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Degenerative Disc Disease
 - Cell Therapy Approaches

Degenerative disc disease (DDD) refers to intervertebral disc (IVD) degeneration and represents a major cause of the low back pain (LBP).

The IVD contains three components: nucleus pulposus (NP), annulus fibrosis (AF) and cartilaginous end plate (EP). NP cells are chondrocyte-like cells situated within a collagen type 2- and proteoglycan-enriched matrix that absorbs spinal load. AF cells are fibroblast-like cellsare embedded in a collagen type 1-enriched expansion-resistant matrix. EP is composed of hyaline cartilage that connects the IVD to the bone of the neighboring vertebra.  Structural or compositional alterations in any of the three components alter the disc's ability to withstand load applied to the spine. The exact mechanisms that induce the DDD-associated pain are not well understood, but it is assumed that its development may be secondary to inflammation, injury or age-related. In all cases, changes occurring in disc structure are identical, initially noted in the EP, followed by alterations in the NP composition and finally in the AF. Notochordal cells responsible for the NP maintenance and production of aggrecan tend to slow their proliferation rate and even disappear throughout life. The resulting decrease in aggrecan and water content and consequential IVD dehydration due to loss of osmotic pressure is considered the most prominent biochemical alteration in DDD.

To date, no curative treatment is available for DDD and the management includes bed rest, physiotherapy and analgesic pain relief. Traditional treatments, including surgical and pharmacological therapy, target pain relief but fail to address the underlying pathology. 

Cell Therapy Approaches

Novel therapies are aimed to regenerate and repair degenerated disc and to provide a cure rather than symptomatic care. In addition to development of bio-molecular treatments designed to induce production of factors leading to regeneration of the extracellular matrix (ECM), two major non-pharmaceutical approaches have been investigated: Cell-based therapies – involve direct injection of cells, primarily proteoglycan- and collagen-producing cells, capable of proliferating and restoring the ECM. The transplantable cells suitable for this purpose include: mature IVD cells, articular chondrocytes and mesenchymal stem cells (MSCs) obtained from bone marrow, umbilical cord or adipose tissue.

Mature IVD cells seem to be the most appropriate for transplantation, as they naturally produce all the required ECM molecules and are capable of adapting to the hypoxic IVD microenvironment. Preclinical studies demonstrated the ability of these cells to reduce matrix damage and to improve disc recovery. Clinical trials have demonstrated that discectomy combined with transplantation of autologous disc chondrocytes, augments IVD fluid content and yields more significant pain relief compared to discectomy alone. However, the main disadvantage of this type of cellular therapy is the requirement for two surgical procedures, the first to harvest the disc cells and the second, for implantation. In addition, harvested cells differentiate and lose their ability to produce aggrecan during in vitro expansion.  

Articular chondrocytes can be surgically obtained from the non-weight bearing region of the knee joint. These cells produce aggrecan and collagen type 2 and carry a potential to recapitulate the IVD properties upon transplantation. Several in vitro and pre-clinical studies demonstrated the ability of chondrocytes to form hyaline-like cartilage, though its proteoglycan-to-collagen ratio is lower than in NP cells. Hence, additional research is required to bring articular chondrocytes to mimic biochemical and biomechanical properties of the IVD. Similarly to mature IVD cells transplantation, a significant drawback is presented by the requirement for two surgeries.

Mesenchymal stem cells (MSCs) are multipotent stem cells with a strong potential to differentiate into various types of mesenchyme-derived cells. MSCs can be obtained from various tissues in the body, including bone marrow, adipose tissue and umbilical cord, although the number of derived cells varies significantly from one source to another. MSCs are the most abundant source of cells for clinical use and are currently being explored in various fields of regenerative medicine. These cells can differentiate towards the chondrogenic lineages, both in vitro and in vivo, and produce proteoglycan- and collagen-comprising disc ECM. Moreover, MSCs carry anti-inflammatory properties and can improve DDD by reducing local inflammation.

Clinical trials demonstrated safety and feasibility of MSC implantation in DDD. Several clinical studies showed that disc height and water content were significantly improved in MSC-treated discs. Tissue engineering

During the early stage of disc degeneration, regeneration of functional tissue can be achieved by injection of MSCs or by administration of biomolecules which stimulate ECM production. However, at the progressive stage, when damage to IVD matrix is extensive, total IVD replacement may be necessary. Currently, methods based on combination of cells and supportive materials or scaffolds are widely explored in attempt to find an optimal substitute to the natural IVD, while materials mimicking the anatomical IVD architecture and mechanical properties are of highest interest. Hydrogels are hydrophilic polymers are able to absorb large volumes of water and swell without dissolution. Methacrylated gellan gum is a novel hydrogel that has water content and rheological properties strikingly similar to those of NP. Alginate- and agarose-based hydrogel scaffolds, and hydrogels comprised of hyaluronic acid, a native NP ECM component, have been clinically tested. For example, mesenchymal precursor cells (MPCs) mixed with hyaluronic acid carrier were injected into DDD patients to achieve IVD repair. A single low-dose MPC injection resulted in reduced lower back pain and improved function with no cell-related serious adverse events. Injectable biomaterials, such as atelocollagen and chitosan, can be delivered to the patient by minimally invasive methods, and serve as carriers for cell-based regeneration. It has been demonstrated that chitosan can effectively entrap IVD cells and ECM proteins.  Osteocell®Plus, a cellular bone matrix incorporating viable MSCs, contains osteogenic cells and an osteoinductive scaffold, the natural components necessary for bone fusion.  Osteocell®Plus treatment is combined with bone grafting during spinal fusion surgery to stimulate new bone formation for DDD treatment.

Despite intensive in vitro and pre-clinical research, a limited number of cell therapies and tissue-construct based applications have entered clinical trials. Incomplete understanding of DDD pathophysiology and its underlying molecular mechanisms significantly delays progress to effective cell-based treatments. Design of multi-compartmental artificial discs by tissue engineering methods, that will mimic IVD tissue growth and remodeling, might facilitate our understanding of the physiological and pathologic processes in IVD and serve as a platform for effective cell-based treatments.

Degenerative Disc Disease