Nanoparticles as Versatile Tools for Mechanotransduction in Tissues and Organoids

Abstract

Organoids are 3D multicellular constructs that rely on self-organized cell differentiation, patterning and morphogenesis to recapitulate key features of the form and function of tissues and organs of interest. Dynamic changes in these systems are orchestrated by biochemical and mechanical microenvironments, which can be engineered and manipulated to probe their role in developmental and disease mechanisms. In particular, the in vitro investigation of mechanical cues has been the focus of recent research, where mechanical manipulations imparting local as well as large-scale mechanical stresses aim to mimic in vivo tissue deformations which occur through proliferation, folding, invagination, and elongation. However, current in vitro approaches largely impose homogeneous mechanical changes via a host matrix and lack the required positional and directional specificity to mimic the diversity of in vivo scenarios. Thus, while organoids exhibit limited aspects of in vivo morphogenetic events, how local forces are coordinated to enable large-scale changes in tissue architecture remains a difficult question to address using current techniques. Nanoparticles, through their efficient internalization by cells and dispersion through extracellular matrices, have the ability to provide local or global, as well as passive or active modulation of mechanical stresses on organoids and tissues. In this review, we explore how nanoparticles can be used to manipulate matrix and tissue mechanics, and highlight their potential as tools for fate regulation through mechanotransduction in multicellular model systems.

Mechanical Studies of the Third Dimension in Cancer: From 2D to 3D Model

“…To address this feature, nanoparticles (NPs) were adopted to engineer the mechanical microenvironment in organoids [ 140 ]. They can be dispersed in the matrix with a controlled distribution (local or global) and affect mechanical forces, but they exhibit heterogeneity in magnitude and direction, similar to what occurs in vivo.…”

Nanomaterial Additives for Fabrication of Stimuli‐Responsive Skeletal Muscle Tissue Engineering Constructs

“…[ 17,20 ] This process may be amplified through the inclusion of magnetically responsive nanomaterials in SMTE constructs, as such nanomaterials can impart heterogeneous mechanical forces upon application of an external field. [ 171 ] When an external magnetic field was applied to embryo stem cells labeled with dextran‐coated superparamagnetic iron oxide nanoparticles, increased expression of MyoG and Myh2 was observed during a 5 day differentiation period. [ 172 ] The effect on Myh2 was most profound for nanoparticles with a positively charged surface.…”

Paramagnetic Functionalization of Biocompatible Scaffolds for Biomedical Applications: A Perspective

“…In fact, their presence is connected to the improved mechanical integrity of the polymer in terms of localized reduction in deformation and increase in stiffness. The accumulation of these localized variations of the mechanical properties of the polymer induces an overall improvement in the stiffness of the entire matrix [ 128 , 129 ]. This technically means that the scaffold stiffness can be regulated by changing the embedded micro/nanoparticles amount [ 130 ], making the developed 3D structures more suitable to mimic a specific soft tissue rather than another one with different mechanical properties.…”

“…In particular, the mechanotransduction can be defined as the cells’ ability to respond to mechanical stimuli through biochemical signals [ 133 ]. By applying a magnetic field to magnetic NPs containing polymeric matrices, physical modifications close to the embedded MNPs can be induced creating heterogeneous forces that are perceived by the surrounding cells [ 129 ]. The magnetic stimulation of MNPs would therefore allow the mechanical regulation of different cellular functions such as the re-arrangement of the cytoskeleton and the alignment of the myotubes in muscle cells [ 29 , 134 ] or the regulation of intracellular calcium levels in excitable cells such as neurons and heart cells [ 29 ].…”

“…Cells respond to mechanical changes of the ECM by constantly reshaping it [ 135 , 136 ]. A magnetic hydrogel can be designed to have reversible and tunable mechanical properties, such as viscoelastic properties [ 137 ] and load capacity (load bearing capacity) [ 138 ], in order to imitate the dynamic mechanical variations of the extracellular matrix improving the regeneration of many soft tissues [ 129 ]. For example, Abdeen and collaborators designed a magneto-active hydrogel based on polyacrylamide and carbonyl iron particles with elasticity and stiffness tunable upon external magnetic field application [ 139 ].…”