ovine-lumbar-intervertebral-disc-degeneration-model-utilizing-lateral

Ovine Lumbar Intervertebral Disc Degeneration Model Utilizing a Lateral Retroperitoneal Drill Bit Injury

Intervertebral disc degeneration is a significant contributor to the development of back pain and the leading cause of disability worldwide. Numerous ...

St Vincent's Hospital

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Headache, collapse and coma. Deep cerebral venous sinus thrombosis.

Maux de t&ecirc;te, effondrement et coma. Thrombose du sinus veineux c&eacute;r&eacute;brales profondes.

Kopfschmerz, Kollaps und Koma. Tief zerebrale ven&ouml;se Sinus Thrombose.

Mal di testa, al collasso e coma. Trombosi del seno venoso profondo cerebrale.

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Dolor de cabeza, colapso y coma. Trombosis de seno venoso cerebral profunda.

The sheep is becoming increasingly used as a large animal model for preclinical spine surgery studies. Access to the ovine lumbar intervertebral discs has traditionally been via an anterior or anterolateral approach, which requires larger wound incisions and, at times, significant abdominal retraction. We present a new minimally invasive operative technique for a far-lateral approach to the ovine lumbar spine that allows for smaller incisions, excellent visualisation of intervertebral discs, and minimal abdominal retraction and is well tolerated by animals with minimal morbidity.

Lateral surgical approach to lumbar intervertebral discs in an ovine model.

Spinal surgery involves the bone-cartilage-neural interface. It is a field of surgery that is rapidly changing and evolving; not only through the development of novel techniques, approaches and devices but also through evidence from large clinical trials assessing indications, efficacy and outcomes. The use of biologics in spine surgery has now become widespread. Biologics in the form of autologous or allogeneic stem cells or progenitor cells are not yet in routine clinical use in spine surgery. However it is likely that they will have a significant role in the future, since increasing numbers of preclinical and clinical studies have demonstrated the safety and efficacy of progenitor cells to treat a variety of spinal conditions. Such studies have paved the way to larger clinical trials. Cell therapies encompass a wide range of stem cell and progenitor cell types. Stem cells subtypes differ in their lineage potential often being described as pluripotent or multipotent, some of which have potential application in therapies to treat diseases of the spine having the ability to differentiate into tissues including bone and cartilage and to secrete factors that promote matrix repair and regeneration. Furthermore, studies have shown that some cells, particularly mesenchymal stromal cells, modulate oxidative stress and secrete cytokines and growth factors that have immunomodulatory, antiinflammatory, angiogenic and antiapoptotic effects. It is these combined characteristics that make cell based therapies prime candidates for advancing current techniques in spine surgery and for providing new strategies directed at targeting the underlying causes of spinal diseases and disorders to promote repair and regeneration. This review will explore the characteristics of various stem cells and other progenitor cells derived from different sources. The authors are not suggesting that all these cells are necessarily suitable clinically. The review will thus focus on their application to both current and potentially future areas of spine surgery based on results of the available evidence and clinical trials. This review will not address spinal cord injury.

Current and future applications for stem cell therapies in spine surgery.

Following microdiscectomy, discs generally fail to undergo spontaneous regeneration and patients may experience chronic low-back pain and recurrent disc prolapse. In published studies, formulations of mesenchymal progenitor cells combined with pentosan polysulfate (MPCs+PPS) have been shown to regenerate disc tissue in animal models, suggesting that this approach may provide a useful adjunct to microdiscectomy. The goal of this preclinical laboratory study was to determine if the transplantation of MPCs+PPS, embedded in a gelatin/fibrin scaffold (SCAF), and transplanted into a defect created by microdiscectomy, could promote disc regeneration.

Mesenchymal progenitor cells combined with pentosan polysulfate mediating disc regeneration at the time of microdiscectomy: a preliminary study in an ovine model.

Concern over the use of recombinant bone morphogenetic protein in spinal fusion surgery: are stem cells an alternative?

