The Host Response in Tissue Engineering: Crosstalk Between Immune cells and Cell-laden Scaffolds

Abstract

Implantation of cell-laden scaffolds is a promising strategy for regenerating tissue that has been damaged due to injury or disease. However, the act of implantation initiates an acute inflammatory response. If the scaffold is non-biologic (i.e., a modified biologic scaffold or synthetic-based scaffold), inflammation will be prolonged through the foreign body response (FBR), which eventually forms a fibrous capsule and walls off the implant from the surrounding host tissue. This host response, from a cellular perspective, can create a harsh environment leading to long-lasting effects on the tissue engineering outcome. At the same time, cells embedded within the scaffold can respond to this environment and influence the interrogating immune cells (e.g., macrophages). This crosstalk, depending on the type of cell, can dramatically influence the host response. This review provides an overview of the FBR and highlights important and recent advancements in the host response to cell-laden scaffolds with a focus on the impact of the communication between immune cells and cells embedded within a scaffold. Understanding this complex interplay between the immune cells, notably macrophages, and the tissue engineering cells is a critically important component to a successful in vivo tissue engineering therapy.

Keywords: Foreign Body Response; Macrophage; Mesechymal Stem Cells; Scaffold.

Figure 1

The temporal host response upon implantation of a cell-laden scaffold. An acute inflammatory response initiates as part of the surgical implantation, which creates a wound. This initial response is accompanied by recruitment of leukocytes, notably inflammatory macrophages (shown in red), which release pro-inflammatory cytokines. If the scaffold is non-biologic, the host response evolves eventually shifting to an altered healing phase that is accompanied by a polarization shift in the macrophage and formation of multinucleated foreign body giant cells (shown in green) and the eventual walling off of the implant by a fibrous capsule. The resolution of the foreign body response is the presence of macrophages and FBGCs at the implant surface, maintaining low grade chronic inflammation, and the isolation of the implant from the host tissue.

Figure 2

In vitro assessment of the inflammatory environment (A), the one-way signals from macrophages to differentiating stem cells (B), and the two-way signals in a simulated FBR with macrophages at the surface of a cell-laden hydrogel (C, D). In (A), cartilage cells (i.e., chondrocytes) embedded in an agarose hydrogel and cultured continuously with interleukin-1β (IL-1β) led to reduce cartilage extracellular matrix deposition shown by the red staining for sulfated glycosaminoglycans. Reproduced with permission from [26]. In (B), macrophages were conditioned with different activators (i.e., no activator (CM0), lipopolysaccharide (LPS) + interferon gamma (IFN-γ) for a classically activated (inflammatory) macrophage (CM1), or interleukin-4 (IL-4) for an alternatively activated macrophage (CM2). After 24 hours, the medium with activator was removed, and fresh media applied without activator for 24 hours, to create the conditioned medium (CM). The CM was then supplemented with osteogenic factors and applied to bone marrow derived mesenchymal stem cells (MSCs) for seven days. Gene expression of two osteogenic genes, osterix and osteocalcin, are shown. Reproduced from [30]. In (C), macrophages were seeded on top of a fibroblast-laden poly(ethylene glycol) (PEG) hydrogel with RGD and cultured with or without LPS. The cell populations were separated after 24 hours and gene expression analyzed for the macrophage by IL-1β and tumor necrosis factor-α (TNF-α) and for the fibroblast for collagen 1α and IL-1β. The horizontal line represents the corresponding mono-culture. Reproduced with permission from [39]. In (D), macrophages were seeded on top of a MSC-laden poly(ethylene glycol) (PEG) hydrogel with RGD and cultured with or without LPS for 24 hours. Relative expression for the macrophage was assessed by TNF-α and TNF-α protein was measured in the medium. Reproduced with permission from [35].

Figure 3

In vivo assessment of cell-laden scaffolds. In (A), a PEG-RGD hydrogel with no cells (labeled as PEG) or with embedded MSCs at varying stages of osteogenic differentiation (i.e., MSCs or differentiated for 4, 10, or 21 days prior to encapsulation and implantation). Top row shows the host response after 28 days by Masson’s Trichrome and plots indicate quantitative assessment of the thickness of inflammatory cells at the surface of the hydrogel implant and the thickness of the resulting fibrous capsule. Reproduced with permission from [35]. In (B), a polysaccharide coating was applied to a MSC-laden gelatin crosslinked hydrogel. Far left image of scaffold (green) with coating (blue). Histological assessment of the fibrous capsule by Masson’ts trichrome staining and corresponding fibrous capsule thickness quantified. Reproduced with permission from [52].