Tissue engineering tools for modulation of the immune response

Abstract

Tissue engineering scaffolds have emerged as a powerful tool within regenerative medicine. These materials are being designed to create environments that promote regeneration through a combination of: (i) scaffold architecture, (ii) the use of scaffolds as vehicles for transplanting progenitor cells, and/or (iii) localized delivery of inductive factors or genes encoding for these inductive factors. This review describes the techniques associated with each of these components. Additionally, the immune response is increasingly recognized as a factor influencing regeneration. The immune reaction to an implant begins with an acute response to the injury and innate recognition of foreign materials, with the subsequent chronic immune response involving specific recognition of antigens (e.g., transplanted cells) by the adaptive immune response, which can eventually lead to rejection of the implant. Thus, we also describe the impact of each component on the immune response, and strategies (e.g., material design, anti-inflammatory cytokine delivery, and immune cell recruitment/transplantation) to modulate, yet not eliminate, the local immune response in order to promote regeneration, which represents another important tool for regenerative medicine.

Figure 1. Acute Immune Response to Therapeutic Biomaterial Delivery System

The acute innate immune response is initiated by tissue injury and the presence of foreign materials. Resident cells (e.g., tissue macrophages (Mϕ)) respond to increased damage/pathogen-associated molecular pattern molecules (DAMPs/PAMPs) by producing chemokines to recruit immune cells (PMNs and monocytes) from the blood stream. PMNs (the first immune cells recruited to the implant) produce large amounts of inflammatory molecules that can hinder regeneration. As monocytes enter the tissue, they differentiate into macrophages. Macrophages are induced to an M1 phenotype by inflammatory cytokines and contribute additional inflammatory molecules to the environment. Additionally, the adaptive immune response can be initiated during this acute phase by recognition of specific antigens on the viruses or cells that are delivered with the biomaterial. These factors activate APCs, which then transmigrate to the draining lymph node and spleen for antigen presentation.

Figure 2. Chronic Immune Response to Therapeutic Biomaterial Delivery System

The chronic immune response is dominated by the adaptive immune response that is controlled by infiltrating T cells. Th cells can be induced to either Th1 or Th2 cells, which can have functionally disparate immune responses. Activated APCs (from the spleen) or IL-12 can induce Th1 cells to activate CTLs and M1 macrophages, which potentially hinders regeneration and can lead to the destruction of transplanted cells. Th2 cells, which are induced by IL-10, inhibit Th1 processes and can alternatively induce an M2 macrophage phenotype, which may aid regeneration. Tregs also contribute to the inhibition of adaptive inflammatory processes (Th1 cells and activated APCs) and the promotion of M2 macrophages by producing IL-10. Additionally, phagocytosis of cellular debris may aid the natural progression of macrophages toward an M2 phenotype.