From fiber meshwork mechanotransduction to cartilage tissue engineering

Mingkun Wang

doi:10.17918/vbqb-jz29

Cells adhere to the extracellular matrix (ECM) through integrins and probe the physical properties of the matrix by applying contractile forces at integrin adhesions (known as mechanosensing). They convert this mechanical information into biochemical signaling pathways that affect activation of downstream gene transcriptions, ultimately controlling cell migration, proliferation, differentiation and apoptosis (known as mechanotransduction). In the past decade, mechanosensing and mechanotransduction have been demonstrated as a critical role in many essential biological processes such as tissue regeneration, as well as pathological processes such as cancer metastasis. This role has driven the emergence of mechanobiology as a new research field. Biomaterials have been created in effort to reveal mechanotransduction processes. Initial studies were on linear elastic two-dimensional (2D) hydrogels and established the stiffness or linear elasticity as a key parameter in mediating cell behavior. Now the field has begun to move into 3D encapsulating materials with degradability and time-dependent mechanical properties such as viscoelasticity and plasticity. However, there is also a growing realization that these simple models cannot capture the complex material properties of ECM, which consists of 3D meshwork of biopolymer fibers with diameters typically of the order of micrometers. Unlike homogenous and isotropic hydrogels, biopolymer networks show a strong nonlinear elasticity, due to entropic or non-thermal strain-stiffen or softening in response to loading. As shown by pioneering work using 2D electrospun microfiber sheets, cells sense the physical properties (ex: stiffness and topography) of the bundles of microfibers and can reorganize the microfibers. However, extending this study into 3D fiber meshwork, which better resembles the native ECM, was hindered by the technological limitation of electrospinning, as densely packed electrospun fibers present a barrier that does not allow a uniform distribution of cells in 3D. Due to the lack of 3D platform, how cells sense and respond to 3D fiber meshwork remains largely unknown. My PhD research focused on: 1. Invent a new fabrication technique that can ensure a uniform 3D cell distribution, in which fibers' diameter and alignment can be independently tuned. This platform enables a direct control of 3D fiber architecture that cells sense. 2. Study how cells sense and respond to 3D fiber meshwork (3D mechanotransduction). The above microfibers platform was used to study how spatial confinement affects 3D mechanotransduction. 3. Study how 3D microfibrous structures affects the chondrogenic differentiation of mesenchymal stem cells. The results showed that 3D, microfibrous architecture regulates chondrogenic differentiation, leading to either cartilage-like genes and matrix production, in which cells produced mainly type II collagen, or fibrocartilage-like genes and matrix production, in which cells produced mainly type I collagen. 4. Use an ex vivo model to evaluate the feasibility of applying the microfibers platform to cartilage repair. A main challenge of the current strategy for cartilage repair is the lack of optimal scaffolds for cartilage production. The integration between new cartilage and the host cartilage is another long-standing hurdle. Horse cartilages, a well-established model to resemble the human cartilages, were used for this study. The microfiber platform was used to examine which fiber architecture better promotes cartilage matrix formation. Horse chondrocytes and horse mesenchymal stem cells were used as model cells.

From fiber meshwork mechanotransduction to cartilage tissue engineering

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From fiber meshwork mechanotransduction to cartilage tissue engineering

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