The past, present, and the future of disc nucleus replacement. A systematic review of a large diversity of ideas and experiences.

Disc nucleus replacement (NR) is a challenging surgical technique used as a medical treatment for early-stage disc herniation to restore disc height and the biomechanical function of a motion segment, which may reduce low back pain. The surgical procedure involves the removal and replacement of the degenerated nucleus pulposus with a substitute by accessing the annulus fibrosos via a created hole. Over the decades, nucleus replacement has been an important issue, leading to the development of different substitute alternatives. The first ideas are dated to the 1950s and since then, more than a hundred nucleus replacement concepts can be identified. There were numerous attempts and several clinical trials; however, after more than 70 years of research, no gold standard for nucleus pulposus replacement has been identified. This review aims to collect the different nucleus replacements reported in the literature, thus understanding what failed, what could be improved and what are the opportunities for the future. A systematic review of the literature was performed using a keyword-based search on PubMed, Web of Science, and Scopus databases to detect all nucleus replacements presented in the past by clinicians and engineers. Several studies were extracted from which the main nucleus replacements over the years were investigated, including the ones that received CE mark, FDA approval, or IDE approval and, also those involved in clinical trials. A total of 116 studies were included in this review. The extracted data concern the nucleus replacements proposed over the years to create a historical background as complete as possible, including their mechanical and biomechanical characterization and the clinical trials conducted over the years. Nucleus disc arthroplasty has been explored for many years. Unfortunately, even today there is still nothing safe and definitive in this surgical practice. This review provides an overview of the nucleus replacement history. A breakthrough could be the improvements in technologies for the annulus fibrous closing or sealing and the tissue engineering and medical regenerative techniques which could certainly ensure a higher NR implantation success rate in the future of this clinical treatment. It is not yet clear what is the future of this clinical practice. Only scientific research can answer the question: is the nucleus replacement still a possible clinical solution?

Papain Injection Creates a Nucleotomy-like Cavity for Testing Gels in Intervertebral Discs.

Biomaterials, such as hydrogels, have an increasingly important role in the development of regenerative approaches for the intervertebral disc. Since animal models usually resist biomaterial injection due to high intradiscal pressure, preclinical testing of the biomechanical performance of biomaterials after implantation remains difficult. Papain reduces the intradiscal pressure, creates cavities within the disc, and allows for biomaterial injections. But papain digestion needs time, and cadaver experiments that are limited to 24 h for measuring range of motion (ROM) cannot not be combined with papain digestion just yet. In this study, we successfully demonstrate a new organ culture approach, facilitating papain digestion to create cavities in the disc and the testing of ROM, neutral zone (NZ), and disc height. Papain treatment increased the ROM by up to 109.5%, extended NZ by up to 210.9%, and decreased disc height by 1.96 ± 0.74 mm. A median volume of 0.73 mL hydrogel could be injected after papain treatment, and histology revealed a strong loss of proteoglycans in the remaining nucleus tissue. Papain has the same biomechanical effects as known from nucleotomies or herniations and thus creates a disc model to study such pathologies in vitro. This new model can now be used to test the performance of biomaterials.

How cervical and cervicothoracic scoliosis influence the atlantoaxial joint.

