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Abstract One of the most fundamental characteristics of a biomaterial tailored for bone repair and regeneration is its ability to promote bone regeneration and healing of large defects. This work reports producing a functionalized and hieratically porous bone scaffold that significantly supports cell adhesion and proliferation by providing bone mimicry structure and controlled release of protein. The Slit Guidance Ligand 3 (SLIT3) protein was previously tested to promote bone formation and control the resorption process in natural bone healing. In this study, our goal was to design a nanocomposite bone scaffold to be functionalized with SLIT3 protein and then evaluate the uptake and release profile from surface into culture media to support bone marrow-derived mesenchymal stem cells (MSC) 3D culture. Indirect 3D printing of a polylactic-co-glycolic acid (PLGA), hydroxyapatite nanoparticles, and polydopamine coated (PLGA-HANPs-PDA) was utilized to obtain a hierarchically porous and SLIT3 protein-releasing scaffold. The produced scaffold was evaluated and optimized using chemical, architectural, mechanical, and biological characterization techniques. Optimal physicochemical properties resulted in a unique microstructure with an average pore size of 178.06 ± 45 µm, 63% porosity, and stable and homogenous chemical composition. Mechanical testing demonstrated a compression strength up to 1.5 MPa at 75% strain, with a compression modulus of 0.58 ± 0.05 MPa. Preliminary biological experiments showed that the scaffold exhibited gradual SLIT3 protein release, biodegradability, and reliable biocompatibility for MSC cell culture. Finally, we showed for first time the bioactivity of SLIT3 protein within PLGA-HANPs-PDA scaffold to promote attachment and growth of mesenchymal stem cell (MSCs) seeded in bone mimicry scaffold matrix. The collected findings will serve as a bedrock for thorough and targeted in vitro studies to evaluate anticipated osteogenesis the MSCs. 

Cells are adept at sensing changes in their environment, transmitting signals internally to coordinate responses to external stimuli, and thereby influencing adaptive changes in cell states and behavior. Often, this response involves modulation of gene expression in the nucleus, which is seen largely as a physically separated process from the rest of the cell. Mechanosensing, whereby a cell senses physical stimuli, and integrates and converts these inputs into downstream responses including signaling cascades and gene regulatory changes, involves the participation of several macromolecular structures. Of note, the extracellular matrix (ECM) and its constituent macromolecules comprise an essential part of the cellular microenvironment, allowing cells to interact with each other, and providing both structural and biochemical stimuli sensed by adhesion transmembrane receptors. This highway of information between the ECM, cell adhesion proteins, and the cytoskeleton regulates cellular behavior, the disruption of which results in disease. Emerging evidence suggests a more direct role for some of these adhesion proteins in chromatin structure and gene regulation, RNA maturation and other non-canonical functions. While many of these discoveries were previously limited to observations of cytoplasmic-nuclear transport, recent advances in microscopy, and biochemical, proteomic and genomic technologies have begun to significantly enhance our understanding of the impact of nuclear localization of these proteins. This review will briefly cover known cell adhesion proteins that migrate to the nucleus, and their downstream functions. We will outline recent advances in this very exciting yet still emerging field, with impact ranging from basic biology to disease states like cancer.