy. Furthermore, tumors on mice treated with phototermal therapy and radiotherapy shrank 32% more than those treated with only radiotherapy. Conclusions These results proved that Cyp-PMAA-Fe@MSCs could realize fluorescence/MRI bimodal imaging, while be used in phototermal-therapy-enhanced radiotherapy, providing desirable nanoplatforms for tumor diagnosis and precise treatment of non-small cell lung cancer. Supplementary Information The online version contains supplementary material available at 10.1186/s12951-021-00823-6.
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Affiliation(s)
- Yipengchen Yin
- Department of Radiation Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, P. R. China
| | - Yongjing Li
- State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, and Laboratory of Advanced Materials, Fudan University, Shanghai, 200438, P. R. China
| | - Sheng Wang
- Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, P. R. China
| | - Ziliang Dong
- Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou, 215123, Jiangsu, P. R. China
| | - Chao Liang
- Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou, 215123, Jiangsu, P. R. China
| | - Jiaxin Sun
- State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, and Laboratory of Advanced Materials, Fudan University, Shanghai, 200438, P. R. China
| | - Changchun Wang
- State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, and Laboratory of Advanced Materials, Fudan University, Shanghai, 200438, P. R. China
| | - Rong Chai
- Department of Radiation Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, P. R. China
| | - Weiwei Fei
- State Key Laboratory of Molecular Engineering of Polymers, Department of Macromolecular Science, and Laboratory of Advanced Materials, Fudan University, Shanghai, 200438, P. R. China
| | - Jianping Zhang
- Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, 200032, P. R. China
| | - Ming Qi
- Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, 200032, P. R. China.,Key Laboratory of Nuclear Physics and Ion-Beam Application (MOE), Fudan University, Shanghai, 200433, P. R. China
| | - Liangzhu Feng
- Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Institute of Functional Nano & Soft Materials (FUNSOM), Soochow University, Suzhou, 215123, Jiangsu, P. R. China
| | - Qin Zhang
- Department of Radiation Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, P. R. China.
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El-Kadiry AEH, Lumbao C, Rafei M, Shammaa R. Autologous BMAC Therapy Improves Spinal Degenerative Joint Disease in Lower Back Pain Patients. Front Med (Lausanne) 2021; 8:622573. [PMID: 33816523 PMCID: PMC8012529 DOI: 10.3389/fmed.2021.622573] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Accepted: 02/26/2021] [Indexed: 01/08/2023] Open
Abstract
Spinal degenerative joint disease (DJD) is associated with lower back pain (LBP) arising from the degeneration of intervertebral discs (IVD), facet joints, intertransversarii muscles, and interspinous ligaments among other anatomical structures. To circumvent the socioeconomic burdens and often-problematic surgical options imposed by DJD therapy, cell-based biologic modalities like bone marrow aspirate concentrate (BMAC) have been investigated in pre-clinical and clinical settings, mostly for IVD degeneration (IDD), with encouraging outcomes. In this study, we evaluated the differences in therapeutic benefits of BMAC between IVD- and facet joint-originating chronic LBP. Eighteen patients diagnosed with chronic LBP met the selection criteria. Following discography and provocation testing, 13 patients tested positive and were assigned into IDD-associated LBP (1st arm), while the remaining 5 tested negative and were assigned into facetogenic LBP (2nd arm). Autologous BMAC was injected intradiscally in the 1st arm, while the 2nd arm received posterior spinal chain injections. No procedure-related serious events ensued. Clinical improvement was evaluated over 12 months based on pain and functionality questionnaires (VAS, BPI, RAND-36), opioid use, and changes in disc parameters assessed by magnetic resonance imaging (MRI). Ameliorated VAS and BPI scores differed significantly between both arms in favor of IDD patients who also took significantly less opioids. Average RAND-36 scores showed no significant difference between groups albeit a trend suggesting improvement was observed in IDD patients. MRI scans conducted on IDD patients demonstrated marked elevation in disc height and spinal canal space size without worsening disc quality. Overall, this is the first study investigating the potency of BMAC as an IDD treatment in Canada and the first globally for addressing facetogenic pain using cellular therapy.
