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Background: Current surgical management of intervertebral disc herniation often fails to adequately address the risk of recurrence, primarily due to the disc's limited regenerative capacity. Regenerative, biomaterial-based approaches for tissue augmentation, while showing preclinical promise, have consistently failed to meet the extreme mechanical demands of the intervertebral disc, impeding their clinical translation., Methods: In this study, we introduce a novel annulus repair strategy that employs the mechanical interpenetration of a non-woven PET scaffold into intervertebral disc tissue to resist reherniation. We investigate the efficacy in preventing herniations under compression using a bovine explant model and validate its performance in a pilot in vivo study in a goat cervical spine injury model. Healing and scaffold integration are assessed over 4 weeks using computed tomography, magnetic resonance imaging, and histopathology., Results: We demonstrate that this approach effectively prevents mechanically induced herniation. In vivo, the scaffold interpenetration enables biological integration at 4 weeks post-surgery, with no evidence of scaffold migration or disc degeneration. The scaffold supports matrix deposition and cell infiltration, with no observed endplate pathologies or osteolysis., Conclusions: These findings highlight a promising combination of biomechanical reliability and favorable histological outcomes, underscoring the potential of this technology for advancing toward human clinical applications., (© 2025 The Author(s). JOR Spine published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

Introduction: Therapeutic interventions for intervertebral disc herniation remain scarce due to the inability of endogenous annulus fibrosus (AF) cells to respond to injury and drive tissue regeneration. Unlike other orthopedic tissues, such as cartilage, delivery of exogenous cells to the site of annular injury remains underdeveloped, largely due to a lack of an ideal cell source and the invasive nature of cell isolation. Human induced pluripotent stem cells (iPSCs) can be differentiated to specific cell fates using biochemical factors and are, therefore, an invaluable tool for cell therapy approaches. While differentiation protocols have been developed for cartilage and fibrous connective tissues (e.g., tendon), the signals that regulate the induction and differentiation of human iPSCs toward the AF fate remain unknown., Methods: iPSC-derived sclerotome cells were treated with various combinations of developmental signals including transforming growth factor beta 3 (TGF-β3), connective tissue growth factor (CTGF), platelet derived growth factor BB (PDGF-BB), insulin-like growth factor 1 (IGF-1), or the Hedgehog pathway activator, Purmorphamine, and gene expression changes in major AF-associated ECM genes were assessed. The top performing combination treatments were further validated by using three distinct iPSC lines and by assessing the production of upregulated ECM proteins of interest. To conduct a broader analysis of the transcriptomic shifts elicited by each factor combination, and to compare genetic profiles of treated cells to mature human AF cells, a 96.96 Fluidigm gene expression array was applied, and principal component analysis was employed to identify the transcriptional signatures of each cell population and treatment group in comparison to native AF cells., Results: TGF-β3, in combination with PDGF-BB, CTGF, or IGF-1, induced an upregulation of key AF ECM genes in iPSC-derived sclerotome cells. In particular, treatment with a combination of TGF-β3 with PDGF-BB for 14 days significantly increased gene expression of collagen II and aggrecan and increased protein deposition of collagen I and elastin compared to other treatment groups. Assessment of genes uniquely highly expressed by AF cells or SCL cells, respectively, revealed a shift toward the genetic profile of AF cells with the addition of TGF-β3 and PDGF-BB for 14 days., Discussion: These findings represent an initial approach to guide human induced pluripotent stem cells toward an AF-like fate for cellular delivery strategies., Competing Interests: Robert L. Mauck is Co‐editor in Chief of JOR Spine and Sarah Gullbrand is an Editorial Board member of JOR Spine; both are co‐authors of this article. They were excluded from editorial decision‐making related to the acceptance of this article for publication in the journal., (© 2024 The Authors. JOR Spine published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

