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Intervertebral Disc Regeneration II
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Intervertebral Disc Regeneration II

A special issue of Applied Sciences (ISSN 2076-3417). This special issue belongs to the section "Applied Biosciences and Bioengineering".

Deadline for manuscript submissions: closed (30 March 2023) | Viewed by 19314

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editor

Prof. Dr. Benjamin Gantenbein

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Guest Editor
Tissue Engineering, Orthopeadic Research & Mechanobiology, Department for BioMedical Research (DBMR), Medical Faculty, University of Bern, 3012 Bern, Switzerland
Interests: hydrogels; progenitor cells; regeneration; tissue engineering; bioreactors; mechanobiology; anterior cruciate ligament; cartilage; intervertebral disc; bone
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

A healthy spine is the backbone of each individual but also of our entire society. Discogenic back pain is a major burden on a global scale. The degeneration of the intervertebral discs (IVD) of the spinal column represents a major challenge for successful biological and tissue-engineered treatments. Alternatives to the surgical “gold standard”, which is a discectomy followed by spinal fusion, are urgently warranted. This Special Issue calls for recent advances in the regeneration of the IVD using a combination of biomaterials with or without cells. Some of our focus will be on the search for ideal cell sources for cell therapy and bioactive compounds or manipulation (e.g., growth factors, peptides and gene therapy). Due to the nature of the IVD, it is important to distinguish between the repair of the outer ring, i.e., the annulus fibrosus, and that of the center, i.e., the nucleus pulposus. These two different tissue types each require a different strategy and likely require composite materials for combined repair. The clinical translation of cell therapy seems to be challenging, as a reliable cell source is essential, and the fate and effects of transplanted cells are often difficult to track. This Special Issue calls for recent advances in the field of regeneration for the IVD of the spinal column.

Prof. Dr. Benjamin Gantenbein
Guest Editor

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Keywords

  • biomaterials
  • tissue engineering
  • nutrition
  • organ culture
  • progenitor cells
  • cell therapy

Published Papers (8 papers)

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Editorial

Jump to: Research, Review

4 pages, 222 KiB  
Editorial
New Developments on Growth Factors, Exosomes, and Single Cell RNA-Sequencing for Regeneration of the Intervertebral Disc
by Benjamin Gantenbein
Appl. Sci. 2023, 13(13), 7346; https://0-doi-org.brum.beds.ac.uk/10.3390/app13137346 - 21 Jun 2023
Viewed by 821
Abstract
Low back pain (LBP) is the number one cause of disability worldwide, with incidences increasing exponentially [...] Full article
(This article belongs to the Special Issue Intervertebral Disc Regeneration II)

