Abstract
In mammals, tissue regeneration is accomplished through a well-regulated, complex cascade of events. The disruption of the cellular and molecular processes involved in tissue healing might lead to scar formation. Most tissue engineering approaches have tried to improve the regenerative outcome following an injury, through the combination of biocompatible materials, stem cells and bioactive factors. However, implanted materials can cause further healing impairments due to the persistent inflammatory stimuli that trigger the onset of chronic inflammation. Here, it is described at the molecular, cellular and tissue level, the body response to a functionalized biomimetic collagen scaffold. The grafting of chondroitin sulfate on the surface of the scaffold is able to induce a pro-regenerative environment at the site of a subcutaneous implant. The early in situ recruitment, and sustained local retention of anti-inflammatory macrophages significantly reduced the pro-inflammatory environment and triggered a different healing cascade, ultimately leading to collagen fibril re-organization, blood vessel formation, and scaffold integration with the surrounding native tissue.
Highlights
Regenerative medicine aims at recovering the functionality of impaired tissues and organs through the use of various biological and tissue-engineered implants
We describe a biomimetic collagen scaffold functionalized with an anti-inflammatory macromolecule, chondroitin sulfate, to trigger a selected inflammatory environment that allows for the formation of a pro-regenerative environment
We previously demonstrated that the grafting of chondroitin sulfate moieties on the surface of the CSCL was sufficient to recapitulate the extracellular matrices (ECM) of the cartilage tissue[15], supported the immune-suppressive potential of bone marrow derived mesenchymal stem cells, and modulated macrophage phenotype, both in vitro and in vivo[24]
Summary
Regenerative medicine aims at recovering the functionality of impaired tissues and organs through the use of various biological and tissue-engineered implants. The more established mechanism involves the complement receptors in a simil-opsonisation process triggered by host protein adsorbed on the implanted material[16,17]. Mφ complement receptors interact with either adsorbed proteins or immunoglobulins (IgG and IgM) in order to activate the opsonization process[18]. We hypothesized that the host reaction to an implant can be controlled through the early recruitment of Mφ into the scaffold and their in situ retention, along with the continuous induction of anti-inflammatory cytokines, leading to the formation of a pro-regenerative environment. We describe a biomimetic collagen scaffold functionalized with an anti-inflammatory macromolecule, chondroitin sulfate, to trigger a selected inflammatory environment that allows for the formation of a pro-regenerative environment. By modulating the response of immune cells we were able to induce the timely cascade of cellular and molecular events responsible for a functionally regenerative outcome
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