Background: Vertebral endplate sclerosis and facet osteoarthritis have been documented in animals and humans. However, it is unclear how these adjacent pathologies engage in crosstalk with the intervertebral disc. This study sought to elucidate this crosstalk by assessing each compartment individually in response to acute disc injury., Methods: Eleven New Zealand White rabbits underwent annular disc puncture using a 16G or 21G needle. At 4 and 10 weeks, individual compartments of the motion segment were analyzed. Discs underwent T 1 relaxation mapping with MRI contrast agent gadodiamide as well T 2 mapping. Both discs and facets underwent mechanical testing via vertebra-disc-vertebra tension-compression creep testing and indentation testing, respectively. Endplate bone density was quantified via μCT. Discs and facets were sectioned and stained for histology scoring., Results: Intervertebral discs became more degenerative with increasing needle diameter and time post-puncture. Bone density also increased in endplates adjacent to both 21G and 16G punctured discs leading to reduced gadodiamide transport at 10 weeks. The facet joints, however, did not follow this same trend. Facets adjacent to 16G punctured discs were less degenerative than facets adjacent to 21G punctured discs at 10 weeks. 16G facets were more degenerative at 4 weeks than at 10, suggesting the cartilage had recovered. The formation of severe disc osteophytes in 16G punctured discs between 4 and 10 weeks likely offloaded the facet cartilage, leading to the recovery observed., Conclusions: Overall, this study supports that degeneration spans the whole spinal motion segment following disc injury. Vertebral endplate thickening occurred in response to disc injury, which limited the diffusion of small molecules into the disc. This work also suggests that altered disc mechanics can induce facet degeneration, and that extreme bony remodeling adjacent to the disc may promote facet cartilage recovery through offloading of the articular cartilage., Competing Interests: Robert L. Mauck is Co‐editor in Chief of JOR Spine. Sarah Gullbrand is an Editorial Board member of JOR Spine and co‐author of this article. They were excluded from editorial decision‐making related to the acceptance of this article for publication in the journal., (© 2023 The Authors. JOR Spine published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

This perspective summarizes the genesis, development, and potential future directions of the multispecies JOR Spine histopathology series., (© 2021 The Authors. JOR Spine published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

Background: The rabbit lumbar spine is a commonly utilized model for studying intervertebral disc degeneration and for the pre-clinical evaluation of regenerative therapies. Histopathology is the foundation for which alterations to disc morphology and cellularity with degeneration, or following repair or treatment are assessed. Despite this, no standardized histology grading scale has yet been established for the spine field for any of the frequently utilized animal models., Aims: The purpose of this study was to establish a new standardized scoring system to assess disc degeneration and regeneration in the rabbit model., Materials and Methods: The scoring system was formulated following a review of the literature and a survey of spine researchers. Validation of the scoring system was carried out using images provided by 4 independent laboratories, which were graded by 12 independent graders of varying experience levels. Reliability testing was performed via the computation of intra-class correlation coefficients (ICC) for each category and the total score. The scoring system was then further refined based on the results of the ICC analysis and discussions amongst the authors., Results: The final general scoring system involves scoring 7 features (nucleus pulposus shape, area, cellularity and matrix condensation, annulus fibrosus/nucleus pulposus border appearance, annulus fibrosus morphology, and endplate sclerosis/thickening) on a 0 (healthy) to 2 (severe degeneration) scale. ICCs demonstrated overall moderate to good agreement across graders. An addendum to the main scoring system is also included for use in studies evaluating regenerative therapeutics, which involves scoring cell cloning and morphology within the nucleus pulposus and inner annulus fibrosus., Discussion: Overall, this new scoring system provides an avenue to improve standardization, allow a more accurate comparison between labs and more robust evaluation of pathophysiology and regenerative treatments across the field., Conclusion: This study developed a histopathology scoring system for degeneration and regeneration in the rabbit model based on reported practice in the literature, a survey of spine researchers, and validation testing., Competing Interests: The authors declare no potential conflicts of interest., (© 2021 The Authors. JOR Spine published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

