Elham Ansari,1Ashrafalsadat Hatamian-Zarmi,2Zahra-Beagom Mokhtari-Hosseini,3,*Mohammad Naji,4Soheil Kianirad,5Zahra Kazemizadeh,6
1. Department of Life Sciences Engineering, Faculty of New Sciences and Technologies, University of Tehran 2. Department of Life Sciences Engineering, Faculty of New Sciences and Technologies, University of Tehran 3. Department of Chemical Engineering, Faculty of Petroleum & Petrochemical Engineering, Hakim Sabzevari University 4. Urology and Nephrology Research Center, Shahid Beheshti University of Medical Sciences 5. Department of Life Sciences Engineering, Faculty of New Sciences and Technologies, University of Tehran 6. Department of Chemical Engineering, Faculty of Petroleum & Petrochemical Engineering, Hakim Sabzevari University
Introduction: Tissue engineering and regenerative medicine are new strategies in tissue development with the aim of replacing, repairing, or improving biological activity of tissues by manipulation of cells through their extracellular environment. Current approach in tissue engineering involves the development of natural tissues’ features by designing biomimetic scaffolds. Scaffolds are engineered structures that, as extracellular matrix (ECM), plays the role of ’home’ to cells. One approach to mimic ECM is the use of gradient scaffolds. Gradient scaffolds have gradual or abrupt transitions in one or some of their properties. These changes can be seen in mechanical properties, cross-linking density and meshing size, porosity, composition, and biochemical properties in the forms of temporal or spatial gradients.
Cells are constantly exposed to temporal or spatial gradient of physical or chemical signals. Gradient scaffolds utilize these gradients to regulate cellular functions. Some advantages of gradient scaffolds are elimination of high local stresses in the interface of different scaffold layers, prevention of delamination, effective signal transmission and regulation of cellular behavior, and efficient ECM simulation.
Methods: In this review, information collected from relevant published articles were used to present a summary of different forms of gradient scaffolds, recent advances of gradient scaffolds fabrication, and their application in tissue engineering.
Results: Gradient scaffolds are mainly classified as physical and chemical gradients. Physical gradients include gradual changes in structure, porosity, composition, stiffness, fiber alignment and architecture that affect the cellular behaviors. Physical gradients are mostly used in soft-to-hard interface scaffolds. By changing the material type or manipulating their feature, it is possible to create multidimensional scaffolds to treat both cartilage and bone layers, bone and muscle layers and so on. Chemical gradients are defined as gradients in morphogens, proteins, drugs, bioactive substances, or cell type that provide necessary biochemical signals to guide tissue formation. The absolute concentration or gradient slope are important factors that should be considered prior to fabrication of these scaffolds, as cells respond differently depending on these factors. Chemical gradients can provide different metabolically needs of various cell types or adjacent tissues and thus mimicking the physiological environment more efficiently. Combination of physical and chemical gradients will further increase the accuracy of tissue engineering outcome. For example, smart drug delivery such as drug release in a particular manner, and sustained release of drugs or bioactive factors can be achieved by designing scaffolds with gradual changes in physical properties of scaffold and embedment of various substances.
There are various fabrication methods for gradient scaffolds such as additive manufacturing, component redistribution, controlled phase changes and post-modification, which are further divided into subcategories. The ideal gradient scaffold should have continuous and smooth transition which some methods such as layering are unable to do so. Some methods such as electric attraction and magnetic attraction use external forces to form gradient changes. Also, methods such as electrospinning and 3D printing can form a range of gradients. But due to the high precision required for gradient formation and its unique complexity, mass production of these scaffolds has not yet been achieved.
Conclusion: By mimicking the extracellular matrix, gradient scaffolds provide more appropriate environment for cellular behavior regulation and tissue engineering. These scaffolds utilize various types of gradients such as gradual transitions in cell type, morphogens, scaffold structure or porosity that make them great option for simulation of soft-to-hard tissue interface. However, one of the main challenges of gradient scaffolds is their fabrication methods. By optimizing fabrication methods, with the aim of development of continuous and smooth gradients, these scaffolds will be able to further mimic the extracellular environment and be of valid choice in tissue engineering, cancer studies and drug discovery.