Macrophages Recruitment and Activation by α-gal NanoparticlesAccelerate Regeneration and Can Improve Biomaterials Efficacy in TissueEngineering

This review describes a novel method for accelerating tissue regeneration by ! -gal nanoparticles and proposes methods for ! -gal nanoparticles mediated increased efficacy of biomaterials used in tissue engineering. ! -Gal nanoparti- cles present multiple ! -gal epitopes (Gal! 1-3Gal" 1-4GlcNAc-R) that bind the most abundant natural antibody in all hu- mans- the anti-Gal antibody, constituting ~1% of immunoglobulins. Anti-Gal/! -gal nanoparticles interaction generates chemotactic complement cleavage peptides that induce rapid and extensive recruitment of macrophages. The subsequent interaction between the Fc portion of anti-Gal coating ! -gal nanoparticles and Fc# receptors on macrophages activates these cells to produce cytokines/growth factors that promote tissue regeneration and recruit stem cells. Intradermal injec- tion of ! -gal nanoparticles induces localized extensive recruitment and activation of macrophages. These macrophages disappear within 3 weeks without altering normal skin architecture. Application of ! -gal nanoparticles onto wounds of anti-Gal producing animals reduces healing time by 40-70%. ! -Gal nanoparticles injected into ischemic myocardium in- duce extensive recruitment of macrophages that secrete cytokines preserving the structure of the ischemic tissue. These macrophages may recruit progenitor cells and/or stem cells that are guided by myocardial microenvironment and extracel- lular matrix to differentiate into cardiomyocytes. ! -Gal nanoparticles applied to nerve injures will recruit macrophages that can promote angiogenesis required for induction of axonal sprouting and thus may regenerate the severed nerve. In tissue engineering, incorporation of ! -gal nanoparticles into decellularized tissue and organ implants may improve in vivo regeneration and restore biological function of implants because of accelerated recruitment of macrophages and stem cells. This review describes a novel method for recruitment and activation of macrophages within injured tissues by ! -gal nanoparticles. The review further proposes the use of these nanoparticles in biomaterials for tissue engineering, in order to accelerate and increase the efficacy of tissue repair and regeneration processes. The method is based on harnessing the immunological potential of the natural anti-Gal antibody, which is the most abundant natural antibody in humans. Anti-Gal interacts specifically with a carbohydrate antigen called "the ! -gal epitope" with the structure Gal! 1-3Gal" 1- 4GlcNAc-R. Nanoparticles presenting multiple ! -gal epi- topes and called ! -gal nanoparticles introduce these epitopes into injury sites or into biomaterials. The interaction of anti- Gal with ! -gal epitopes on ! -gal nanoparticles activates the complement system for rapid chemotactic recruitment of macrophages. This interaction further induces pro-healing functions in the recruited macrophages which may recruit stem cells. The review describes studies on the efficacy of anti-Gal/! -gal nanoparticles interaction in acceleration of