Intervertebral Disc Nucleus Repair: Hype or Hope?

Chronic back pain is a common disability, which is often accredited to intervertebral disc degeneration. Gold standard interventions such as spinal fusion, which are mainly designed to mechanically seal the defect, frequently fail to restore the native biomechanics. Moreover, artificial implants have limited success as a repair strategy, as they do not alter the underlying disease and fail to promote tissue integration and subsequent native biomechanics. The reported high rates of spinal fusion and artificial disc implant failure have pushed intervertebral disc degeneration research in recent years towards repair strategies. Intervertebral disc repair utilizing principles of tissue engineering should theoretically be successful, overcoming the inadequacies of artificial implants. For instance, advances in the development of scaffolds aided with cells and growth factors have opened up new possibilities for repair strategies. However, none has reached the stage of clinical trials in humans. In this review, we describe the hitches encountered in the musculoskeletal field and summarize recent advances in designing tissue-engineered constructs for promoting nucleus pulposus repair. Additionally, the review focuses on the effect of biomaterial aided with cells and growth factors on achieving effective functional reparative potency, highlighting the ways to enhance the efficacy of these treatments.

Exogenous Delivery of Link N mRNA into Chondrocytes and MSCs-The Potential Role in Increasing Anabolic Response.

Musculoskeletal disorders, such as osteoarthritis and intervertebral disc degeneration are causes of morbidity, which concomitantly burdens the health and social care systems worldwide, with massive costs. Link N peptide has recently been described as a novel anabolic stimulator for intervertebral disc repair. In this study, we analyzed the influence on anabolic response, by delivering synthetic Link N encoding mRNA into primary human chondrocytes and mesenchymal stromal cells (SCP1 cells), Furthermore, both cell types were seeded on knitted titanium scaffolds, and the influence of Link N peptide mRNA for possible tissue engineering applications was investigated. Synthetic modified Link N mRNA was efficiently delivered into both cell types and cell transfection resulted in an enhanced expression of aggrecan, Sox 9, and type II collagen with a decreased expression of type X collagen. Interestingly, despite increased expression of BMP2 and BMP7, BMP signaling was repressed and TGFß signaling was boosted by Link N transfection in mesenchymal stromal cells, suggesting possible regulatory mechanisms. Thus, the exogenous delivery of Link N peptide mRNA into cells augmented an anabolic response and thereby increased extracellular matrix synthesis. Considering these findings, we suppose that the cultivation of cells on knitted titanium scaffolds and the exogenous delivery of Link N peptide mRNA into cells could mechanically support the stability of tissue-engineered constructs and improve the synthesis of extracellular matrix by seeded cells. This method can provide a potent strategy for articular cartilage and intervertebral disc regeneration.

How does a novel knitted titanium nucleus prosthesis change the kinematics of a cervical spine segment? A biomechanical cadaveric study.

BACKGROUND: Total disc replacement is a possible treatment alternative for patients with degenerative disc disease, especially in the cervical spine. The aim is to restore the physiological flexibility and biomechanical behavior. A new approach based on these requirements is the novel nucleus prosthesis made of knitted titanium wires. METHODS: The biomechanical functionalities of eight human cervical (C4-C7) spine segments were investigated. The range of motion was quantified using an ultra-sound based motion analysis system. Moreover, X-rays in full flexion and extension of the segment were taken to define the center of rotation before and after implantation of the nucleus prosthesis as well as during and after complex cyclic loading. FINDINGS: The mean range of motion of the index segment (C5/6) in flexion/extension showed a significant reduction of range of motion from 9.7° (SD 4.33) to 6.0° (SD 3.97) after implantation (P = 0.037). Lateral bending and axial rotation were not significantly reduced after implanting and during cyclic loading in our testing. During cyclic loading the mean range of motion for flexion/extension increased to 7.2° (SD 3.67). The center of rotation remained physiological in the ap-plane and moved cranially in the cc-plane (-27% to -5% in cc height) during the testing. INTERPRETATION: The biomechanical behavior of the nucleus implant might lower the risk for adjacent joint disorders and restore native function of the index segment. Further in vivo research is needed for other factors, like long-term effects and patient's satisfaction.

Characterisation of porous knitted titanium for replacement of intervertebral disc nucleus pulposus.

