Modulation of the inflammatory response to decellularized collagen matrix for cartilage regeneration

Abstract

Decellularized extracellular matrices (DECM) are among the most common types of materials used in tissue engineering due to their cell instructive properties, biodegradability, and accessibility. Particularly in cartilage, a natural collagen type II matrix can be a promising means to provide the necessary cues and support for chondrogenic stem and progenitor cells (CSPCs). However, efficient remodeling of the transplanted DECM is largely dependent on the host immune response, with macrophages playing the central role in orchestrating both inflammatory and regenerative processes. Here we assessed the reaction of human primary macrophages to the cartilage DECM. Our findings show that the xenogeneic collagen matrix can elicit a mixed response in human macrophages, whereby the inflammatory response (M1) and the activation of remodeling (M2) type of macrophages are both present. Additionally, we demonstrate the inhibitory effect of macrophage response on the migratory capacity of human CSPCs. We further show that the inflammatory reaction of macrophages to the cartilage DECM, as well as the resulting inhibitory effects on CSPC migration, can be attenuated by interleukin‐4 (IL‐4). Finally, we demonstrate that IL‐4 can effectively bind the matrix, thereby modulating macrophage response by reducing the inflammatory reaction and inducing the M2 phenotype.

3D Bioprinted Patient‐Specific Extracellular Matrix Scaffolds for Soft Tissue Defects

“…A large body of work has already demonstrated the potential of dECM to serve as an instructive scaffold to modulate the immune response towards constructive healing. [57][58][59][60] This includes our previous work showing that dECM sourced from porcine UBM can regenerate VML in vivo in mouse models and human patients. [11,14] However, while these published studies have highlighted the approach's potential and helped decipher the underlying mechanisms of repair, the sheets, powders, and weak hydrogels used have not been able to fully restore tissue volume in most applications.…”

Interaction of Ceramic Implant Materials with Immune System

“…Physicochemical properties of biomaterials and the topography of their surface affect the microenvironment of implants, thereby affecting the intensity and direction of the anti- or pro-inflammatory reaction [ 157 , 158 ]. Modifications to the implant surface, both physical and chemical, are utilized to control the inflammatory response and tissue regeneration, primarily by directing the polarization of macrophages [ 129 , 159 , 160 , 161 , 162 , 163 , 164 , 165 ] ( Table 4 ).…”

Decellularized Extracellular Matrix-Based Bioinks for Tendon Regeneration in Three-Dimensional Bioprinting

“…Other tissues, such as tendons, skeletal muscles, blood vessels, and ligaments have also been decellularized [ 15 , 26 , 32 ]. Currently, there are ECM-based implants, such as AlloDerm ® , Oasis ® , and Chondro-Gide ® , as well as commercialized dECM bioinks such as Bone deCelluid™ [ 25 , 33 ] that are being addressed for clinical use, meaning that in vivo tests are necessary [ 25 , 34 ].…”

“…Typically, tissues are harvested from animals, due to their high availability. Tissue antigenicity represents the main limitation of using xenografts in clinical practice [ 33 ]. Decellularization focuses on removing cells from xenogenic tissues, reducing tissue antigenicity; however, collagens and proteoglycans from xeno-ECM have a high potential to trigger immune responses in the host due to the presence of antigens.…”

“…Decellularization focuses on removing cells from xenogenic tissues, reducing tissue antigenicity; however, collagens and proteoglycans from xeno-ECM have a high potential to trigger immune responses in the host due to the presence of antigens. In particular, collagen type II has been described as a cause of inflammatory response [ 25 , 33 ]. Furthermore, an immune rejection can be triggered by insufficient decellularization that is caused by cell residues.…”