Biomaterial-assisted stem cell-based therapies for intervertebral disc degeneration

Abstract

Degenerative disc disease (DDD) poses an increasing threat to our quality of life as we age. Existing treatments have limitations. New treatment modalities using biological rather than surgical approach are appealing. Mesenchymal stem cells (MSC)-based therapy hold great potential in treating disc degeneration. Numerous studies in mouse, rat, rabbit, porcine and bovine models showed encouraging results with survival, proliferation and differentiation of MSCs, enhanced matrix accumulation, and improved disc height and hydration level. However, during intra-discal injection, the vast majority of cells leaked out even in the presence of hydrogel carrier. Recent evidence even suggests that annulus puncture is associated with cell leakage and contributes to osteophyte formation, an undesirable side-effect. This suggests the significance of developing appropriate cell carriers and effective approaches to prevent leakage and associated osteophyte formation before MSC-based therapies can be applied in a clinical setting.

Using a collagen microencapsulation platform, solid yet porous microspheres entrapping MSCs, and supporting their survival, proliferation, differentiation and matrix remodeling, were fabricated. We hypothesize that intra-discal injection of MSCs in collagen microspheres will outperform MSCs in saline in improving functional outcomes and reducing side effect osteophyte formation. Using a well-established disc degeneration model in rabbits, autologous MSCs, either packaged within collagen microspheres or directly suspended in saline, were intra-discally injected into different disc levels. Comparing with MSC in saline, MSC in collagen microspheres showed slight advantages in disc height maintenance, dynamic mechanical behavior and GAG:HYP ratio. More importantly, delivering MSC in collagen microspheres significantly reduced the risk of osteophyte formation. This work demonstrates the significance of cell carriers during intra-discal injection of MSCs in treating disc degeneration. Nevertheless, osteophyte formation cannot be completely eliminated by using microsphere carriers.

Using a patented photochemical crosslinking technology, an injectable collagen-based annulus plug was fabricated to block the injection portal during intra-discal delivery. A custom-made delivery device was also developed to deliver the plug intradiscally following delivery of MSCs in collagen microsphere carriers. Ex vivo studies showed that the plug survived physiologically relevant loadings and significantly reduced leakage and enhanced retention of the injected materials. In vivo study in the same rabbit model showed encouraging results. Microcomputed tomography imaging and histology revealed that the plug significantly reduced osteophyte formation. This work suggests the potential of the annulus plug as an adjunct or annulus closure device for intra-disc delivery of cells and materials.

Many questions remain to be answered before successful translation of stem cell based therapies for disc degeneration. A discussion on these topics such as better understanding of the niche factors inducing differentiation of MSCs towards nucleus pulposuslike lineages will also be included, depending on the time allocation.