Abstract
Concentration gradients of soluble and matrix-bound guidance cues in the extracellular matrix direct cell growth in native tissues and are of great interest for design of biomedical scaffolds and on implant surfaces. The focus of this review is to demonstrate the importance of gradient guidance for cells as it would be desirable to direct cell growth onto/into biomedical devices. Many studies have been described that illustrate the production and characterization of surface gradients, but three dimensional (3D)-gradients that direct cellular behavior are not well investigated. Hydrogels are considered as synthetic replacements for native extracellular matrices as they share key functions such as 2D- or 3D-solid support, fibrous structure, gas- and nutrition permeability and allow storage and release of biologically active molecules. Therefore this review focuses on current studies that try to implement soluble or covalently-attached gradients of growth factors, cytokines or adhesion sequences into 3D-hydrogel matrices in order to control cell growth, orientation and migration towards a target. Such gradient architectures are especially desirable for wound healing purposes, where defined cell populations need to be recruited from the blood stream and out of the adjacent tissue, in critical bone defects, for vascular implants or neuronal guidance structures where defined cell populations should be guided by appropriate signals to reach their proper positions or target tissues in order to accomplish functional repair.
Highlights
Concentration gradients of soluble growth factors or matrix-immobilized guidance cues play fundamental roles during embryogenesis [1] and in a number of physiological processes in the adult; including recruitment of different cell types in wound healing [2,3,4,5], homing of immune cells [3,6] and nerve regeneration [7,8,9]
Three major mechanisms are described that direct cells along a gradient of attractive guidance cues: haptotaxis is defined as directed movement of cells along the direction of a gradient of matriximmobilized ligands [44,45]
Among these studies one has to differentiate between the culture conditions for cells: some studies produce 3D-gradients of guidance cues or growth factors, culture the cells to be analyzed on top of the gradient such that the cells are only exposed to a gradient substrate
Summary
Concentration gradients of soluble growth factors or matrix-immobilized guidance cues play fundamental roles during embryogenesis [1] and in a number of physiological processes in the adult; including recruitment of different cell types in wound healing [2,3,4,5], homing of immune cells [3,6] and nerve regeneration [7,8,9]. For synthetic tissue substitutes the difficulty lays in producing molecular gradients of chemical or physical guidance cues on top or within a homogeneous scaffold material Such a scaffold material is produced and analyzed on the macromolecular scale, whereas it needs to modulate cellular responses on the molecular scale, since cells sense their 2D- and 3D-environment by forming transient contacts to their surrounding extracellular matrix. Implementation of soluble or covalently attached cell guidance cues within a biomaterial imposes a large challenge to biomaterials research and production This current review will first illustrate the importance of the native extracellular matrix for cellular functions, their potential replacement by 3D-hydrogel matrices and give several examples on how cell guidance cues can be implemented onto and into 3D-hydrogel matrices in order to improve biomaterial functions by inducing directional cell growth
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