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Affiliation(s)
- Abed El-Hakim El-Kadiry
- Laboratory of Thrombosis and Hemostasis, Research Center, Montreal Heart Institute, Montreal, QC, Canada
- Department of Biomedical Sciences, Université de Montréal, Montreal, QC, Canada
| | - Carlos Lumbao
- Canadian Centre for Regenerative Therapy, Toronto, ON, Canada
| | - Moutih Rafei
- Department of Pharmacology and Physiology, Université de Montréal, Montreal, QC, Canada
- Department of Microbiology, Infectious Diseases, and Immunology, Université de Montréal, Montreal, QC, Canada
- Molecular Biology Program, Université de Montréal, Montreal, QC, Canada
- Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada
| | - Riam Shammaa
- Canadian Centre for Regenerative Therapy, Toronto, ON, Canada
- Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada
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Fiani B, Dahan A, El-Farra MH, Kortz MW, Runnels JM, Suliman Y, Miranda A, Nguy A. Cellular transplantation and platelet-rich plasma injections for discogenic pain: a contemporary review. Regen Med 2021; 16:161-174. [PMID: 33650437 DOI: 10.2217/rme-2020-0146] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Degenerative disc disease (DDD) is the leading cause of chronic back pain. It is a pathologic condition associated with aging and is believed to result from catabolic excess in the intervertebral discs' (IVD) extracellular matrix. Two new treatment options are intradiscal cellular transplantation and growth factor therapy. Recent investigations on the use of these therapies are discussed and compared with emerging evidence supporting novel cellular injections. At present, human and animal studies provide a compelling rationale for the use of cellular injections in the treatment of discogenic pain. Since DDD results from the IVD extracellular matrix's unmitigated catabolism, cellular injections are used to induce regeneration and homeostasis in the IVD. Here, we review intervertebral disc anatomy, DDD pathophysiology and clinical considerations, as well as the current and emerging literature investigating outcomes associated with cellular transplantation and platelet-rich plasma for discogenic pain. Further high-quality trials are certainly warranted.
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Affiliation(s)
- Brian Fiani
- Department of Neurosurgery, Desert Regional Medical Center, Palm Springs, 92262 CA, USA
| | - Alden Dahan
- University of California Riverside School of Medicine, Riverside, 92507 CA, USA
| | - Mohamed H El-Farra
- University of California Riverside School of Medicine, Riverside, 92507 CA, USA
| | - Michael W Kortz
- Department of Neurosurgery, University of Colorado Hospital, Aurora, 80045 CO, USA
| | - Juliana M Runnels
- University of New Mexico School of Medicine, Albuquerque, 87106 NM, USA
| | - Yasmine Suliman
- University of California Riverside School of Medicine, Riverside, 92507 CA, USA
| | - Anita Miranda
- University of California Riverside School of Medicine, Riverside, 92507 CA, USA
| | - Austin Nguy
- University of California Riverside School of Medicine, Riverside, 92507 CA, USA
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Binch ALA, Fitzgerald JC, Growney EA, Barry F. Cell-based strategies for IVD repair: clinical progress and translational obstacles. Nat Rev Rheumatol 2021; 17:158-175. [PMID: 33526926 DOI: 10.1038/s41584-020-00568-w] [Citation(s) in RCA: 157] [Impact Index Per Article: 39.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/10/2020] [Indexed: 12/21/2022]
Abstract
Intervertebral disc (IVD) degeneration is a major cause of low back pain, a prevalent and chronic condition that has a striking effect on quality of life. Currently, no approved pharmacological interventions or therapies are available that prevent the progressive destruction of the IVD; however, regenerative strategies are emerging that aim to modify the disease. Progress has been made in defining promising new treatments for disc disease, but considerable challenges remain along the entire translational spectrum, from understanding disease mechanism to useful interpretation of clinical trials, which make it difficult to achieve a unified understanding. These challenges include: an incomplete appreciation of the mechanisms of disc degeneration; a lack of standardized approaches in preclinical testing; in the context of cell therapy, a distinct lack of cohesion regarding the cell types being tested, the tissue source, expansion conditions and dose; the absence of guidelines regarding disease classification and patient stratification for clinical trial inclusion; and an incomplete understanding of the mechanisms underpinning therapeutic responses to cell delivery. This Review discusses current approaches to disc regeneration, with a particular focus on cell-based therapeutic strategies, including ongoing challenges, and attempts to provide a framework to interpret current data and guide future investigational studies.
