DEVELOPING PATIENT-SPECIFIC THERAPY FOR THE INTERVERTEBRAL DISC: WHEN TO REGENERATE AND WHEN TO FUSE?

Low back pain is a significant burden and is often related to the degeneration of the intervertebral disc (IVD). Primary 3D cell or organ cultures can help identify the key parameters that might influence the outcomes in healthy versus pathological discs. These 3D culture systems, or even explant IVD organ cultures with mechanical loading, can help to understand the roles of these factors. This talk will address the problem of regenerating or repairing the IVD with biomaterials and/or cells, i.e., the classical tissue-engineered approach. Here, coccygeal bovine IVDs serve as an animal model with high mechanobiological similarities to the human IVDs. Special emphasis will be given to mechano-biological culture systems using 3D hydrogels and to what extent cartilaginous endplate cells might react to mechanical loading. For tissue engineering, silk material, and several hydrogels are currently being investigated for the application of IVD repair. Here, differences in the repair strategies of nucleus pulposus and the annulus fibrosus will be highlighted. Progenitor cells of various sources may possibly find the way into the clinics. However, ethics and the need for a suitable cell source is still debatable. Here, upscaling and standardization for the clinics would be desirable. Thus, cell-free therapies are emerging such as the delivery of extracellular vesicles (EVs). It is important to note that these regenerative approaches can only be applied to the mildly degenerated disc. However, in clinical practice patients are usually treated when the IVD degeneration has progressed much further at one or at multiple levels and spinal stabilization is needed by discectomy and spinal fusion surgery. Spinal fusion surgery involving cages and pedicle screws for compression is the “gold-standard”. However, it is not successful in up to 30% of the cases. Development of pseudo-athrosis is a highly painful condition, and elderly patients are often affected (> 70 yrs of age). Here, bone morphogenic protein 2 (BMP2) has been approved by the authorities as a medical treatment. It is applied in the order of ∼4 mg per patient per disc. This supra-physiological dose of the cytokine was highly debated, and complications were described. Here, our research group has been investigating what factors could lead to such non-fusions. We and others found evidence that in the disc niche high concentrations of BMP antagonists are present. These seem to inhibit the action of BMP2. Here, I present our recent investigations to use “biologics” to accelerate osteogenesis and fusion outcome.