Coupling Osteogenesis and Vasculogenesis in Engineered Orthopedic Tissues

Abstract

Inadequate vascularization of engineered tissue constructs is a main challenge in developing a clinically impactful therapy for large, complex, and recalcitrant bone defects. It is well established that bone and blood vessels form concomitantly during development, as well as during repair after injury. Endothelial cells (ECs) and mesenchymal stromal cells (MSCs) are known to be key players in orthopedic tissue regeneration and vascularization, and these cell types have been used widely in tissue engineering strategies to create vascularized bone. Coculture studies have demonstrated that there is crosstalk between ECs and MSCs that can lead to synergistic effects on tissue regeneration. At the same time, the complexity in fabricating, culturing, and characterizing engineered tissue constructs containing multiple cell types presents a challenge in creating multifunctional tissues. In particular, the timing, spatial distribution, and cell phenotypes that are most conducive to promoting concurrent bone and vessel formation are not well understood. This review describes the processes of bone and vascular development, and how these have been harnessed in tissue engineering strategies to create vascularized bone. There is an emphasis on interactions between ECs and MSCs, and the culture systems that can be used to understand and control these interactions within a single engineered construct. Developmental engineering strategies to mimic endochondral ossification are discussed as a means of generating vascularized orthopedic tissues. The field of tissue engineering has made impressive progress in creating tissue replacements. However, the development of larger, more complex, and multifunctional engineered orthopedic tissues will require a better understanding of how osteogenesis and vasculogenesis are coupled in tissue regeneration.

Advances in 3D printing of composite scaffolds for the repairment of bone tissue associated defects

“…136 Promoting angiogenesis and vasculogenesis lies at the heart of any study aiming to improve vascularization in bone grafts. 137 The biochemical process and the microenvironment required for vascularization have been well documented. 138 For a fractured bone to heal, MSCs must populate the ruptured area and initiate the regenerative process.…”

“…It is a well‐known fact that osteoblasts and other cells related to bone formation cannot function properly in the absence of ample blood supply 136 . Promoting angiogenesis and vasculogenesis lies at the heart of any study aiming to improve vascularization in bone grafts 137 . The biochemical process and the microenvironment required for vascularization have been well documented 138 .…”

Vascularization Strategies in Bone Tissue Engineering

“…Osteogenesis and vasculogenesis are key processes in the generation of bone tissue, and it is well established that they share common signaling pathways [ 57 , 58 , 59 ]. Therefore, co-culturing vascular and osteogenic lineage cells have become a cornerstone in BTE.…”

“…Most studies have been performed in 2D cultures, but cells can also be co-cultured as spheroids or within a scaffold as 3D cultures. 3D cultures are closer to physiological conditions and they allow for the investigation of more complex cellular behavior (e.g., tube formation by ECs) [ 57 , 59 , 94 , 95 , 96 , 97 ]. 3D cultures on scaffolds are closer to the construct, which is to be implanted in the in vivo part of a study than a 2D culture [ 98 , 99 , 100 ].…”

Biomaterials as a Vital Frontier for Stem Cell-Based Tissue Regeneration

“…In classical scaffold-based 3D culture system, neovasculogenesis is dependent on the media supplement. Unfortunately, the osteogenic supplements in media do not support elongation of new vessels, while the angiogenic factors decrease the osteogenic differentiation ability ( Schott et al, 2021 ). On the other hand, self-assembly bone construct can be associated with spontaneous chondrogenic matrix formation and the extension of capillary like structure.…”