Clinical Application of Bone Marrow Mesenchymal Stem/Stromal Cells to Repair Skeletal Tissue

Abstract

There has been an escalation in reports over the last decade examining the efficacy of bone marrow derived mesenchymal stem/stromal cells (BMSC) in bone tissue engineering and regenerative medicine-based applications. The multipotent differentiation potential, myelosupportive capacity, anti-inflammatory and immune-modulatory properties of BMSC underpins their versatile nature as therapeutic agents. This review addresses the current limitations and challenges of exogenous autologous and allogeneic BMSC based regenerative skeletal therapies in combination with bioactive molecules, cellular derivatives, genetic manipulation, biocompatible hydrogels, solid and composite scaffolds. The review highlights the current approaches and recent developments in utilizing endogenous BMSC activation or exogenous BMSC for the repair of long bone and vertebrae fractures due to osteoporosis or trauma. Current advances employing BMSC based therapies for bone regeneration of craniofacial defects is also discussed. Moreover, this review discusses the latest developments utilizing BMSC therapies in the preclinical and clinical settings, including the treatment of bone related diseases such as Osteogenesis Imperfecta.

Keywords: biomaterials; bone marrow mesenchymal stem cells; bone marrow microenvironment; scaffolds; skeletal tissue regeneration; tissue engineering.

Figure 1

Schematic representation of the current approaches to bone regeneration. Non-cell therapy approaches to bone regeneration encompass bioactive molecules cellular derivatives and hydrogels/scaffolds/implants that can interact with and regulate/influence cellular responses. Cell therapy approach comprise the delivery of exogenous cells, either autologous or allogeneic in combination with non-cell therapy approaches. Alternatively the activation of endogenous cells (stem cells, endothelial cells, hematopoietic populations and/or mesenchymal populations) through non-cell therapy approaches have been and are currently being developed to regenerate the appropriate skeletal tissue. The bioactive molecules include a range of growth factors/cytokines, small molecules/drugs, endocrines/hormones, antibiotics and nucleic acid/genetic manipulation. The cellular derivatives incorporate components that have been derived from cells within the bone, these include exosomes, conditioned media, plasma/platelet rich plasma (PRP) and aspirates from the bone marrow (BM). The hydrogels/scaffolds/implants embodies the fabrication of injectable, microbeads, nanogels, fibers, biofilms, membranes, sponges, bone grafts and solid scaffolds that are derived from either natural materials, synthetic polymers, ceramics, nanoparticles, metal alloys or composites of these components. These bio-compatible hydrogels/scaffolds are also manipulated to incorporate and deliver cells, cellular derivatives and/or bioactive molecules in a temporal and spatial manner to enrich bone regeneration.

Figure 2

Differential osteoconductive properties of bio-materials. Culture expanded human BMSC were seeded onto (A) JAX 100% β-TCP (Smith & Nephew) or (B) Master Graft 15% HA/80% β-TCP granules (Medtronic Sofamor Danek), then transplanted subcutaneously into immunocompromised NOD-SCID mice for eight weeks. Representative cross sections of each transplant are shown stained with H&E depicting new bone formation (arrows). Magnification 200x.