25
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Advancing cell therapies for intervertebral disc regeneration from the lab to the clinic: Recommendations of the ORS spine section

      review-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Intervertebral disc degeneration is strongly associated with chronic low back pain, a leading cause of disability worldwide. Current back pain treatment approaches (both surgical and conservative) are limited to addressing symptoms, not necessarily the root cause. Not surprisingly therefore, long‐term efficacy of most approaches is poor. Cell‐based disc regeneration strategies have shown promise in preclinical studies, and represent a relatively low‐risk, low‐cost, and durable therapeutic approach suitable for a potentially large patient population, thus making them attractive from both clinical and commercial standpoints. Despite such promise, no such therapies have been broadly adopted clinically. In this perspective we highlight primary obstacles and provide recommendations to help accelerate successful clinical translation of cell‐based disc regeneration therapies. The key areas addressed include: (a) Optimizing cell sources and delivery techniques; (b) Minimizing potential risks to patients; (c) Selecting physiologically and clinically relevant efficacy metrics; (d) Maximizing commercial potential; and (e) Recognizing the importance of multidisciplinary collaborations and engaging with clinicians from inception through to clinical trials.

          Related collections

          Most cited references127

          • Record: found
          • Abstract: found
          • Article: not found

          Natural-origin polymers as carriers and scaffolds for biomolecules and cell delivery in tissue engineering applications.

          The present paper intends to overview a wide range of natural-origin polymers with special focus on proteins and polysaccharides (the systems more inspired on the extracellular matrix) that are being used in research, or might be potentially useful as carriers systems for active biomolecules or as cell carriers with application in the tissue engineering field targeting several biological tissues. The combination of both applications into a single material has proven to be very challenging though. The paper presents also some examples of commercially available natural-origin polymers with applications in research or in clinical use in several applications. As it is recognized, this class of polymers is being widely used due to their similarities with the extracellular matrix, high chemical versatility, typically good biological performance and inherent cellular interaction and, also very significant, the cell or enzyme-controlled degradability. These biocharacteristics classify the natural-origin polymers as one of the most attractive options to be used in the tissue engineering field and drug delivery applications.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Nutrition of the intervertebral disc.

            A review of the literature on disc nutrition. To summarize the information on disc nutrition in relation to disc degeneration. The disc is avascular, and the disc cells depend on diffusion from blood vessels at the disc's margins to supply the nutrients essential for cellular activity and viability and to remove metabolic wastes such as lactic acid. The nutrient supply can fail due to changes in blood supply, sclerosis of the subchondral bone or endplate calcification, all of which can block transport from blood supply to the disc or due to changes in cellular demand. A review of the studies on disc blood supply, solute transport, studies of solute transport in animal and human disc in vitro, and of theoretical modeling studies that have examined factors affecting disc nutrition. Small nutrients such as oxygen and glucose are supplied to the disc's cells virtually entirely by diffusion; convective transport, arising from load-induced fluid movement in and out of the disc, has virtually no direct influence on transport of these nutrients. Consequently, there are steep concentration gradients of oxygen, glucose, and lactic acid across the disc; oxygen and glucose concentrations are lowest in the center of the nucleus where lactic acid concentrations are greatest. The actual levels of concentration depend on the balance between diffusive transport and cellular demand and can fall to critical levels if the endplate calcifies or nutritional demand increases. Loss of nutrient supply can lead to cell death, loss of matrix production, and increase in matrix degradation and hence to disc degeneration.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: found
              Is Open Access

              The role of interleukin-1 in the pathogenesis of human Intervertebral disc degeneration

              In this study, we investigated the hypotheses that in human intervertebral disc (IVD) degeneration there is local production of the cytokine IL-1, and that this locally produced cytokine can induce the cellular and matrix changes of IVD degeneration. Immunohistochemistry was used to localize five members of the IL-1 family (IL-1α, IL-1β, IL-1Ra (IL-1 receptor antagonist), IL-1RI (IL-1 receptor, type I), and ICE (IL-1β-converting enzyme)) in non-degenerate and degenerate human IVDs. In addition, cells derived from non-degenerate and degenerate human IVDs were challenged with IL-1 agonists and the response was investigated using real-time PCR for a number of matrix-degrading enzymes, matrix proteins, and members of the IL-1 family. This study has shown that native disc cells from non-degenerate and degenerate discs produced the IL-1 agonists, antagonist, the active receptor, and IL-1β-converting enzyme. In addition, immunopositivity for these proteins, with the exception of IL-1Ra, increased with severity of degeneration. We have also shown that IL-1 treatment of human IVD cells resulted in increased gene expression for the matrix-degrading enzymes (MMP 3 (matrix metalloproteinase 3), MMP 13 (matrix metalloproteinase 13), and ADAMTS-4 (a disintegrin and metalloproteinase with thrombospondin motifs)) and a decrease in the gene expression for matrix genes (aggrecan, collagen II, collagen I, and SOX6). In conclusion we have shown that IL-1 is produced in the degenerate IVD. It is synthesized by native disc cells, and treatment of human disc cells with IL-1 induces an imbalance between catabolic and anabolic events, responses that represent the changes seen during disc degeneration. Therefore, inhibiting IL-1 could be an important therapeutic target for preventing and reversing disc degeneration.
                Bookmark