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Affiliation(s)
- Abbie L A Binch
- Regenerative Medicine Institute (REMEDI), National University of Ireland Galway, Galway, Ireland
| | - Joan C Fitzgerald
- Regenerative Medicine Institute (REMEDI), National University of Ireland Galway, Galway, Ireland
| | - Emily A Growney
- Regenerative Medicine Institute (REMEDI), National University of Ireland Galway, Galway, Ireland
| | - Frank Barry
- Regenerative Medicine Institute (REMEDI), National University of Ireland Galway, Galway, Ireland.
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Binch ALA, Ratcliffe LPD, Milani AH, Saunders BR, Armes SP, Hoyland JA. Site-Directed Differentiation of Human Adipose-Derived Mesenchymal Stem Cells to Nucleus Pulposus Cells Using an Injectable Hydroxyl-Functional Diblock Copolymer Worm Gel. Biomacromolecules 2021; 22:837-845. [PMID: 33470795 DOI: 10.1021/acs.biomac.0c01556] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Adipose-derived mesenchymal stem cells (ASCs) have been identified for their promising therapeutic potential to regenerate and repopulate the degenerate intervertebral disk (IVD), which is a major cause of lower back pain. The optimal cell delivery system remains elusive but encapsulation of cells within scaffolds is likely to offer a decisive advantage over the delivery of cells in solution by ensuring successful retention within the tissue. Herein, we evaluate the use of a fully synthetic, thermoresponsive poly(glycerol monomethacrylate)-poly(2-hydroxypropyl methacrylate) (PGMA-PHPMA) diblock copolymer worm gel that mimics the structure of hydrophilic glycosaminoglycans. The objective was to use this gel to direct differentiation of human ASCs toward a nucleus pulposus (NP) phenotype, with or without the addition of discogenic growth factors TGFβ or GDF6. Accordingly, human ASCs were incorporated into a cold, free-flowing aqueous dispersion of the diblock copolymer, gelation induced by warming to 37 °C and cell culture was conducted for 14 days with or without such growth factors to assess the expression of characteristic NP markers compared to those produced when using collagen gels. In principle, the shear-thinning nature of the biocompatible worm gel enables encapsulated human ASCs to be injected into the IVD using a 21G needle. Moreover, we find significantly higher gene expression levels of ACAN, SOX-9, KRT8, and KR18 for ASCs encapsulated within worm gels compared to collagen scaffolds, regardless of the growth factors employed. In summary, such wholly synthetic worm gels offer considerable potential as an injectable cell delivery scaffold for the treatment of degenerate disk disease by promoting the transition of ASCs toward an NP-phenotype.
