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Applied Sciences
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Intervertebral Disc Regeneration
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Intervertebral Disc Regeneration

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 (28 February 2021) | Viewed by 26170

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,

The healthy spine is the backbone of each individual but also for our entire society. Discogenic back pain is a major burden on the global scale. 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 discectomy followed by spinal fusion, are urgently warranted. This Special Issue calls for recent advances in approaching 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, gene therapy). Due to the nature of the IVD, it is important to distinguish between repair of the outer ring, i.e., the annulus fibrosus, and of the center, i.e., the nucleus pulposus. These two different tissue types require each a different strategy and likely require composite materials for a combined repair. Clinical translation of cell therapy seems challenging as a reliable cell source is essential, and the fate and effects of transplanted cells are often difficult to track. The Special Issue calls for recent advances in the field of regeneration for the IVD of the spinal column.

Prof. Dr. Benjamin Gantenbein
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2400 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

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

Published Papers (8 papers)

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Editorial

Jump to: Research, Review

3 pages, 171 KiB  
Editorial
New Frontiers towards Regeneration of the Intervertebral Disc: On Progenitor Cells, Growth Factors and Biomaterials
by Benjamin Gantenbein
Appl. Sci. 2021, 11(24), 11913; https://doi.org/10.3390/app112411913 - 15 Dec 2021
Viewed by 1670
Abstract
This Special Issue on intervertebral disc (IVD) regeneration focuses on novel advances in understanding the cell sources and culture conditions of various cell types, i.e., progenitor and IVD cells. The issue consists of seven articles that provide a comprehensive overview of recently applied [...] Read more.
This Special Issue on intervertebral disc (IVD) regeneration focuses on novel advances in understanding the cell sources and culture conditions of various cell types, i.e., progenitor and IVD cells. The issue consists of seven articles that provide a comprehensive overview of recently applied research insights: (1) into how IVD herniation can be provoked in a controlled in vitro biomechanical testing set-up, (2) how cells can be used for IVD repair, (3) the physiological conditions of IVD cells and (4) how hyaluronic acid could be used for IVD repair, and (5) how nucleus pulposus progenitor cells (NPPCs) and mesenchymal stromal cells (MSCs) shall be cultured and expanded towards a possible cell therapy. Full article
(This article belongs to the Special Issue Intervertebral Disc Regeneration)