Background: Rats are a widely accepted preclinical model for evaluating intervertebral disc (IVD) degeneration and regeneration. IVD morphology is commonly assessed using histology, which forms the foundation for quantifying the state of IVD degeneration. IVD degeneration severity is evaluated using different grading systems that focus on distinct degenerative features. A standard grading system would facilitate more accurate comparison across laboratories and more robust comparisons of different models and interventions., Aims: This study aimed to develop a histology grading system to quantify IVD degeneration for different rat models., Materials & Methods: This study involved a literature review, a survey of experts in the field, and a validation study using 25 slides that were scored by 15 graders from different international institutes to determine inter- and intra-rater reliability., Results: A new IVD degeneration grading system was established and it consists of eight significant degenerative features, including nucleus pulposus (NP) shape, NP area, NP cell number, NP cell morphology, annulus fibrosus (AF) lamellar organization, AF tears/fissures/disruptions, NP-AF border appearance, as well as endplate disruptions/microfractures and osteophyte/ossification. The validation study indicated this system was easily adopted, and able to discern different severities of degenerative changes from different rat IVD degeneration models with high reproducibility for both experienced and inexperienced graders. In addition, a widely-accepted protocol for histological preparation of rat IVD samples based on the survey findings include paraffin embedding, sagittal orientation, section thickness < 10 μm, and staining using H&E and/or SO/FG to facilitate comparison across laboratories., Conclusion: The proposed histological preparation protocol and grading system provide a platform for more precise comparisons and more robust evaluation of rat IVD degeneration models and interventions across laboratories., Competing Interests: The authors declare no conflicts of interest., (© 2021 The Authors. JOR Spine published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

Intervertebral disc (IVD) herniations, caused by annulus fibrosus (AF) tears that enable disc tissue extrusion beyond the disc space, are very prevalent, especially among adults in the third to fifth decade of life. Symptomatic herniations, in which the extruded tissue compresses surrounding nerves, are characterized by back pain, numbness, and tingling and can cause extreme physical disability. Patients whose symptoms persist after nonoperative intervention may undergo surgical removal of the herniated tissue via microdiscectomy surgery. The AF, however, which has a poor endogenous healing ability, is left unrepaired increasing the risk for re-herniation and pre-disposing the IVD to degenerative disc disease. The lack of understanding of the mechanisms involved in native AF repair limits the design of repair systems that overcome the impediments to successful AF restoration. Moreover, the complexity of the AF structure and the challenging anatomy of the repair environment represents a significant challenge for the design of new repair devices. While progress has been made towards the development of an effective AF repair technique, these methods have yet to demonstrate long-term repair and recovery of IVD biomechanics. In this review, the limitations of endogenous AF healing are discussed and key cellular events and factors involved are highlighted to identify potential therapeutic targets that can be integrated into AF repair methods. Clinical repair strategies and their limitations are described to further guide the design of repair approaches that effectively restore native tissue structure and function., Competing Interests: Ana P. Peredo has no competing financial interests. Sarah E. Gullbrand has no competing financial interests. Harvey E. Smith has no competing financial interests. Robert L. Mauck has no competing financial interests., (© 2021 The Authors. JOR Spine published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

Tissue-engineered whole disc replacements are an emerging treatment strategy for advanced intervertebral disc degeneration. A challenge facing the translation of tissue-engineered disc replacement to clinical use are the opposing needs of initial immobilization to advantage integration contrasted with physiologic loading and its anabolic effects. Here, we utilize our established rat tail model of tissue engineered disc replacement with external fixation to study the effects of remobilization at two time points postimplantation on engineered disc structure, composition, and function. Our results suggest that the restoration of mechanical loading following immobilization enhanced collagen and proteoglycan content within the nucleus pulposus and annulus fibrosus of the engineered discs, in addition to improving the integration of the endplate region of the construct with native bone. Despite these benefits, angulation of the vertebral bodies at the implanted level occurred following remobilization at both early and late time points, reducing tensile failure properties in the remobilized groups compared to the fixed group. These results demonstrate the necessity of restoring physiologic mechanical loading to engineered disc implants in vivo, and the need to transition toward their evaluation in larger animal models with more human-like anatomy and motion compared to the rat tail., Competing Interests: R. L. M. is a co‐editor of JOR Spine., (© 2020 The Authors. JOR Spine published by Wiley Periodicals LLC on behalf of Orthopaedic Research Society.)

