Biomaterials for Mimicking and Modelling Tumor Microenvironment.

This chapter summarizes the current biomaterials and associated technologies used to mimic and characterize the tumor microenvironment (TME) for developing preclinical therapeutics. Research in conventional 2D cancer models systematically fails to provide physiological significance due to their discrepancy with diseased tissue's native complexity and dynamic nature. The recent developments in biomaterials and microfabrication have enabled the popularization of 3D models, displacing the traditional use of Petri dishes and microscope slides to bioprinters or microfluidic devices. These technologies allow us to gather large amounts of time-dependent information on tissue-tissue, tissue-cell, and cell-cell interactions, fluid flows, and biomechanical cues at the cellular level that were inaccessible by traditional methods. In addition, the wave of new tools producing unprecedented amounts of data is also triggering a new revolution in the development and use of new tools for analysis, interpretation, and prediction, fueled by the concurrent development of artificial intelligence. Together, all these advances are crystalizing a new era for biomedical engineering characterized by high-throughput experiments and high-quality data.Furthermore, this new detailed understanding of disease and its multifaceted characteristics is enabling the long searched transition to personalized medicine.Here we outline the various biomaterials used to mimic the extracellular matrix (ECM) and redesign the tumor microenvironment, providing a comprehensive overview of cancer research's state of the art and future.

Cellulose Nanofibers for Encapsulation and Pluripotency Preservation in the Early Development of Embryonic Stem Cells.

Materials for three-dimensional cultures aim to reproduce the function of the extracellular matrix, enabling cell adhesion and growth by remodeling the environment. However, embryonic stem cells (ESCs) must develop in environments that prevent adhesion and preserve their pluripotency. In this study, we used cellulose nanofiber hydrogels to mimic the developing conditions required for ESCs. These plant-based hydrogels are simultaneously biocompatible and exogenous to mammalian cells, preventing remodeling and attachment. The storage modulus of these hydrogels could be fine-tuned by varying the degree of oxidation to enable selective degradation. The ESCs proliferated in the artificial environment, forming increasingly large embryoid bodies for 15 days. Unlike traditional cultures in which ESCs begin differentiating upon the removal of the chemical inhibition, the expression of pluripotency markers in the ESC population remained high for the entire two weeks. Cellulase from Trichoderma reesei was used to retrieve the ESC cultures selectively. The proposed unique system is a prospective model with which to study the early development of embryonic cells, as well as a nonchemical method of preserving undifferentiated populations of ESCs.

Quantitative mass spectrometry of human reticulocytes reveal proteome-wide modifications during maturation.

Erythropoiesis is marked by progressive changes in morphological, biochemical and mechanical properties of erythroid precursors to generate red blood cells (RBC). The earliest enucleated forms derived in this process, known as reticulocytes, are multi-lobular and spherical. As reticulocytes mature, they undergo a series of dynamic cytoskeletal re-arrangements and the expulsion of residual organelles, resulting in highly deformable biconcave RBCs (normocytes). To understand the significant, yet neglected proteome-wide changes associated with reticulocyte maturation, we undertook a quantitative proteomics approach. Immature reticulocytes (marked by the presence of surface transferrin receptor, CD71) and mature RBCs (devoid of CD71) were isolated from human cord blood using a magnetic separation procedure. After sub-fractionation into triton-extracted membrane proteins and luminal samples (isobaric tags for relative and absolute quantitation), quantitative mass spectrometry was conducted to identify more than 1800 proteins with good confidence and coverage. While most structural proteins (such as Spectrins, Ankyrin and Band 3) as well as surface glycoproteins were conserved, proteins associated with microtubule structures, such as Talin-1/2 and ß-Tubulin, were detected only in immature reticulocytes. Atomic force microscopy (AFM)-based imaging revealed an extended network of spectrin filaments in reticulocytes (with an average length of 48 nm), which shortened during reticulocyte maturation (average spectrin length of 41 nm in normocytes). The extended nature of cytoskeletal network may partly account for increased deformability and shape changes, as reticulocytes transform to normocytes.

Biocompatibility of Biomaterials for Tissue Regeneration or Replacement.

Emerging biomaterials for tissue engineering applications witness a multitude of interaction (both along their interface and internally) with human tissue. Insufficient consideration of the spatial and temporal aspects of these biomaterial-tissue interactions often raise biocompatibility concerns. This review focuses on strategies implemented in some of the recently developed biomaterials-particularly for soft and hard tissue regeneration or replacement-to overcome potential foreign body response and ensure effective functioning of the biomaterial.

Tough and Strong: Cross-Lamella Design Imparts Multifunctionality to Biomimetic Nacre.

The creation of structural composites with combined strength, toughness, low density, and biocompatibility remains a long-standing challenge. On the other hand, bivalve marine shells-Clinocardiumspp.-exhibit strength, stiffness, and toughness that surpass even that of the nacre that is the most widely mimicked model for structural composites. The superior mechanical properties of Clinocardiumspp. shells originate from their cross-lamella design, comprising CaCO3 mineral platelets arranged in an "interlocked" herringbone fashion. Reproduction of such hierarchical designs could offer multifunctionality, potentially combining strength and toughness at low densities, and the capability for seamless integration with biological systems. Here, we demonstrate manufacturing of the cross-lamella design by biomineralizing aragonite films with sawtooth patterns and assembling them in a chitosan/fibroin matrix to generate a composite with interlocked mineral layers. The resultant composite, with a similar constitution to that of the biological counterpart, nearly doubles the strength of previous nacre-mimetic composites while improving the tensile toughness and simultaneously exhibiting stiffness and biocompatibility.

Stimuli-responsive injectable cellulose thixogel for cell encapsulation.

Herein, we present the synthesis of surface-oxidized cellulose nanofiber (CNF) hydrogel and characterization with various physicochemical analyses and spectroscopic tools as well as its suitability for cellular encapsulation and delivery. The structure-property relationship as shear thinning, thixotropy, creep-recovery and stimuli responsiveness are explored. The CNF hydrogel is capable to inject possessing shear thinning behavior at shear rate (~10 s-1) range in the normal injecting process. In time-dependent thixotropy, the hydrogel showed rapid transform from flowable fluid back to structured hydrogel fully recovering in less than 60 s. The presence of cell-culture media did not alter shear thinning behavior of CNF hydrogel and showed increased thixotropicity with respect to the control gel. The CNF hydrogel forms 3D structures, without any crosslinker, with a wide range of tunable moduli (~36-1000 Pa) based on concentration and external stimuli. The biological characteristics of the thixotropic gels are studied for human breast cancer cells and mouse embryonic stem cells and indicated high cell viability, long-term survival, and spherical morphology.