Research

Jump to: Editorial, Review

16 pages, 26497 KiB  
Article
Screening for Growth-Factor Combinations Enabling Synergistic Differentiation of Human MSC to Nucleus Pulposus Cell-Like Cells
by Kosuke Morita, Jordy Schol, Tibo N. E. Volleman, Daisuke Sakai, Masato Sato and Masahiko Watanabe
Appl. Sci. 2021, 11(8), 3673; https://doi.org/10.3390/app11083673 - 19 Apr 2021
Cited by 7 | Viewed by 2184
Abstract
Background: Multiple studies have examined the potential of growth factors (GF) to enable mesenchymal stromal cells (MSC) to nucleus pulposus (NP) cell-like cell differentiation. Here we screened a wide range of GF and GF combinations for supporting NP cell-like cell differentiation. Methods: Human [...] Read more.
Background: Multiple studies have examined the potential of growth factors (GF) to enable mesenchymal stromal cells (MSC) to nucleus pulposus (NP) cell-like cell differentiation. Here we screened a wide range of GF and GF combinations for supporting NP cell-like cell differentiation. Methods: Human MSC were stimulated using 86 different GF combinations of TGF-β1, -2, -3, GDF5, -6, Wnt3a, -5a, -11, and Shh. Differentiation potency was assessed by alcian blue assay and NP cell marker expression (e.g., COL2A1, CD24, etc.). The top four combinations and GDF5/TGF-β1 were further analyzed in 3D pellet cultures, on their ability to similarly induce NP cell differentiation. Results: Almost all 86 GF combinations showed their ability to enhance proteoglycan production in alcian blue assay. Subsequent qPCR analysis revealed TGF-β2/Wnt3a, TGF-β1/Wnt3a, TGF-β1/Wnt3a/GDF6, and Wnt3a/GDF6 as the most potent combinations. Although in pellet cultures, these combinations supported NP marker expression, none showed the ability to significantly induce chondrogenic NP matrix production. Only GDF5/TGF-β1 resulted in chondrogenic pellets with significantly enhanced glycosaminoglycan content. Conclusion: GDF5/TGF-β1 was suggested as an optimal GF combination for MSC to NP cell induction, although further assessment using a 3D and in vivo environment is required. Wnt3a proved promising for monolayer-based NP cell differentiation, although further validation is required. Full article
(This article belongs to the Special Issue Intervertebral Disc Regeneration)
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15 pages, 2341 KiB  
Article
Optimization of Spheroid Colony Culture and Cryopreservation of Nucleus Pulposus Cells for the Development of Intervertebral Disc Regenerative Therapeutics
by Kosuke Sako, Daisuke Sakai, Yoshihiko Nakamura, Erika Matsushita, Jordy Schol, Takayuki Warita, Natsumi Horikita, Masato Sato and Masahiko Watanabe
Appl. Sci. 2021, 11(8), 3309; https://doi.org/10.3390/app11083309 - 7 Apr 2021
Cited by 7 | Viewed by 2373
Abstract
After the discovery of functionally superior Tie2-positive nucleus pulposus (NP) progenitor cells, new methods were needed to enable mass culture and cryopreservation to maintain these cells in an undifferentiated state with high cell yield. We used six types of EZSPHERE® dishes, which [...] Read more.
After the discovery of functionally superior Tie2-positive nucleus pulposus (NP) progenitor cells, new methods were needed to enable mass culture and cryopreservation to maintain these cells in an undifferentiated state with high cell yield. We used six types of EZSPHERE® dishes, which support spheroid-forming colony culture, and examined NP cell spheroid-formation ability, number, proliferation, and mRNA expression of ACAN, COL1A2, COL2A1, and ANGPT1. Six different types of cryopreservation solutions were examined for potential use in clinical cryopreservation by comparing the effects of exposure time during cryopreservation on cell viability, Tie2-positivity, and cell proliferation rates. The spheroid formation rate was 45.1% and the cell proliferation rate was 7.75 times using EZSPHERE® dishes. The mRNA levels for COL2A1 and ANGPT1 were also high. In cryopreservation, CryoStor10 (CS10) produced ≥90% cell viability and a high proliferation rate after thawing. CS10 had a high Tie2-positive rate of 12.6% after culturing for 5 days after thawing. These results suggest that EZSPHERE enabled colony formation in cell culture without the use of hydrogel products and that CS10 is the best cryopreservation medium for retaining the NP progenitor cell phenotype and viability. Together, these data provide useful information of NP cell-based therapeutics to the clinic. Full article
(This article belongs to the Special Issue Intervertebral Disc Regeneration)
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12 pages, 3793 KiB  
Article
In Vitro Model for Lumbar Disc Herniation to Investigate Regenerative Tissue Repair Approaches
by Laura Zengerle, Elisabeth Debout, Bruno Kluger, Lena Zöllner and Hans-Joachim Wilke
Appl. Sci. 2021, 11(6), 2847; https://doi.org/10.3390/app11062847 - 22 Mar 2021
Cited by 3 | Viewed by 2627
Abstract
Lumbar disc herniation (LDH) is the most common reason for low back pain in the working society. New regenerative approaches and novel implants are directed towards the restoration of the disc or its biomechanical properties. Aiming to investigate these new therapies under physiological [...] Read more.