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Affiliation(s)
- Abbie L A Binch
- Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9PL, U.K
| | - Liam P D Ratcliffe
- Department of Chemistry, University of Sheffield Brook Hill, Sheffield S3 7HF, South Yorkshire, U.K
| | - Amir H Milani
- Department of Materials, University of Manchester, Manchester M13 9PL, U.K
| | - Brian R Saunders
- Department of Materials, University of Manchester, Manchester M13 9PL, U.K
| | - Steven P Armes
- Department of Chemistry, University of Sheffield Brook Hill, Sheffield S3 7HF, South Yorkshire, U.K
| | - Judith A Hoyland
- Division of Cell Matrix Biology and Regenerative Medicine, School of Biological Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Sciences Centre, University of Manchester, Manchester M13 9PL, U.K.,NIHR Manchester Biomedical Research Centre, Central Manchester Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, U.K
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44
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Silverman LI, Heaton W, Farhang N, Saxon LH, Dulatova G, Rodriguez-Granrose D, Flanagan F, Foley KT. Perspectives on the Treatment of Lumbar Disc Degeneration: The Value Proposition for a Cell-Based Therapy, Immunomodulatory Properties of Discogenic Cells and the Associated Clinical Evaluation Strategy. Front Surg 2020; 7:554382. [PMID: 33392242 PMCID: PMC7772215 DOI: 10.3389/fsurg.2020.554382] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 11/25/2020] [Indexed: 12/12/2022] Open
Abstract
Low back pain (LBP) is a serious medical condition that affects a large percentage of the population worldwide. One cause of LBP is disc degeneration (DD), which is characterized by progressive breakdown of the disc and an inflamed disc environment. Current treatment options for patients with symptomatic DD are limited and are often unsuccessful, so many patients turn to prescription opioids for pain management in a time when opioid usage, addiction, and drug-related deaths are at an all-time high. In this paper, we discuss the etiology of lumbar DD and currently available treatments, as well as the potential for cell therapy to offer a biologic, non-opioid alternative to patients suffering from the condition. Finally, we present an overview of an investigational cell therapy called IDCT (Injectable Discogenic Cell Therapy), which is currently under evaluation in multiple double-blind clinical trials overseen by major regulatory agencies. The active ingredient in IDCT is a novel allogeneic cell population known as Discogenic Cells. These cells, which are derived from intervertebral disc tissue, have been shown to possess both regenerative and immunomodulatory properties. Cell therapies have unique properties that may ultimately lead to decreased pain and improved function, as well as curb the numbers of patients pursuing opioids. Their efficacy is best assessed in rigorous double-blinded and placebo-controlled clinical studies.
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Affiliation(s)
- Lara Ionescu Silverman
- DiscGenics Inc., Salt Lake City, UT, United States.,Department of Neurosurgery, University of Tennessee Health Science Center, Memphis, TN, United States
| | - Will Heaton
- DiscGenics Inc., Salt Lake City, UT, United States
| | | | | | | | | | | | - Kevin T Foley
- DiscGenics Inc., Salt Lake City, UT, United States.,Department of Neurosurgery, University of Tennessee Health Science Center, Memphis, TN, United States.,Semmes-Murphey Clinic, Memphis, TN, United States
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45
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Kangari P, Talaei-Khozani T, Razeghian-Jahromi I, Razmkhah M. Mesenchymal stem cells: amazing remedies for bone and cartilage defects. Stem Cell Res Ther 2020; 11:492. [PMID: 33225992 PMCID: PMC7681994 DOI: 10.1186/s13287-020-02001-1] [Citation(s) in RCA: 157] [Impact Index Per Article: 31.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 10/27/2020] [Indexed: 12/15/2022] Open
Abstract
Skeletal disorders are among the leading debilitating factors affecting millions of people worldwide. The use of stem cells for tissue repair has raised many promises in various medical fields, including skeletal disorders. Mesenchymal stem cells (MSCs) are multipotent stromal cells with mesodermal and neural crest origin. These cells are one of the most attractive candidates in regenerative medicine, and their use could be helpful in repairing and regeneration of skeletal disorders through several mechanisms including homing, angiogenesis, differentiation, and response to inflammatory condition. The most widely studied sources of MSCs are bone marrow (BM), adipose tissue, muscle, umbilical cord (UC), umbilical cord blood (UCB), placenta (PL), Wharton's jelly (WJ), and amniotic fluid. These cells are capable of differentiating into osteoblasts, chondrocytes, adipocytes, and myocytes in vitro. MSCs obtained from various sources have diverse capabilities of secreting many different cytokines, growth factors, and chemokines. It is believed that the salutary effects of MSCs from different sources are not alike in terms of repairing or reformation of injured skeletal tissues. Accordingly, differential identification of MSCs' secretome enables us to make optimal choices in skeletal disorders considering various sources. This review discusses and compares the therapeutic abilities of MSCs from different sources for bone and cartilage diseases.