Intervertebral disc degeneration is frequently implicated as a cause of back and neck pain, which are pervasive musculoskeletal complaints in modern society. For the treatment of end stage disc degeneration, replacement of the disc with a viable, tissue-engineered construct that mimics native disc structure and function is a promising alternative to fusion or mechanical arthroplasty techniques. Substantial progress has been made in the field of whole disc tissue engineering over the past decade, with a variety of innovative designs characterized both in vitro and in vivo in animal models. However, significant barriers to clinical translation remain, including construct size, cell source, culture technique, and the identification of appropriate animal models for preclinical evaluation. Here we review the clinical need for disc tissue engineering, the current state of the field, and the outstanding challenges that will need to be addressed by future work in this area., Competing Interests: The authors declare no potential conflicts of interest with respect to the authorship and/or publication of this manuscript.

This study investigated current trends in spine publications of the membership of Orthopaedic Research Society Spine Section (ORS3) and the more global and clinically focused International Society for the Study of the Lumbar Spine (ISSLS). The PubMed database was probed to quantify trends in the overall number of articles published, the number of journals these articles were published in, and the number of active scientists producing new manuscripts. We also evaluated trends in flagship spine journals ( Spine , European Spine Journal , and The Spine Journal ) and in the Journal of Orthopaedic Research. The total number of active ORS3 and ISSLS authors and articles published have increased over the last 10 years. These articles are being published in hundreds of distinct journals; the number of journals is also increasing. Members of both societies published their work in Spine more than any other journal. Yet, publications in Spine decreased over the last 5 years for both ORS3 and ISSLS members, while those in European Spine Journal , and The Spine Journal remained unchanged. Furthermore, members of both societies have published in Journal of Orthopaedic Research at a consistent level. The increasing number of manuscripts and journals reflects a characteristic intrinsic to science as a whole-the global scientific workforce and output are growing and new journals are being created to accommodate the demand. These data suggest that existing spine journals do not fully serve the diverse publication needs of ORS3 and ISSLS members and highlight an unmet need for consolidating the premiere basic and translational spine research in an open access spine-specific journal. This analysis was an important part of a decision process by the ORS to introduce JOR Spine., Competing Interests: J.T.M.: ORS3 Member. S.E.G.: ORS3 Member. A.J.F.: ORS3 Member, ISSLS Member. D.P.: ORS3 Member. A.D.D.: ORS3 Member, ISSLS Treasurer, Asian Spine Journal Deputy Editor, European Spine Journal Editorial Board, International Journal of Spine Surgery Section Editor, JOR Spine Advisory Review Board. T.R.O: ORS Member, ISSLS First Vice President, Spine Associate Editorial Board, Journal of Orthopaedic Research Editorial Review Board, JOR Spine Advisory Review Board. K.C.: ORS3 Member, ISSLS Secretary, Spine Associate Editorial Board, Spine Surgery and Related Research Deputy Editor. F.G.: ORS3 Member, ORS Past President (current) and President (during the formation of JOR Spine), Journal of Biomechanics Editor‐in‐Chief, Osteoarthritis & Cartilage Associate Editor, DNA and Cell Biology Editorial Board, Current Rheumatology Reviews Editorial Board, Clinical Medicine: Arthritis and Musculoskeletal Disorders Editorial Board, Stem Cell Research & Therapy Editorial Board, Orthopedic Research and Reviews Editorial Board, Biomedical Engineering Letters Advisory Board, Bioengineering Editorial Board, TECHNOLOGY Editorial Board, Journal of Experimental Orthopaedics Editorial Board, Techniques in Orthopaedics Editorial Board – Bioengineering, European Cells & Materials International Review Panel, Journal of Orthopaedic Research Editorial Review Board. J.A.H.: ORS3 Chair, JOR Spine Advisory Review Board. J.C.I.: ORS3 Past Chair, ORS Second Vice President, ISSLS Member, JOR Spine Advisory Review Board, Journal of Biomechanics Editorial Consultant, Journal of Orthopaedic Research Publications Advisory Board, Orthopaedic Research Society Executive Board.