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

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.

SUBMITTER: Smith LJ

PROVIDER: S-EPMC6419951 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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

Smith Lachlan J LJ Silverman Lara L Sakai Daisuke D Le Maitre Christine L CL Mauck Robert L RL Malhotra Neil R NR Lotz Jeffrey C JC Buckley Conor T CT

JOR spine 20181008 4

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 approa ...[more]

PMID: 30895277

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Project description:BackgroundRats 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.AimsThis study aimed to develop a histology grading system to quantify IVD degeneration for different rat models.Materials & methodsThis 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.ResultsA 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.ConclusionThe 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.

Project description:Mice have been increasingly used as preclinical model to elucidate mechanisms and test therapeutics for treating intervertebral disc degeneration (IDD). Several intervertebral disc (IVD) histological scoring systems have been proposed, but none exists that reliably quantitate mouse disc pathologies. Here, we report a new robust quantitative mouse IVD histopathological scoring system developed by building consensus from the spine community analyses of previous scoring systems and features noted on different mouse models of IDD. The new scoring system analyzes 14 key histopathological features from nucleus pulposus (NP), annulus fibrosus (AF), endplate (EP), and AF/NP/EP interface regions. Each feature is categorized and scored; hence, the weight for quantifying the disc histopathology is equally distributed and not driven by only a few features. We tested the new histopathological scoring criteria using images of lumbar and coccygeal discs from different IDD models of both sexes, including genetic, needle-punctured, static compressive models, and natural aging mice spanning neonatal to old age stages. Moreover, disc sections from common histological preparation techniques and stains including H&E, SafraninO/Fast green, and FAST were analyzed to enable better cross-study comparisons. Fleiss's multi-rater agreement test shows significant agreement by both experienced and novice multiple raters for all 14 features on several mouse models and sections prepared using various histological techniques. The sensitivity and specificity of the new scoring system was validated using artificial intelligence and supervised and unsupervised machine learning algorithms, including artificial neural networks, k-means clustering, and principal component analysis. Finally, we applied the new scoring system on established disc degeneration models and demonstrated high sensitivity and specificity of histopathological scoring changes. Overall, the new histopathological scoring system offers the ability to quantify histological changes in mouse models of disc degeneration and regeneration with high sensitivity and specificity.

Project description:BackgroundHistopathological analysis of intervertebral disc (IVD) tissues is a critical domain of back pain research. Identification, description, and classification of attributes that distinguish abnormal tissues form a basis for probing disease mechanisms and conceiving novel therapies. Unfortunately, lack of standardized methods and nomenclature can limit comparisons of results across studies and prevent organizing information into a clear representation of the hierarchical, spatial, and temporal patterns of IVD degeneration. Thus, the following Orthopaedic Research Society (ORS) Spine Section Initiative aimed to develop a standardized histopathology scoring scheme for human IVD degeneration.MethodsGuided by a working group of experts, this prospective process entailed a series of stages that consisted of reviewing and assessing past grading schemes, surveying IVD researchers globally on current practice and recommendations for a new grading system, utilizing expert opinion a taxonomy of histological grading was developed, and validation performed.ResultsA standardized taxonomy was developed, which showed excellent intra-rater reliability for scoring nucleus pulposus (NP), annulus fibrosus (AF), and cartilaginous end plate (CEP) regions (interclass correlation [ICC] > .89). The ability to reliably detect subtle changes varied by IVD region, being poorest in the NP (ICC: .89-.95) where changes at the cellular level were important, vs the AF (ICC: .93-.98), CEP (ICC: .97-.98), and boney end plate (ICC: .96-.99) where matrix and structural changes varied more dramatically with degeneration.ConclusionsThe proposed grading system incorporates more comprehensive descriptions of degenerative features for all the IVD sub-tissues than prior criteria. While there was excellent reliability, our results reinforce the need for improved training, particularly for novice raters. Future evaluation of the proposed system in real-world settings (eg, at the microscope) will be needed to further refine criteria and more fully evaluate utility. This improved taxonomy could aid in the understanding of IVD degeneration phenotypes and their association with back pain.

Project description:Tissue-engineered intervertebral discs (IVDs) have been proposed as a useful therapeutic strategy for the treatment of intervertebral disc degeneration (IDD). However, most studies have focused on fabrication and assessment of tissue-engineered IVDs in small animal models and the mechanical properties of the scaffolds are far below those of native human IVDs. The aim of this study was to produce a novel tissue-engineered IVD for IDD regeneration in the porcine lumbar spine. Firstly, a novel whole tissue-engineered IVD scaffold was fabricated using chitosan hydrogel to simulate the central nucleus pulposus (NP) structure, surrounded with a poly(butylene succinate-co-terephthalate) (PBST) fiber film for inner annulus fibrosus (IAF). And, a poly(ether ether ketone) (PEEK) ring was used to stimulate the outer annulus fibrosus (OAF). Then, the scaffolds were seeded with IVD cells and the cell-scaffold hybrids were transplanted into the porcine damaged spine and harvested at 4 and 8 weeks. In vitro cell experiments showed that IVD cells distributed and grew well in the scaffolds including porous hydrogel and PBST fibers. After implantation into pigs, radiographic and MRI images indicated that the tissue-engineered IVD construct could preserve the disc height in the case of discectomy as the normal disc height and maintain a large extracellular matrix and water content in the NP. Combined with the histological and gene expression results, it was concluded that the tissue-engineered IVD had similar morphological and histological structure to the natural IVD. Moreover, after implantation for 8 weeks, the tissue-engineered IVD showed a good compressive stress and elastic moduli, approaching those of natural porcine IVD. Therefore, the prepared tissue-engineered IVD construct had similar morphological and biofunctional properties to the native tissue. Also, the tissue-engineered IVD construct with excellent biocompatibility and mechanical properties provides a promising candidate for human IDD regeneration.

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

Publications

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

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