Osteoinductive Small Molecules: Growth Factor Alternatives for Bone Tissue Engineering

Abstract

Tissue engineering aims to repair, restore, and regenerate lost or damaged tissues by using biomaterials, cells, mechanical forces and factors (chemical and biological) alone or in combination. Growth factors are routinely used in the tissue engineering approach to expedite the process of regeneration. The growth factor approach has been hampered by several complications including high dose requirements, lower half-life, protein instability, higher costs and undesired side effects. Recently a variety of alternative small molecules of both natural and synthetic origin have been explored as alternatives to growth factors for tissue regeneration applications. Small molecules are simple biochemical components that elicit certain cellular responses through signaling cascades. Small molecules present a viable alternative to biological factors. Small molecule strategies can reduce various side effects, maintain bioactivity in a biological environment and minimize cost issues associated with complex biological growth factors. This manuscript focuses on three-osteoinductive small molecules, namely melatonin, resveratrol (from natural sources) and purmorphamine (synthetically designed) as inducers of bone formation and osteogenic differentiation of stem cells. Efforts have been made to summarize possible biological pathways involved in the action of each of these drugs. Melatonin is known to affect Mitogen Activated Protein (MAP) kinase, Bone morphogenic protein (BMP) and canonical wnt signaling. Resveratrol is known to activate cascades involving Wnt and NAD-dependent deacetylase sirtuin-1 (Sirt1). Purmorphamine is a Hedgehog (Hh) pathway agonist as it acts on Smoothened (Smo) receptors. These mechanisms and the way they are affected by the respective small molecules will also be discussed in the manuscript.

Synergistic effects of dimethyloxalylglycine and butyrate incorporated into α-calcium sulfate on bone regeneration

“…Small molecules are appealing for regenerative medicine applications because many exhibit extended in vivo stability, a limited period of action, low cost, and scalable production [5,7]. A number of small molecules have been investigated for bone regeneration.…”

“…Nevertheless, growth factor approaches have been hampered by several complications, including high dose requirements, lower half-life, protein instability, higher costs and undesired side effects [5,7]. Recently, various small molecules have been explored as alternatives to growth factors for tissue regeneration applications.…”

“…Small molecules are simple biochemical components that elicit specific cellular responses through signaling cascades. It is proposed that small molecule-based strategies can reduce various side effects of high dosage growth factors, maintain bioactivity in a biological environment, and minimize cost issues associated with complex biological growth factors [5,7,8].…”

Hierarchical Structures of Bone and Bioinspired Bone Tissue Engineering

“…[186] It has been shown that fluoroalcohols result in conformational change of native proteins, [187] and electrospun fibers lack typical 67nm cross-banding of native collagen. [187][188][189][190] Although collagenous bone grafts provide greater bioactivity and biocompatibility with bone tissue, thereby favoring tissue regeneration, [191,192] these biological functions depend on the unique ultrastructural axial periodicity of collagen. [188] Electrospun collagen nanofibers present poor mechanical properties and thermal stability, which result in collagen denature during the electrospinning process.…”

Design of biocomposite materials for bone tissue regeneration

“…The cost and lower half life of the growth factors limit their use and hence small molecules with osteoinductive ability including melatonin, resveratrol, flavonoids, quinones, etc. are being explored as alternatives [116,117]. Another approach to enhance the bone repair is by culturing mesenchymal [118] or embryonic [119] stem cells onto the synthetic bone grafts which can differentiate in vivo to the desired lineage and perform the local cell function.…”