Unraveling and Harnessing the Immune Response at the Cell-Biomaterial Interface for Tissue Engineering Purposes

Abstract

Biomaterials are defined as "engineered materials" and include a range of natural and synthetic products, designed for their introduction into and interaction with living tissues. Biomaterials are considered prominent tools in regenerative medicine that support the restoration of tissue defects and retain physiologic functionality. Although commonly used in the medical field, these constructs are inherently foreign toward the host and induce an immune response at the material-tissue interface, defined as the foreign body response (FBR). A strong connection between the foreign body response and tissue regeneration is suggested, in which an appropriate amount of immune response and macrophage polarization is necessary to trigger autologous tissue formation. Recent developments in this field have led to the characterization of immunomodulatory traits that optimizes bioactivity, the integration of biomaterials and determines the fate of tissue regeneration. This review addresses a variety of aspects that are involved in steering the inflammatory response, including immune cell interactions, physical characteristics, biochemical cues, and metabolomics. Harnessing the advancing knowledge of the FBR allows for the optimization of biomaterial-based implants, aiming to prevent damage of the implant, improve natural regeneration, and provide the tools for an efficient and successful in vivo implantation.

Keywords: biofabrication; biomaterials; foreign body response; immune response.

Figure 1

A progression chart of the foreign body response induced by a biomaterial, displaying the major cell types and effects over time. 1) Upon implantation, blood–matrix interactions recruit platelets in order to initiate site sterilization and wound closure. 2) Neutrophils and platelets excrete products to form a provisional matrix, which aids in further recruitment of inflammatory cells (A). 3) A collection of inflammatory cells, including monocytes, Th cells, and fibroblasts migrate to the wound site and initiate the inflammatory response to phagocytose pathogens and remodel the microenvironment (B). Over time, monocytes differentiate to macrophages and take on either a proinflammatory (M1) or anti‐inflammatory (M2) phenotype. Chronic inflammation of the wound site is often caused by the foreign nature of the biomaterial resulting in further macrophage polarization and recruitment of fibroblasts (C). 4) Persisting inflammation leads to the fusion of macrophages, forming a foreign body giant cell. FBGCs attempt to engulf the biomaterial in order to isolate the implant from the environment through frustrated phagocytosis (D). The combination of FBGCs and continuous collagen output by fibroblasts forms a fibrous foreign body capsule around the implant, indicating a chronically inflamed state.

Figure 2

The macrophage phenotype spectrum is directly related to the stimulation of either inflammation (orange) or regeneration (blue) within the implant site. A combination of biochemical compounds and adaptive cell types affect monocyte behavior and the subsequent differentiation to macrophages. The differentiation to varying polarization states, either proinflammatory (M1) or anti‐inflammatory (M2), is defined by a unique mix of cytokines and chemokines present in the microenvironment. Additionally, the physical traits of the implant are able to steer polarized macrophages toward expressing inflammatory or regenerative effects.

Figure 3

An overview of the crosstalk network between key cell types and inflammatory responses of the FBR. Each feature is categorized according to either inflammatory (orange) or regenerative (blue) effects it exerts on the progression of the FBR. Cellular interaction occurs through either cytokine crosstalk or direct differentiation into the directed cell type.

Figure 4

A qualitative analysis on the effect of physical biomaterial properties on the inflammatory response. Upon implantation, varying features can display a multitude of positive (↑) or negative (↓) effects on inflammatory cell types and the FBR progression. Preferred anti‐inflammatory effects are usually defined by an optimal range. A) Surface roughness is defined in µm where a roughness between 0.2 and 20 µm results in macrophage elongation and M2 polarization. Optimal polarization occurred between 0.4 and 0.5 µm. Generally, rougher surfaces are always more effective over smooth material surfaces. B) Material stiffness is expressed in kPa and concerns both the flexibility and resistance to deformation. A lower stiffness (<88 kPa) causes increased cell migration and promotes an overall anti‐inflammatory environment whilst higher stiffnesses (>300 kPa) impairs phagocytosis and stimulates inflammation. C) Porosity measures the empty space between a material that allows for cellular integration and migration. Pore ranges between 5 and 60 µm have been found to support an anti‐inflammatory environment, where pore ranges between 30 and 60 µm stimulate angiogenesis, macrophage elongation, and M2 polarization. Of note is that different cell types may prefer different pore sizes. Extremely small (<0.1 µm) or large (>160 µm) are generally unfavorable since this may stimulate fibrosis and FBC formation. Nanoporous materials could also exert positive effects on the FBR by modulating the fundamental properties of the material. D) Wettability is defined by the level of hydrophilicity of a material. Increasingly hydrophilic materials create a more anti‐inflammatory environment through providing enhanced protein absorption, cell motility, and M2 polarization. E) Crystallinity indicates the structural arrangement of atoms in a material and becomes increasingly important in stiffer components (e.g., bone tissue). Amorphous materials supported the growth and proliferation of stem cells like osteoblasts, whilst crystalline materials resulted in increased fibroblast proliferation. Of note is that a higher crystallinity may negatively affect the FBR, since persistent fibroblast activity can result in chronic inflammation through increased levels of inflammatory cytokines and a buildup of fibrous matrix.

Figure 5

A simplified overview of metabolomic products influencing the FBR. Natural metabolic products may originate from the degradation of the biomaterial implant, be excreted by cells, or are present in the ECM. These products include signaling molecules (cytokines and interleukins), fats (lipopolysaccharides), proteins or metabolic products created through the breakdown of larger substances. Within the microenvironment of the FBR, the mixture of these products bidirectionally influences the interaction between stromal and inflammatory cells and may directly contribute toward skewing the FBR toward an inflammatory or resolutory state.

Figure 6

A predictive model depicting the creation of novel biomaterials based on products derived from the metabolome. First, naturally occurring metabolites can be isolated or synthesized as basic, biocompatible building blocks. Next, these monomers are functionalized through the addition of functional groups, creating synthons with the desired properties. These synthons are polymerized to create biomaterials, after which these can be implanted in vivo. As the material degrades over time, the compounds will revert to their original, biocompatible monomers, which are then processed and excreted through the metabolome.