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Affiliation(s)
- Parisa Kangari
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Tahereh Talaei-Khozani
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
- Tissue Engineering Laboratory, Department of Anatomy, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Mahboobeh Razmkhah
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
- Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
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46
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Mern DS, Walsen T, Beierfuß A, Thomé C. Animal models of regenerative medicine for biological treatment approaches of degenerative disc diseases. Exp Biol Med (Maywood) 2020; 246:483-512. [PMID: 33175609 DOI: 10.1177/1535370220969123] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Degenerative disc disease (DDD) is a painful, chronic and progressive disease, which is characterized by inflammation, structural and biological deterioration of the intervertebral disc (IVD) tissues. DDD is specified as cell-, age-, and genetic-dependent degenerative process that can be accelerated by environmental factors. It is one of the major causes of chronic back pain and disability affecting millions of people globally. Current treatment options, such as physical rehabilitation, pain management, and surgical intervention, can provide only temporary pain relief. Different animal models have been used to study the process of IVD degeneration and develop therapeutic options that may restore the structure and function of degenerative discs. Several research works have depicted considerable progress in understanding the biological basis of disc degeneration and the therapeutic potentials of cell transplantation, gene therapy, applications of supporting biomaterials and bioactive factors, or a combination thereof. Since animal models play increasingly significant roles in treatment approaches of DDD, we conducted an electronic database search on Medline through June 2020 to identify, compare, and discuss publications regarding biological therapeutic approaches of DDD that based on intradiscal treatment strategies. We provide an up-to-date overview of biological treatment strategies in animal models including mouse, rat, rabbit, porcine, bovine, ovine, caprine, canine, and primate models. Although no animal model could profoundly reproduce the clinical conditions in humans; animal models have played important roles in specifying our knowledge about the pathophysiology of DDD. They are crucial for developing new therapy approaches for clinical applications.
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Affiliation(s)
| | - Tanja Walsen
- Department of Neurosurgery, Medical University of Innsbruck, Innsbruck A-6020, Austria
| | - Anja Beierfuß
- Laboratory Animal Facility, Medical University of Innsbruck, Innsbruck A-6020, Austria
| | - Claudius Thomé
- Department of Neurosurgery, Medical University of Innsbruck, Innsbruck A-6020, Austria
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Muttigi MS, Kim BJ, Kumar H, Park S, Choi UY, Han I, Park H, Lee SH. Efficacy of matrilin-3-primed adipose-derived mesenchymal stem cell spheroids in a rabbit model of disc degeneration. Stem Cell Res Ther 2020; 11:363. [PMID: 32831130 PMCID: PMC7444036 DOI: 10.1186/s13287-020-01862-w] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 05/27/2020] [Accepted: 07/28/2020] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND Chronic low back pain is a prevalent disability, often caused by intervertebral disc (IVD) degeneration. Mesenchymal stem cell (MSC) therapy could be a safe and feasible option for repairing the degenerated disc. However, for successful translation to the clinic, various challenges need to be overcome including unwanted adverse effects due to acidic pH, hypoxia, and limited nutrition. Matrilin-3 is an essential extracellular matrix (ECM) component during cartilage development and ossification and exerts chondrocyte protective effects. METHODS This study evaluated the effects of matrilin-3-primed adipose-derived MSCs (Ad-MSCs) on the repair of the degenerated disc in vitro and in vivo. We determined the optimal priming concentration and duration and developed an optimal protocol for Ad-MSC spheroid generation. RESULTS Priming with 10 ng/ml matrilin-3 for 5 days resulted in the highest mRNA expression of type 2 collagen and aggrecan in vitro. Furthermore, Ad-MSC spheroids with a density of 250 cells/microwell showed the increased secretion of favorable growth factors such as transforming growth factor beta (TGF-β1), TGF-β2, interleukin-10 (IL-10), granulocyte colony-stimulating factor (G-CSF), and matrix metalloproteinase 1 (MMP1) and decreased secretion of hypertrophic ECM components. In addition, matrilin-3-primed Ad-MSC spheroid implantation was associated with optimal repair in a rabbit model. CONCLUSION Our results suggest that priming MSCs with matrilin-3 and spheroid formation could be an effective strategy to overcome the challenges associated with the use of MSCs for the treatment of IVD degeneration.