Research

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13 pages, 1088 KiB  
Article
Using Natural Language Processing to Identify Low Back Pain in Imaging Reports
by Yeji Kim, Chanyoung Song, Gyuseon Song, Sol Bi Kim, Hyun-Wook Han and Inbo Han
Appl. Sci. 2022, 12(24), 12521; https://0-doi-org.brum.beds.ac.uk/10.3390/app122412521 - 07 Dec 2022
Cited by 1 | Viewed by 1239
Abstract
A natural language processing (NLP) pipeline was developed to identify lumbar spine imaging findings associated with low back pain (LBP) in X-radiation (X-ray), computed tomography (CT), and magnetic resonance imaging (MRI) reports. A total of 18,640 report datasets were randomly sampled (stratified by [...] Read more.
A natural language processing (NLP) pipeline was developed to identify lumbar spine imaging findings associated with low back pain (LBP) in X-radiation (X-ray), computed tomography (CT), and magnetic resonance imaging (MRI) reports. A total of 18,640 report datasets were randomly sampled (stratified by imaging modality) to obtain a balanced sample of 300 X-ray, 300 CT, and 300 MRI reports. A total of 23 radiologic findings potentially related to LBP were defined, and their presence was extracted from radiologic reports. In developing NLP pipelines, section and sentence segmentation from the radiology reports was performed using a rule-based method, including regular expression with negation detection. Datasets were randomly split into 80% for development and 20% for testing to evaluate the model’s extraction performance. The performance of the NLP pipeline was evaluated by using recall, precision, accuracy, and the F1 score. In evaluating NLP model performances, four parameters—recall, precision, accuracy, and F1 score—were greater than 0.9 for all 23 radiologic findings. These four scores were 1.0 for 10 radiologic findings (listhesis, annular fissure, disc bulge, disc extrusion, disc protrusion, endplate edema or Type 1 Modic change, lateral recess stenosis, Schmorl’s node, osteophyte, and any stenosis). In the seven potentially clinically important radiologic findings, the F1 score ranged from 0.9882 to 1.0. In this study, a rule-based NLP system identifying 23 findings related to LBP from X-ray, CT, and MRI reports was developed, and it presented good performance in regards to the four scoring parameters. Full article
(This article belongs to the Special Issue Intervertebral Disc Regeneration II)
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13 pages, 1804 KiB  
Article
Diagnostic Limitations and Aspects of the Lumbosacral Transitional Vertebrae (LSTV)
by Franz Landauer and Klemens Trieb
Appl. Sci. 2022, 12(21), 10830; https://0-doi-org.brum.beds.ac.uk/10.3390/app122110830 - 25 Oct 2022
Cited by 3 | Viewed by 4342
Abstract
The regeneration of an intervertebral disc can only be successful if the cause of the degeneration is known and eliminated. The lumbosacral transitional vertebrae (LSTV) offer itself as a model for IVD (intervertebral disc) regeneration. The aim of this work is to support [...] Read more.
The regeneration of an intervertebral disc can only be successful if the cause of the degeneration is known and eliminated. The lumbosacral transitional vertebrae (LSTV) offer itself as a model for IVD (intervertebral disc) regeneration. The aim of this work is to support this statement. In our scoliosis outpatient clinic, 1482 patients were radiologically examined, and ambiguous lumbosacral junction underwent MRI examination. Patients with Castellvi classification type II–IV were included and the results are compared with the current literature in PubMed (12 October 2022). The LSTV are discussed as a possible IVD model. A total of 115 patients were diagnosed with LSTV Castellvi type II–IV. A Castellvi distribution type IIA (n-55), IIB (n-24), IIIA (n-20), IIIB (n-10) and IV (n-6) can be found. In all, 64 patients (55.7%) reported recurrent low-back pain (LBP). Scoliosis (Cobb angle >10°) was also confirmed in 72 patients (58 female and 14 male) and 56 (75.7%) had unilateral pathology. The wide variation in the literature regarding the prevalence of the LSTV (4.6–35.6%) is reasoned by the doubtful diagnosis of Castellvi type I. The LSTV present segments with reduced to absent mobility and at the same time leads to overload of the adjacent segments. This possibility of differentiation is seen as the potential for a spinal model. Full article
(This article belongs to the Special Issue Intervertebral Disc Regeneration II)
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22 pages, 4991 KiB  
Article
Single Cell RNA-Sequence Analyses Reveal Uniquely Expressed Genes and Heterogeneous Immune Cell Involvement in the Rat Model of Intervertebral Disc Degeneration
by Milad Rohanifar, Sade W. Clayton, Garrett W.D. Easson, Deepanjali S. Patil, Frank Lee, Liufang Jing, Marcos N. Barcellona, Julie E. Speer, Jordan J. Stivers, Simon Y. Tang and Lori A. Setton
Appl. Sci. 2022, 12(16), 8244; https://0-doi-org.brum.beds.ac.uk/10.3390/app12168244 - 18 Aug 2022
Cited by 5 | Viewed by 3252
Abstract
Intervertebral disc (IVD) degeneration is characterized by a loss of cellularity, and changes in cell-mediated activity that drives anatomic changes to IVD structure. In this study, we used single-cell RNA-sequencing analysis of degenerating tissues of the rat IVD following lumbar disc puncture. Two [...] Read more.
Intervertebral disc (IVD) degeneration is characterized by a loss of cellularity, and changes in cell-mediated activity that drives anatomic changes to IVD structure. In this study, we used single-cell RNA-sequencing analysis of degenerating tissues of the rat IVD following lumbar disc puncture. Two control, uninjured IVDs (L2-3, L3-4) and two degenerated, injured IVDs (L4-5, L5-6) from each animal were examined either at the two- or eight-week post-operative time points. The cells from these IVDs were extracted and transcriptionally profiled at the single-cell resolution. Unsupervised cluster analysis revealed the presence of four known cell types in both non-degenerative and degenerated IVDs based on previously established gene markers: IVD cells, endothelial cells, myeloid cells, and lymphoid cells. As a majority of cells were associated with the IVD cell cluster, sub-clustering was used to further identify the cell populations of the nucleus pulposus, inner and outer annulus fibrosus. The most notable difference between control and degenerated IVDs was the increase of myeloid and lymphoid cells in degenerated samples at two- and eight-weeks post-surgery. Differential gene expression analysis revealed multiple distinct cell types from the myeloid and lymphoid lineages, most notably macrophages and B lymphocytes, and demonstrated a high degree of immune specificity during degeneration. In addition to the heterogenous infiltrating immune cell populations in the degenerating IVD, the increased number of cells in the AF sub-cluster expressing Ngf and Ngfr, encoding for p75NTR, suggest that NGF signaling may be one of the key mediators of the IVD crosstalk between immune and neuronal cell populations. These findings provide the basis for future work to understand the involvement of select subsets of non-resident cells in IVD degeneration. Full article
(This article belongs to the Special Issue Intervertebral Disc Regeneration II)
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17 pages, 4892 KiB  
Article
Effects of Growth Factor Combinations TGFβ3, GDF5 and GDF6 on the Matrix Synthesis of Nucleus Pulposus and Nasoseptal Chondrocyte Self-Assembled Microtissues
by Shani Samuel, Emily E. McDonnell and Conor T. Buckley
Appl. Sci. 2022, 12(3), 1453; https://0-doi-org.brum.beds.ac.uk/10.3390/app12031453 - 29 Jan 2022
Cited by 3 | Viewed by 1581
Abstract
There has been significant interest in identifying alternative cell sources and growth factor stimulation to improve matrix synthesis for disc repair. Recent work has identified nasoseptal chondrocytes (NC) as a possible alternative cell source with significant matrix-forming abilities. While various growth factors such [...] Read more.
There has been significant interest in identifying alternative cell sources and growth factor stimulation to improve matrix synthesis for disc repair. Recent work has identified nasoseptal chondrocytes (NC) as a possible alternative cell source with significant matrix-forming abilities. While various growth factors such as members of the TGFβ superfamily have been explored to enhance matrix formation, no consensus exists as to the optimum growth factor needed to induce cells towards a discogenic phenotype. This study assessed both nucleus pulposus (NP) and NC microtissues of different densities (1000, 2500 or 5000 cells/microtissue) stimulated by individual or combinations of the growth factors TGFβ3, GDF5, and GDF6. Lower cell densities result in increased sGAG/DNA and collagen/DNA levels due to higher nutrient availability levels. Our findings suggest that growth factors exert differential effects on matrix synthesis depending on the cell type. NP cells were found to be relatively insensitive to the different growth factor types examined in isolation or in combination. Overall, NCs exhibited a higher propensity to form extracellular matrix compared to NP cells. In addition, stimulating NC-microtissues with GDF5 or TGFβ3 alone induced enhanced matrix formation and may be an appropriate growth factor to stimulate this cell type for disc regeneration. Full article
(This article belongs to the Special Issue Intervertebral Disc Regeneration II)
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18 pages, 2253 KiB  
Article
Influence of Angiopoietin Treatment with Hypoxia and Normoxia on Human Intervertebral Disc Progenitor Cell’s Proliferation, Metabolic Activity, and Phenotype
by Muriel C. Bischof, Sonja Häckel, Andrea Oberli, Andreas S. Croft, Katharina A. C. Oswald, Christoph E. Albers, Benjamin Gantenbein and Julien Guerrero
Appl. Sci. 2021, 11(15), 7144; https://0-doi-org.brum.beds.ac.uk/10.3390/app11157144 - 02 Aug 2021
Cited by 3 | Viewed by 2099
Abstract
Increasing evidence implicates intervertebral disc (IVD) degeneration as a major contributor to low back pain. In addition to a series of pathogenic processes, degenerated IVDs become vascularized in contrast to healthy IVDs. In this context, angiopoietin (Ang) plays a crucial role and is [...] Read more.
Increasing evidence implicates intervertebral disc (IVD) degeneration as a major contributor to low back pain. In addition to a series of pathogenic processes, degenerated IVDs become vascularized in contrast to healthy IVDs. In this context, angiopoietin (Ang) plays a crucial role and is involved in cytokine recruitment, and anabolic and catabolic reactions within the extracellular matrix (ECM). Over the last decade, a progenitor cell population has been described in the nucleus pulposus (NP) of the IVD to be positive for the Tie2 marker (also known as Ang-1 receptor). In this study, we investigated the influence of Ang-1 and Ang-2 on human NP cell (Tie2+, Tie2− or mixed) populations isolated from trauma patients during 7 days in normoxia (21% O2) or hypoxia (≤5% O2). At the end of the process, the proliferation and metabolic activity of the NP cells were analyzed. Additionally, the relative gene expression of NP-related markers was evaluated. NP cells showed a higher proliferation depending on the Ang treatment. Moreover, the study revealed higher NP cell metabolism when cultured in hypoxia. Additionally, the relative gene expression followed, with an increase linked to the oxygen level and Ang concentration. Our study comparing different NP cell populations may be the start of new approaches for the treatment of IVD degeneration. Full article
(This article belongs to the Special Issue Intervertebral Disc Regeneration II)
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Graphical abstract