INTRODUCTION: Children with cervical or cervicothoracic congenital scoliosis are limited in their ability to compensate for the main curve of the deformity because there are only a few mobile segments in their cervical spine. Over the years, we have frequently observed coronal atlantoaxial dislocation (CAAD) in a lateral direction (from left to right or vice versa) in these patients. It was anticipated that CAAD might compensate for the horizontal position of the head, and it is hypothesized that CAAD depends on the degree of scoliotic deformity. Thus, the aim of our study was to investigate whether there is a correlation between CAAD and scoliosis parameters in these patients. METHODS: Retrospective analysis was performed based on CAT scans and preoperative X-rays of patients with cervical and cervicothoracic scoliosis with an apex between C4 and T6. Seventeen patients, with a mean age of 7.25 years, who were 9 girls and 8 boys, and who were treated between 2006 and 2022 were included. Cobb`s angle of the main curve (CA-MC), Cobb`s angle of the secondary curve (CA-SC), and T1-, C2- and UEV (upper end vertebra) tilt were measured on whole-spine radiographs in the standing position. The CAAD was measured via coronal CAT scan reconstruction and defined as the difference in the distances of the lateral masses to the midline of the axis. Pearson`s linear correlation coefficients (r) were determined using SPSS to evaluate correlations between CAAD and the measured parameters. p < 0.05 indicated statistical significance. RESULTS: CAAD toward the convex region in patients with scoliosis was typically observed; the mean CAAD was 3 mm ± 3.7 mm. The mean CA-MC was 46° ± 13°, the mean CA-SC was 16° ± 9.6°, the mean T1 tilt was 17° ± 8.8°, the mean C2 tilt was 9°± 8.8°, and the mean UEV tilt was 24° ± 7.2°. There was a strong linear correlation between CAAD and CA-MC (r = 0.784, p < 0.001), C2 tilt (r = 0.745; p < 0.001), and UEV tilt (r = 0.519; p = 0.033). There was no correlation between CAAD and either CA-SC or T1 tilt. DISCUSSION: Children with cervical or cervicothoracic scoliosis tend to have a CAAD toward the convexity of the scoliosis that correlates to CA-MC, C2-tilt, and UEV-tilt. CAAD may be seen as a compensatory mechanism to keep the head in a horizontal position. Severe or progressive CAAD may result in destruction of the atlantoaxial joint, including severe complaints, thus necessitating close follow-up and possibly early surgical treatment. Moreover, CAAD might be a useful additional radiographic parameter to be checked in future scoliosis studies.

Comparative FEM study on intervertebral disc modeling: Holzapfel-Gasser-Ogden vs. structural rebars.

Introduction: Numerical modeling of the intervertebral disc (IVD) is challenging due to its complex and heterogeneous structure, requiring careful selection of constitutive models and material properties. A critical aspect of such modeling is the representation of annulus fibers, which significantly impact IVD biomechanics. This study presents a comparative analysis of different methods for fiber reinforcement in the annulus fibrosus of a finite element (FE) model of the human IVD. Methods: We utilized a reconstructed L4-L5 IVD geometry to compare three fiber modeling approaches: the anisotropic Holzapfel-Gasser-Ogden (HGO) model (HGO fiber model) and two sets of structural rebar elements with linear-elastic (linear rebar model) and hyperelastic (nonlinear rebar model) material definitions, respectively. Prior to calibration, we conducted a sensitivity analysis to identify the most important model parameters to be calibrated and improve the efficiency of the calibration. Calibration was performed using a genetic algorithm and in vitro range of motion (RoM) data from a published study with eight specimens tested under four loading scenarios. For validation, intradiscal pressure (IDP) measurements from the same study were used, along with additional RoM data from a separate publication involving five specimens subjected to four different loading conditions. Results: The sensitivity analysis revealed that most parameters, except for the Poisson ratio of the annulus fibers and C01 from the nucleus, significantly affected the RoM and IDP outcomes. Upon calibration, the HGO fiber model demonstrated the highest accuracy (R2 = 0.95), followed by the linear (R2 = 0.89) and nonlinear rebar models (R2 = 0.87). During the validation phase, the HGO fiber model maintained its high accuracy (RoM R2 = 0.85; IDP R2 = 0.87), while the linear and nonlinear rebar models had lower validation scores (RoM R2 = 0.71 and 0.69; IDP R2 = 0.86 and 0.8, respectively). Discussion: The results of the study demonstrate a successful calibration process that established good agreement with experimental data. Based on our findings, the HGO fiber model appears to be a more suitable option for accurate IVD FE modeling considering its higher fidelity in simulation results and computational efficiency.

Range of international surgical strategies for adolescent idiopathic scoliosis: Evaluation of a multi-center survey.