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Affiliation(s)
- Manjunatha S Muttigi
- School of Integrative Engineering, Chung-Ang University, Seoul, 06911, South Korea
| | - Byoung Ju Kim
- Department of Medical Biotechnology, Dongguk University-Seoul, Seoul, 04620, South Korea
| | - Hemant Kumar
- Department of Pharmacology and Toxicology, National Institute of Pharmaceutical Education and Research (NIPER)-Ahmedabad, Gandhinagar, Gujarat, 382010, India
| | - Sunghyun Park
- Department of Medical Biotechnology, Dongguk University-Seoul, Seoul, 04620, South Korea
- Department of Biomedical Science, CHA University, Seongnam-si, 13488, South Korea
| | - Un Yong Choi
- Department of Neurosurgery, School of Medicine, CHA Bundang Medical Center, CHA University, Seongnam-si, 13496, South Korea
| | - Inbo Han
- Department of Neurosurgery, School of Medicine, CHA Bundang Medical Center, CHA University, Seongnam-si, 13496, South Korea.
| | - Hansoo Park
- School of Integrative Engineering, Chung-Ang University, Seoul, 06911, South Korea.
| | - Soo-Hong Lee
- Department of Medical Biotechnology, Dongguk University-Seoul, Seoul, 04620, South Korea.
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48
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Hirase T, Jack RA, Sochacki KR, Harris JD, Weiner BK. Systematic Review: Is Intradiscal Injection of Bone Marrow Concentrate for Lumbar Disc Degeneration Effective? Cureus 2020; 12:e9045. [PMID: 32782864 PMCID: PMC7410505 DOI: 10.7759/cureus.9045] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Current studies evaluating the outcomes of an intradiscal injection of bone marrow concentrate (BMC) for lumbar disc degeneration are limited. The purpose of this review was to determine if an intradiscal injection of BMC for lumbar disc degeneration results in a statistically significant improvement in clinical outcomes. A systematic review was performed using Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Levels I-IV investigations of intradiscal BMC injections in symptomatic lumbar disc degeneration were included in the analysis. Modified Coleman Methodology Scores (MCMS) were used to analyze study methodological quality. Only outcome measurements used by more than 50% of included studies, with a minimum follow-up of 12 months, were eligible for final data analysis. Pre-injection and post-injection visual analog scale (VAS) and Oswestry disability index (ODI) were compared using two-sample Z-tests. Seven articles (97 subjects (47 males, 38 females, 12 unspecified), mean age 33.9 ± 14.3 years, mean follow-up 44.4 ± 25.4 months) were analyzed. Six articles were level IV evidence and one article was level II. Mean MCMS was 56.6 ± 9.1. All subjects received single injections into the nucleus pulposus of one or more affected discs. VAS (66.0 mm to 20.9 mm; p<0.001) and ODI (44.4 to 19.1; p<0.001) significantly improved following the intradiscal BMC injection. One patient (1.0%) experienced herniated nucleus pulposus (HNP) following treatment. No other complications or re-injections were reported. In conclusion, despite our skepticism regarding the efficacy of the procedure, intradiscal injection of BMC for lumbar disc degeneration resulted in statistically significant improvement in VAS and ODI with low re-injection and complication rates in the studies assessed. Given that this study is limited to level IV evidence, the findings suggest that further randomized controlled studies may be worthwhile to evaluate the true efficacy of this treatment.
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Affiliation(s)
- Takashi Hirase
- Orthopedics and Sports Medicine, Houston Methodist Hospital, Houston, USA
| | - Robert A Jack
- Orthopedics and Sports Medicine, Houston Methodist Hospital, Houston, USA
| | - Kyle R Sochacki
- Orthopedics and Sports Medicine, Houston Methodist Hospital, Houston, USA
| | - Joshua D Harris
- Orthopedics and Sports Medicine, Houston Methodist Hospital, Houston, USA
| | - Bradley K Weiner
- Orthopedics and Sports Medicine, Houston Methodist Hospital, Houston, USA
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49
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Ramos O, Speirs JN, Danisa O. Lumbar Discitis and Osteomyelitis After a Spinal Stem Cell Injection?: A Case Report and Literature Review. JBJS Case Connect 2020; 10:e1900636. [PMID: 32773702 DOI: 10.2106/jbjs.cc.19.00636] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
CASE A 32-year-old man developed lumbar discitis and osteomyelitis after receiving a cell-based injection for the treatment of degenerative disc disease. Initial cultures were negative, but he continued to worsen, and a repeat set of cultures was taken. On day 10, Cutibacterium acnes was isolated. He was then successfully treated with 12 weeks of intravenous antibiotics. CONCLUSIONS There is minimal regulation on the preparation or administration of cell-based interventions. It is important to consider slow growing organisms such as C. acnes in patients presenting with spinal infection with insidious onset after these treatments.
