Substrate Stress‐Relaxation Regulates Scaffold Remodeling and Bone Formation In Vivo

Abstract

The rate of stress relaxation of adhesion substrates potently regulates cell fate and function in vitro, and here we tested whether it could regulate bone formation in vivo by implanting alginate gels with differing rates of stress-relaxation carrying human mesenchymal stem cells into rat calvarial defects. After three months, the rats that received fast-relaxing hydrogels (t1/2 ~ 50s) showed significantly more new bone growth than those that received slow-relaxing, stiffness-matched hydrogels. Strikingly, substantial bone regeneration resulted from rapidly relaxing hydrogels even in the absence of transplanted cells. Histological analysis revealed that the new bone formed with rapidly relaxing hydrogels was mature and accompanied by extensive matrix remodeling and hydrogel disappearance. This tissue invasion was found to be prominent after just two weeks and the ability of stress relaxation to modulate cell invasion was confirmed with in vitro analysis. These results suggest that substrate stress relaxation can mediate scaffold remodeling and thus tissue formation, giving tissue engineers a new parameter for optimizing bone regeneration.

Regulating osteogenesis and adipogenesis in adipose‐derived stem cells by controlling underlying substrate stiffness

“…As physiological extracellular matrix of natural cells are viscoelastic, also exhibits stress relaxation, traction forces exerted by cells are partly stored by the surrounding ECM. Time dependent stress relaxation of ECM in reverse influences cell spreading, stromal cells fate and activity (Chaudhuri et al, , ; Darnell et al, ). Thus, it is more reasonable to set up experiment that whether low stiffness groups mattered as viscoelastic substrates in our study.…”

Mechanical forces direct stem cell behaviour in development and regeneration

“…130 An alginate matrix with rapid relaxation has been shown to enhance bone regeneration compared to more slowly relaxing hydrogels, even in the absence of stem cell delivery, presumably by promoting osteoblast differentiation and matrix remodeling. 131 Similarly, an appropriate combination of a material’s chemical and physical properties can regulate stem cell migration into a site of injury, and be used to support rapid cutaneous tissue regeneration. 132 The challenge of controlling stem cell fate and morphogenesis after transplantation may be addressed by harnessing the potential for organogenesis in vitro.…”

Physical Polyurethane Hydrogels via Charge Shielding through Acids or Salts

“…[5][6][7][8] Moreover, physical hydrogels are viscoelastic and stress-relaxing, which is relevant for biological applications where stress-relaxation rates of hydrogels have recently been found to regulate cell spreading and stem cell fate. [9][10][11][12] Stress-relaxation has therefore become a powerful parameter in mechanotransduction which is currently thoroughly studied with physically crosslinked alginate Based on this model, we propose the following gelation mechanism, which will be consistently supported throughout the experiments presented in this work: The polyurethane we designed undergoes gelation through aggregation, driven by hydrogen bonding. Since upon synthesis the polymer is initially fully protonated and insoluble in water, the polymer must first be dissolved by deprotonation in order to move freely and assemble to aggregates.…”

“…Physical hydrogels based on noncovalent associations such as hydrogen bonding, electrostatic or hydrophobic interactions, can offer a nontoxic alternative . Moreover, physical hydrogels are viscoelastic and stress‐relaxing, which is relevant for biological applications where stress‐relaxation rates of hydrogels have recently been found to regulate cell spreading and stem cell fate . Stress‐relaxation has therefore become a powerful parameter in mechanotransduction which is currently thoroughly studied with physically crosslinked alginate gels .…”

“…Moreover, physical hydrogels are viscoelastic and stress‐relaxing, which is relevant for biological applications where stress‐relaxation rates of hydrogels have recently been found to regulate cell spreading and stem cell fate . Stress‐relaxation has therefore become a powerful parameter in mechanotransduction which is currently thoroughly studied with physically crosslinked alginate gels . Especially in mechanotransduction, there is a growing interest in synthetic materials with broadly tunable stiffness and stress‐relaxation.…”