Background: Surgical treatment of adolescent idiopathic scoliosis (AIS) is very complex and modern instrumentation techniques offer multiple possibilities. Despite numerous publications, there is no clear consensus on the optimal strategy for the correction of scoliotic deformities. The goal of this study was to summarize the current surgical strategies for specific AIS cases within various countries. Method: Thirty-two experienced scoliosis surgeons from 15 countries were asked to plan surgeries on 12 representative AIS cases. All AIS cases had an indication for surgery. A questionnaire was provided to document surgical planning. The surgeons were provided with the patients' age and sex, together with radiographs in the lateral and sagittal planes during upright standing and in lateral bending to the left and right, as well as with clinical images. The angles of the main spinal curvatures were specified in the questionnaire. The surgeons were asked to specify their preferred classification system, their surgical approach, the planned fusion length, the type of implants, the rod type, and the resection steps. The data were analyzed with respect to the inter-rater variability, which was quantified using the Fleiss-Kappa Method. Results: There was a good agreement (k = 0.61) between the surgeons in choosing the Lenke curve type, and a moderate agreement for the lumbar (0.41) and sagittal (0.56) modifiers. The most frequently planned resection procedure was complete facetectomy (67%). The posterior approach was the most commonly (91%) selected strategy to treat AIS. Anterior approaches were chosen most for Lenke 5 type with a rate of 20%. The upper instrumented vertebra (UIV) varied most for Lenke 1, 5, and 6 cases, with a vertebral level discrepancy of up to 10 levels at Lenke 6. The lowest instrumented vertebra varied most for Lenke 1 and 4 by up to five levels. Polyaxial screws were chosen most (56%), followed by monoaxial (20%) and uniplanar (19%) screws and hooks (5%). Conclusions: The results highlight the commonalities and discrepancy in the surgical treatment of AIS in between surgeons. The selected LIV and UIV can vary depending on the curve type and surgeon. Hook constructs appear to be generally replaced by transpedicular screws. The survey indicates open questions in the AIS treatment and in the understanding of scoliosis biomechanics.

Automatic grading of intervertebral disc degeneration in lumbar dog spines.

Background: Intervertebral disc degeneration is frequent in dogs and can be associated with symptoms and functional impairments. The degree of disc degeneration can be assessed on T2-weighted MRI scans using the Pfirrmann classification scheme, which was developed for the human spine. However, it could also be used to quantify the effectiveness of disc regeneration therapies. We developed and tested a deep learning tool able to automatically score the degree of disc degeneration in dog spines, starting from an existing model designed to process images of human patients. Methods: MRI midsagittal scans of 5991 lumbar discs of dog patients were collected and manually evaluated with the Pfirrmann scheme and a modified scheme with transitional grades. A deep learning model was trained to classify the disc images based on the two schemes and tested by comparing its performance with the model processing human images. Results: The determination of the Pfirrmann grade showed sensitivities higher than 83% for all degeneration grades, except for grade 5, which is rare in dog spines, and high specificities. In comparison, the correspondent human model had slightly higher sensitivities, on average 90% versus 85% for the canine model. The modified scheme with the fractional grades did not show significant advantages with respect to the original Pfirrmann grades. Conclusions: The novel tool was able to accurately and reliably score the severity of disc degeneration in dogs, although with a performance inferior than that of the human model. The tool has potential in the clinical management of disc degeneration in canine patients as well as in longitudinal studies evaluating regenerative therapies in dogs used as animal models of human disorders.

The Injection of Gels Through an Intact Annulus Maintains Biomechanical Performance without Extrusion Risk.

For autologous-disc-derived chondrocyte transplantation (ADCT) a transglutaminase crosslinked gelatine gel and an albumin hyaluronic acid gel, crosslinked with bis-thio-polyethylene glycol, were injected through a syringe into a degenerated intervertebral disc, where they solidified in situ. This biomechanical in vitro study with lumbar bovine motion segments evaluated disc height changes, motion characteristics in a quasi-static spine loading simulators, and the potential extrusion risk of these biomaterials in a complex dynamic multi-axial loading set-up with 100,000 loading cycles. After the injection and formation of the gel in the center of the nucleus, the disc height increase was about 0.3 mm. During cyclic testing, a gradual decrease in height could be detected due to viscoelastic effects and fluid loss. No gel extrusion could be observed for all specimens during the entire test procedure. A macroscopic inspection after dissections showed an accumulation of the solidified gel in the center of the nucleus. The results demonstrate that the injection of in situ solidifying gels through the intact annulus allows for the stable maintenance of the injected gel at the target location, with high potential for use as a suitable scaffold to anchor therapeutically applied cells for disc regeneration within the treated nucleus pulposus.

Variability of intervertebral joint stiffness between specimens and spine levels.

