Mechanisms of Foreign Body Giant Cell Formation in Response to Implantable Biomaterials.

Long term function of implantable biomaterials are determined by their integration with the host's body. Immune reactions against these implants could impair the function and integration of the implants. Some biomaterial-based implants lead to macrophage fusion and the formation of multinucleated giant cells, also known as foreign body giant cells (FBGCs). FBGCs may compromise the biomaterial performance and may lead to implant rejection and adverse events in some cases. Despite their critical role in response to implants, there is a limited understanding of cellular and molecular mechanisms involved in forming FBGCs. Here, we focused on better understanding the steps and mechanisms triggering macrophage fusion and FBGCs formation, specifically in response to biomaterials. These steps included macrophage adhesion to the biomaterial surface, fusion competency, mechanosensing and mechanotransduction-mediated migration, and the final fusion. We also described some of the key biomarkers and biomolecules involved in these steps. Understanding these steps on a molecular level would lead to enhance biomaterials design and improve their function in the context of cell transplantation, tissue engineering, and drug delivery.

A label-free SPR biosensor for specific detection of TLR4 expression; introducing of 10-HDA as an antagonist.

Toll-like receptor 4 (TLR4) is actively involved in many health-related problems, including transplantation rejection and autoimmune diseases. Therefore, it is important to identify an antagonist to inhibit the TLR4-induced immune cell activation. In our previous study, 10-hydroxy-2-decanoic acid (10-HDA) was introduced as a potential antagonist for TLR4; however, possible interaction between 10-HDA and TLR4 needed to be detected. Due to the ability of surface plasmon resonance (SPR) biosensor to confirm the specific interactions between receptors and ligands, a new configuration of SPR biosensor proposed to detect the possible interaction between 10-HDA and TLR4. Hence, 10-HDA was immobilized using the (3-aminopropyl) triethoxysilane (APTES) polymer as a crosslinking agent on the Ag-MgF2 surface. Besides, genetically modified HEK293T cells with high TLR4 expression were used to study the possible interaction between 10-HDA and TLR4. Surprisingly, the SPR angle was significantly reduced in the presence of HEK cells expressing TLR4, while HEK cells without TLR4 did not affect the SPR angle. So, the proposed SPR biosensor successfully detected the interaction betweenTLR4 and 10-HDA. The sensitivity and detection limit of the biosensor were achieved at 0.05 and 0.5 million cells expressing TLR4, respectively, with a two-fold dynamic range.

10-hydroxy-2-decenoic acid a bio-immunomodulator in tissue engineering; generates tolerogenic dendritic cells by blocking the toll-like receptor4.

Dendritic cells (DCs), in response to the biomaterials, utilize toll-like receptors (TLRs) to become mature or tolerogenic through TLRs-dependent signaling pathways, especially TLR4. Regarding the physicochemical properties of biomaterials, some of such signaling pathways are activated. Unsaturated fatty acids have been explored as an antagonist for TLRs and lead to the tolerogenic phenotype of DCs. Here we showed that, although cultured DCs on both chitosan and Alginate-polyethyleneimine (Alg-PEI) films became fully mature, 10-hydroxy-2-decanoic acid (10-HDA), an unsaturated fatty acid found in royal jelly, led to the tolerogenic immunophenotype of DCs on both films. The cultured cells on the films possessed iDCs-like morphology in the presence of 10-HDA. Moreover, 10-HDA expressed lower levels of CD80, CD83, CD86, and HLA-DR, a higher level of IL-10, and lower level of IL-12 in the cultured DCs on both films. Furthermore, HEK293T cells expressing only TLR4 (HEK-TLR4 cells) were co-cultured with LPS, a specific agonist for TLR4, and 10-HDA. The 10-HDA significantly reduced the expression of tumor necrosis factor-a (TNF-α) in the HEK-TLR4 cells compared to treated only with LPS. These findings indicate that the 10-HDA acts as an antagonist of TLR4; therefore, potentially can be used in autoimmune diseases and preventing the rejection of biomaterials implantation and allograft transplantation.

Dendritic Cells as Targets for Biomaterial-Based Immunomodulation.

Various subtypes of immunocytes react against implanted biomaterials to eliminate the foreign body object from the host's body. Among these cells, dendritic cells (DCs) play a key role in early immune response, later engaging lymphocytes through antigens presentation. Due to their capability to induce tolerogenic or immunogenic responses, DCs have been considered as key therapeutic targets for immunomodulatory products. For instance, tolerogenic DCs are applied in the treatment of autoimmune diseases, rejection of allograft transplantation, and implanted biomaterial. Due to the emerging importance of DCs in immunomodulatory biomaterials, this Review summarizes DCs' responses-such as adhesion, migration, and maturation-to biomaterials. We also review some examples of key molecules and their applications in DCs' immunoengineering. These evaluations would pave the way for designing advanced biomaterials and nanomaterials to modulate the immune system, applicable in tissue engineering, transplantation, and drug delivery technologies.