Strategies and Applications for Incorporating Physical and Chemical Signal Gradients in Tissue Engineering

Abstract

From embryonic development to wound repair, concentration gradients of bioactive signaling molecules guide tissue formation and regeneration. Moreover, gradients in cellular and extracellular architecture as well as in mechanical properties are readily apparent in native tissues. Perhaps tissue engineers can take a cue from nature in attempting to regenerate tissues by incorporating gradients into engineering design strategies. Indeed, gradient-based approaches are an emerging trend in tissue engineering, standing in contrast to traditional approaches of homogeneous delivery of cells and/or growth factors using isotropic scaffolds. Gradients in tissue engineering lie at the intersection of three major paradigms in the field—biomimetic, interfacial, and functional tissue engineering—by combining physical (via biomaterial design) and chemical (with growth/differentiation factors and cell adhesion molecules) signal delivery to achieve a continuous transition in both structure and function. This review consolidates several key methodologies to generate gradients, some of which have never been employed in a tissue engineering application, and discusses strategies for incorporating these methods into tissue engineering and implant design. A key finding of this review was that two-dimensional physicochemical gradient substrates, which serve as excellent high-throughput screening tools for optimizing desired biomaterial properties, can be enhanced in the future by transitioning from two dimensions to three dimensions, which would enable studies of cell–protein–biomaterial interactions in a more native tissue–like environment. In addition, biomimetic tissue regeneration via combined delivery of graded physical and chemical signals appears to be a promising strategy for the regeneration of heterogeneous tissues and tissue interfaces. In the future, in vivo applications will shed more light on the performance of gradient-based mechanical integrity and signal delivery strategies compared to traditional tissue engineering approaches.

Moving from static to dynamic complexity in hydrogel design

“…In cartilage tissue engineering approaches (with both PEG 39 and hyaluronic acid 37 hydrogels), the inclusion of fractions of hydrolytically degradable components has improved this distribution and led to improved properties, particularly functional mechanical properties. Likewise, simple hydrolytic degradation mechanisms have also hinted at the concept of dynamically influencing tissue formation via local release of 'morphogens' 40,41 . The adaptability of hydrogel synthesis allows one to introduce signalling molecules via covalent linkage, non-covalent tethering or physical entrapment 42 , or as localized depots 40,41,43 , leading to spatial morphogen gradients that mimic a common paradigm in tissue development and regeneration.…”

“…Likewise, simple hydrolytic degradation mechanisms have also hinted at the concept of dynamically influencing tissue formation via local release of 'morphogens' 40,41 . The adaptability of hydrogel synthesis allows one to introduce signalling molecules via covalent linkage, non-covalent tethering or physical entrapment 42 , or as localized depots 40,41,43 , leading to spatial morphogen gradients that mimic a common paradigm in tissue development and regeneration. Non-covalent tethering in a hydrogel can be used as a mechanism to control diffusivity of general classes of growth factors such as heparin binders 44 , or specific growth factors such as nerve growth factor 45 .…”

Endochondral Ossification for Enhancing Bone Regeneration: Converging Native Extracellular Matrix Biomaterials and Developmental Engineering In Vivo

“…6,9,33,34 Several important reviews have focused on physical (e.g., osmotic gradients and hydrodynamic forces) and chemical (e.g., chemokines) cellular recruitment strategies for tissue regeneration. 55,56 Within the realm of developmental engineering and native ECM biomaterials, the subsequent differentiation pathway should also be emphasized with regard to overall cellular recruitment strategy. Since critical-sized defects are primarily avascular and hypoxic.…”

Whole-organ engineering with natural extracellular materials

“…It has been shown to be an oversimplification that cells behave the same in 3D as they behave in 2D [74][75][76][77][78]. Cell-matrix adhesions to the ECM are exaggerated in 2D cell cultures-the adhesions are stronger than those of cells in 3D models and of the cell in vivo [76].…”