Introduction: Musculoskeletal multibody models of the spine can be used to investigate the biomechanical behaviour of the spine. In this context, a correct characterisation of the passive mechanical properties of the intervertebral joint is crucial. The intervertebral joint stiffness, in particular, is typically derived from the literature, and the differences between individuals and spine levels are often disregarded. Methods: This study tested if an optimisation method of personalising the intervertebral joint stiffnesses was able to capture expected stiffness variation between specimens and between spine levels and if the variation between spine levels could be accurately captured using a generic scaling ratio. Multibody models of six T12 to sacrum spine specimens were created from computed tomography data. For each specimen, two models were created: one with uniform stiffnesses across spine levels, and one accounting for level dependency. Three loading conditions were simulated. The initial stiffness values were optimised to minimize the kinematic error. Results: There was a range of optimised stiffnesses across the specimens and the models with level dependent stiffnesses were less accurate than the models without. Using an optimised stiffness substantially reduced prediction errors. Discussion: The optimisation captured the expected variation between specimens, and the prediction errors demonstrated the importance of accounting for level dependency. The inaccuracy of the predicted kinematics for the level-dependent models indicated that a generic scaling ratio is not a suitable method to account for the level dependency. The variation in the optimised stiffnesses for the different loading conditions indicates personalised stiffnesses should also be considered load-specific.

Influence of cervical total disc replacement on motion in the target and adjacent segments.

BACKGROUND CONTEXT: The motion limitation after cervical discectomy and fusion alters the spine´s kinematics. Unphysiological strains may be the result and possible explanation for adjacent segment degeneration. Alterations to cervical kinematics due to cervical total disc replacement (TDR), especially two-level, are still under investigated. PURPOSE: To investigate cervical motion including coupled motions after one-level and two-level TDR in the treated and also the adjacent segments. STUDY DESIGN: An in-vitro study using pure moment loading of human donor spines. METHODS: Seven fresh frozen human cervical spine specimens (C4-T1, median age 46 with range 19-60 years, four female) were included in this study. Specimens were tested in the intact condition first, followed by one-level TDR at C5-6 which was subsequently extended one level further caudal (C5-7). Each specimen was quasistatically loaded with pure moments up to 1.5 Nm in flexion/extension (FE), lateral bending (LB), and axial rotation (AR) in a universal spine tester for 3.5 cycles at 1 °/s. During the tests three dimensional motion tracking was performed for each vertebral body individually. From that, the primary and coupled ROM of each spinal level during the third full cycle of motion were evaluated. Nonparametric statistical analysis was performed using a Friedman-test and post hoc correction with Dunn-Bonferroni-tests (p<.05). Ethics approval was obtained in advance. RESULTS: In FE, one-level TDR (C5-6) moderately increased primary FE in all four segments, but only significantly at the cranial adjacent level C4-5. Additional TDR at C6-7 further increased the ROM at the target segment without much influence on the other levels. Increasing implant height at C6-7 partially counteracted the increased FE. Coupled motions were minimal in all test conditions at all levels. In LB, coupled AR was observed in all test conditions at all levels. One-level TDR decreased primary LB at the target segment C5-6 significantly, without much influence on the other levels. Extending TDR to C6-7 decreased ROM in the target segment but without gaining statistical significance. Increasing implant height at C6-7 further decreased primary LB at the target segment, still without significance. Notably, coupled AR was significantly decreased at the cranial adjacent segment C4-5 compared to the intact condition. In AR, coupled LB was observed in all test conditions at the levels C4-5, C5-6, and C6-7, while the transition level to the thoracic spine C7-T1 showed only little coupled LB. Both one-level and two-level TDR showed little influence on primary AR or coupled motions at any level. Only after increasing implant height at C6-7 was the motion of the caudally adjacent level C7-T1 significantly altered. CONCLUSION: Evaluating primary FE, LB, and AR together with the associated coupled motions revealed widespread influence of cervical TDR not only on the motion of the treated level but also at the adjacent segments. The influence of two-level TDR is more widespread and involves more levels than one-level TDR. CLINICAL SIGNIFICANCE: The prevention of unphysiological strains due to altered kinematics after cervical fusion, which could possibly explain adjacent segment degeneration, were a driving factor in the development of TDR. These experimental findings suggest cervical TDR influences the whole cervical spine, not only the treated segment. The effect becomes more extensive, involving more levels and motion directions, after two-level than after one-level TDR.

Decreasing implant load indicates spinal fusion when measured continuously.