Effective restoration of human intervertebral disc degeneration is challenged by numerous limitations of the currently available spinal fusion and arthroplasty treatment strategies. Consequently, use of artificial biomaterial implant is gaining attention as a potential therapeutic strategy. Our study is aimed at investigating and characterizing a novel knitted titanium (Ti6Al4V) implant for the replacement of nucleus pulposus to treat early stages of chronic intervertebral disc degeneration. Specific knitted geometry of the scaffold with a porosity of 67.67 ± 0.824% was used to overcome tissue integration failures. Furthermore, to improve the wear resistance without impairing original mechanical strength, electro-polishing step was employed. Electro-polishing treatment changed a surface roughness from 15.22 ± 3.28 to 4.35 ± 0.87 µm without affecting its wettability which remained at 81.03 ± 8.5°. Subsequently, cellular responses of human mesenchymal stem cells (SCP1 cell line) and human primary chondrocytes were investigated which showed positive responses in terms of adherence and viability. Surface wettability was further enhanced to super hydrophilic nature by oxygen plasma treatment, which eventually caused substantial increase in the proliferation of SCP1 cells and primary chondrocytes. Our study implies that owing to scaffolds physicochemical and biocompatible properties, it could improve the clinical performance of nucleus pulposus replacement.

Imaging Cell Viability on Non-transparent Scaffolds - Using the Example of a Novel Knitted Titanium Implant.

Intervertebral disc degeneration and disc herniation is one of the major causes of lower back pain. Depletion of extracellular matrix, culminating in nucleus pulposus (NP) extrusion leads to intervertebral disc destruction. Currently available surgical treatments reduce the pain but do not restore the mechanical functionality of the spine. In order to preserve mechanical features of the spine, total disc or nucleus replacement thus became a wide interest. However, this arthroplasty era is still in an immature state, since none of the existing products have been clinically evaluated. This study intends to test the biocompatibility of a novel nucleus implant made of knitted titanium wires. Despite all mechanical advantages, the material has its limits for conventional optical analysis as the resulting implant is non-transparent. Here we present a strategy that describes in vitro visualization, tracking and viability testing of osteochondro-progenitor cells on the scaffold. This protocol can be used to visualize the efficiency of the cleaning protocol as well as to investigate the biocompatibility of these and other non-transparent scaffolds. Furthermore, this protocol can be used to show adherence pattern of cells as well as cell viability and proliferation rates on/in the scaffold. This in vitro biocompatibility testing assay provides a propitious tool to analyze cell-material interaction in non-transparent and opaque scaffolds.

Biomechanical behavior of a new nucleus prosthesis made of knitted titanium filaments.

BACKGROUND: One of the greatest challenges in the development of a nucleus prosthesis is to minimize the risk of implant expulsion. At the same time, the physiological flexibility, compressive behavior, and height of the disc should be restored. In this biomechanical in vitro study we investigated the ability of a new nucleus prosthesis made of knitted titanium filaments to meet these challenges. METHODS: Flexibility, axial deformation, and height of six bovine lumbar spine segments were measured in the intact condition, after implantation of the new prosthesis, and during and after complex cyclic loading (100,000 cycles). For this purpose, six new prostheses preformed according to the shape of the bovine nucleus pulposus were manufactured. Flexibility was tested in the three main planes under pure moment loads of 7.5 Nm. Axial deformation was measured under application of an axial force of 1000 N. Radiographs taken before and after cyclic testing were used to assess implant migration and expulsion. RESULTS: In lateral bending, the intact range of motion (RoM) could almost be restored after implantation. However, in axial rotation, the RoM increased slightly with the implant. This was also the case in extension, with an increase from -2.9° to -6.4°, whereas in flexion, RoM decreased from 4.3° to 3.2°. In all loading planes, cyclic loading caused the RoM to increase asymptotically by 0.1° to 1.8°. The axial deformation of the specimens was nearly equivalent in all tested states, as was their height. Cyclic loading did not cause implant expulsion. CONCLUSIONS: In this feasibility study, the new knitted nucleus prosthesis showed promising results in segmental flexibility, axial deformability, height, and implant expulsion. However, further study is needed for other factors, such as wear and fatigue behavior.

Experimental strategies to promote spinal cord regeneration--an integrative perspective.

Detailed pathophysiological findings of secondary damage phenomena after spinal cord injury (SCI) as well as the identification of inhibitory and neurotrophic proteins have yielded a plethora of experimental therapeutic approaches. Main targets are (i) to minimize secondary damage progression (neuroprotection), (ii) to foster axon conduction (neurorestoration) and (iii) to supply a permissive environment to promote axonal sprouting (neuroregenerative therapies). Pre-clinical studies have raised hope in functional recovery through the antagonism of growth inhibitors, application of growth factors, cell transplantation, and vaccination strategies. To date, even though based on successful pre-clinical animal studies, results of clinical trials are characterized by dampened effects attributable to difficulties in the study design (patient heterogeneity) and species differences. A combination of complementary therapeutic strategies might be considered pre-requisite for future synergistic approaches. Here, we line out pre-clinical interventions resulting in improved functional neurological outcome after spinal cord injury and track them on their intended way to bedside.