13 pages, 1615 KiB  
Article
EGR2, IGF1 and IL6 Expression Are Elevated in the Intervertebral Disc of Patients Suffering from Diffuse Idiopathic Skeletal Hyperostosis (DISH) Compared to Degenerative or Trauma Discs
by Benjamin Gantenbein, Rahel D. May, Paola Bermudez-Lekerika, Katharina A. C. Oswald, Lorin M. Benneker and Christoph E. Albers
Appl. Sci. 2021, 11(9), 4072; https://0-doi-org.brum.beds.ac.uk/10.3390/app11094072 - 29 Apr 2021
Cited by 1 | Viewed by 2251
Abstract
Diffuse idiopathic skeletal hyperostosis (DISH) is characterised by ectopic ossification along the anterior spine and the outer intervertebral discs (IVD). However, the centre of the IVD, i.e., the nucleus pulposus, always remains unaffected, which could be due to the inhibition of the bone [...] Read more.
Diffuse idiopathic skeletal hyperostosis (DISH) is characterised by ectopic ossification along the anterior spine and the outer intervertebral discs (IVD). However, the centre of the IVD, i.e., the nucleus pulposus, always remains unaffected, which could be due to the inhibition of the bone morphogenetic protein (BMP) pathway. In this study, we investigated the transcriptome for the BMP pathway of DISH-IVD cells versus disc cells of traumatic or degenerative discs. The disc cells originated from nucleus pulposus (NP), annulus fibrosus (AF) and from cartilaginous endplate (CEP) tissue. Here, ninety genes of the transforming growth factor β-BMP signalling pathway were screened by qPCR. Furthermore, the protein expression of genes of interest was further investigated by immune-staining and semi-quantitative microscopy. IVDs of three DISH patients were tested against three control patients (same disc level and similar age). Early Growth Response 2 (EGR2) and Interleukin 6 (IL6) were both significantly up-regulated in DISH-IVD cells compared to controls (12.8 ± 7.6-fold and 54.0 ± 46.5-fold, respectively, means ± SEM). Furthermore, Insulin-like Growth Factor 1 (IGF1) tended to be up-regulated in DISH-IVD donors, i.e., 174.13 ± 120.6-fold. IGF1 was already known as a serum marker for DISH and other rheumatoid diseases and is confirmed here to play a possible key role in DISH-IVD. Full article
(This article belongs to the Special Issue Intervertebral Disc Regeneration II)
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Review