Reliable and timely assessment of bone union between vertebrae is considered a key challenge after spinal fusion surgery. Recently, a novel sensor concept demonstrated the ability to objectively assess posterolateral fusion based on continuous implant load monitoring. The aim of this study was to investigate systematically the concept in a mono-segmental fusion model using an updated sensor setup. Three sheep underwent bilateral facetectomy at level L2-L3 and L4-L5. The segments were stabilized using two unconnected pedicle-screw-rod constructs per level. Sensing devices were attached to the rods between each pedicle screw pair and the loads were continuously monitored over 16 weeks. After euthanasia, the spines were biomechanically tested for their range of motion and high-resolution CT scans were performed to confirm the fusion success. After an initial increase in implant load until reaching a maximum (100 %) at approximately week 4, eleven out of twelve sensors measured a constant decrease in implant load to 52 ± 9 % at euthanasia. One sensor measurement was compromised by newly forming bone growing against the sensor clamp. Bridging bone at each facet and minor remnant segmental motion (<0.7°) confirmed the fusion of all motion segments. Data obtained by continuous measurement of implant loading of spinal screw-rod constructs enables objective monitoring of spinal fusion progression. The sensor concept provides valuable real-time information, offering quantifiable data as an alternative to traditional imaging techniques. However, the design of the current sensor concept needs to be matured, tailored to, and validated for the human spine.

Range of surgical strategies for individual adolescent idiopathic scoliosis cases: evaluation of a multi-centre survey.

PURPOSE: Surgical treatment of adolescent idiopathic scoliosis (AIS) is very complex, involves many critical decisions and modern instrumentation techniques, and offers multiple possibilities. It is known that the surgical strategy may vary strongly between surgeons for AIS cases. The goal of this study was to document, summarize, and analyse the current biomechanical relevant variabilities in the surgical treatments of individual AIS patient cases. METHODS: Eight experienced scoliosis surgeons from different hospitals were asked to plan surgeries on 12 representative patients with AIS. The surgeons were provided with radiographs during upright standing in the coronal and sagittal plane, as well as lateral bending images to the left and right. The surgeons were asked to specify the Lenke type, their surgical approach, the resection steps, the planned fusion length, and the type of implants. The data were analysed with respect to the inter-rater variability, which was quantified using the Fleiss Kappa method. RESULTS: In the selection of the surgical approach, the surgeons concurred most with Lenke curve types 2 (κ = 0.88) and 4 (κ = 0.75). The largest differences were shown at Lenke 1 (κ = 0.39) and 5 (κ = 0.32). Anterior approaches were selected in the majority of cases at Lenke types 5, with an average of 50%. The strongest deviation in fusion length was documented at Lenke curve type 6. CONCLUSION: The survey highlighted differences in the surgical strategy depending on the Lenke curve type, the direction of the surgical approach, and the surgeon. The main discrepancies between the surgeons were found for Lenke 1, 5, and 6 curves, and consistencies for Lenke 2, 3, and 4. The documented discrepancies indicate the remaining open questions in the surgical treatment and understanding of scoliosis biomechanics.

The move-C cervical artificial disc can restore intact range of motion and 3-D kinematics.

BACKGROUND CONTEXT: In contrast to cervical discectomy and fusion, total disc replacement (TDR) aims at preserving the motion at the treated vertebral level. Spinal motion is commonly evaluated with the range of motion (ROM). However, more qualitative information about cervical kinematics before and after TDR is still lacking. PURPOSE: The aim of this in vitro study was to investigate the influence of cervical TDR on ROM, instantaneous centers of rotation (ICR) and three-dimensional helical axes. STUDY DESIGN: An in vitro study with human spine specimens under pure moment loading was conducted to evaluate the kinematics of the intact cervical spine and compare it to cervical TDR. METHODS: Six fresh frozen human cervical specimens (C4-5, median age 28 years, range 19-47 years, two female and four male) were biomechanically characterized in the intact state and after implantation of a cervical disc prosthesis (MOVE-C, NGMedical, Germany). To mimic in vivo conditions regarding temperature and humidity, water steam was used to create a warm and humid test environment with 37°C. Each specimen was quasistatically loaded with pure moments up to ±2.5 Nm in flexion/extension (FE), lateral bending (LB) and axial rotation (AR) in a universal spine tester for 3.5 cycles at 1 °/s. For each third cycle of motion the ROM was evaluated and an established method was used to determine the helical axis and COR and to project them into three planar X-rays. Statistical analysis was conducted using a Friedman-test and post hoc correction with Dunn-Bonferroni-tests (p<.05). RESULTS: After TDR, total ROM was increased in FE from 19.1° to 20.1°, decreased in LB from 14.6° to 12.6° and decreased in AR from 17.7° to 15.5°. No statistical differences between the primary ROM in the intact condition and ROM after TDR were detected. Coupled rotation between LB and AR were also maintained. The position and orientation of the helical axes after cervical TDR was in good agreement with the results of the intact specimens in all three motion directions. The ICR in FE and AR before and after TDR closely matched, while in LB the ICR after TDR were more caudal. The intact in vitro kinematics we found also resembled in vivo results of healthy individuals. CONCLUSION: The results of this in vitro study highlight the potential of artificial cervical disc implants to replicate the quantity as well as the quality of motion of the intact cervical spine. CLINICAL SIGNIFICANCE: Physiological motion preservation was a driving factor in the development of cervical TDR. Our results demonstrate the potential of cervical TDR to replicate in vivo kinematics in all three motion directions.

