Dynamic Stimulations with Bioengineered Extracellular Matrix‐Mimicking Hydrogels for Mechano Cell Reprogramming and Therapy

Abstract

Cells interact with their surrounding environment through a combination of static and dynamic mechanical signals that vary over stimulus types, intensity, space, and time. Compared to static mechanical signals such as stiffness, porosity, and topography, the current understanding on the effects of dynamic mechanical stimulations on cells remains limited, attributing to a lack of access to devices, the complexity of experimental set-up, and data interpretation. Yet, in the pursuit of emerging translational applications (e.g., cell manufacturing for clinical treatment), it is crucial to understand how cells respond to a variety of dynamic forces that are omnipresent in vivo so that they can be exploited to enhance manufacturing and therapeutic outcomes. With a rising appreciation of the extracellular matrix (ECM) as a key regulator of biofunctions, researchers have bioengineered a suite of ECM-mimicking hydrogels, which can be fine-tuned with spatiotemporal mechanical cues to model complex static and dynamic mechanical profiles. This review first discusses how mechanical stimuli may impact different cellular components and the various mechanobiology pathways involved. Then, how hydrogels can be designed to incorporate static and dynamic mechanical parameters to influence cell behaviors are described. The Scopus database is also used to analyze the relative strength in evidence, ranging from strong to weak, based on number of published literatures, associated citations, and treatment significance. Additionally, the impacts of static and dynamic mechanical stimulations on clinically relevant cell types including mesenchymal stem cells, fibroblasts, and immune cells, are evaluated. The aim is to draw attention to the paucity of studies on the effects of dynamic mechanical stimuli on cells, as well as to highlight the potential of using a cocktail of various types and intensities of mechanical stimulations to influence cell fates (similar to the concept of biochemical cocktail to direct cell fate). It is envisioned that this progress report will inspire more exciting translational development of mechanoresponsive hydrogels for biomedical applications.

Efficient Myogenic Activities Achieved through Blade-Casting-Assisted Bioprinting of Aligned Myoblasts Laden in Collagen Bioink

“…In contrast, TGF-b pathways enhance NF-kB activation, facilitating muscle growth and increasing cellular proliferation. 32,33 To assess the impact of the mechanical stimulation on cells during the blade-casting process, we measured gene expression 1 day after cell culture, which is related to mechanical stimulation (Figure 2B). The results indicated that the addition of blade casting to the bioprinting process significantly increased gene expression in the blade-casted cell construct compared with that in cell constructs fabricated solely through bioprinting, indicating that the mechanical stress applied through blade casting may play an important role in organizing the cytoskeleton, aligning cells, and facilitating muscle development.…”

“…Figure A shows that cells within a collagen bioink experience mechanical stimulation during the blade casting process, wherein mechanical forces are transmitted via the extracellular matrix (ECM) and neighboring cells. This stimulation is detected by integrin receptors and mechanosensitive ion channels such as transient receptor protein ion channels and Piezo ion channels, activating focal adhesion kinase (FAK) and initiating various signaling pathways, including RhoA/Rock, Wnt/b-catenin, MAPK, TGF-b, and Pi3K. − The activation of these pathways regulates cellular responses, such as proliferation, cytoskeleton formation, and gene expression. − The RhoA/Rock pathway promotes actin stress fiber formation, and the activated Wnt/b-catenin pathway stimulates nuclear activity and gene expression. In contrast, TGF-b pathways enhance NF-kB activation, facilitating muscle growth and increasing cellular proliferation. , …”

Steering cell orientation through light-based spatiotemporal modulation of the mechanical environment

“…Since cells in vivo are surrounded by 3D ECM, whose architecture is influenced and dynamically changed by the cells in an inter-dependent fashion [49], we next aimed at developing an analogous system allowing for a similar spatiotemporal control of cell and ECM orientation in 3D. In particular, knowing that uniaxially constrained static tissues can provide stiffness cues aligning cells and ECM [29,30,42,50], we leveraged the crosslinking properties of GelMA to develop uniaxially constrained and temporally dynamic 3D tissues.…”

Construction of cardiac fibrosis for biomedical research

“…Current research suggests that immoderate stretching could act as a significant stimulant for myocardial injury and continuing activation of myofibroblasts, ultimately leading to the development of fibrosis. [93][94][95] McCain et al imitated mechanical overexertion by circularly stretching designed layered cardiovascular tissues on an elastic chip. 96 Periodic stretching was found to activate indicators of abnormal heart hypertrophy, change myocyte morphology and filament orientation, modify calcium transient, and diminish stress production.…”