The nucleus pulposus microenvironment in the intervertebral disc: the fountain of youth?

The intervertebral disc (IVD) is a complex tissue, and its degeneration remains a problem for patients, without significant improvement in treatment strategies. This mostly age-related disease predominantly affects the nucleus pulposus (NP), the central region of the IVD. The NP tissue, and especially its microenvironment, exhibit changes that may be involved at the outset or affect the progression of IVD pathology. The NP tissue microenvironment is unique and can be defined by a variety of specific factors and components characteristic of its physiology and function. NP progenitor cell interactions with their surrounding microenvironment may be a key factor for the regulation of cellular metabolism, phenotype, and stemness. Recently, celltransplantation approaches have been investigated for the treatment of degenerative disc disease, highlighting the need to better understand if and how transplanted cells can give rise to healthy NP tissue. Hence, understanding all the components of the NP microenvironment seems to be critical to better gauge the success and outcomes of approaches for tissue engineering and future clinical applications. Knowledge about the components of the NP microenvironment, how NP progenitor cells interact with them, and how changes in their surroundings can alter their function is summarised. Recent discoveries in NP tissue engineering linked to the microenvironment are also reviewed, meaning how crosstalk within the microenvironment can be adjusted to promote NP regeneration. Associated clinical problems are also considered, connecting bench-to-bedside in the context of IVD degeneration

Gender authorship trends in spine research publications - Research across different countries from 1976 to 2020.

•Gender trends in authorship showed an increase in female authors from 1976 to 2020.•In 2020, Europe had the highest and Asia the lowest proportion of female authors.•The Netherlands had the highest proportion of women and Japan the lowest

Celecoxib alleviates nociceptor sensitization mediated by interleukin-1beta-primed annulus fibrosus cells.

PURPOSE This study aims to analyze the effect of pro-inflammatory cytokine-stimulated human annulus fibrosus cells (hAFCs) on the sensitization of dorsal root ganglion (DRG) cells. We further hypothesized that celecoxib (cxb) could inhibit hAFCs-induced DRG sensitization. METHODS hAFCs from spinal trauma patients were stimulated with TNF-α or IL-1β. Cxb was added on day 2. On day 4, the expression of pro-inflammatory and neurotrophic genes was evaluated using RT-qPCR. Levels of prostaglandin E2 (PGE-2), IL-8, and IL-6 were measured in the conditioned medium (CM) using ELISA. hAFCs CM was then applied to stimulate the DRG cell line (ND7/23) for 6 days. Then, calcium imaging (Fluo4) was performed to evaluate DRG cell sensitization. Both spontaneous and bradykinin-stimulated (0.5 μM) calcium responses were analyzed. The effects on primary bovine DRG cell culture were performed in parallel to the DRG cell line model. RESULTS IL-1ß stimulation significantly enhanced the release of PGE-2 in hAFCs CM, while this increase was completely suppressed by 10 µM cxb. hAFCs revealed elevated IL-6 and IL-8 release following TNF-α and IL-1β treatment, though cxb did not alter this. The effect of hAFCs CM on DRG cell sensitization was influenced by adding cxb to hAFCs; both the DRG cell line and primary bovine DRG nociceptors showed a lower sensitivity to bradykinin stimulation. CONCLUSION Cxb can inhibit PGE-2 production in hAFCs in an IL-1β-induced pro-inflammatory in vitro environment. The cxb applied to the hAFCs also reduces the sensitization of DRG nociceptors that are stimulated by the hAFCs CM

Drug delivery in intervertebral disc degeneration and osteoarthritis : Selecting the optimal platform for the delivery of disease-modifying agents

Acknowledgement We would like to acknowledge Prof. Gerjo Van Osch and prof Molly Stevens for their careful and critical revision of the manuscript. We wish to thank all principal investigators of the TargetCaRe consortium for their enormous support during the years: Prof G. van Osch. Prof. Mauro Alini, Prof. Bruce Caterson, Dr. Alan Chan, Prof. Cosimo De Bari, Prof. Ron Heeren, Prof. Kennet Howard, Prof. Marcelle Machluf, Prof. Molly M. Stevens and Prof. Avner Yayon. This work was supported by European Union's Horizon 2020 Research And Innovation Programme under Marie Sklodowska Curie Grant agreement no. 642414.Peer reviewedproofPublisher PD

