Vascular Mechanobiology: Towards Control of In Situ Regeneration

The paradigm of regenerative medicine has recently shifted from in vitro to in situ tissue engineering: implanting a cell-free, biodegradable, off-the-shelf available scaffold and inducing the development of functional tissue by utilizing the regenerative potential of the body itself. This approach offers a prospect of not only alleviating the clinical demand for autologous vessels but also circumventing the current challenges with synthetic grafts. In order to move towards a hypothesis-driven engineering approach, we review three crucial aspects that need to be taken into account when regenerating vessels: (1) the structure-function relation for attaining mechanical homeostasis of vascular tissues, (2) the environmental cues governing cell function, and (3) the available experimental platforms to test instructive scaffolds for in situ tissue engineering. The understanding of cellular responses to environmental cues leads to the development of computational models to predict tissue formation and maturation, which are validated using experimental platforms recapitulating the (patho)physiological micro-environment. With the current advances, a progressive shift is anticipated towards a rational and effective approach of building instructive scaffolds for in situ vascular tissue regeneration

Image-based analysis of uniaxial ring test for mechanical characterization of soft materials and biological tissues

Uniaxial ring test is a widely used mechanical characterization method for a variety of materials, from industrial elastomers to biological materials. Here we show that the combination of local material compression, bending, and stretching during uniaxial ring test results in a geometry-dependent deformation profile that can introduce systematic errors in the extraction of mechanical parameters. We identify the stress and strain regimes under which stretching dominates and develop a simple image-based analysis approach that eliminates these systematic errors. We rigorously test this approach computationally and experimentally, and demonstrate that we can accurately estimate the sample mechanical properties for a wide range of ring geometries. As a proof of concept for its application, we use the approach to analyze explanted rat vascular tissues and find a clear temporal change in the mechanical properties of these explants after graft implantation. The image-based approach can therefore offer a straightforward, versatile, and accurate method for mechanically characterizing new classes of soft and biological materials

Image-based analysis of uniaxial ring test for mechanical characterization of soft materials and biological tissues

\u3cp\u3eUniaxial ring test is a widely used mechanical characterization method for a variety of materials, from industrial elastomers to biological materials. Here we show that the combination of local material compression, bending, and stretching during uniaxial ring test results in a geometry-dependent deformation profile that can introduce systematic errors in the extraction of mechanical parameters. We identify the stress and strain regimes under which stretching dominates and develop a simple image-based analysis approach that eliminates these systematic errors. We rigorously test this approach computationally and experimentally, and demonstrate that we can accurately estimate the sample mechanical properties for a wide range of ring geometries. As a proof of concept for its application, we use the approach to analyze explanted rat vascular tissues and find a clear temporal change in the mechanical properties of these explants after graft implantation. The image-based approach can therefore offer a straightforward, versatile, and accurate method for mechanically characterizing new classes of soft and biological materials.\u3c/p\u3

The initial repair response of articular cartilage after mechanically induced damage

\u3cp\u3eThe regenerative potential of articular cartilage (AC) defects is limited and depends on defect size, biomechanical conditions, and age. Early events after overloading might be predictive for cartilage degeneration in the long term. Therefore, the present aim is to investigate the temporal response of cartilage to overloading at cell, matrix, and tissue level during the first period after mechanical overloading. In the present study, the effect of high loading (∼8 MPa) at a high rate (∼14 MPa/s) at day 0 during a 9 day period on collagen damage, gene expression, cell death, and biochemical composition in AC was investigated. A model system was developed which enabled culturing osteochondral explants after loading. Proteoglycan content was repeatedly monitored over time using μCT, whereas other evaluations required destructive measurements. Changes in matrix related gene expressions indicated a degenerative response during the first 6 h after loading. After 24 h, this was restored and data suggested an initial repair response. Cell death and microscopic damage increased after 24 h following loading. These degradative changes were not restored within the 9 day culture period, and were accompanied by a slight loss of proteoglycans at the articular surface that extended into the middle zones. The combined findings indicate that high magnitude loading of articular cartilage at a high rate induces an initial damage that later initiates a healing response that can probably not be retained due to loss of cell viability. Consequently, the matrix cannot be restored in the short term.\u3c/p\u3

Vascular mechanobiology:towards control of in situ regeneration

\u3cp\u3eThe paradigm of regenerative medicine has recently shifted from in vitro to in situ tissue engineering: implanting a cell-free, biodegradable, off-the-shelf available scaffold and inducing the development of functional tissue by utilizing the regenerative potential of the body itself. This approach offers a prospect of not only alleviating the clinical demand for autologous vessels but also circumventing the current challenges with synthetic grafts. In order to move towards a hypothesis-driven engineering approach, we review three crucial aspects that need to be taken into account when regenerating vessels: (1) the structure-function relation for attaining mechanical homeostasis of vascular tissues, (2) the environmental cues governing cell function, and (3) the available experimental platforms to test instructive scaffolds for in situ tissue engineering. The understanding of cellular responses to environmental cues leads to the development of computational models to predict tissue formation and maturation, which are validated using experimental platforms recapitulating the (patho)physiological micro-environment. With the current advances, a progressive shift is anticipated towards a rational and effective approach of building instructive scaffolds for in situ vascular tissue regeneration.\u3c/p\u3

Computationally guided in-vitro vascular growth model reveals causal link between flow oscillations and disorganized neotissue

Disturbed shear stress is thought to be the driving factor of neointimal hyperplasia in blood vessels and grafts, for example in hemodialysis conduits. Despite the common occurrence of neointimal hyperplasia, however, the mechanistic role of shear stress is unclear. This is especially problematic in the context of in situ scaffold-guided vascular regeneration, a process strongly driven by the scaffold mechanical environment. To address this issue, we herein introduce an integrated numerical-experimental approach to reconstruct the graft-host response and interrogate the mechanoregulation in dialysis grafts. Starting from patient data, we numerically analyze the biomechanics at the vein-graft anastomosis of a hemodialysis conduit. Using this biomechanical data, we show in an in vitro vascular growth model that oscillatory shear stress, in the presence of cyclic strain, favors neotissue development by reducing the secretion of remodeling markers by vascular cells and promoting the formation of a dense and disorganized collagen network. These findings identify scaffold-based shielding of cells from oscillatory shear stress as a potential handle to inhibit neointimal hyperplasia in grafts

Impact of Additives on Mechanical Properties of Supramolecular Electrospun Scaffolds

The mechanical properties of scaffolds used for mechanically challenging applications such as cardiovascular implants are unequivocally important. Here, the effect of supramolecular additive functionalization on mechanical behavior of electrospun scaffolds was investigated for one bisurea-based model additive and two previously developed antifouling additives. The model additive has no effect on the mechanical properties of the bulk material, whereas the stiffness of electrospun scaffolds was slightly decreased compared to pristine PCL-BU following the addition of the three different additives. These results show the robustness of supramolecular additives used in biomedical applications, in which mechanical properties are important, such as vascular grafts and heart valve constructs

Impact of Additives on Mechanical Properties of Supramolecular Electrospun Scaffolds

The mechanical properties of scaffolds used for mechanically challenging applications such as cardiovascular implants are unequivocally important. Here, the effect of supramolecular additive functionalization on mechanical behavior of electrospun scaffolds was investigated for one bisurea-based model additive and two previously developed antifouling additives. The model additive has no effect on the mechanical properties of the bulk material, whereas the stiffness of electrospun scaffolds was slightly decreased compared to pristine PCL-BU following the addition of the three different additives. These results show the robustness of supramolecular additives used in biomedical applications, in which mechanical properties are important, such as vascular grafts and heart valve constructs