Lumbar disc herniation (LDH) is the most common reason for low back pain in the working society. New regenerative approaches and novel implants are directed towards the restoration of the disc or its biomechanical properties. Aiming to investigate these new therapies under physiological conditions, in this study, a model for LDH was established by developing a new physiological in vitro test method. In 14 human lumbar motion segments, different daily-life and worst-case activities were simulated successfully by applying a physiological range of motion and axial loading in order to create physiological intradiscal pressure. An LDH could be provoked in 11 of the 14 specimens through vertical and round annular defects of different sizes. Interestingly, the defect and the LDH hardly influenced the biomechanical properties of the disc. For the investigation of regenerative approaches in further experiments, the recommendation based on the results of this study is to create an LDH in non-degenerated motion segments by the application of the new physiological in vitro test method after setting the round annular defects to a size of 4 mm in diameter. Full article
(This article belongs to the Special Issue Intervertebral Disc Regeneration)
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19 pages, 3485 KiB  
Article
Angiotensin II Type 1 Receptor Antagonist Losartan Inhibits TNF-α-Induced Inflammation and Degeneration Processes in Human Nucleus Pulposus Cells
by Babak Saravi, Zhen Li, Judith Pfannkuche, Laura Wystrach, Sonja Häckel, Christoph E. Albers, Sibylle Grad, Mauro Alini, Robert Geoffrey Richards, Corinna Lang, Norbert Südkamp, Hagen Schmal and Gernot Lang
Appl. Sci. 2021, 11(1), 417; https://doi.org/10.3390/app11010417 - 4 Jan 2021
Cited by 5 | Viewed by 2540
Abstract
Our recent study detected the expression of a tissue renin–angiotensin system (tRAS) in human intervertebral discs (IVDs). The present study sought to investigate the impact of the angiotensin II receptor type 1 (AGTR1) antagonist losartan on human nucleus pulposus (NP) cell inflammation and [...] Read more.
Our recent study detected the expression of a tissue renin–angiotensin system (tRAS) in human intervertebral discs (IVDs). The present study sought to investigate the impact of the angiotensin II receptor type 1 (AGTR1) antagonist losartan on human nucleus pulposus (NP) cell inflammation and degeneration induced by tumor necrosis factor-α (TNF-α). Human NP cells (4 donors; Pfirrmann grade 2–3; 30–37-years–old; male) were isolated and expanded. TNF-α (10 ng/mL) was used to induce inflammation and degeneration. We examined the impact of losartan supplementation and measured gene expression of tRAS, anabolic, catabolic, and inflammatory markers in NP cells after 24 and 72 h of exposure. T0070907, a PPAR gamma antagonist, was applied to examine the regulatory pathway of losartan. Losartan (1 mM) significantly impaired the TNF-α-induced increase of pro-inflammatory (nitric oxide and TNF-α), catabolic (matrix metalloproteinases), and tRAS (AGTR1a and angiotensin-converting enzyme) markers. Further, losartan maintained the NP cell phenotype by upregulating aggrecan and downregulating collagen type I expression. In summary, losartan showed anti-inflammatory, anti-catabolic, and positive phenotype-modulating effects on human NP cells. These results indicate that tRAS signaling plays an important role in IVD degeneration, and tRAS modulation with losartan could represent a novel therapeutic approach. Full article
(This article belongs to the Special Issue Intervertebral Disc Regeneration)
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17 pages, 3796 KiB  
Article
Synergistic Effects of Acidic pH and Pro-Inflammatory Cytokines IL-1β and TNF-α for Cell-Based Intervertebral Disc Regeneration
by Chiara Borrelli and Conor T. Buckley
Appl. Sci. 2020, 10(24), 9009; https://doi.org/10.3390/app10249009 - 17 Dec 2020
Cited by 9 | Viewed by 2447
Abstract
The intervertebral disc (IVD) relies mainly on diffusion through the cartilaginous endplates (CEP) to regulate the nutrient and metabolites exchange, thus creating a challenging microenvironment. Degeneration of the IVD is associated with intradiscal acidification and elevated levels of pro-inflammatory cytokines. However, the synergistic [...] Read more.
The intervertebral disc (IVD) relies mainly on diffusion through the cartilaginous endplates (CEP) to regulate the nutrient and metabolites exchange, thus creating a challenging microenvironment. Degeneration of the IVD is associated with intradiscal acidification and elevated levels of pro-inflammatory cytokines. However, the synergistic impact of these microenvironmental factors for cell-based therapies remains to be elucidated. The aim of this study was to investigate the effects of low pH and physiological levels of interleukin-1ß (IL-1β) and tumour necrosis factor-α (TNF-α) on nasal chondrocytes (NCs) and subsequently compare their matrix forming capacity to nucleus pulposus (NP) cells in acidic and inflamed culture conditions. NCs and NP cells were cultured in low glucose and low oxygen at different pH conditions (pH 7.1, 6.8 and 6.5) and supplemented with physiological levels of IL-1β and TNF-α. Results showed that acidosis played a pivotal role in influencing cell viability and matrix accumulation, while inflammatory cytokine supplementation had a minor impact. This study demonstrates that intradiscal pH is a dominant factor in determining cell viability and subsequent cell function when compared to physiologically relevant inflammatory conditions. Moreover, we found that NCs allowed for improved cell viability and more effective NP-like matrix synthesis compared to NP cells, and therefore may represent an alternative and appropriate cell choice for disc regeneration. Full article
(This article belongs to the Special Issue Intervertebral Disc Regeneration)
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Review