[Biomechanics of thoracic wall instability]. / Biomechanik der Thoraxwandinstabilität.

Traumatic injuries of the thorax can entail thoracic wall instability (flail chest), which can affect both the shape of the thorax and the mechanics of respiration; however, so far little is known about the biomechanics of the unstable thoracic wall and the optimal surgical fixation. This review article summarizes the current state of research regarding experimental models and previous findings. The thoracic wall is primarily burdened by complex muscle and compression forces during respiration and the mechanical coupling to spinal movement. Previous experimental models focused on the burden caused by respiration, but are mostly not validated, barely established, and severely limited with respect to the simulation of physiologically occurring forces. Nevertheless, previous results suggested that osteosynthesis of an unstable thoracic wall is essential from a biomechanical point of view to restore the native respiratory mechanics, thoracic shape and spinal stability. Moreover, in vitro studies also showed better stabilizing properties of plate osteosynthesis compared to intramedullary splints, wires or screws. The optimum number and selection of ribs to be fixated for the different types of thoracic wall instability is still unknown from a biomechanical perspective. Future biomechanical investigations should simulate respiratory and spinal movement by means of validated models.

Automatic Calculation of Cervical Spine Parameters Using Deep Learning: Development and Validation on an External Dataset.

STUDY DESIGN: Retrospective data analysis. OBJECTIVES: This study aims to develop a deep learning model for the automatic calculation of some important spine parameters from lateral cervical radiographs. METHODS: We collected two datasets from two different institutions. The first dataset of 1498 images was used to train and optimize the model to find the best hyperparameters while the second dataset of 79 images was used as an external validation set to evaluate the robustness and generalizability of our model. The performance of the model was assessed by calculating the median absolute errors between the model prediction and the ground truth for the following parameters: T1 slope, C7 slope, C2-C7 angle, C2-C6 angle, Sagittal Vertical Axis (SVA), C0-C2, Redlund-Johnell distance (RJD), the cranial tilting (CT) and the craniocervical angle (CCA). RESULTS: Regarding the angles, we found median errors of 1.66° (SD 2.46°), 1.56° (1.95°), 2.46° (SD 2.55), 1.85° (SD 3.93°), 1.25° (SD 1.83°), .29° (SD .31°) and .67° (SD .77°) for T1 slope, C7 slope, C2-C7, C2-C6, C0-C2, CT, and CCA respectively. As concerns the distances, we found median errors of .55 mm (SD .47 mm) and .47 mm (.62 mm) for SVA and RJD respectively. CONCLUSIONS: In this work, we developed a model that was able to accurately predict cervical spine parameters from lateral cervical radiographs. In particular, the performances on the external validation set demonstrate the robustness and the high degree of generalizability of our model on images acquired in a different institution.

Chemonucleolysis combined with dynamic loading for inducing degeneration in bovine caudal intervertebral discs.

Chemonucleolysis has become an established method of producing whole organ culture models of intervertebral disc (IVD) degeneration. However, the field needs more side-by-side comparisons of the degenerative effects of the major enzymes used in chemonucleolysis towards gaining a greater understanding of how these organ culture models mimic the wide spectrum of characteristics observed in human degeneration. In the current work we induced chemonucleolysis in bovine coccygeal IVDs with 100 µL of papain (65 U/mL), chondroitinase ABC (chABC, 5 U/mL), or collagenase II (col'ase, 0.5 U/mL). Each enzyme was applied in a concentration projected to produce moderate levels of degeneration. After 7 days of culture with daily dynamic physiological loading (0.02-0.2 MPa, 0.2 Hz, 2 h), the cellular, biochemical and histological properties of the IVDs were evaluated in comparison to a PBS-injected control. Papain and collagenase, but not chABC, produced macroscopic voids in the tissues. Compared to day 0 intact IVDs, papain induced the greatest magnitude glycosaminoglycan (GAG) loss compared to chABC and col'ase. Papain also induced the greatest height loss (3%), compared to 0.7%, 1.2% and 0.4% for chABC, col'ase, and PBS, respectively. Cell viability in the region adjacent to papain and PBS-injection remained at nearly 100% over the 7-day culture period, whereas it was reduced to 60%-70% by chABC and col'ase. Generally, enzyme treatment tended to downregulate gene expression for major ECM markers, type I collagen (COL1), type II collagen (COL2), and aggrecan (ACAN) in the tissue adjacent to injection. However, chABC treatment induced an increase in COL2 gene expression, which was significant compared to the papain treated group. In general, papain and col'ase treatment tended to recapitulate aspects of advanced IVD degeneration, whereas chABC treatment captured aspects of early-stage degeneration. Chemonucleolysis of whole bovine IVDs is a useful tool providing researchers with a robust spectrum of degenerative changes and can be utilized for examination of therapeutic interventions.

