Phagocytes are key cellular participants determining important aspects of host exposure to nanomaterials, initiating clearance, biodistribution and the tenuous balance between host tolerance and adverse nanotoxicity. Macrophages in particular are believed to be among the first and primary cell types that process nanoparticles, mediating host inflammatory and immunological biological responses. These processes occur ubiquitously throughout tissues where nanomaterials are present, including the host mononuclear phagocytic system (MPS) residents in dedicated host filtration organs (i.e., liver, kidney spleen, and lung). Thus, to understand nanomaterials exposure risks it is critical to understand how nanomaterials are recognized, internalized, trafficked and distributed within diverse types of host macrophages and how possible cell-based reactions resulting from nanomaterial exposures further inflammatory host responses in vivo. This review focuses on describing macrophage-based initiation of downstream hallmark immunological and inflammatory processes resulting from phagocyte exposure to and internalization of nanomaterials.

Inflammatory responses to biomaterials heavily influence the environment surrounding implanted devices, often producing foreign body reactions. The macrophage is a key immunomodulatory cell type consistently associated with implanted biomaterials and routinely employed in short term in vitro cell studies of biomaterials aiming to reproduce host responses. Inconsistencies within these studies, including differently sourced cells, different durations of culture, and assessment of different activation markers, lead to many conflicting results in vitro that confound consistency and conclusions. We hypothesize that different experimentally popular monocyte-macrophage cell types have intrinsic in vitro culture-specific differences that yield conflicting results. Recent studies demonstrate changes in cultured macrophage cytokine expression over time, leading to the hypothesis that changes in macrophage phenotype also occur in response to extended culture. Here, macrophage cells of different transformed and primary-derived origins were cultured for 21 days on model polymer biomaterials. Cell type-based differences in morphology and cytokine/chemokine expression as well as changes in cell surface biomarkers associated with differentiation stage, activation state, and adhesion were compared. Results reflect consistent macrophage development towards an M2 phenotype via up-regulation of the macrophage mannose receptor for all cell types following 21-day extended culture. Significantly, implanted biomaterials experiencing the foreign body response and encapsulation in vivo often elicit a shift towards an analogous M2 macrophage phenotype. In vitro “default” of macrophage cultures, regardless of lineage, to this M2 state in the presence of biomaterials at long culture periods is not recognized but has important implications to in vitro modeling of in vivo host response.

RationaleMyocardial infarction (MI) results in damaged heart tissue which can progress to severely reduce cardiac function, leading to death. Recent studies have injected dissociated, suspended cardiac cells into coronary arteries to restore function with limited results attributed to poor cell retention and cell death. Extracellular matrix (ECM) injected into damaged cardiac tissue sites show some promising effects. However, combined use of human cardiac ECM and cardiac cells may produce superior benefits to restore cardiac function.ObjectiveThis study was designed to assess use of new three-dimensional human heart ECM-derived scaffolds to serve as vehicles to deliver cardiac-derived cells directly to damaged heart tissue and improve cell retention at these sites while also providing biomechanical support and attracting host cell recruitment.Methods and ResultsECM-derived porous protein scaffolds were fabricated from human heart tissues. These scaffolds were designed to carry, actively promote and preserve cardiac cell phenotype, viability and functional retention in tissue sites. ECM scaffolds were optimized and were seeded with human cardiomyocytes, cultured and subsequently implanted ex vivo onto infarcted murine epicardium. Seeded human cardiomyocytes readily adhered to human cardiac-derived ECM scaffolds and maintained representative phenotypes including expression of cardiomyocyte-specific markers, and remained electrically synchronous within the scaffold in vitro. Ex vivo, cardiomyocyte-seeded ECM scaffolds spontaneously adhered and incorporated into murine ventricle.ConclusionsDecellularized human cardiac tissue-derived 3D ECM scaffolds are effective delivery vehicles for human cardiac cells to directly target ischemic heart tissue and warrant further studies to assess their therapeutic potential in restoring essential cardiac functions.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-015-0559-0) contains supplementary material, which is available to authorized users.