Jump to: Editorial, Research

15 pages, 1004 KiB  
Review
Advances in Tissue Engineering for Disc Repair
by Chang Kyu Lee, Dong Hwa Heo, Hungtae Chung, Eun Ji Roh, Anjani Darai, Jae Won Kyung, Hyemin Choi, Su Yeon Kwon, Basanta Bhujel and Inbo Han
Appl. Sci. 2021, 11(4), 1919; https://doi.org/10.3390/app11041919 - 22 Feb 2021
Cited by 10 | Viewed by 3621
Abstract
Intervertebral disc (IVD) degeneration is a leading cause of chronic low back pain (LBP) that results in serious disability and significant economic burden. IVD degeneration alters the disc structure and spine biomechanics, resulting in subsequent structural changes throughout the spine. Currently, treatments of [...] Read more.
Intervertebral disc (IVD) degeneration is a leading cause of chronic low back pain (LBP) that results in serious disability and significant economic burden. IVD degeneration alters the disc structure and spine biomechanics, resulting in subsequent structural changes throughout the spine. Currently, treatments of chronic LBP due to IVD degeneration include conservative treatments, such as pain medication and physiotherapy, and surgical treatments, such as removal of herniated disc without or with spinal fusion. However, none of these treatments can completely restore a degenerated disc and its function. Thus, although the exact pathogenesis of disc degeneration remains unclear, there are studies examining the effectiveness of biological approaches, such as growth factor injection, gene therapy, and cell transplantation, in promoting IVD regeneration. Furthermore, tissue engineering using a combination of cell transplantation and biomaterials has emerged as a promising new approach for repair or restoration of degenerated discs. The main purpose of this review was to provide an overview of the current status of tissue engineering applications for IVD regenerative therapy by performing literature searches using PubMed. Significant advances in tissue engineering have opened the door to a new generation of regenerative therapies for the treatment of chronic discogenic LBP. Full article
(This article belongs to the Special Issue Intervertebral Disc Regeneration)
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24 pages, 1739 KiB  
Review
The Role of Hyaluronic Acid in Intervertebral Disc Regeneration
by Zepur Kazezian, Kieran Joyce and Abhay Pandit
Appl. Sci. 2020, 10(18), 6257; https://doi.org/10.3390/app10186257 - 9 Sep 2020
Cited by 10 | Viewed by 7622
Abstract
Intervertebral disc (IVD) degeneration is a leading cause of low back pain worldwide, incurring a significant burden on the healthcare system and society. IVD degeneration is characterized by an abnormal cell-mediated response leading to the stimulation of different catabolic biomarkers and activation of [...] Read more.
Intervertebral disc (IVD) degeneration is a leading cause of low back pain worldwide, incurring a significant burden on the healthcare system and society. IVD degeneration is characterized by an abnormal cell-mediated response leading to the stimulation of different catabolic biomarkers and activation of signalling pathways. In the last few decades, hyaluronic acid (HA), which has been broadly used in tissue-engineering, has popularised due to its anti-inflammatory, analgesic and extracellular matrix enhancing properties. Hence, there is expressed interest in treating the IVD using different HA compositions. An ideal HA-based biomaterial needs to be compatible and supportive of the disc microenvironment in general and inhibit inflammation and downstream cascades leading to the innervation, vascularisation and pain sensation in particular. High molecular weight hyaluronic acid (HMW HA) and HA-based biomaterials used as therapeutic delivery platforms have been trialled in preclinical models and clinical trials. In this paper, we reviewed a series of studies focused on assessing the effect of different compositions of HA as a therapeutic, targeting IVD degeneration. Overall, tremendous advances have been made towards an optimal form of a HA biomaterial to target specific biomarkers associated with IVD degeneration, but further optimization is necessary to address regeneration. Full article
(This article belongs to the Special Issue Intervertebral Disc Regeneration)
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