Engineering Biomaterials and Approaches for Mechanical Stretching of Cells in Three Dimensions

Abstract

Mechanical stretch is widely experienced by cells of different tissues in the human body and plays critical roles in regulating their behaviors. Numerous studies have been devoted to investigating the responses of cells to mechanical stretch, providing us with fruitful findings. However, these findings have been mostly observed from two-dimensional studies and increasing evidence suggests that cells in three dimensions may behave more closely to their in vivo behaviors. While significant efforts and progresses have been made in the engineering of biomaterials and approaches for mechanical stretching of cells in three dimensions, much work remains to be done. Here, we briefly review the state-of-the-art researches in this area, with focus on discussing biomaterial considerations and stretching approaches. We envision that with the development of advanced biomaterials, actuators and microengineering technologies, more versatile and predictive three-dimensional cell stretching models would be available soon for extensive applications in such fields as mechanobiology, tissue engineering, and drug screening.

Keywords: cell mechanotransduction; hydrogels; mechanobiology; stretch; tissue engineering.

FIGURE 1

Mechanical stretch in the human body. Representative stretching forces in different human tissues and organs are indicated by white arrows. (A) Cells in the alveoli undergo cyclic dilatational stretching during pulmonary respiration. (B) Cells in the myocardium experience cyclic circumferential and longitudinal stretching during heart beating. (C) Cells in the vessel wall are continuously subjected to circumferential stretching due to the action of blood pressure. (D) Cells in the skeletal muscle experience uniaxial stretching when moving the body. (E) Cells in the intestinal wall undergo circumferential stretching during intestinal peristalsis. (F) Cells in the bladder wall experience circumferential and longitudinal stretching at the time of urination.

FIGURE 2

Many aspects of cell behaviors, including cell spreading, migration, orientation or alignment, proliferation, apoptosis and lineage differentiation, can be influenced by 3D mechanical stretching. The middle illustration was reprinted with permission from (Huang et al., 2017).

FIGURE 3

Material considerations when engineering hydrogels for mechanical stretching of cells in three dimensions. Hydrogels can provide diverse mechanical, structural and biochemical cues that may greatly affect cell responses to mechanical stretching in three dimensions. The middle illustration was reprinted with permission from Huang et al. (2017).

FIGURE 4

Representative approaches for stretching 3D engineered tissue constructs. (A) Hydrogel tissue constructs are fabricated into macroscale ring-like shapes, physically anchored with two stiff rods, and actuated to undergo stretching by using motor-driven approach. (B) Hydrogel tissue constructs are chemically bonded on stretchable membranes that are driven to stretch by using step motors. (C) Hydrogel tissue constructs are chemically bonded on stretchable membranes that are driven to stretch by applying vacuum pressure. (D) Hydrogel microtissue constructs are constrained by elastic micropillars. The distance between the micropillars changes when the underlying elastomeric membranes are stretched by either motor-driven or pneumatic actuation approaches, leading to deformation of the constrained microtissues. (E) Pneumatic actuation of micropillar-anchored microtissues by applying vacuum pressure to the side chambers of microtissues. (F) The microtissues are magnetically actuated by applying a non-uniform magnetic field to attract the magnetic microspheres fixed to the micropillars. (G) Enabling magnetic actuation by fabricating magnetic responsive layer onto photopatterned microtissues that chemically anchored on glass substrates.