Advances in the Fabrication of Biomaterials for Gradient Tissue Engineering

There has been a recent surge in the number of tissue-engineering protocols that use gradient biomaterials to replicate key developmental processes or functional roles. Recent advances in additive manufacturing (e.g., 3D bioprinting, microfluidics) have led to increased structural complexity in bottom-up gradient biomaterial fabrication. A growing number of reports are seeking to use applied forces that redistribute components of homogeneous systems to fabricate biomaterials with well-integrated gradients. A small number of recent studies have fabricated gradient biomaterials by controlling the temperature or light exposure during hydrogel crosslinking. Recent reports have demonstrated the fabrication of gradient biomaterials by postmodifying precast hydrogels or solid scaffolds using mechanisms based on temperature, light, or diffusion. Natural tissues and organs exhibit an array of spatial gradients, from the polarized neural tube during embryonic development to the osteochondral interface present at articulating joints. The strong structure–function relationships in these heterogeneous tissues have sparked intensive research into the development of methods that can replicate physiological gradients in engineered tissues. In this Review, we consider different gradients present in natural tissues and discuss their critical importance in functional tissue engineering. Using this basis, we consolidate the existing fabrication methods into four categories: additive manufacturing, component redistribution, controlled phase changes, and postmodification. We have illustrated this with recent examples, highlighted prominent trends in the field, and outlined a set of criteria and perspectives for gradient fabrication. Natural tissues and organs exhibit an array of spatial gradients, from the polarized neural tube during embryonic development to the osteochondral interface present at articulating joints. The strong structure–function relationships in these heterogeneous tissues have sparked intensive research into the development of methods that can replicate physiological gradients in engineered tissues. In this Review, we consider different gradients present in natural tissues and discuss their critical importance in functional tissue engineering. Using this basis, we consolidate the existing fabrication methods into four categories: additive manufacturing, component redistribution, controlled phase changes, and postmodification. We have illustrated this with recent examples, highlighted prominent trends in the field, and outlined a set of criteria and perspectives for gradient fabrication. load-bearing collagenous tissue present at the end of long bones. the fluids, typically containing viable cells, deposited during bioprinting. the use of computer-aided transfer processes for the patterning and assembly of living and nonliving materials with a defined 2D or 3D architecture. dense mineralized tissue found predominantly at the surface of long bones and flat bones. mononucleate, rounded cells of mesenchymal origin that are responsible for the formation and remodeling of cartilage tissue. relating to the formation of cartilage. a processing method that uses electric fields to generate fibrous scaffolds from polymer solutions. interfacial tissue where bone forms a connection to a tendon, ligament, fascia, or capsule. a cancer cell type thought to arise from nonmalignant glial cells. nonproliferative swollen chondrocytes that direct mineralization and vascularization during endochondral bone formation. the sublimation of ice from frozen materials at reduced pressure; synonym for ‘freeze-drying.’ multipotent cells that give rise to cells of chondrogenic, osteogenic, and adipogenic lineage. the embryonic precursor to the central nervous system. mononucleate, cuboid cells of mesenchymal origin that are responsible for the formation of bone tissue. interfacial tissue comprising subchondral bone and articular cartilage. progenitor cells of mesenchymal origin that give rise to osteoblasts or chondrocytes. relating to the formation of bone.