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Affiliation(s)
- Omar Ramos
- 1Department of Orthopaedic Surgery, Loma Linda University, Loma Linda, California
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50
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Eder C, Schmidt-Bleek K, Geissler S, Sass FA, Maleitzke T, Pumberger M, Perka C, Duda GN, Winkler T. Mesenchymal stromal cell and bone marrow concentrate therapies for musculoskeletal indications: a concise review of current literature. Mol Biol Rep 2020; 47:4789-4814. [PMID: 32451926 PMCID: PMC7295724 DOI: 10.1007/s11033-020-05428-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Accepted: 04/03/2020] [Indexed: 12/17/2022]
Abstract
The interest on applying mesenchymal stromal cells (MSCs) in orthopedic disorders has risen tremendously in the last years due to scientific successes in preclinical in vitro and animal model studies. In a wide range of diseases and injuries of the musculoskeletal system, MSCs are currently under evaluation, but so far have found access to clinical use only in few cases. The current assignment is to translate the acquired knowledge into clinical practice. Therefore, this review aims at presenting a synopsis of the up-to-date status of the use of MSCs and MSC related cell products in musculoskeletal indications. Clinical studies were included, whereas preclinical and animal study data not have been considered. Most studies published so far investigate the final outcome applying bone marrow derived MSCs. In fewer trials the use of adipose tissue derived MSCs and allogenic MSCs was investigated in different applications. Although the reported results are equivocal in the current literature, the vast majority of the studies shows a benefit of MSC based therapies depending on the cell sources and the indication in clinical use. In summary, the clinical use of MSCs in patients in orthopedic indications has been found to be safe. Standardized protocols and clear definitions of the mechanisms of action and the mode and timing of application as well as further coordinated research efforts will be necessary for finally adding MSC based therapies in standard operating procedures and guidelines for the clinicians treating orthopedic disorders.
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Affiliation(s)
- Christian Eder
- Center for Musculoskeletal Surgery, Charité - Universitaetsmedizin Berlin, Chariteplatz 1, 10117 Berlin, Germany
| | - Katharina Schmidt-Bleek
- Julius Wolff Institute, Charité - Universitaetsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Institute of Health Center for Regenerative Therapies, Charité – Universitaetsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Sven Geissler
- Julius Wolff Institute, Charité - Universitaetsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Institute of Health Center for Regenerative Therapies, Charité – Universitaetsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - F. Andrea Sass
- Julius Wolff Institute, Charité - Universitaetsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Institute of Health Center for Regenerative Therapies, Charité – Universitaetsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Tazio Maleitzke
- Center for Musculoskeletal Surgery, Charité - Universitaetsmedizin Berlin, Chariteplatz 1, 10117 Berlin, Germany
| | - Matthias Pumberger
- Center for Musculoskeletal Surgery, Charité - Universitaetsmedizin Berlin, Chariteplatz 1, 10117 Berlin, Germany
| | - Carsten Perka
- Center for Musculoskeletal Surgery, Charité - Universitaetsmedizin Berlin, Chariteplatz 1, 10117 Berlin, Germany
- Berlin-Brandenburg School for Regenerative Therapies, Charité – Universitaetsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Georg N. Duda
- Julius Wolff Institute, Charité - Universitaetsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Institute of Health Center for Regenerative Therapies, Charité – Universitaetsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin-Brandenburg School for Regenerative Therapies, Charité – Universitaetsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
| | - Tobias Winkler
- Center for Musculoskeletal Surgery, Charité - Universitaetsmedizin Berlin, Chariteplatz 1, 10117 Berlin, Germany
- Julius Wolff Institute, Charité - Universitaetsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
- Berlin Institute of Health Center for Regenerative Therapies, Charité – Universitaetsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
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