Encapsulated piezoelectric nanoparticle-hydrogel smart material to remotely regulate cell differentiation and proliferation: a finite element model

Regenerative medicine is one of the most promising future approaches for the treatment of damaged tissues and organs. Its methodologies are based on a good understanding and control of cellular behavior within in-vivo tissues, and this represents an important challenge. Cell behavior can be controlled, among other stimuli, by changing the mechanical properties of the extracellular matrix, applying external/internal forces, and/or reproducing an electric stimulus. To remotely control the local cell micro-environment, we consider in this work a microsphere of cell size made of a piezoelectric material and charged with nanomagnetic particles. This microsphere is integrated within an extracellular matrix, in such a way that internal forces can be generated within the microsphere by means of an external magnetic field. As a result, a stiffness gradient and an electric field are generated around the microsphere. These stimuli can be controlled externally by changing the magnetic field intensity and direction. To fine-tune this process and achieve the desired cell numbers, a computational numerical simulation has been developed and employed for several cell phenotypes using the ABAQUS software with the user-define subroutine UEL. The 3D numerical model presented can successfully predict the fundamental aspects of cell maturation, differentiation, proliferation, and apoptosis within a nonlinear substrate. The results obtained, which are in agreement with previous experimental and computational works, show that the generated stiffness gradient as well as the electric field within the cell micro-environment can play a highly significant role in remotely controlling the lineage specification of the Mesenchymal Stem Cells and accelerating cell migration and proliferation, which opens the door to new methodologies of tissue regeneration.