Deep phenotyping the cervical spine: automatic characterization of cervical degenerative phenotypes based on T2-weighted MRI.

PURPOSE: Radiological degenerative phenotypes provide insight into a patient's overall extent of disease and can be predictive for future pathological developments as well as surgical outcomes and complications. The objective of this study was to develop a reliable method for automatically classifying sagittal MRI image stacks of cervical spinal segments with respect to these degenerative phenotypes. METHODS: We manually evaluated sagittal image data of the cervical spine of 873 patients (5182 motion segments) with respect to 5 radiological phenotypes. We then used this data set as ground truth for training a range of multi-class multi-label deep learning-based models to classify each motion segment automatically, on which we then performed hyper-parameter optimization. RESULTS: The ground truth evaluations turned out to be relatively balanced for the labels disc displacement posterior, osteophyte anterior superior, osteophyte posterior superior, and osteophyte posterior inferior. Although we could not identify a single model that worked equally well across all the labels, the 3D-convolutional approach turned out to be preferable for classifying all labels. CONCLUSIONS: Class imbalance in the training data and label noise made it difficult to achieve high predictive power for underrepresented classes. This shortcoming will be mitigated in the future versions by extending the training data set accordingly. Nevertheless, the classification performance rivals and in some cases surpasses that of human raters, while speeding up the evaluation process to only require a few seconds.

Evidence- and data-driven classification of low back pain via artificial intelligence: Protocol of the PREDICT-LBP study.

In patients presenting with low back pain (LBP), once specific causes are excluded (fracture, infection, inflammatory arthritis, cancer, cauda equina and radiculopathy) many clinicians pose a diagnosis of non-specific LBP. Accordingly, current management of non-specific LBP is generic. There is a need for a classification of non-specific LBP that is both data- and evidence-based assessing multi-dimensional pain-related factors in a large sample size. The "PRedictive Evidence Driven Intelligent Classification Tool for Low Back Pain" (PREDICT-LBP) project is a prospective cross-sectional study which will compare 300 women and men with non-specific LBP (aged 18-55 years) with 100 matched referents without a history of LBP. Participants will be recruited from the general public and local medical facilities. Data will be collected on spinal tissue (intervertebral disc composition and morphology, vertebral fat fraction and paraspinal muscle size and composition via magnetic resonance imaging [MRI]), central nervous system adaptation (pain thresholds, temporal summation of pain, brain resting state functional connectivity, structural connectivity and regional volumes via MRI), psychosocial factors (e.g. depression, anxiety) and other musculoskeletal pain symptoms. Dimensionality reduction, cluster validation and fuzzy c-means clustering methods, classification models, and relevant sensitivity analyses, will classify non-specific LBP patients into sub-groups. This project represents a first personalised diagnostic approach to non-specific LBP, with potential for widespread uptake in clinical practice. This project will provide evidence to support clinical trials assessing specific treatments approaches for potential subgroups of patients with non-specific LBP. The classification tool may lead to better patient outcomes and reduction in economic costs.

Biomechanical in vitro evaluation of the kangaroo spine in comparison with human spinal data.

