DEVELOPMENT OF SCAFFOLDS FOR BRAIN TISSUE ENGINEERING
Tissue engineering has experienced an intense development aimed at addressing the growing demand for restoration or replacement tissues that have undergone structural or functional damage. To induce and guide the tissue growth, three tools need to be combined: porous scaffolds that provide mechanical support structure; cells or biomolecules that attract cells of the host to the scaffold; and growth factors that regulate cell differentiation and function. In most mammalian species including humans, new neurons are generated throughout life from neural stem cells (NSC) by a process known as “neurogenesis”. NSCs are multipotent and self-renewing cells that have the ability to generate all three types of cells in the brain: neurons, astrocytes, and oligodendrocytes. It is known that neurogenesis is negatively regulated by age, stress, and sleep deprivation and
increased by caloric restriction, exercise, and physiological activation. Several animal and clinical studies suggest reduced neurogenesis in neurodegenerative disorders such as Parkinson's disease (PD), Alzheimer's disease (AD), and Huntington's disease (HD). In response to injuries/diseases, NSCs proliferate and migrate to the lesioned site, and differentiate into new neurons. Nevertheless, this endogenous regenerative program is inefficient and only few NSC-derived newborn neurons are able to survive under the injured environment. The inevitable loss of nerve/brain tissue caused by these neurodegenerative diseases and traumatic injuries is particularly devastating because of these limited regenerative capabilities of the CNS. To this end, there is a clear unmet need for effective strategies to replace the destroyed neural tissue and attenuate the debilitating symptoms, specifically in neurodegenerative disorders. Considering the multifaceted complications incurred by damage to CNS, stem-cell therapies have emerged probably as the most promising treatment option. Direct injection of stem cells into the injured/disease site minimizes surgical invasiveness; however, low retention and engrafment, and poor cell survival of directly injected cells is gained as a consequence of mechanical shear forces that damage cell membrane during the injection or by a lack of 3D structure to enhance the engrafment, viability, and function of the injected cells. One potential attractive strategy for neural stem cell delivery that overcomes these limitations is to suspend NSCs in hydrogels which can be injected and solidified in situ. Hydrogels have a high water content, similar to tissues, which not only enables homogeneous encapsulation of cells and growth factors, but also allows for facile delivery via injection. Apart from providing a suitable transpantable medium to insert NSC cells in a diseased neuronal tissue, hydrogel-forming materials should mimick the complex 3D environment of NSCs within tissues, especially, the extracellular matrix (ECM). ECM and their constitutive proteins not only serves as a physical scaffold but also controls chemical cues, serving as a reservoir for cytokines and nutrients, and as a patchbay for integrin-mediated mechano-signals, but also can mediate key cellular interactions in the stem cell niche such as adhesion, migration, proliferation and differentiation. Hence, we are interested in developing new strategies and materials is order to design new patterned 3D hydrogel matrix and microdroplet scaffolds with nanotopographies formed by “intelligent” particles able to sustain the release of bioactive molecules for controlled induction of neuronal differentiation and fate for cell therapy of injured brain tissue, and to decipher the roles played by physical and biochemical cues on such processes. The “intelligent” particles will be self-assembled in ordered nanostructures within the 3D scaffold and remotely controlled upon application of external stimuli, enabling the on-demand activation of the encapsulated bioactive factors for selective cell orientation differentiation and fate within the 3D extracellular matrix-mimicking scaffolds.