Bone marrow mesenchymal stem cells combined with ultra-purified alginate gel as a regenerative therapeutic strategy after discectomy for degenerated intervertebral discs

Abstract

Background: Because the regenerative ability of intervertebral discs (IVDs) is restricted, defects caused by discectomy may induce insufficient tissue repair leading to further IVD degeneration. An acellular bioresorbable biomaterial based on ultra-purified alginate (UPAL) gel was developed to fill the IVD cavity and prevent IVD degeneration. However, an acellular matrix-based strategy may have limitations, particularly in the elderly population, who exhibit low self-repair capability. Therefore, further translational studies involving product combinations, such as UPAL gel plus bone marrow-derived mesenchymal stem cells (BMSCs), are required to evaluate the regenerative effects of BMSCs embedded in UPAL gel on degenerated IVDs. Methods: Rabbit BMSCs and nucleus pulposus cells (NPCs) were co-cultured in a three-dimensional (3D) system in UPAL gel. In addition, rabbit or human BMSCs combined with UPAL gel were implanted into IVDs following partial discectomy in rabbits with degenerated IVDs. Findings: Gene expression of NPC markers, growth factors, and extracellular matrix was significantly increased in the NPC and BMSC 3D co-culture compared to that in each 3D mono-culture. In vivo, whereas UPAL gel alone suppressed IVD degeneration as compared to discectomy, the combination of BMSCs and UPAL gel exerted a more potent effect to induce IVD regeneration. Similar IVD regeneration was observed using human BMSCs. Interpretation: These findings demonstrate the therapeutic potential of BMSCs combined with UPAL gel as a regenerative strategy following discectomy for degenerated IVDs.

Combination of ultra-purified stem cells with an in situ-forming bioresorbable gel enhances intervertebral disc regeneration

“…3,4,8,11À14,16 To identify the course of post-surgical IVD degeneration from the onset, we generated a rabbit model of IVD degeneration. 2,15 We demonstrated that following discectomy, the use of UPAL gel alone suppressed IVD degeneration compared to the extent of degeneration without UPAL gel treatment. Additionally, the combination of allogenic BMSCs and UPAL gel was more effective at inducing IVD regeneration compared to UPAL alone.…”

“…18 A carrier biomaterial is necessary to prevent cell leakage during discectomy. 2,15 To date, no biomaterials have been clinically approved for this purpose because each biomaterial did not meet criteria for both biologic and mechanical safety. We had previously developed an original, acellular, bioresorbable, ultra-purified alginate (UPAL) gel to repair IVD degeneration in small 2,3,15,16 and large animal models in vivo.…”

Gel and cells: A promising reparative strategy for degenerated intervertebral discs

“…In an article in EBioMedicine, Ukeda and co-workers report the development of a novel regenerative therapeutic strategy that involves the application of bone marrow-derived mesenchymal stem cells (BMSCs) combined with a hydrogel [6]. The bioresorbable hydrogel consisted of ultra-purified alginate (UPAL), a polysaccharide derived from the brown seaweed, Phaeophyceae, which gelates via calcium ion-mediated crosslinking.…”

“…However, it is not known that BMSCs have a reciprocal stimulatory effect on NPCs. The Contents lists available at ScienceDirect EBioMedicine journal homepage: www.elsevier.com/locate/ebiom encapsulation of BMSCs by Ukeda et al [6] likely enhanced the retention of BMSC-secreted factors, resulting in enhancement of NPC bioactivity observed in the 3D in vitro cultures, as well as activation of resident NPCs in the site of IVD degeneration in vivo. The absence of osteophyte formation also indicated that the rapid curing of the UPAL hydrogel prevented leakage of BMSCs.…”

“…There are, however, some remaining hurdles for successful and practicable translation of the technology described by Ukeba et al [6]. These include: (1) effective repair of the AF, the outer fibrous structure of the IVD, which is often compromised in degenerative disc diseases; (2) achieving material properties in the regenerated tissue that are comparable to those of the native NP, a critical requirement for its mechanical function; and (3) functional integration of the regenerated NP with the other components of the IVD, i.e., the AF and the cartilage endplates, for structural integrity and mechanical stability.…”