Atomic-scale confinement of optical fields

In the presence of matter there is no fundamental limit preventing confinement of visible light even down to atomic scales. Achieving such confinement and the corresponding intensity enhancement inevitably requires simultaneous control over atomic-scale details of material structures and over the optical modes that such structures support. By means of self-assembly we have obtained side-by-side aligned gold nanorod dimers with robust atomically-defined gaps reaching below 0.5 nm. The existence of atomically-confined light fields in these gaps is demonstrated by observing extreme Coulomb splitting of corresponding symmetric and anti-symmetric dimer eigenmodes of more than 800 meV in white-light scattering experiments. Our results open new perspectives for atomically-resolved spectroscopic imaging, deeply nonlinear optics, ultra-sensing, cavity optomechanics as well as for the realization of novel quantum-optical devices

Emerging IT risks: insights from German banking

How do German banks manage the emerging risks stemming from IT innovations such as cyber risk? With a focus on process, roles and responsibilities, field data from ten banks participating in the 2014 ECB stress test were collected by interviewing IT managers, risk managers and external experts. Current procedures for handling emerging risks in German banks were identified from the interviews and analysed, guided by the extant literature. A clear gap was found between enterprise risk management (ERM) as a general approach to risks threatening firms’ objectives and ERM’s neglect of emerging risks, such as those associated with IT innovations. The findings suggest that ERM should be extended towards the collection and sharing of knowledge to allow for an initial understanding and description of emerging risks, as opposed to the traditional ERM approach involving estimates of impact and probability. For example, as cyber risks emerge from an IT innovation, the focus may need to switch towards reducing uncertainty through knowledge acquisition. Since individual managers seldom possess all relevant knowledge of an IT innovation, various stakeholders may need to be involved to exploit their expertise

Exposure of the Lumbosacral Plexus by Using the Pararectus Approach: A Technical Note.

BACKGROUND Surgical exploration of the lumbosacral plexus is challenging. Previously described approaches reach from invasive open techniques with osteotomy of the ilium to laparoscopic techniques. OBJECTIVE To describe a novel surgical technique to explore lumbosacral plexopathies such as benign nerve tumors or iatrogenic lesions of the lumbosacral plexus in 4 case examples. METHODS We retrospectively evaluated 4 patients suffering from pathologies or injuries of the lumbosacral plexus between 2017 and 2019. The mean follow-up period after surgery was 23.5 (range 11-52) months. All patients underwent neurolysis of the lumbosacral plexus using the single incision, intrapelvic, extraperitoneal pararectus approach. RESULTS In all patients, the pathology of the lumbosacral plexus was successfully visualized, proving feasibility of the extraperitoneal pararectus approach for this indication. There were no major complications, and all patients recovered well. CONCLUSION The pararectus approach allows excellent visualization of the lumbar plexus and intrapelvic lesions of the femoral and sciatic nerves

Proinflammatory intervertebral disc cell and organ culture models induced by tumor necrosis factor alpha.

Inflammation plays an important role in the pathogenesis of intervertebral disc (IVD) degeneration. The proinflammatory cytokine tumor necrosis factor alpha (TNF-α) has shown markedly higher expression in degenerated human disc tissue compared with healthy controls. Anti-inflammatory treatment targeting TNF-α has shown to alleviate discogenic pain in patients with low back pain. Therefore, in vitro and ex vivo inflammatory models utilizing TNF-α provide relevant experimental conditions for drug development in disc degeneration research. The current method article addressed several specific questions related to the model establishment. (a) The effects of bovine and human recombinant TNF-α on bovine nucleus pulposus (NP) cells were compared. (b) The required dose for an inflammatory IVD organ culture model with intradiscal TNF-α injection was studied. (c) The effect of TNF-α blocking at different stages of inflammation was evaluated. Outcomes revealed that bovine and human recombinant TNF-α induced equivalent inflammatory effects in bovine NP cells. A bovine whole IVD inflammatory model was established by intradiscal injection of 100 ng TNF-α/ cm3 disc volume, as indicated by increased nitric oxide, glycosaminoglycan, interleukin 6 (IL-6), and interleukin 8 (IL-8) release in culture media, and upregulation of MMP3, ADAMTS4, IL-8, IL-6, and cyclooxygenase (COX)-2 expression in NP tissue. However, results in human NP cells showed that the time point of anti-inflammatory treatment was crucial to achieve significant effects. Furthermore, anticatabolic therapy in conjunction with TNF-α inhibition would be required to slow down the pathologic cascade of disc degeneration