Jump to: Editorial, Research

19 pages, 2010 KiB  
Review
Mesenchymal Stem Cell-Derived Exosomes: The New Frontier for the Treatment of Intervertebral Disc Degeneration
by Veronica Tilotta, Gianluca Vadalà, Luca Ambrosio, Fabrizio Russo, Claudia Cicione, Giuseppina Di Giacomo, Rocco Papalia and Vincenzo Denaro
Appl. Sci. 2021, 11(23), 11222; https://0-doi-org.brum.beds.ac.uk/10.3390/app112311222 - 26 Nov 2021
Cited by 5 | Viewed by 2230
Abstract
Low back pain (LBP) is one of the most frequent symptoms associated with intervertebral disc degeneration (IDD) and affects more than 80% of the population, with strong psychosocial and economic impacts. The main cause of IDD is a reduction in the proteoglycan content [...] Read more.
Low back pain (LBP) is one of the most frequent symptoms associated with intervertebral disc degeneration (IDD) and affects more than 80% of the population, with strong psychosocial and economic impacts. The main cause of IDD is a reduction in the proteoglycan content within the nucleus pulposus (NP), eventually leading to the loss of disc hydration, microarchitecture, biochemical and mechanical properties. The use of mesenchymal stem cells (MSCs) has recently arisen as a promising therapy for IDD. According to numerous reports, MSCs mediate their regenerative and immunomodulatory effects mainly through paracrine mechanisms. Recent studies have suggested that extracellular vesicles (EVs) extracted from MSCs may be a promising alternative to cell therapy in regenerative medicine. EVs, including exosomes and microvesicles, are secreted by almost all cell types and have a fundamental role in intercellular communication. Early results have demonstrated the therapeutic potential of MSCs-derived EVs for the treatment of IDD through the promotion of tissue regeneration, cell proliferation, reduction in apoptosis and modulation of the inflammatory response. The aim of this review is to focus on the biological properties, function, and regulatory properties of different signaling pathways of MSCs-derived exosomes, highlighting their potential applicability as an alternative cell-free therapy for IDD. Full article
(This article belongs to the Special Issue Intervertebral Disc Regeneration II)
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