In tissue engineering and regenerative medicine, the conditions in the immediate vicinity of the cells have a direct effect on cells' behaviour and subsequently on clinical outcomes. Physical, chemical, and biological control of cell microenvironment are of crucial importance for the ability to direct and control cell behaviour in 3-dimensional tissue engineering scaffolds spatially and temporally. In this review, we will focus on the different aspects of cell microenvironment such as surface micro-, nanotopography, extracellular matrix composition and distribution, controlled release of soluble factors, and mechanical stress/strain conditions and how these aspects and their interactions can be used to achieve a higher degree of control over cellular activities. The effect of these parameters on the cellular behaviour within tissue engineering context is discussed and how these parameters are used to develop engineered tissues is elaborated. Also, recent techniques developed for the monitoring of the cell microenvironment in vitro and in vivo are reviewed, together with recent tissue engineering applications where the control of cell microenvironment has been exploited. Cell microenvironment engineering and monitoring are crucial parts of tissue engineering efforts and systems which utilize different components of the cell microenvironment simultaneously can provide more functional engineered tissues in the near future.
Porous scaffolds have been employed for decades in the biomedical field where researchers have been seeking to produce an environment which could approach one of the extracellular matrixes supporting cells in natural tissues. Such three-dimensional systems offer many degrees of freedom to modulate cell activity, ranging from the chemistry of the structure and the architectural properties such as the porosity, the pore, and interconnection size. All these features can be exploited synergistically to tailor the cell–material interactions, and further, the tissue growth within the voids of the scaffold. Herein, an overview of the materials employed to generate porous scaffolds as well as the various techniques that are used to process them is supplied. Furthermore, scaffold parameters which modulate cell behavior are identified under distinct aspects: the architecture of inert scaffolds (i.e., pore and interconnection size, porosity, mechanical properties, etc.) alone on cell functions followed by comparison with bioactive scaffolds to grasp the most relevant features driving tissue regeneration. Finally, in vivo outcomes are highlighted comparing the accordance between in vitro and in vivo results in order to tackle the future translational challenges in tissue repair and regeneration.
Adverse immune reactions to implanted devices can seriously hamper the efficacy of implants. Monocyte derived macrophages play a crucial role in both initiation and resolution of the inflammatory response toward foreign bodies. As the surface microtopography is shown to exert significant effects on cell phenotype, it is hypothesized that the presence of micropatterns on implant/medical device surfaces can attenuate the immune response. To this end, enzymatically crosslinked micropatterned gelatin films of varying groove widths (2, 5, 10, 20, and 40 µm) are tested for their effect on incoming monocyte behavior. In order to distinguish the effect of cytokine microenvironment on pattern presence, monocytes are seeded on micropatterned films in normal culture medium or M1/M2 inducing media and their morphology and cytokine secretions are observed for 6 d. The presence of the patterns induces microenvironment‐specific changes on the secretions of the attached cells and also on their size. IL‐1ß, IL‐4, IL‐12, TNF‐α, and CCL‐18 secretions are significantly affected particularly in M1 induction media by pattern presence. It is demonstrated for the first time that micropatterned surfaces can be used to control the initial attachment and cytokine secretion of incoming macrophages if they are linked with a polarization inducing cytokine microenvironment.
Various methods have been tried to treat the main meniscus problem, meniscal tears, for which we believe tissue engineering could be a viable solution. In this study, a three dimensional, collagen-based meniscus substitute was prepared by tissue engineering using human fibrochondrocytes and a collagen based-scaffold. This construct was made with 3 different collagen-based foams interspaced with two electrospun nano/microfibrous mats. The top layer was made of collagen type I-chondroitin sulfate-hyaluronic acid (Coll-CS-HA), and the middle and the bottom layers were made of only collagen type I with different porosities and thus with different mechanical properties. The mats of aligned fibers were a blend of collagen type I and poly(L-lactic acid-co-glycolic acid) (PLGA). After seeding with human fibrochondrocytes, cell attachment, proliferation, and production of extracellular matrix and glucoseaminoglycan were studied. Cell seeding had a positive effect on the compressive properties of foams and the 3D construct. The 3D construct with all its 5 layers had better mechanical properties than the individual foams.
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