GP16: The effects of 3D culture on the expansion and maintenance of nucleus pulposus progenitor cell multipotency

Low back pain (LBP) is a global health concern that affects as many as 75–80% of people during their lifetime (1). The cause of LBP is multifactorial; however, intervertebral disc (IVD) degeneration is a major factor (2). Therefore, stem cell therapy to activate self-repair of the IVD appears to be an exciting treatment strategy (3). In this respect, tissue-specific progenitors may play a crucial role for IVD regeneration, as these cells are perfectly adapted to the IVD niche. Such a rare progenitor cell population residing in the nucleus pulposus (NP) was found to be positive for the angiopoietin-1 receptor (Tie2+) and was demonstrated to possess self-renewal capacity and in vitro multipotency (4). However, extremely low numbers of Tie2+ cells in NP limits the feasibility of potential cell therapy strategies. In this study, the first aim was to optimize culture conditions to mimic NP microenvironment for Tie2+ cells expansion. The second aim was to study the influence of cells expansion in various conditions on the chondrogenic potential of those cells. Here, cells were obtained from NP tissue of IVD in vertebrae of donors undergoing spinal surgery with written consent. Briefly, after mild overnight digestion of the NP tissue cells were cultivated within different conditions (in 2D or 3D) and culture media (fibronectin coating, TGFβ-1 and/or FGF-2) to mimic the microenvironment and the niche of the native NP of IVD. Subsequently, to study their regenerative potential cells were seeded into a 3D hydrogel scaffold collagen based and induced into the chondrogenic lineage for 2-3 weeks and analyzed. The present study proposes to exploit physiological niches in order to better maintain the functionality of cells during their in vitro expansion. This project not only has a scientific impact by evaluating the role of native physiological niches on the functionality of NP progenitors but could also lead to an innovative clinical approach with cell therapy for IVD regeneration and repair in a context of LBP. Acknowledgements: Financial support was received from iPSpine H2020 project #825925. References: (1) – Hartvigsen et al., 2018, Lancet; (2) – Martirosyan et al., 2016, Frontiers in Surgery; (3) – Sakai et al., 2015, Nature Reviews, Rheumathology; (4) – Frauchiger et al., 2019, Tissue Engineering. Part C, Methods

Direct anterior decompression of L4 and L5 nerve root in sacral fractures using the pararectus approach: a technical note.

PURPOSE To describe a new surgical technique for neurolysis and decompression of L4 and L5 nerve root entrapment after vertical sacral fractures via the pararectus approach for acetabular fractures, and to present four case examples. PATIENTS AND METHODS We retrospectively evaluated four patients suffering radiculopathy from entrapment of the L4 or L5 nerve root in vertical sacral fractures between January and December 2016. The mean follow-up period after surgery was 18 (range 7-27) months. All patients underwent direct decompression and neurolysis of the L4 and L5 nerve roots via the single-incision, intrapelvic, extraperitoneal pararectus approach. RESULTS In all patients, the L4 and L5 nerve root was successfully visualized and decompressed, proving feasibility of the pararectus approach for this indication. No patient presented with a neural tear. Complete neurologic recovery was present in one patient at last follow-up; two patients had incomplete recovery of their radiculopathy; and one patient had no improvement after nerve root decompression. CONCLUSIONS The pararectus approach allows for sufficient visualisation and direct decompression and neurolysis of the L4 and L5 nerve root entrapped in vertical sacral fractures. Although neurologic recovery was not achieved in all patients in this small case series, the approach may be a suitable alternative to posterior approaches and other anterior approaches such as the lateral window of the ilioinguinal approach