Low back pain is a common clinical problem, which leads to significant social, economic and public health costs. Intervertebral disc (IVD) degeneration is accepted as a common cause of low back pain. Initially, this is characterized by a loss of proteoglycans from the nucleus pulposus resulting in loss of tissue hydration and hydrostatic pressure. Conservative management, including analgesia and physiotherapy often fails and surgical treatment, such as spinal fusion, is required. Stem cells offer an exciting possible regenerative approach to IVD disease. Preclinical research has demonstrated promising biochemical, histological and radiological results in restoring degenerate IVDs. Cell tracking provides an opportunity to develop an in-depth understanding of stem cell survival, differentiation and migration, enabling optimization of stem cell treatment. Magnetic Resonance Imaging (MRI) is a non-invasive, non-ionizing imaging modality with high spatial resolution, ideally suited for stem cell tracking. Furthermore, novel MRI sequences have the potential to quantitatively assess IVD disease, providing an improved method to review response to biological treatment. Superparamagnetic iron oxide nanoparticles have been extensively researched for the purpose of cell tracking. These particles are biocompatible, non-toxic and act as excellent MRI contrast agents. This review will explore recent advances and issues in stem cell tracking and molecular imaging in relation to the IVD.

Mesenchymal stem cell tracking in the intervertebral disc.

Degenerative conditions of the lumbar spine are extremely common. Ninety percent of people over the age of 60 years have degenerative change on imaging; however, only a small minority of people will require spine surgery (Hicks et al. Spine (Phila Pa 1976) 34(12):1301-1306, 2009). This minority, however, constitutes a core element of spinal surgery practice. Whilst the patient outcomes from spinal surgeries have improved in recent years, some patients will remain with pain and disability despite technically successful surgery. Advances in regenerative medicine and stem cell therapies, particularly the use of mesenchymal stem cells and allogeneic mesenchymal precursor cells, have led to numerous clinical trials utilising these cell-based therapies to treat degenerative spinal conditions. Through cartilage formation and disc regeneration, fusion enhancement or via modification of pain pathways, stem cells are well suited to enhance spinal surgery practice. This review will focus on the outcomes of lumbar spinal procedures and the role of stem cells in the treatment of degenerative lumbar conditions to enhance clinical practice. The current status of clinical trials utilising stem cell therapies will be discussed, providing clinicians with an overview of the various cell-based treatments likely to be available to patients in the near future.

The role of stem cell therapies in degenerative lumbar spine disease: a review.

Low back pain and degenerative disc disease are a significant cause of pain and disability worldwide. Advances in regenerative medicine and cell-based therapies, particularly the transplantation of mesenchymal stem cells and intervertebral disc chondrocytes, have led to the publication of numerous studies and clinical trials utilising these biological therapies to treat degenerative spinal conditions, often reporting favourable outcomes. Stem cell mediated disc regeneration may bridge the gap between the two current alternatives for patients with low back pain, often inadequate pain management at one end and invasive surgery at the other. Through cartilage formation and disc regeneration or via modification of pain pathways stem cells are well suited to enhance spinal surgery practice. This paper will systematically review the current status of basic science studies, preclinical and clinical trials utilising cell-based therapies to repair the degenerate intervertebral disc. The mechanism of action of transplanted cells, as well as the limitations of published studies, will be discussed.

Cell-Based Therapies Used to Treat Lumbar Degenerative Disc Disease: A Systematic Review of Animal Studies and Human Clinical Trials.

Over the past decade, mounting evidence has shown that mesenchymal stromal cells have the potential to exert protective and reparative effects in a variety of disease settings. Clinical trials are being increasingly established to investigate the therapeutic potential of these cells; however, several safety concerns remain to be addressed, of which dosage safety for intravenous administration is paramount. Published safety studies thus far have predominantly been carried out in small-animal models, whereas data for high-dose allogeneic intravenous administration in large-animal models are limited. This study investigates the safety and tolerability of a single high-dose intravenous infusion of 450 million allogeneic ovine mesenchymal precursor cells (oMPCs) in adult sheep.

Evaluation of the safety and tolerability of a high-dose intravenous infusion of allogeneic mesenchymal precursor cells.