                Author and article information

                Contributors
                lachlans@pennmedicine.upenn.edu
                conor.buckley@tcd.ie
                Journal
                JOR Spine
                JOR Spine
                10.1002/(ISSN)2572-1143
                JSP2
                Jor Spine
                John Wiley & Sons, Inc. (Hoboken, USA )
                2572-1143
                08 October 2018
                December 2018
                : 1
                : 4 ( doiID: 10.1002/jsp2.2018.1.issue-4 )
                : e1036
                Affiliations
                [ 1 ] Department of Neurosurgery University of Pennsylvania Philadelphia Pennsylvania
                [ 2 ] Department of Orthopaedic Surgery University of Pennsylvania Philadelphia Pennsylvania
                [ 3 ] Translational Musculoskeletal Research Center Corporal Michael J. Crescenz VA Medical Center Philadelphia Pennsylvania
                [ 4 ] DiscGenics Inc. Salt Lake City Utah
                [ 5 ] Department of Neurosurgery University of Tennessee Health Science Center Memphis Tennessee
                [ 6 ] Department of Orthopaedic Surgery, Surgical Science Tokai University School of Medicine Isehara Japan
                [ 7 ] Biomolecular Sciences Research Centre Sheffield Hallam University Sheffield UK
                [ 8 ] Department of Bioengineering University of Pennsylvania Philadelphia Pennsylvania
                [ 9 ] Department of Orthopaedic Surgery University of California San Francisco California
                [ 10 ] Trinity Centre for Bioengineering Trinity Biomedical Sciences Institute, Trinity College Dublin, The University of Dublin Dublin Ireland
                [ 11 ] School of Engineering Trinity College Dublin, The University of Dublin Dublin Ireland
                [ 12 ] Advanced Materials and Bioengineering Research (AMBER) Centre Royal College of Surgeons in Ireland & Trinity College Dublin, The University of Dublin Dublin Ireland
                Author notes
                [*] [* ] Correspondence

                Lachlan J. Smith, Assistant Professor, Department of Neurosurgery, University of Pennsylvania, 110 Stemmler Hall, 3450 Hamilton Walk, Philadelphia, PA.

                Email: lachlans@ 123456pennmedicine.upenn.edu

                Conor T. Buckley, Associate Professor, Trinity Center for Bioengineering, Trinity College Dublin, The University of Dublin, Dublin 2, Ireland.

                Email: conor.buckley@ 123456tcd.ie

                Author information
                https://orcid.org/0000-0001-5823-6073
                https://orcid.org/0000-0002-7497-847X
                https://orcid.org/0000-0003-4189-9270
                https://orcid.org/0000-0003-4489-7107
                https://orcid.org/0000-0001-7452-4534
                Article
                JSP21036
                10.1002/jsp2.1036
                6419951
                30895277
                f2679b58-2d9b-47ac-875f-147c3ddb821a
                © 2018 The Authors. JOR Spine published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 25 July 2018
                : 09 September 2018
                : 10 September 2018
                Page count
                Figures: 1, Tables: 1, Pages: 14, Words: 13860
                Funding
                Funded by: Arthritis Research UK
                Funded by: Catherine D. Sharp Foundation
                Funded by: Medical Research Council (UK)
                Award ID: MR/P026796/1
                Funded by: National Institute of Arthritis and Musculoskeletal and Skin Diseases
                Award ID: R01AR063705
                Award ID: R01AR071975
                Award ID: R21AR070959
                Funded by: Science Foundation Ireland
                Award ID: 15/CDA/3476
                Funded by: U.S. Department of Veterans Affairs
                Award ID: I01RX001321
                Categories
                Review
                Reviews
                Custom metadata
                2.0
                jsp21036
                December 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.6.1 mode:remove_FC converted:15.03.2019

                biological therapies,biomaterials,preclinical models,stem cells

                Comments

                Comment on this article