3 – Growth factors for musculoskeletal tissue engineering

Despite significant progress in the past two decades, the formation and homeostasis of multicellular structures in musculoskeletal tissues remains a major challenge to be solved. Although assembly approaches, such as bioprinting and directed assembly of tissue building blocks, are powerful tools for mimicking cellular organization of native tissues, one should bear in mind that cells are highly connected to their microenvironment and their fate changes with the spatiotemporal release of growth factors from their microenvironment. Improper signals can direct cells toward apoptosis or carcinogenic pathways with undesired and harmful side effects. The proper cellular commitment toward a selected number of lineages is critical to mimicking the functionality of the native tissue. Growth factors play a critical role as signaling molecules to regulate cell behavior during embryonic development and postnatal tissue regeneration. Leveraging growth factors for the full benefit of tissue engineering in the context of musculoskeletal tissues depends on our understanding of molecular regulatory mechanisms involved in natural development of different compartments of the musculoskeletal system. The first part of this chapter provides an overview of the molecular regulatory development for embryonic development of the musculoskeletal system. In brief, Wnt and Shh signaling are the main regulators of myogenic lineage differentiation, whereas combination of BMP4 and Notch signaling sustain a certain population of muscle progenitor cells in an undifferentiated state. Tendon development is regulated by the interplay between TGF-β, Wnt, and FGF signaling pathways. Formation of trunk and back muscles depends on the secretion of FGF-4 and FGF-8 from myotome, whereas formation of limb tendons is regulated by the inductive effect of Wnt 3, 6, and 7a excreted from ectoderm. In addition, excretion of TGF-β from differentiating muscle and cartilage tissues at the late stages of tissue development causes the recruitment of a second wave of tendon progenitor cells, which contribute to the formation of connections between the developing tendons, muscle, and skeletal tissues. Articular cartilage is a highly organized tissue composed of multiple distinct zones with defined cell phenotypes, ECM composition, and growth factors. Formation and homeostasis of the complex organization of articular cartilage is regulated by various interactions between IGF, TGF-β, and BMP signaling pathways. Embryonic and postnatal bone tissue formation is a highly dynamic process and involves the reciprocal interactions between different cell types including MSCs, osteoprogenitors, and endothelial cells. Cortical bone formation involves several cross talks among Wnt, TGF-β, Ihh/PTHrP, and Notch signaling pathways. Unlike current approaches to bone tissue engineering, which mostly leads to the formation of spongiform bone, mimicking mechanisms of native cortical bone tissue formation can be a promising approach for engineering of tissue constructs with biomechanical properties similar to the native tissue. Growth factor-based tissue engineering by recapitulating regulatory mechanisms behind normal tissue development and homeostasis can be applied as an efficient approach to restore function of damaged musculoskeletal tissues. To this end, novel methodologies and technologies are needed to mimic in engineered constructs the natural pattern and gradient of multiple growth factors that exist in musculoskeletal tissues. In the second part of the chapter, recent advances in spatiotemporal release of growth factors from tissue engineering scaffolds and their presentation to the seeded cells are discussed.