OBJECTIVE Disc degeneration and associated low-back pain are major causes of suffering and disability. The authors examined the potential of mesenchymal precursor cells (MPCs), when formulated with pentosan polysulfate (PPS), to ameliorate disc degeneration in an ovine model. METHODS Twenty-four sheep had annular incisions made at L2-3, L3-4, and L4-5 to induce degeneration. Twelve weeks after injury, the nucleus pulposus of a degenerated disc in each animal was injected with ProFreeze and PPS formulated with either a low dose (0.1 million MPCs) or a high dose (0.5 million MPCs) of cells. The 2 adjacent injured discs in each spine were either injected with PPS and ProFreeze (PPS control) or not injected (nil-injected control). The adjacent noninjured L1-2 and L5-6 discs served as noninjured control discs. Disc height indices (DHIs) were obtained at baseline, before injection, and at planned death. After necropsy, 24 weeks after injection, the spines were subjected to MRI and morphological, histological, and biochemical analyses. RESULTS Twelve weeks after the annular injury, all the injured discs exhibited a significant reduction in mean DHI (low-dose group 17.19%; high-dose group 18.01% [p < 0.01]). Twenty-four weeks after injections, the discs injected with the low-dose MPC+PPS formulation recovered disc height, and their mean DHI was significantly greater than the DHI of PPS- and nil-injected discs (p < 0.001). Although the mean Pfirrmann MRI disc degeneration score for the low-dose MPC+PPS-injected discs was lower than that for the nil- and PPS-injected discs, the differences were not significant. The disc morphology scores for the nil- and PPS-injected discs were significantly higher than the normal control disc scores (p < 0.005), whereas the low-dose MPC+PPS-injected disc scores were not significantly different from those of the normal controls. The mean glycosaminoglycan content of the nuclei pulposus of the low-dose MPC+PPS-injected discs was significantly higher than that of the PPS-injected controls (p < 0.05) but was not significantly different from the normal control disc glycosaminoglycan levels. Histopathology degeneration frequency scores for the low-dose MPC+PPS-injected discs were lower than those for the PPS- and Nil-injected discs. The corresponding high-dose MPC+PPS-injected discs failed to show significant improvements in any outcome measure relative to the controls. CONCLUSIONS Intradiscal injections of a formulation composed of 0.1 million MPCs combined with PPS resulted in positive effects in reducing the progression of disc degeneration in an ovine model, as assessed by improvements in DHI and morphological, biochemical, and histopathological scores.

Reconstitution of degenerated ovine lumbar discs by STRO-3-positive allogeneic mesenchymal precursor cells combined with pentosan polysulfate.

Headache, dysphasia and a left temporal lobe mass: question.

Lower back pain is the leading cause of disability worldwide. Discogenic pain secondary to intervertebral disc degeneration is a significant cause of low back pain. Disc degeneration is a complex multifactorial process. Animal models are essential to furthering understanding of the degenerative process and testing potential therapies. The adult human lumbar intervertebral disc is characterized by the loss of notochordal cells, relatively large size, essentially avascular nature, and exposure to biomechanical stresses influenced by bipedalism. Animal models are compared with regard to the above characteristics. Numerous methods of inducing disc degeneration are reported. Broadly these can be considered under the categories of spontaneous degeneration, mechanical and structural models. The purpose of such animal models is to further our understanding and, ultimately, improve treatment of disc degeneration. The role of animal models of disc degeneration in translational research leading to clinical trials of novel cellular therapies is explored.

Article	Year
Headache, collapse and coma. Deep cerebral venous sinus thrombosis. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia\| PubMed ID: 21789783	2011
Lateral surgical approach to lumbar intervertebral discs in an ovine model. TheScientificWorldJournal\| PubMed ID: 23028255	2012
Current and future applications for stem cell therapies in spine surgery. Current stem cell research & therapy\| PubMed ID: 23971834	2013
Mesenchymal progenitor cells combined with pentosan polysulfate mediating disc regeneration at the time of microdiscectomy: a preliminary study in an ovine model. Journal of neurosurgery. Spine\| PubMed ID: 24702507	2014
Concern over the use of recombinant bone morphogenetic protein in spinal fusion surgery: are stem cells an alternative? ANZ journal of surgery\| PubMed ID: 24877230	2014
Mesenchymal stem cell tracking in the intervertebral disc. World journal of stem cells\| PubMed ID: 25621106	2015
The role of stem cell therapies in degenerative lumbar spine disease: a review. Neurosurgical review\| PubMed ID: 25749802	2015
Cell-Based Therapies Used to Treat Lumbar Degenerative Disc Disease: A Systematic Review of Animal Studies and Human Clinical Trials. Stem cells international\| PubMed ID: 26074979	2015
Evaluation of the safety and tolerability of a high-dose intravenous infusion of allogeneic mesenchymal precursor cells. Cytotherapy\| PubMed ID: 26188968	2015
Reconstitution of degenerated ovine lumbar discs by STRO-3-positive allogeneic mesenchymal precursor cells combined with pentosan polysulfate. Journal of neurosurgery. Spine\| PubMed ID: 26799116	2016
Headache, dysphasia and a left temporal lobe mass: question. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia\| PubMed ID: 27170952	2016
A Review of Animal Models of Intervertebral Disc Degeneration: Pathophysiology, Regeneration, and Translation to the Clinic. BioMed research international\| PubMed ID: 27314030	2016

David Oehme

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