Stem cell- and scaffold-based tissue engineering approaches to osteochondral regenerative medicine

Abstract

In osteochondral tissue engineering, cell recruitment, proliferation, differentiation, and patterning are critical for forming biologically and structurally viable constructs for repair of damaged or diseased tissue. However, since constructs prepared ex vivo lack the multitude of cues present in the in vivo microenvironment, cells often need to be supplied with external biological and physical stimuli to coax them toward targeted tissue functions. To determine which stimuli to present to cells, bioengineering strategies can benefit significantly from endogenous examples of skeletogenesis. As an example of developmental skeletogenesis, the developing limb bud serves as an excellent model system in which to study how osteochondral structures form from undifferentiated precursor cells. Alongside skeletal formation during embryogenesis, bone also possesses innate regenerative capacity, displaying remarkable ability to heal after damage. Bone fracture healing shares many features with bone development, driving the hypothesis that the regenerative process generally recapitulates development. Similarities and differences between the two modes of bone formation may offer insight into the special requirements for healing damaged or diseased bone. Thus, endogenous fracture healing, as an example of regenerative skeletogenesis, may also inform bioengineering strategies. In this review, we summarize the key cellular events involving stem and progenitor cells in developmental and regenerative skeletogenesis, and discuss in parallel the corresponding cell- and scaffold-based strategies that tissue engineers employ to recapitulate these events in vitro.

Figure 1

Progenitor and stem cell sources for bone development, bone healing, and bone tissue engineering (A) During limb bud development, mesenchymal progenitor cells from the lateral plate mesoderm (LPM) migrate into the presumptive limb bud (LB) region and initiate endochondral ossification under the apical ectodermal ridge (AER). (B) During bone fracture healing, mesenchymal cells migrate into the wound from the periosteum (P), the surrounding soft tissues such as muscle (M), the bone marrow (BM), and the neighboring cortical bone (CB). (C) Many bone tissue engineering approaches utilize human mesenchymal stem cells, which are commonly derived from bone marrow aspirates taken from the iliac crest (IC) of the pelvic bone. These cells are seeded onto a porous scaffold (PS) of choice and cultured under osteogenic stimulatory conditions.

Figure 2

Matrix changes during endochondral ossification Tissue engineers invest much effort into biomaterial design to provide cells with the appropriate growth-inducing microenvironment. As an in vivo example of the critical role of the extracellular matrix (ECM) during tissue development, Figure 2 illustrates ECM changes during endochondral ossification. The ECM evolves in each stage of the ossification process: it is remodeled by the cells while also providing physical and biochemical stimuli to the cells.

Figure 3

Biologically-informed design specifications for biomaterials in tissue engineering Scaffold properties such as material biocompatibility, geometry, porosity, mechanical strength, degradation rate, and incorporation of signaling molecules can be optimized to address various physiological requirements of an engineered tissue.

Figure 4

Silk fibroin-based porous scaffolds Silk fibroin can be processed into porous sponges in organic (A) or aqueous (B) solvents. Scaffolds were prepared by salt leaching using 500–600 μm-sized porogens. Aqueous-based silk fibroin sponges have rougher pore surfaces and demonstrate better cell attachment, greater mechanical strength, and faster degradation rates compared to organic solvent-based sponges. Scale bar = 500 μm.