On the basis of the kangaroo's pseudo-biped locomotion and its upright position, it could be assumed that the kangaroo might be an interesting model for spine research and that it may serve as a reasonable surrogate model for biomechanical in vitro tests. The purpose of this in vitro study was to provide biomechanical properties of the kangaroo spine and compare them with human spinal data from the literature. In addition, references to already published kangaroo anatomical spinal parameters will be discussed. Thirteen kangaroo spines from C4 to S4 were sectioned into single-motion segments. The specimens were tested by a spine tester under pure moments. The range of motion and neutral zone of each segment were determined in flexion and extension, right and left lateral bending and left and right axial rotation. Overall, we found greater flexibility in the kangaroo spine compared to the human spine. Similarities were only found in the cervical, lower thoracic and lumbar spinal regions. The range of motion of the kangaroo and human spines displayed comparable trends in the cervical (C4-C7), lower thoracic and lumbar regions independent of the motion plane. In the upper and middle thoracic regions, the flexibility of the kangaroo spine was considerably larger. These results suggested that the kangaroo specimens could be considered to be a surrogate, but only in particular cases, for biomechanical in vitro tests.

Endplate abnormalities, Modic changes and their relationship to alignment parameters and surgical outcomes in the cervical spine.

Modic changes (MC) and endplate abnormalities (EA) have been shown to impact preoperative symptoms and outcomes following spinal surgery. However, little is known about how these phenotypes impact cervical alignment. This study aimed to evaluate the impact that these phenotypes have on preoperative, postoperative, and changes in cervical alignment in patients undergoing anterior cervical discectomy and fusion (ACDF). We performed a retrospective study of prospectively collected data of ACDF patients at a single institution. Preoperative magnetic resonance imagings (MRIs) were used to assess for the MC and EA. Patients were subdivided into four groups: MC-only, EA-only, the combined Modic-Endplate-Complex (MEC), and patients without either phenotype. Pre and postoperative MRIs were used to assess alignment parameters. Associations with imaging phenotypes and alignment parameters were assessed, and statistical significance was set at p < 0.5. A total of 512 patients were included, with 84 MC-only patients, 166 EA-only patients, and 71 patients with MEC. Preoperative MC (p = 0.031) and the MEC (p = 0.039) had significantly lower preoperative T1 slope compared to controls. Lower preoperative T1 slope was a risk factor for MC (p = 0.020) and MEC (p = 0.029) and presence of MC (Type II) and the MEC (Type III) was predictive of lower preoperative T1 slope. There were no differences in postoperative alignment measures or patient reported outcome measures. MC and endplate pathologies such as the MEC appear to be associated with worse cervical alignment at baseline relative to patients without these phenotypes. Poor alignment may be an adaptive response to these degenerative findings or may be a risk factor for their development.

Neoepitope fragments as biomarkers for different phenotypes of intervertebral disc degeneration.

Background: During the intervertebral disc (IVD) degeneration process, initial degenerative events occur at the extracellular matrix level, with the appearance of neoepitope peptides formed by the cleavage of aggrecan and collagen. This study aims to elucidate the spatial and temporal alterations of aggrecan and collagen neoepitope level during IVD degeneration. Methods: Bovine caudal IVDs were cultured under four different conditions to mimic different degenerative situations. Samples cultured after 1- or 8-days were collected for analysis. Human IVD samples were obtained from patients diagnosed with lumbar disc herniation (LDH) or adolescent idiopathic scoliosis (AIS). After immunohistochemical (IHC) staining of Aggrecanase Cleaved C-terminus Aggrecan Neoepitope (NB100), MMP Cleaved C-terminus Aggrecan Neoepitope (MMPCC), Collagen Type 1α1 1/4 fragment (C1α1) and Collagenase Cleaved Type I and II Collagen Neoepitope (C1,2C), staining optical density (OD)/area in extracellular matrix (OECM) and pericellular zone (OPCZ) were analyzed. Conditioned media of the bovine IVD was collected to measure protein level of inflammatory cytokines and C1,2C. Results: For the bovine IVD sections, the aggrecan MMPCC neoepitope was accumulated in nucleus pulposus (NP) and cartilage endplate (EP) regions following mechanical overload in the one strike model after long-term culture; as for the TNF-α induced degeneration, the OECM and OPCZ of collagen C1,2C neoepitope was significantly increased in the outer AF region after long-term culture; moreover, the C1,2C was only detected in conditioned medium from TNF-α injection + Degenerative loading group after 8 days of culture. LDH patients showed higher MMPCC OECM in NP and higher C1,2C OECM in AF region compared with AIS patients. Conclusions: In summary, aggrecan and collagen neoepitope profiles showed degeneration induction trigger- and region-specific differences in the IVD organ culture models. Different IVD degeneration types are correlated with specific neoepitope expression profiles. These neoepitopes may be helpful as biomarkers of ECM degradation in early IVD degeneration and indicators of different degeneration phenotypes.